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DRAXIMAGE® M A A
Kit for the Preparation of
Technetium Tc 99m
Albumin Aggregated Injection
DIAGNOSTIC - For Intravenous Use
DESCRIPTION
The kit consists of reaction vials which contain the sterile, nonpyrogenic, non-radioactive
ingredients necessary to produce Technetium Tc 99m Albumin Aggregated Injection for
diagnostic use by intravenous injection.
Each 10 mL reaction vial contains 2.5 mg of albumin aggregated, 5.0 mg of Albumin
Human, 0.06 mg (minimum) stannous chloride (maximum stannous and stannic chloride
0.11 mg) and 1.2 mg of sodium chloride; the contents are in a lyophilized form under an
atmosphere of nitrogen. Sodium hydroxide or hydrochloric acid has been used for pH
adjustment. No bacteriostatic preservative is present.
The Albumin Human was non-reactive when tested for Hepatitis-B Surface Antigen
(HBsAg), antibodies to Human immunodeficiency Virus (HIV-1/HIV-2), antibody to
Hepatitis C virus (anti-HCV) and Antigen to Human Immunodeficiency Virus (HIV-1).
The aggregated particles are formed by denaturation of Albumin Human in a heating and
aggregation process. Each vial contains 4 to 8 million particles. By light microscopy,
more than 90% of the particles are between 10 and 70 micrometers, while the typical
average size is 20 to 40 micrometers; none is greater than 150 micrometers.
Technetium Tc 99m Albumin Aggregated Injection for intravenous use is in its final
dosage form when sterile isotonic sodium pertechnetate solution is added to each vial. No
less than 90% of the pertechnetate Tc 99m added to a reaction vial is bound to aggregate
at preparation time and remains bound throughout the 6 hour lifetime of the preparation.
PHYSICAL CHARACTERISTICS
Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.1
The principal photon that is useful for detection and imaging studies is listed in Table 1.
Table 1. Principal Radiation Emission Data
Radiation
Mean %/Disintegration
Mean Energy (keV)
Gamma-2
89.07
140.5
1 Kocher, David C.; “Radioactive Decay Data Tables’’, DOE/TIC-11026, 108, (1981)
® Registered Trademark of DRAXIS Specialty Pharmaceuticals Inc.
EXTERNAL RADIATION
The specific gamma ray constant for Tc 99m is 0.78 R/mCi-hr at 1 cm.
The first half value layer is 0.017 cm of lead. A range of values for the relative
attenuation of the radiation resulting from the interposition of various thicknesses of lead
is shown in Table 2. For example, the use of 0.25 cm thickness of lead will attenuate the
radiation emitted by a factor of about 1000.
Table 2. Radiation Attenuation by Lead (Pb) Shielding
Shield Thickness
Coefficient of
(Pb) cm
Attenuation
0.017
0.5
0.08
10-1
0.16
10-2
0.25
10-3
0.33
10-4
To correct for physical decay of this radionuclide, the fractions hat remain at selected
intervals after the time of calibration are shown in Table 3.
Table 3. Physical Decay Chart: Tc 99m half-life 6.02 hours
Hours
Fraction
Hours
Fraction
0*
Remaining
1.000
5
Remaining
0.562
1
0.891
6
0.501
2
0.794
8
0.398
3
0.708
10
0.316
4
0.631
12
0.251
*Calibration Time
CLINICAL PHARMACOLOGY
Immediately following intravenous injection, more than 80% of the albumin aggregated
is trapped in the pulmonary alveolar capillary bed. The imaging procedure can thus be
started as soon as the injection is complete. Assuming that a sufficient number of
radioactive particles has been used, the distribution of radioactive aggregated particles in
the normally perfused lung is uniform throughout the vascular bed, and will produce a
uniform image. Areas of reduced perfusion will be revealed by a corresponding
decreased accumulation of the radioactive particles, and are imaged as areas of reduced
photon density.
Organ selectivity is a direct result of particle size. Below 1-10 micrometers, the material
is taken up by the reticuloendothelial system. Above 10 micrometers, the aggregates
become lodged in the lung by a purely mechanical process. Distribution of particles in
the lungs is a function of regional pulmonary blood flow.
The albumin aggregated is sufficiently fragile for the capillary micro-occlusion to be
temporary. Erosion and fragmentation reduce the particle size, allowing passage of the
aggregates through the pulmonary alveolar capillary bed. The fragments are then
accumulated by the reticuloendothelial system.
Lung to liver ratios greater than 20:1 are obtained in the first few minutes post-injection.
Elimination of the technetium Tc 99m aggregated albumin from the lungs occurs with a
half-life of about 2 to 3 hours. Cumulative urinary excretion studies show an average of
20% elimination of the injected technetium Tc 99m dose 24 hours post-administration.
Following administration of technetium Tc 99m albumin aggregated by intraperitoneal
injection, the radiopharmaceutical mixes with the peritoneal fluid. Clearance from the
peritoneal cavity varies from insignificant, which may occur with complete shunt
blockage, to very rapid clearance with subsequent transfer into the systemic circulation
when the shunt is patent.
Serial images should be obtained of both the shunt and lung (target organ). However, an
adequate evaluation of the difference between total blockage of the shunt and partial
blockage may not be feasible in all cases.
INDICATIONS AND USAGE
Technetium Tc 99m Albumin Aggregated Injection is a lung imaging agent which may
be used as an adjunct in the evaluation of pulmonary perfusion in adults and pediatric
patients.
Technetium Tc 99m Albumin Aggregated Injection may be used in adults as an imaging
agent to aid in the evaluation of peritoneovenous (LeVeen) shunt patency.
CONTRAINDICATIONS
Technetium Tc 99m Albumin Aggregated Injection should not be administered to
patients with severe pulmonary hypertension.
The use of Technetium Tc 99m Albumin Aggregated Injection is contraindicated in
persons with a history of hypersensitivity reactions to products containing human serum
albumin.
WARNINGS
Although adverse reactions specifically attributable to Technetium Tc 99m Albumin
Aggregated Injection have not been noted, the literature contains reports of deaths
occurring after the administration of albumin aggregated to patients with pre-existing
severe pulmonary hypertension. Instances of hemodynamic or idiosyncratic reactions to
preparations of technetium Tc 99m albumin aggregated have been reported.
PRECAUTIONS
General
The contents of the kit before preparation are not radioactive. However, after the sodium
pertechnetate Tc 99m is added, adequate shielding of the final preparation must be
maintained.
In patients with right to left heart shunts, additional risk may exist due to the rapid entry
of albumin aggregated into the systemic circulation. The safety of this agent in such
patients has not been established. Hypersensitivity reactions are possible whenever
protein-containing materials such as pertechnetate labeled albumin aggregated are used in
man. Epinephrine, antihistamines, and cortico-steroids should be available for immediate
use.
The intravenous administration of any particulate materials such as albumin aggregated
imposes a temporary small mechanical impediment to blood flow. While this effect is
probably physiologically insignificant in most patients, the administration of albumin
aggregated is possibly hazardous in acute cor pulmonale and other states of severely
impaired pulmonary blood flow.
The components of the kit are sterile and non-pyrogenic. It is essential to follow
directions carefully and to adhere to strict aseptic procedures during preparation.
Contents of the vials are intended only for use in the preparation of Technetium Tc 99m
Albumin Aggregated Injection and are NOT to be administered directly to the patient.
The technetium Tc 99m labeling reactions involved depend on maintaining the stannous
ion in the reduced state. Hence, sodium pertechnetate Tc 99m containing oxidants should
not be employed.
The preparation contains no bacteriostatic preservative. Technetium Tc 99m Albumin
Aggregated Injection should be stored at 2-8ºC (36-46ºF) and discarded 6 hours after
reconstitution.
Technetium Tc 99m Albumin Aggregated Injection is physically unstable and
consequently the particles settle with time. Failure to agitate the vial adequately before
use may result in nonuniform distribution of radioactive particles.
If blood is drawn into the syringe, unnecessary delay prior to injection may result in clot
formation in situ.
Do not use if clumping of the contents is observed.
Technetium Tc 99m Albumin Aggregated Injection, as well as other radioactive drugs,
must be handled with care. Once sodium pertechnetate Tc 99m is added to the vial,
appropriate safety measures must be used to minimize radiation exposure to clinical
personnel. Care must also be taken to minimize the radiation exposure to patients in a
manner consistent with proper patient management.
Radiopharmaceuticals should be used only by physicians who are qualified by training
and experience in the safe use and handling of radionuclides and whose experience and
training have been approved by the appropriate government agency authorized to license
the use of radionuclides.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term animal studies have been performed to evaluate carcinogenic potential or
whether Technetium Tc 99m Albumin Aggregated Injection affects fertility in males or
females.
Pregnancy Category C
Animal reproduction and teratogenicity studies have not been conducted with
Technetium Tc 99m Albumin Aggregated Injection. It is also not known whether
Technetium Tc 99m Albumin Aggregated Injection can cause fetal harm when
administered to a pregnant woman or can affect reproductive capacity. There have been
no studies in pregnant women. Technetium Tc 99m Albumin Aggregated Injection
should be given to a pregnant woman only if clearly needed.
Ideally, examinations using radiopharmaceuticals, especially those elective in nature, of a
woman of childbearing capability, should be performed during the first few
(approximately 10) days following the onset of menses.
Nursing Mothers
Technetium Tc 99m is excreted in human milk during lactation. Therefore, formula
feedings should be substituted for breast feedings.
Pediatric Use
The lowest possible number of particles should be used in right-to-left shunting, in
neonates, and in severe pulmonary disease.
ADVERSE REACTIONS
The literature contains reports of deaths occurring after the administration of albumin
aggregated to patients with pre-existing severe pulmonary hypertension. Instances of
hemodynamic or idiosyncratic reactions to preparations of technetium Tc 99m albumin
aggregated have been reported (see Warnings).
DOSAGE AND ADMINISTRATION
The recommended intravenous dose range for the average (70 kg) ADULT patient for
lung imaging is 37 to 148 megabecquerels (1-4 millicuries) of Technetium Tc 99m
Albumin Aggregated Injection after reconstitution with oxidant-free Sodium
Pertechnetate Tc 99m Injection.
The suggested intraperitoneal dosage range used in the average patient (70 kg) for
peritoneovenous (LeVeen) shunt patency evaluation is 37 to 111 megabecquerels (1 to 3
millicuries). Adequate measures should be taken to assure uniform mixing with
peritoneal fluid. Serial images of both the shunt and target organ should be obtained and
correlated with other clinical findings. Alternatively, the drug may be administered by
percutaneous transtubal injection. The suggested percutaneous transtubal (efferent limb)
dosage range for the average patient (70 kg) is 12 to 37 megabecquerels (0.3 to 1.0
millicurie) in a volume not to exceed 0.5 mL.
The recommended number of particles per single injection is 200,000-700,000 with the
suggested number being approximately 350,000. Depending on the activity added and
volume of the final reconstituted product, the volume of the dose may vary from 0.2 to
1.4 mL.
The number of particles available per dose of Technetium Tc 99m Albumin Aggregated
Injection will vary depending on the physical decay of the technetium Tc 99m that has
occurred. The number of particles in any dose and volume to be administered may be
calculated as follows:
Assume the average number of particles per vial = 6.0 x 106.
If:
VTc = volume of solution added to reaction vial
D = desired dose to be administered in MBq (mCi)
C = concentration at calibration time of sodium pertechnetate solution to be added to
the reaction vial in MBq/mL (mCi/mL)
Va = volume to be administered in mL
P
= number of particles in dose to be administered
Fr = fraction of technetium Tc 99m remaining after the time of calibration (see Table
3)
Then:
Va =
D
and
P = Va x 6.0 x 106
C x Fr
VTc
In PEDIATRIC patients, the suggested intravenous dose to be employed for perfusion
lung imaging is in the range of 0.925 to 1.85 MBq per kilogram (25 to 50 μCi/kg) of
body weight; a usual dose is 1.11 MBq per kilogram (30 μCi/kg), except in newborns, in
whom the administered dose should be 7.4 to 18.5 MBq (200 to 500 μCi). Not less than
the minimum dose of 7.4 MBq (200 μCi) should be employed for this procedure. The
number of particles will vary with age and weight of the pediatric patient as indicated in
Table 5.
Parenteral drug products should be visually inspected for particulate matter and
discoloration prior to administration whenever solution and container permit.
The patient dose should be measured by a suitable radioactivity calibration system
immediately prior to administration. Mix the contents of the vial by gentle inversion just
prior to with drawing a patient dose.
Mix the contents of the syringe just before injection. If blood is drawn into the syringe,
any unnecessary delay prior to injection may lead to clot formation. For optimum results
and because of rapid lung clearance of the radiopharmaceutical, it is suggested that the
patient be positioned under the imaging apparatus before administration. Slow injection
is recommended. Lung imaging may begin immediately after intravenous injection of the
radiopharmaceutical. Due to high kidney uptake, imaging later than one-half hour after
administration will yield poor results.
RADIATION DOSIMETRY
The estimated absorbed radiation doses2 to an average ADULT patient (70 kg) from an
intravenous injection of 148 MBq (4 mCi) of Technetium Tc 99m Albumin Aggregated
Injection are shown in Table 4.
2 Method of calculation: “S” Absorbed Dose per Unit Cumulated Activity for Selected Radionuclides and
Organs, MIRD Pamphlet No. 11 (1975).
Table 4. Absorbed Radiation Doses
Organs
mGy/148 MBq
rads/4 mCi
Total body
0.60
0.060
Lungs
8.8
0.88
Liver
0.72
0.072
Spleen
0.68
0.068
Kidneys
0.44
0.044
Bladder Wall
2.0 hr. void
1.2
0.12
4.8 hr. void
2.2
0.22
Testes
2.0 hr. void
0.24
0.024
4.8 hr. void
0.26
0.026
Ovaries
2.0 hr. void
0.30
0.030
4.8 hr. void
0.34
0.034
In PEDIATRIC patients, the radiation absorbed doses using the maximum recommended
dose for lung imaging are based on 1.85 MBq (50 μCi) per kilogram of body weight
[except in the newborn where the maximum recommended dose of 18.5 MBq (500 μCi)
is used] and are shown in Table 5, which lists the maximum dose for pediatric patients
from newborn to adults. Note the recommendations regarding number of particles to be
administered.
Table 6 represents the absorbed radiation dose resulting from the intraperitoneal
administration of 111 megabecquerels (3 millicuries) of technetium Tc 99m albumin
aggregated.
Table 5. Pediatric Radiation Dose from Tc 99m MAA for Lung Imaging*
Age
Newborn
1 year
5 years
10 years
15 years
Weight (kg)
3.5
12.1
20.3
33.5
55.0
Max.
MBq
mCi
MBq
mCi
MBq
mCi
MBq
mCi
MBq
mCi
Recommended
Dose in
Megabecquerels
and Millicuries
18.5
0.5
22.2
0.6
37
1.0
62.9
1.7
103.6
2.8
Range of Particles
Administered
10-50,000
50-150,000
200-300,000
200-300,000
200-700,000
Absorbed
Radiation Dose in
milliGreys and
Rads for the
Maximum Dose
mGy
Rads
mGy
Rads
mGy
Rads
mGy
Rads
mGy
Rads
ORGANS
Total Body
0.60
0.06
0.30
0.03
0.31
0.031
0.48
0.048
0.41
0.041
Lungs
19.00
1.9
6.60
0.66
5.80
0.58
8.70
0.87
7.70
0.77
Liver
1.40
0.14
0.60
0.06
0.62
0.062
1.80
0.18
1.20
0.12
Bladder Wall
2.10
0.21(1)
1.50
0.15(1)
3.10
0.31(2)
3.90
0.39(2)
4.10
0.41
Ovaries
0.38
0.038
0.20
0.020
0.19
0.019
0.44
0.044
0.41
0.041
Testes
0.31
0.031
0.13
0.013
0.19
0.019
0.20
0.020
0.36
0.036
*Assumptions:
(1) 2.0 hour voiding interval
(2) 4.8 hour voiding interval
1. Used biologic data from Kaul et al., Berlin, 1973.
2. For the newborn, 1-year old, and 5-year old, the “S” values calculated from the preliminary phantoms of
ORNL were used. The 10-year old, 15-year old and adult “S” values were taken from Henrichs et al.,
Berlin, 1980.
Table 6. Absorbed Radiation Doses
Shunt
Shunt
Patency
Patency
Organs
(Open)
(Closed)
mGy
Rads
mGy
Rads
Lung
6.9
0.69
1.68
0.168
Ovaries
0.18
0.018
1.68
0.168
& Testes
to 0.30
to 0.030
Organs in the
Peritoneal Cavity
-
-
1.68
0.168
Total Body
0.36
0.036
0.57
0.057
Assumptions:
Calculations for the absorbed radiation dose are based upon an effective half-time of 3 hours for the open
shunt and 6.02 hours for the closed shunt and an even distribution of the radiopharmaceutical in the
peritoneal cavity with no biological clearance.
HOW SUPPLIED
DRAXIMAGE® MAA
Kit for the Preparation of Technetium Tc 99m Albumin Aggregated Injection
Each kit contains 30 reaction vials, each vial containing in lyophilized form, sterile and
non-pyrogenic:
Albumin Aggregated
2.5 mg
Albumin Human
5.0 mg
Stannous Chloride (minimum)
0.06 mg
(Maximum stannous and stannic chloride 0.11 mg)
Sodium Chloride
1.2 mg
HCl or NaOH has been used for pH adjustment. The vials are sealed under an atmosphere
of nitrogen.
Thirty labels with radiation warning symbols and a package insert are supplied in each
carton.
STORAGE
Store the unreconstituted reaction vials at (2 to 25ºC (36-77ºF). After labeling with
Technetium Tc 99m, store the solution at 2 to 8ºC (36-46ºF) in a suitable lead shield and
discard after 6 hours.
DIRECTIONS FOR PREPARATION
Note: Use aseptic procedures throughout and take precautions to minimize exposure by
use of suitable shielding. Waterproof gloves should be worn during the preparation
procedure.
Before reconstituting a vial, it should be inspected for cracks and/or a melted plug or any
other indication that the integrity of the vacuum seal has been lost.
To prepare Technetium Tc 99m Albumin Aggregated Injection:
1. Remove the protective disc from a reaction vial and swab the rubber septum with
either an alcohol swab or a suitable bacteriostatic agent to disinfect the surface.
2. Place the vial in a suitable lead vial shield which has a fitted cap. Obtain 2-8 mL of
a sterile pyrogen-free Sodium Pertechnetate Tc 99m Injection using a shielded
syringe. The recommended maximum amount of Tc 99m to be added to a reaction
vial is 3.7 GBq (100 mCi). Sodium pertechnetate Tc 99m solutions containing an
oxidizing agent are not suitable for use.
3. Using a shielded syringe, add the Sodium Pertechnetate Tc 99m Injection to the
reaction vial aseptically.
4. Place the lead cap on the vial shield and mix the contents of the shielded vial by
repeated gentle inversion until all the material is suspended. Avoid formation of
foam. Using proper shielding, the vial should be visually inspected to ensure that
the suspension is free of foreign matter before proceeding. Do not administer if
foreign particulates are found in the preparation. To ensure maximum tagging,
allow the preparation to stand for 15 minutes after mixing.
5. Assay the product in a suitable calibrator, record the radioassay information on the
label with radiation warning symbol, and attach it to the vial shield.
6. Withdrawals for administration must be made aseptically using a sterile needle
(18-21 gauge) and syringe. Since the vials contain nitrogen to prevent oxidation of
the complex, the vials should not be vented. If repeated withdrawals are made from
the vial, replacement of the contents with air should be minimized.
7. The finished preparation should be refrigerated at 2 to 8ºC (36-46ºF) when not in
use and discarded after 6 hours.
(The preparation contains no bacteriostatic
preservative.) The vial should also be retained during its life in the reaction vial
shield with cap in place.
Disposal
The residual materials may be discarded in the ordinary trash, provided the radioactivity
in the vials and syringes measures no more than background with an appropriate low-
range survey meter. All identifying labels should be destroyed before discarding.
This reagent kit is approved by the U.S. Nuclear Regulatory Commission for distribution
to persons licensed to use byproduct material identified in §35.200 of 10 CFR Part 35, to
persons who have a similar authorization issued by an Agreement State, and, outside the
United States, to persons authorized by the appropriate authority.
DRAXIMAGE, a division of DRAXIS Specialty Pharmaceuticals Inc.
Kirkland, Québec, H9H 4J4 Canada
| custom-source | 2025-02-12T13:43:19.270381 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017881s010lbl.pdf', 'application_number': 17881, 'submission_type': 'SUPPL ', 'submission_number': 10} |
1,070 |
1
A2.0 NL 4550 AMP
1
INFORMATION FOR THE PATIENT
2
HUMULIN® R
3
REGULAR
4
INSULIN HUMAN INJECTION, USP
5
(rDNA ORIGIN)
6
100 Units per mL (U-100)
7
8
WARNINGS
9
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM
10
ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL
11
TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND
12
BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS.
13
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
14
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
15
MANUFACTURER, TYPE (E.G., REGULAR, NPH, LENTE), SPECIES (BEEF,
16
PORK, BEEF-PORK, HUMAN), OR METHOD OF MANUFACTURE
17
(rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED
18
FOR A CHANGE IN DOSAGE.
19
SOME PATIENTS TAKING HUMULIN (HUMAN INSULIN, rDNA ORIGIN)
20
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH
21
ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY
22
OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS
23
OR MONTHS.
24
DIABETES
25
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
26
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
27
the pancreas does not make enough insulin to meet your body’s needs.
28
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
29
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
30
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
31
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
32
sugar is maintained as close to normal as possible. The American Diabetes Association
33
recommends that if your pre-meal glucose levels are consistently above 140 mg/dL or your
34
hemoglobin A1c (HbA1c) is more than 8%, consult your doctor. A change in your diabetes
35
therapy may be needed. If your blood tests consistently show below-normal glucose levels you
36
should also let your doctor know. Proper control of your diabetes requires close and constant
37
cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat
38
a balanced diet, exercise regularly, and take your insulin injections as prescribed.
39
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
40
wear diabetic identification so that appropriate treatment can be given if complications occur
41
away from home.
42
REGULAR HUMAN INSULIN
43
Description
44
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia
45
coli bacteria that has been genetically altered by the addition of the gene for human insulin
46
production. Humulin R consists of zinc-insulin crystals dissolved in a clear fluid. Humulin R has
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
had nothing added to change the speed or length of its action. It takes effect rapidly and has a
48
relatively short duration of activity (4 to 12 hours) as compared with other insulins. The time
49
course of action of any insulin may vary considerably in different individuals or at different
50
times in the same individual. As with all insulin preparations, the duration of action of
51
Humulin R is dependent on dose, site of injection, blood supply, temperature, and physical
52
activity. Humulin R is a sterile solution and is for subcutaneous injection. It should not be used
53
intramuscularly. The concentration of Humulin R is 100 units/mL (U-100).
54
Identification
55
Human insulin by Eli Lilly and Company has the trademark Humulin and is available in
56
6 formulations — Regular (R), NPH (N), Lente (L), Ultralente (U), 50% Human Insulin
57
Isophane Suspension [NPH]/50% Human Insulin Injection [regular] (50/50), and 70% Human
58
Insulin Isophane Suspension [NPH]/30% Human Insulin Injection [regular] (70/30). Your doctor
59
has prescribed the type of insulin that he/she believes is best for you. DO NOT USE ANY
60
OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION.
61
Always check the carton and the bottle label for the name and letter designation of the insulin
62
you receive from your pharmacy to make sure it is the same as that your doctor has prescribed.
63
Always examine the appearance of your bottle of insulin before withdrawing each dose.
64
Humulin R is a clear and colorless liquid with a water-like appearance and consistency. Do not
65
use if it appears cloudy, thickened, or slightly colored or if solid particles are visible. Always
66
check the appearance of your bottle of insulin before using, and if you note anything unusual in
67
the appearance of your insulin or notice your insulin requirements changing markedly, consult
68
your doctor.
69
Storage
70
Humulin R should be stored in a refrigerator (2º to 8º C [36º to 46º F]), but not in the freezer. If
71
refrigeration is not possible, the bottle of Humulin R that you are currently using can be kept
72
unrefrigerated as long as it is kept as cool as possible (below 30ºC [86º F]), and away from heat
73
and light. Do not use Humulin R if it has been frozen. Do not use a bottle of Humulin R after the
74
expiration date stamped on the label.
75
INJECTION PROCEDURES
76
Correct Syringe
77
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
78
With Humulin R, it is important to use a syringe that is marked for U-100 insulin preparations.
79
Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for
80
you, such as a blood glucose level that is too low or too high.
81
Syringe Use
82
To help avoid contamination and possible infection, follow these instructions exactly.
83
Disposable syringes and needles should be used only once and then discarded. NEEDLES
84
AND SYRINGES MUST NOT BE SHARED.
85
Reusable syringes and needles must be sterilized before each injection. Follow the package
86
directions supplied with your syringe. Described below are 2 methods of sterilizing.
87
Boiling
88
1. Put syringe, plunger, and needle in strainer, place in saucepan, and cover with water. Boil
89
for 5 minutes.
90
2. Remove articles from water. When they have cooled, insert plunger into barrel, and fasten
91
needle to syringe with a slight twist.
92
3. Push plunger in and out several times until water is completely removed.
93
Isopropyl Alcohol
94
If the syringe, plunger, and needle cannot be boiled, as when you are traveling, they may be
95
sterilized by immersion for at least 5 minutes in Isopropyl Alcohol, 91%. Do not use bathing,
96
rubbing, or medicated alcohol for this sterilization. If the syringe is sterilized with alcohol, it
97
must be absolutely dry before use.
98
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Preparing the Dose
99
1. Wash your hands.
100
2. Inspect the insulin. Humulin R should look clear and colorless. Do not use Humulin R if it
101
appears cloudy, thickened, or slightly colored or if solid particles are visible.
102
3. If using a new bottle, flip off the plastic protective cap, but do not remove the stopper.
103
When using a new bottle, wipe the top of the bottle with an alcohol swab.
104
4. If you are mixing insulins, refer to the instructions for mixing that follow.
105
5. Draw air into the syringe equal to your insulin dose. Put the needle through rubber top of
106
the insulin bottle and inject the air into the bottle.
107
6. Turn the bottle and syringe upside down. Hold the bottle and syringe firmly in one hand.
108
7. Making sure the tip of the needle is in the insulin, withdraw the correct dose of insulin
109
into the syringe.
110
8. Before removing the needle from the bottle, check your syringe for air bubbles which
111
reduce the amount of insulin in it. If bubbles are present, hold the syringe straight up and
112
tap its side until the bubbles float to the top. Push them out with the plunger and withdraw
113
the correct dose.
114
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
115
touch anything.
116
Mixing Humulin R with Longer-acting Human Insulins
117
1. Regular human insulin should be mixed with longer-acting human insulins only on the
118
advice of your doctor.
119
2. Draw air into your syringe equal to the amount of longer-acting insulin you are taking.
120
Insert the needle into the longer-acting insulin bottle and inject the air. Withdraw the
121
needle.
122
3. Now inject air into your regular human insulin bottle in the same manner, but do not
123
withdraw the needle.
124
4. Turn the bottle and syringe upside down.
125
5. Making sure the tip of the needle is in the insulin, withdraw the correct dose of regular
126
insulin into the syringe.
127
6. Before removing the needle from the bottle, check your syringe for air bubbles which
128
reduce the amount of insulin in it. If bubbles are present, hold the syringe straight up and
129
tap its side until the bubbles float to the top. Push them out with the plunger and withdraw
130
the correct dose.
131
7. Remove the needle from the bottle of regular insulin and insert it into the bottle of the
132
longer-acting insulin. Turn the bottle and syringe upside down. Hold the bottle and
133
syringe firmly in one hand and shake gently. Making sure the tip of the needle is in the
134
insulin, withdraw your dose of longer-acting insulin.
135
8. Remove the needle and lay the syringe down so that the needle does not touch anything.
136
Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before
137
giving your injection. It is important to be consistent in your method.
138
Syringes from different manufacturers may vary in the amount of space between the bottom
139
line and the needle. Because of this, do not change:
140
• the sequence of mixing, or
141
• the model and brand of syringe or needle that the doctor has prescribed.
142
Injection
143
Cleanse the skin with alcohol where the injection is to be made. Stabilize the skin by spreading
144
it or pinching up a large area. Insert the needle as instructed by your doctor. Push the plunger in
145
as far as it will go. Pull the needle out and apply gentle pressure over the injection site for
146
several seconds. Do not rub the area. To avoid tissue damage, give the next injection at a site at
147
least 1/2” from the previous site. Place the used needle in a puncture-resistant disposable
148
container and properly dispose of it as directed by your Health Care Professional.
149
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
DOSAGE
150
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
151
Because each patient’s case of diabetes is different, this schedule has been individualized for
152
you.
153
Your usual insulin dose may be affected by changes in your food, activity, or work schedule.
154
Carefully follow your doctor’s instructions to allow for these changes. Other things that may
155
affect your insulin dose are:
156
Illness
157
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
158
Even if you are not eating, you will still require insulin. You and your doctor should establish a
159
sick day plan for you to use in case of illness. When you are sick, test your blood/urine
160
frequently and call your doctor as instructed.
161
Pregnancy
162
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
163
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
164
are nursing a baby, consult your doctor.
165
Medication
166
Insulin requirements may be increased if you are taking other drugs with hyperglycemic
167
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
168
requirements may be reduced in the presence of drugs with hypoglycemic activity, such as oral
169
hypoglycemics, salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
170
Always discuss any medications you are taking with your doctor.
171
Exercise
172
Exercise may lower your body’s need for insulin during and for some time after the activity.
173
Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the
174
area of injection site (for example, the leg should not be used for injection just prior to running).
175
Discuss with your doctor how you should adjust your regimen to accommodate exercise.
176
Travel
177
Persons traveling across more than 2 time zones should consult their doctor concerning
178
adjustments in their insulin schedule.
179
COMMON PROBLEMS OF DIABETES
180
Hypoglycemia (Insulin Reaction)
181
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
182
experienced by insulin users. It can be brought about by:
183
1. Taking too much insulin
184
2. Missing or delaying meals
185
3. Exercising or working more than usual
186
4. An infection or illness (especially with diarrhea or vomiting)
187
5. A change in the body’s need for insulin
188
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
189
disease
190
7. Interactions with other drugs that lower blood glucose, such as oral hypoglycemics,
191
salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants
192
8. Consumption of alcoholic beverages
193
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
194
• sweating
• drowsiness
195
• dizziness
• sleep disturbances
196
• palpitation
• anxiety
197
• tremor
• blurred vision
198
• hunger
• slurred speech
199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
• restlessness
• depressed mood
200
• tingling in the hands, feet, lips, or tongue
• irritability
201
• lightheadedness
• abnormal behavior
202
• inability to concentrate
• unsteady movement
203
• headache
• personality changes
204
Signs of severe hypoglycemia can include:
205
• disorientation
• seizures
206
• unconsciousness
• death
207
Therefore, it is important that assistance be obtained immediately.
208
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
209
conditions, such as long duration of diabetes, diabetic nerve disease, medications such as
210
beta-blockers, change in insulin preparations, or intensified control (3 or more insulin injections
211
per day) of diabetes.
212
A few patients who have experienced hypoglycemic reactions after transfer from
213
animal-source insulin to human insulin have reported that the early warning symptoms of
214
hypoglycemia were less pronounced or different from those experienced with their
215
previous insulin.
216
Without recognition of early warning symptoms, you may not be able to take steps to avoid
217
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
218
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
219
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
220
glucose is below your normal fasting glucose, you should consider eating or drinking
221
sugar-containing foods to treat your hypoglycemia.
222
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
223
Patients should always carry a quick source of sugar, such as candy mints or glucose tablets.
224
More severe hypoglycemia may require the assistance of another person. Patients who are unable
225
to take sugar orally or who are unconscious require an injection of glucagon or should be treated
226
with intravenous administration of glucose at a medical facility.
227
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
228
about these symptoms, you should monitor your blood glucose frequently to help you learn to
229
recognize the symptoms that you experience with hypoglycemia.
230
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
231
symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans,
232
and/or exercise programs to help you avoid hypoglycemia.
233
Hyperglycemia and Diabetic Acidosis
234
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
235
Hyperglycemia can be brought about by:
236
1. Omitting your insulin or taking less than the doctor has prescribed
237
2. Eating significantly more than your meal plan suggests
238
3. Developing a fever, infection, or other significant stressful situation
239
In patients with insulin-dependent diabetes, prolonged hyperglycemia can result in diabetic
240
acidosis. The first symptoms of diabetic acidosis usually come on gradually, over a period of
241
hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor
242
on the breath. With acidosis, urine tests show large amounts of glucose and acetone. Heavy
243
breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia
244
or diabetic acidosis can lead to nausea, vomiting, dehydration, loss of consciousness or death.
245
Therefore, it is important that you obtain medical assistance immediately.
246
Lipodystrophy
247
Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the
248
skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these
249
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
conditions, consult your doctor. A change in your injection technique may help alleviate the
250
problem.
251
Allergy to Insulin
252
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
253
injection of insulin. This condition, called local allergy, usually clears up in a few days to a few
254
weeks. In some instances, this condition may be related to factors other than insulin, such as
255
irritants in the skin cleansing agent or poor injection technique. If you have local reactions,
256
contact your doctor.
257
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
258
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
259
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
260
threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor
261
immediately.
262
ADDITIONAL INFORMATION
263
Additional information about diabetes may be obtained from your diabetes educator.
264
DIABETES FORECAST is a national magazine designed especially for patients with
265
diabetes and their families and is available by subscription from the American Diabetes
266
Association, National Service Center, 1660 Duke Street, Alexandria, Virginia 22314,
267
1-800-DIABETES (1-800-342-2383).
268
Another publication, DIABETES COUNTDOWN, is available from the Juvenile Diabetes
269
Foundation International (JDF), 120 Wall Street, 19th Floor, New York, New York 10005,
270
1-800-JDF-CURE (1-800-533-2873).
271
Additional information about Humulin can be obtained by calling 1-888-88-LILLY
272
(1-888-885-4559).
273
274
Literature issued XXX, 2003
275
Manufactured by Abbott Laboratories
276
North Chicago, IL 60064, USA
277
for Eli Lilly and Company
278
Indianapolis, IN 46285, USA
279
A2.0 NL 4550 AMP
PRINTED IN USA
280
Copyright 1997, 2003, Eli Lilly and Company. All rights reserved.
281
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C-671
C-671
CARTON HAS
BEEN OPENED
IMPORTANT—SEE WARNINGS
ON ACCOMPANYING CIRCULAR
Warning:
Any change of Insulin
should be made cautiously
and only under medical
supervision. See enclosed
circular.
As with any drug, if you
are pregnant or nursing a
baby, seek professional
advice when using this
product.
Contains Metacresol 0.25%
added during manufacture
as a preservative.
Neutral
For information call
1-888-885-4559
Exp. Date/Control No.
NDC 0002-8215-01
10 mL HI-210
Keep in a cold place.
Avoid freezing.
U-100
U-100
®
®
NDC 0002-8215-01
10 mL HI-210
100 units per mL
U-100
100 units per mL
®
3
2
0002-8215-01
NL 3820 AMS
NL 3820 AMS
NL 3820 AMS
Manufactured by Abbott Laboratories
North Chicago, IL 60064, USA
for Eli Lilly and Company
Indianapolis, IN 46285, USA
AZ20
1 "
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Humulin R
10 mL HI-210
100 units per mL
®
U-100
Exp. Date/Control No.
NL 4050 AMX
NDC 0002-8215-01
Important: See enclosed insert.
Keep in a cold place. Avoid freezing.
Neutral
Manufactured by Abbott Laboratories
North Chicago, IL 60064, USA
for Eli Lilly and Company
Indianapolis, IN 46285, USA
1 "
This label may not be the latest approved by FDA.
beling information, please visit https://www.fda.go
| custom-source | 2025-02-12T13:43:19.319839 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18780scm080_humalog_lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 80} |
738 |
DRAXIMAGE® M A A
Kit for the Preparation of
Technetium Tc 99m
Albumin Aggregated Injection
DIAGNOSTIC - For Intravenous Use
DESCRIPTION
The kit consists of reaction vials which contain the sterile, non-pyrogenic, non
radioactive ingredients necessary to produce Technetium Tc 99m Albumin Aggregated
Injection for diagnostic use by intravenous injection.
Each 10 mL reaction vial contains 2.5 mg of albumin aggregated, 5.0 mg of albumin
human, 0.06 mg (minimum) stannous chloride (maximum stannous and stannic chloride
0.11 mg) and 1.2 mg of sodium chloride; the contents are in a lyophilized form under an
atmosphere of nitrogen. Sodium hydroxide or hydrochloric acid has been used for pH
adjustment. No bacteriostatic preservative is present.
The albumin human was non-reactive when tested for Hepatitis B Surface Antigen
(HBsAg), antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2), antibody to
Hepatitis C Virus (anti-HCV) and Antigen to Human Immunodeficiency Virus (HIV-1).
The aggregated particles are formed by denaturation of albumin human in a heating and
aggregation process. Each vial contains 4 to 8 million particles. By light microscopy,
more than 90% of the particles are between 10 and 70 micrometers, while the typical
average size is 20 to 40 micrometers; none is greater than 150 micrometers.
Technetium Tc 99m Albumin Aggregated Injection for intravenous use is in its final
dosage form when sterile isotonic sodium pertechnetate solution is added to each vial. No
less than 90% of the pertechnetate Tc-99m added to a reaction vial is bound to aggregate
at preparation time and remains bound throughout the 6 hour lifetime of the preparation.
PHYSICAL CHARACTERISTICS
Technetium Tc-99m decays by isomeric transition with a physical half-life of 6.02
hours.1 The principal photon that is useful for detection and imaging studies is listed in
Table 1.
Table 1
Principal Radiation Emission Data
Radiation
Mean % per Disintegration
Mean Energy (keV)
Gamma-2
89.07
140.5
1 Kocher, David C.; “Radioactive Decay Data Tables’’, DOE/TIC-11026, 108, (1981)
® Registered Trademark of Jubilant DraxImage Inc.
Reference ID: 3019371
Reference ID: 3019533
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For current labeling information, please visit https://www.fda.gov/drugsatfda
EXTERNAL RADIATION
The specific gamma ray constant for technetium Tc-99m is 5.44 µC•kg-1•MBq-1•hr-1
(0.78 R/mCi-hr) at 1 cm.
The first half value layer is 0.017 cm of lead. A range of values for the relative
attenuation of the radiation resulting from the interposition of various thicknesses of lead
is shown in Table 2. For example, the use of 0.25 cm thickness of lead will attenuate the
radiation emitted by a factor of about 1000.
Table 2
Radiation Attenuation by Lead (Pb) Shielding
Shield Thickness
Coefficient of
(Pb) cm
Attenuation
0.017
0.08
0.16
0.25
0.33
0.5
10-1
10-2
10-3
10-4
To correct for physical decay of this radionuclide, the fractions that remain at selected
intervals after the time of calibration are shown in Table 3.
Table 3
Physical Decay Chart of Technetium Tc-99m
half-life: 6.02 hours
Hours
0*
1
2
3
4
Fraction
Remaining
1.000
0.891
0.794
0.708
0.631
Hours
5
6
8
10
12
Fraction
Remaining
0.562
0.501
0.398
0.316
0.251
*Calibration Time
CLINICAL PHARMACOLOGY
Immediately following intravenous injection, more than 80% of the albumin aggregated
is trapped in the pulmonary alveolar capillary bed. The imaging procedure can thus be
started as soon as the injection is complete. Assuming that a sufficient number of
radioactive particles has been used, the distribution of radioactive aggregated particles in
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the normally perfused lung is uniform throughout the vascular bed, and will produce a
uniform image. Areas of reduced perfusion will be revealed by a corresponding
decreased accumulation of the radioactive particles, and are imaged as areas of reduced
photon density.
Organ selectivity is a direct result of particle size. Below 1 to 10 micrometers, the
material is taken up by the reticuloendothelial system. Above 10 micrometers, the
aggregates become lodged in the lung by a purely mechanical process. Distribution of
particles in the lungs is a function of regional pulmonary blood flow.
The albumin aggregated is sufficiently fragile for the capillary micro-occlusion to be
temporary. Erosion and fragmentation reduce the particle size, allowing passage of the
aggregates through the pulmonary alveolar capillary bed. The fragments are then
accumulated by the reticuloendothelial system.
Lung to liver ratios greater than 20:1 are obtained in the first few minutes post-injection.
Elimination of the Technetium Tc 99m Aggregated Albumin from the lungs occurs with
a half-life of about 2 to 3 hours. Cumulative urinary excretion studies show an average
of 20% elimination of the injected technetium Tc 99m dose 24 hours post-administration.
Following administration of Technetium Tc 99m Albumin Aggregated by intraperitoneal
injection, the radiopharmaceutical mixes with the peritoneal fluid. Clearance from the
peritoneal cavity varies from insignificant, which may occur with complete shunt
blockage, to very rapid clearance with subsequent transfer into the systemic circulation
when the shunt is patent.
Serial images should be obtained of both the shunt and lung (target organ). However, an
adequate evaluation of the difference between total blockage of the shunt and partial
blockage may not be feasible in all cases.
INDICATIONS AND USAGE
Technetium Tc 99m Albumin Aggregated Injection is a lung imaging agent which may
be used as an adjunct in the evaluation of pulmonary perfusion in adults and pediatric
patients.
Technetium Tc 99m Albumin Aggregated Injection may be used in adults as an imaging
agent to aid in the evaluation of peritoneovenous (LeVeen) shunt patency.
CONTRAINDICATIONS
Technetium Tc 99m Albumin Aggregated Injection should not be administered to
patients with severe pulmonary hypertension.
Reference ID: 3019371
Reference ID: 3019533
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The use of Technetium Tc 99m Albumin Aggregated Injection is contraindicated in
persons with a history of hypersensitivity reactions to products containing human serum
albumin.
WARNINGS
Although adverse reactions specifically attributable to Technetium Tc 99m Albumin
Aggregated Injection have not been noted, the literature contains reports of deaths
occurring after the administration of albumin aggregated to patients with pre-existing
severe pulmonary hypertension. Instances of hemodynamic or idiosyncratic reactions to
preparations of Technetium Tc 99m Albumin Aggregated have been reported.
PRECAUTIONS
General
The contents of the kit before preparation are not radioactive. However, after the sodium
pertechnetate Tc-99m is added, adequate shielding of the final preparation must be
maintained.
In patients with right-to-left heart shunts, additional risk may exist due to the rapid entry
of albumin aggregated into the systemic circulation. The safety of this agent in such
patients has not been established. Hypersensitivity reactions are possible whenever
protein-containing materials such as pertechnetate labeled albumin aggregated are used in
man. Epinephrine, antihistamines, and corticosteroids should be available for immediate
use.
The intravenous administration of any particulate materials such as albumin aggregated
imposes a temporary small mechanical impediment to blood flow. While this effect is
probably physiologically insignificant in most patients, the administration of albumin
aggregated is possibly hazardous in acute cor pulmonale and other states of severely
impaired pulmonary blood flow.
The components of the kit are sterile and non-pyrogenic. It is essential to follow
directions carefully and to adhere to strict aseptic procedures during preparation.
Contents of the vials are intended only for use in the preparation of Technetium Tc 99m
Albumin Aggregated Injection and are NOT to be administered directly to the patient.
The technetium Tc-99m labeling reactions involved depend on maintaining the stannous
ion in the reduced state. Hence, sodium pertechnetate Tc-99m containing oxidants
should not be employed.
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The preparation contains no bacteriostatic preservative. Technetium Tc 99m Albumin
Aggregated Injection should be stored at 2 to 8 ºC (36 to 46 ºF) and discarded 6 hours
after reconstitution.
Technetium Tc 99m Albumin Aggregated Injection is physically unstable and
consequently the particles settle with time. Failure to agitate the vial adequately before
use may result in nonuniform distribution of radioactive particles.
If blood is drawn into the syringe, unnecessary delay prior to injection may result in clot
formation in situ.
Do not use if clumping of the contents is observed.
Technetium Tc 99m Albumin Aggregated Injection, as well as other radioactive drugs,
must be handled with care. Once sodium pertechnetate Tc-99m is added to the vial,
appropriate safety measures must be used to minimize radiation exposure to clinical
personnel. Care must also be taken to minimize the radiation exposure to patients in a
manner consistent with proper patient management.
Radiopharmaceuticals should be used only by physicians who are qualified by training
and experience in the safe use and handling of radionuclides and whose experience and
training have been approved by the appropriate government agency authorized to license
the use of radionuclides.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term animal studies have been performed to evaluate carcinogenic potential or
whether Technetium Tc 99m Albumin Aggregated Injection affects fertility in males or
females.
Pregnancy Category C
Animal reproduction and teratogenicity studies have not been conducted with
Technetium Tc 99m Albumin Aggregated Injection. It is also not known whether
Technetium Tc 99m Albumin Aggregated Injection can cause fetal harm when
administered to a pregnant woman or can affect reproductive capacity. There have been
no studies in pregnant women. Technetium Tc 99m Albumin Aggregated Injection
should be given to a pregnant woman only if clearly needed.
Ideally, examinations using radiopharmaceuticals, especially those elective in nature, of a
woman of childbearing capability, should be performed during the first few
(approximately 10) days following the onset of menses.
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers
Technetium Tc-99m is excreted in human milk during lactation. Therefore, formula
feedings should be substituted for breast feedings.
Pediatric Use
The lowest possible number of particles should be used in right-to-left shunting, in
neonates, and in severe pulmonary disease.
ADVERSE REACTIONS
The literature contains reports of deaths occurring after the administration of albumin
aggregated to patients with pre-existing severe pulmonary hypertension. Instances of
hemodynamic or idiosyncratic reactions to preparations of Technetium Tc 99m Albumin
Aggregated have been reported (see WARNINGS).
DOSAGE AND ADMINISTRATION
The recommended intravenous dose range for the average (70 kg) ADULT patient for
lung imaging is 37 to 148 megabecquerels (1 to 4 millicuries) of Technetium Tc 99m
Albumin Aggregated Injection after reconstitution with oxidant-free Sodium
Pertechnetate Tc 99m Injection.
The suggested intraperitoneal dosage range used in the average patient (70 kg) for
peritoneovenous (LeVeen) shunt patency evaluation is 37 to 111 megabecquerels (1 to 3
millicuries). Adequate measures should be taken to assure uniform mixing with
peritoneal fluid. Serial images of both the shunt and target organ should be obtained and
correlated with other clinical findings. Alternatively, the drug may be administered by
percutaneous transtubal injection. The suggested percutaneous transtubal (efferent limb)
dosage range for the average patient (70 kg) is 12 to 37 megabecquerels (0.3 to 1.0
millicurie) in a volume not to exceed 0.5 mL.
The recommended number of particles per single injection is 200,000 to 700,000 with the
suggested number being approximately 350,000. Depending on the activity added and
volume of the final reconstituted product, the volume of the dose may vary from 0.2 to
1.4 mL.
The number of particles available per dose of Technetium Tc 99m Albumin Aggregated
Injection will vary depending on the physical decay of the technetium Tc-99m that has
occurred. The number of particles in any dose and volume to be administered may be
calculated as follows:
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Assume the average number of particles per vial = 6.0 x 106.
If:
VTc = volume of solution added to reaction vial
D = desired dose to be administered in MBq (mCi)
C = concentration at calibration time of sodium pertechnetate solution to be added to
the reaction vial in MBq/mL (mCi/mL)
Va = volume to be administered in mL
P
= number of particles in dose to be administered
Fr = fraction of technetium Tc-99m remaining after the time of calibration (see Table
3)
Then:
Va =
D
and
P = Va x 6.0 x 106
C x Fr
VTc
In PEDIATRIC patients, the suggested intravenous dose to be employed for perfusion
lung imaging is in the range of 0.925 to 1.85 MBq per kilogram (25 to 50 μCi/kg) of
body weight; a usual dose is 1.11 MBq per kilogram (30 μCi/kg), except in newborns, in
whom the administered dose should be 7.4 to 18.5 MBq (200 to 500 μCi). Not less than
the minimum dose of 7.4 MBq (200 μCi) should be employed for this procedure. The
number of particles will vary with age and weight of the pediatric patient as indicated in
Table 5.
Parenteral drug products should be visually inspected for particulate matter and
discoloration prior to administration whenever solution and container permit.
The patient dose should be measured by a suitable radioactivity calibration system
immediately prior to administration. Mix the contents of the vial by gentle inversion just
prior to withdrawing a patient dose.
Mix the contents of the syringe just before injection. If blood is drawn into the syringe,
any unnecessary delay prior to injection may lead to clot formation. For optimum results
and because of rapid lung clearance of the radiopharmaceutical, it is suggested that the
patient be positioned under the imaging apparatus before administration. Slow injection
is recommended. Lung imaging may begin immediately after intravenous injection of the
radiopharmaceutical. Due to high kidney uptake, imaging later than one-half hour after
administration will yield poor results.
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RADIATION DOSIMETRY
The estimated absorbed radiation doses2 to an average ADULT patient (70 kg) from an
intravenous injection of 148 MBq (4 mCi) of Technetium Tc 99m Albumin Aggregated
Injection are shown in Table 4.
2 Method of calculation: “S” Absorbed Dose per Unit Cumulated Activity for Selected Radionuclides and
Organs, MIRD Pamphlet No. 11 (1975).
Table 4
Absorbed Radiation Doses
Organs
mGy/148 MBq
rad/4 mCi
Total body
0.60
0.060
Lungs
8.8
0.88
Liver
0.72
0.072
Spleen
0.68
0.068
Kidneys
Bladder Wall
0.44
0.044
2.0 hr. void
1.2
0.12
4.8 hr. void
Testes
2.2
0.22
2.0 hr. void
0.24
0.024
4.8 hr. void
Ovaries
0.26
0.026
2.0 hr. void
0.30
0.030
4.8 hr. void
0.34
0.034
In PEDIATRIC patients, the radiation absorbed doses using the maximum recommended
dose for lung imaging are based on 1.85 MBq (50 μCi) per kilogram of body weight
[except in the newborn where the maximum recommended dose of 18.5 MBq (500 μCi)
is used] and are shown in Table 5, which lists the maximum dose for pediatric patients
from newborn to adults. Note the recommendations regarding number of particles to be
administered.
Table 6 represents the absorbed radiation dose resulting from the intraperitoneal
administration of 111 megabecquerels (3 millicuries) of Technetium Tc 99m Albumin
Aggregated.
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Age
Newborn
1 year
5 years
10 years
15 years
Weight (kg)
3.5
12.1
20.3
33.5
55.0
Max.
MBq
mCi
MBq
mCi
MBq
mCi
MBq
mCi
MBq
mCi
recommended dose
in megabecquerels
and millicuries
18.5
0.5
22.2
0.6
37
1.0
62.9
1.7
103.6
2.8
Range of particles
administered
10,000 to
50,000
50, 000 to
150,000
200,000 to
300,000
200,000 to
300,000
200,000 to
700,000
Absorbed radiation
dose in milligray
and rad for the
maximum dose
mGy
rad
mGy
rad
mGy
rad
mGy
rad
mGy
rad
ORGANS
Total body
0.60
0.06
0.30
0.03
0.31
0.031
0.48
0.048
0.41
0.041
Lungs
19.00
1.9
6.60
0.66
5.80
0.58
8.70
0.87
7.70
0.77
Liver
1.40
0.14
0.60
0.06
0.62
0.062
1.80
0.18
1.20
0.12
Bladder wall
2.10
0.21(1)
1.50
0.15(1)
3.10
0.31(2)
3.90
0.39(2)
4.10
0.41
Ovaries
0.38
0.038
0.20
0.020
0.19
0.019
0.44
0.044
0.41
0.041
Testes
0.31
0.031
0.13
0.013
0.19
0.019
0.20
0.020
0.36
0.036
*Assumptions:
1. Used biologic data from Kaul et al., Berlin, 1973.
2. For the newborn, 1-year old, and 5-year old, the “S” values calculated from the preliminary phantoms of
ORNL were used. The 10-year old, 15-year old and adult “S” values were taken from Henrichs et al.,
Berlin, 1980.
Table 5
Pediatric Radiation Dose from Tc 99m MAA for Lung Imaging*
(1) 2.0 hour voiding interval
(2) 4.8 hour voiding interval
Table 6
Absorbed Radiation Doses
Organs
Shunt
Patency
(Open)
Shunt
Patency
(Closed)
mGy
rad
mGy
rad
Lung
Ovaries
& testes
Organs in the peritoneal
cavity
Total body
6.9
0.18
to 0.30
-
0.36
0.69
0.018
to 0.030
-
0.036
1.68
1.68
1.68
0.57
0.168
0.168
0.168
0.057
Assumptions:
Calculations for the absorbed radiation dose are based upon an effective half-time of 3 hours for the open
shunt and 6.02 hours for the closed shunt and an even distribution of the radiopharmaceutical in the
peritoneal cavity with no biological clearance.
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
DRAXIMAGE® MAA
Kit for the Preparation of Technetium Tc 99m Albumin Aggregated Injection
Each kit contains 30 reaction vials, each vial containing in lyophilized form, sterile and
non-pyrogenic:
Albumin aggregated
2.5 mg
Albumin human
5.0 mg
Stannous Chloride (minimum)
0.06 mg
(Maximum stannous and stannic chloride
0.11 mg)
Sodium chloride
1.2 mg
HCl and/or NaOH has been used for pH adjustment. The vials are sealed under an
atmosphere of nitrogen.
Thirty labels with radiation warning symbol and a package insert are supplied in each
carton.
STORAGE
Store the unreconstituted reaction vials at 2 to 25 ºC (36 to 77 ºF). After labeling with
Technetium Tc-99m, store the solution at 2 to 8 ºC (36 to 46 ºF) in a suitable lead shield
and discard after 6 hours.
DIRECTIONS FOR PREPARATION
NOTE: Use aseptic procedures throughout and take precautions to minimize radiation
exposure by use of suitable shielding. Waterproof gloves should be worn during the
preparation procedure.
Before reconstituting a vial, it should be inspected for cracks and/or a melted plug or any
other indication that the integrity of the vacuum seal has been lost.
To prepare Technetium Tc 99m Albumin Aggregated Injection:
1. Remove the protective disc from a reaction vial and swab the rubber septum with
either an alcohol swab or a suitable bacteriostatic agent to disinfect the surface.
2. Place the vial in a suitable lead vial shield which has a fitted cap. Obtain 2 to 8 mL
of a sterile pyrogen-free Sodium Pertechnetate Tc 99m Injection using a shielded
syringe. The recommended maximum amount of Tc-99m to be added to a reaction
Reference ID: 3019371
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
vial is 3.7 GBq (100 mCi). Sodium pertechnetate Tc 99m solutions containing an
oxidizing agent are not suitable for use.
3. Using a shielded syringe, add the Sodium Pertechnetate Tc 99m Injection to the
reaction vial aseptically.
4. Place the lead cap on the vial shield and mix the contents of the shielded vial by
repeated gentle inversion until all the material is suspended. Avoid formation of
foam. Using proper shielding, the vial should be visually inspected to ensure that
the suspension is free of foreign matter before proceeding. Do not administer if
foreign particulates are found in the preparation. To ensure maximum tagging,
allow the preparation to stand for 15 minutes after mixing.
5. Assay the product in a suitable calibrator, record the radioassay information on the
label with radiation warning symbol, and attach it to the vial shield.
6. Withdrawals for administration must be made aseptically using a sterile needle (18
to 21 gauge) and syringe. Since the vials contain nitrogen to prevent oxidation of
the complex, the vials should not be vented. If repeated withdrawals are made from
the vial, replacement of the contents with air should be minimized.
7. The finished preparation should be refrigerated at 2 to 8 ºC (36 to 46 ºF) when not
in use and discarded after 6 hours. (The preparation contains no bacteriostatic
preservative.) The vial should also be retained during its life in the reaction vial
shield with cap in place.
DISPOSAL
The residual materials may be discarded in the ordinary trash, provided the radioactivity
in the vials and syringes measures no more than background with an appropriate low-
range survey meter. All identifying labels should be destroyed before discarding.
This reagent kit is approved by the U.S. Nuclear Regulatory Commission for distribution
to persons licensed to use byproduct material identified in §35.200 of 10 CFR Part 35, to
persons who have a similar authorization issued by an Agreement State, and, outside the
United States, to persons authorized by the appropriate authority.
Jubilant DraxImage Inc.
Kirkland, Québec, H9H 4J4 Canada
Reference ID: 3019533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:19.317159 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017881s016lbl.pdf', 'application_number': 17881, 'submission_type': 'SUPPL ', 'submission_number': 16} |
1,071 | This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:19.393704 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/18780s086,18781s080lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 86} |
1,078 |
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN R U-500 safely and effectively. See full prescribing
information for HUMULIN R U-500.
HUMULIN R U-500 (insulin human injection), for subcutaneous use
Initial U.S. Approval: 1994
--------------------------- RECENT MAJOR CHANGES -------------------------
Dosage and Administration (2)
07/2016
Warnings and Precautions (5)
07/2016
----------------------------INDICATIONS AND USAGE --------------------------
HUMULIN® R U-500 is a concentrated human insulin indicated to improve
glycemic control in adults and children with diabetes mellitus requiring more
than 200 units of insulin per day. (1)
Limitation of Use: The safety and efficacy of HUMULIN R U-500 used in
combination with other insulins has not been determined. The safety and
efficacy of HUMULIN R U-500 delivered by continuous subcutaneous
infusion has not been determined. (1.1)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
•
Adhere to administration instructions to reduce the risk of dosing errors.
(2.1, 2.3, 2.4, 5.1)
•
HUMULIN R U-500 is available as a KwikPen or multiple dose vial.
Patients using the vial must be prescribed the U-500 insulin syringe to
avoid medication errors. (2.1)
•
Individualize dose of HUMULIN R U-500 based on metabolic needs,
blood glucose monitoring results and glycemic control goal. (2.2)
•
Administer HUMULIN R U-500 subcutaneously two or three times
daily 30 minutes before a meal. Rotate injection sites to reduce the risk
of lipodystrophy. (2.1, 2.2)
•
Do NOT mix HUMULIN R U-500 with other insulins. (2.1)
•
Do NOT administer HUMULIN R U-500 intravenously or
intramuscularly. (2.1)
•
Do NOT perform dose conversion when using the HUMULIN R U-500
KwikPen. The dose window of the HUMULIN R U-500 KwikPen
shows the number of units of HUMULIN R U-500 to be injected. (2.3)
•
Do NOT transfer HUMULIN R U-500 from the HUMULIN R U-500
KwikPen into any syringe. (2.3)
•
Do NOT perform dose conversion when using a U-500 insulin syringe.
Use only a U-500 insulin syringe with the HUMULIN R U-500 vial.
(2.4)
----------------------DOSAGE FORMS AND STRENGTHS --------------------
HUMULIN R U-500 (500 units per mL) is available in a colorless solution as:
(3)
•
3 mL HUMULIN® R U-500 KwikPen® (prefilled pen containing
1,500 units of insulin)
•
20 mL multiple dose vial (containing 10,000 units of insulin)
-------------------------------CONTRAINDICATIONS-----------------------------
•
Do not use during episodes of hypoglycemia. (4)
•
Do not use in patients with hypersensitivity to HUMULIN R U-500 or
any of its excipients. (4)
------------------------ WARNINGS AND PRECAUTIONS ----------------------
•
Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial
Presentation: Can be life-threatening. Overdose has occurred as a result
of dispensing, prescribing or administration errors. Attention to details at
all levels is required to prevent these errors. (2.1, 2.3, 2.4, 5.1)
•
Never share a HUMULIN R U-500 KwikPen or U-500 insulin syringe
between patients, even if the needle is changed. (5.2)
•
Hyper- or Hypoglycemia with Changes in Insulin Regimen: Carry out
under close medical supervision and increase frequency of blood glucose
monitoring. (5.3)
•
Hypoglycemia: May be life-threatening. Increase monitoring with
changes to: insulin dosage, co-administered glucose lowering
medications, meal pattern, physical activity; and in patients with renal
impairment or hepatic impairment or hypoglycemia unawareness. (5.4)
•
Hypersensitivity Reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur. Discontinue HUMULIN R U-500,
monitor, and treat if indicated. (5.5)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk for hypokalemia and treat if indicated. (5.6)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure
occurs. (5.7)
-------------------------------ADVERSE REACTIONS -----------------------------
Adverse reactions associated with HUMULIN R U-500 include
hypoglycemia, allergic reactions, injection site reactions, lipodystrophy,
pruritus, and rash. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -----------------------------
•
Certain drugs may affect glucose metabolism and may necessitate
insulin dose adjustment. (7.1, 7.2, 7.3)
•
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine). (7.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 07/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Limitation of Use
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Dosing Instructions
2.3
Delivery of HUMULIN R U-500 using the HUMULIN R U-500
Disposable Prefilled KwikPen Device
2.4
Delivery of HUMULIN R U-500 using the vial presentation and
the U-500 Insulin Syringe
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hyperglycemia, Hypoglycemia or Death due to Dosing Errors
with the Vial Presentation
5.2
Never Share a HUMULIN R U-500 KwikPen or U-500 Insulin
Syringe Between Patients
5.3
Hyperglycemia or Hypoglycemia with Changes in Insulin
Regimen
5.4
Hypoglycemia
5.5
Hypersensitivity and Allergic Reactions
5.6
Hypokalemia
5.7
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect
of HUMULIN R U-500
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN R U-500
7.4
Drugs That May Affect Signs and Symptoms of Hypoglycemia
Reference ID: 3956468
2
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients
with diabetes mellitus requiring more than 200 units of insulin per day.
1.1
Limitation of Use
The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined.
The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
•
Prescribe HUMULIN R U-500 ONLY to patients who require more than 200 units of insulin per day.
•
HUMULIN R U-500 is available as a KwikPen or multiple dose vial. Patients using the vial must be prescribed the U-500
insulin syringe to avoid medication errors.
•
Instruct patients using the vial presentation to use only a U-500 insulin syringe and on how to correctly draw the
prescribed dose of HUMULIN R U-500 into the U-500 insulin syringe. Confirm that the patient has understood these
instructions and can correctly draw the prescribed dose of HUMULIN R U-500 with their syringe [see Dosage and
Administration (2.4) and Warnings and Precautions (5.1)].
•
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Train
patients on proper use and injection technique before initiating HUMULIN R U-500. Training reduces the risk of
administration errors such as needle sticks and dosing errors.
•
Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being
used [see Warnings and Precautions (5.1)].
•
Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the
solution appears clear and colorless.
•
Instruct patients to inject HUMULIN R U-500 subcutaneously into the thigh, upper arm, abdomen, or buttocks.
•
Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy [see
Adverse Reactions (6)].
•
DO NOT administer HUMULIN R U-500 intravenously or intramuscularly.
•
DO NOT dilute or mix HUMULIN R U-500 with any other insulin products or solutions.
2.2
Dosing Instructions
•
Instruct patients to inject HUMULIN R U-500 subcutaneously usually two or three times daily approximately 30 minutes
before meals.
•
Individualize and titrate the dosage of HUMULIN R U-500 based on the patient’s metabolic needs, blood glucose
monitoring results, and glycemic control goal.
•
Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient
content or timing of food intake), changes in renal or hepatic function, changes in medications or during acute illness to
minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.3)].
Reference ID: 3956468
3
2.3
Delivery of HUMULIN R U-500 using the HUMULIN R U-500 Disposable Prefilled KwikPen Device
•
DO NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the
HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected and NO dose conversion
is required.
•
DO NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe for administration as
overdose and severe hypoglycemia can occur [see Warnings and Precautions (5.4)].
•
The HUMULIN R U-500 KwikPen is for single patient use only [see Warnings and Precautions (5.2)].
2.4
Delivery of HUMULIN R U-500 using the vial presentation and the U-500 Insulin Syringe
•
DO NOT perform dose conversion when using a U-500 insulin syringe. The markings on the U-500 insulin syringe show
the number of units of HUMULIN R U-500 to be injected. Each marking on the syringe represents 5 units of insulin.
•
Prescribe patients a U-500 insulin syringe to administer HUMULIN R U-500 from the vial to avoid administration errors.
DO NOT use any other type of syringe [see Warnings and Precautions (5.1)].
3
DOSAGE FORMS AND STRENGTHS
HUMULIN R U-500 (500 units per mL) is available in a colorless solution as:
•
3 mL HUMULIN R U-500 KwikPen (prefilled, 1,500 units of insulin)
•
20 mL multiple dose vial (containing 10,000 units of insulin)
4
CONTRAINDICATIONS
HUMULIN R U-500 is contraindicated:
•
During episodes of hypoglycemia
•
In patients who are hypersensitive to HUMULIN R U-500 or any of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with the Vial Presentation
Medication errors associated with the HUMULIN R U-500 vial presentation resulting in patients experiencing hyperglycemia,
hypoglycemia or death have been reported. The majority of errors occurred due to errors in dispensing, prescribing or administration.
Attention to details at all levels may prevent these errors.
Dispensing Errors
Instruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct insulin
brand and concentration.
The HUMULIN R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement
consisting of white lettering on a green rectangular background, and a green “U-500” statement prominently displayed next to the
trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and
a statement advising use with only U-500 insulin syringes.
Prescribing Errors
Dosing errors have occurred when the HUMULIN R U-500 dose was administered with syringes other than a U-500 insulin
syringe. Patients should be prescribed U-500 syringes for use with the HUMULIN R U-500 vials. The prescribed dose of
HUMULIN R U-500 should always be expressed in units of insulin [see Dosage and Administration (2.4)].
Administration Errors
Instruct patients to always check the insulin label before each injection.
Use only a U-500 insulin syringe with HUMULIN R U-500 to avoid administration errors. Do not use any other type of
syringe to administer Humulin R U-500. Adhere to administration instructions [see Dosage and Administration (2.1, 2.4)].
Instruct the patient to inform hospital or emergency department staff of the dose of HUMULIN R U-500 prescribed, in the
event of a future hospitalization or visit to the Emergency Department.
Reference ID: 3956468
4
5.2
Never Share a HUMULIN R U-500 KwikPen or U-500 Insulin Syringe Between Patients
HUMULIN R U-500 KwikPens should never be shared between patients, even if the needle is changed. Patients using
HUMULIN R U-500 vials should never share needles or U-500 insulin syringes with another person. Sharing poses a risk for
transmission of blood-borne pathogens.
5.3
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in insulin, manufacturer, type, or method of administration may affect glycemic control and predispose to
hypoglycemia or hyperglycemia. These changes should be made cautiously and only under medical supervision and the frequency of
blood glucose monitoring should be increased. For patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic
treatment may be needed.
5.4
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulin, including HUMULIN R U-500. Severe
hypoglycemia can cause seizures, may be life-threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours
after an injection of HUMULIN R U-500. Hypoglycemia can impair concentration ability and reaction time; this may place an
individual and others at risk in situations where these abilities are important (e.g., driving, or operating other machinery).
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic
nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions
(7.3, 7.4)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulin
preparations, the glucose lowering effect time course of HUMULIN R U-500 may vary in different individuals or at different times in
the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and
temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content
or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7.1, 7.2,
7.3, 7.4)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6,
8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an
essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have
reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. To minimize
the risk of hypoglycemia do not administer HUMULIN R U-500 intravenously, intramuscularly or in an insulin pump or dilute or mix
HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].
5.5
Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMULIN R
U-500 [see Adverse Reactions (6)]. If hypersensitivity reactions occur, discontinue HUMULIN R U-500; treat per standard of care
and monitor until symptoms and signs resolve [see Adverse Reactions (6)].
5.6
Hypokalemia
All insulin products, including HUMULIN R U-500, cause a shift in potassium from the extracellular to intracellular space,
possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use
caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations).
5.7
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-
related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.
Patients treated with insulin, including HUMULIN R U-500, and a PPAR-gamma agonist should be observed for signs and symptoms
of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose
reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
Reference ID: 3956468
5
•
Hypoglycemia [see Warnings and Precautions (5.4)].
•
Hypokalemia [see Warnings and Precautions (5.6)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or to establish a causal relationship to drug exposure.
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMULIN R U-500 [see
Warnings and Precautions (5.4)].
Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, rash, angioedema,
bronchospasm, hypotension, and shock may occur with any insulin, including HUMULIN R U-500 and may be life threatening [see
Warnings and Precautions (5.5)].
Lipodystrophy
Long-term use of insulin, including HUMULIN R U-500, can cause lipodystrophy at the site of repeated insulin injections.
Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect
insulin absorption. Rotate insulin injections sites within the same region to reduce the risk of lipodystrophy [see Dosage and
Administration (2.1)].
Injection Site Reactions
Patients taking HUMULIN R U-500 may experience injection site reactions, including injection site hematoma, pain,
hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass.
Weight Gain
Weight gain can occur with insulin therapy, including HUMULIN R U-500, and has been attributed to the anabolic effects of
insulin.
Peripheral Edema
Insulin, including HUMULIN R U-500, may cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
Immunogenicity
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The presence of antibodies
that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper- or hypoglycemia.
The incidence of antibody formation with HUMULIN R U-500 is unknown.
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN R U-500 use may be increased with antidiabetic agents, ACE inhibitors,
angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide,
propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased
frequency of glucose monitoring may be required when HUMULIN R U-500 is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN R U-500
The glucose lowering effect of HUMULIN R U-500 may be decreased when co-administered with atypical antipsychotics
(e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives,
phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol,
epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required
when HUMULIN R U-500 is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN R U-500
The glucose lowering effect of HUMULIN R U-500 may be increased or decreased when co-administered with alcohol, beta-
blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN R U-500 is co-administered with
these drugs.
Reference ID: 3956468
6
7.4
Drugs That May Affect Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)] may be blunted when beta-blockers,
clonidine, guanethidine, and reserpine are co-administered with HUMULIN R U-500.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This
background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is
essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. In patients with diabetes or gestational diabetes, insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is
essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they
become pregnant while taking HUMULIN R U-500.
Human Data
While there are no adequate and well-controlled studies in pregnant women, evidence from published literature suggests that
good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal benefits.
Animal Data
Reproduction and fertility studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the gastrointestinal tract. No adverse
reactions associated with infant exposure to insulin through the consumption of human milk have been reported. In a study of eight
preterm infants between 26 to 30 weeks gestation, enteral administration of biosynthetic human insulin did not result in hypoglycemia.
Good glucose control supports lactation in patients with diabetes. Women with diabetes who are lactating may require adjustments in
their insulin dose.
8.4
Pediatric Use
There are no well-controlled studies of use of HUMULIN R U-500 in children. Standard precautions as applied to use of
HUMULIN R U-500 in adults are appropriate for use in children. As in adults, the dosage of HUMULIN R U-500 in pediatric patients
must be individualized based on metabolic needs and results of frequent monitoring of blood glucose.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution
should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial
dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.
8.6
Renal Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.
8.7
Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma,
seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery.
Hypokalemia must be corrected appropriately.
Reference ID: 3956468
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11
DESCRIPTION
HUMULIN R U-500 (insulin human injection, USP) is a human insulin solution used to lower blood glucose. Human insulin
is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. HUMULIN R has the
empirical formula C257H383N65O77S6 with a molecular weight of 5808.
HUMULIN R U-500 is a sterile, aqueous, and colorless solution. HUMULIN R U-500 contains 500 units of insulin in each
milliliter. Each milliliter of HUMULIN R U-500 also contains glycerin 16 mg, metacresol 2.5 mg, zinc oxide to supplement the
endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric
acid may be added during manufacture to adjust the pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. Insulins lower blood
glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins
inhibit lipolysis and proteolysis, and enhance protein synthesis.
12.2
Pharmacodynamics
In a euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m2), single doses of HUMULIN R U-500 at
50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both
doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal
activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.
Figure 1 should be considered a representative example since the time course of action of insulin may vary in different
individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected
by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)]. graph
Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 in
Healthy Obese Subjects
12.3
Pharmacokinetics
Absorption — In a euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between 4
hours (50 unit dose) and 8 hours (100 unit dose) with a range of 0.5-8 hours.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the
liver being the major organ involved in the clearance of insulin.
Elimination — Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy
obese subjects (N≥21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN R U-500.
Reference ID: 3956468
8 graph
Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of a 100 U Dose of HUMULIN R
U-500 Healthy Obese Subjects
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed with HUMULIN R U-500 in animals. Biosynthetic human insulin
was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis
assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN R U-500 (500 units per mL) is available as:
2 x 3 mL HUMULIN R U-500 KwikPen (prefilled)
20 mL multiple dose vials
NDC 0002-8824-27
NDC 0002-8501-01
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use HUMULIN R U-500 after the expiration date printed on the label or if it
has been frozen. Do not shake the vial.
Not In Use (Unopened) HUMULIN R U-500 KwikPen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 28 days.
In-Use (Opened) HUMULIN R U-500 KwikPen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 28 days, even if the pen still contains
HUMULIN R U-500. See storage table below:
Reference ID: 3956468
B5.0LINR500-0004-USPI-YYYYMMDD
9
17
Not In Use (Unopened) HUMULIN R U-500 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 40 days.
In-Use (Opened) HUMULIN R U-500 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must be used
within 40 days or be discarded, even if they still contain HUMULIN R U-500.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 40 days, even if the vial still contains
HUMULIN R U-500. See storage table below:
Not In-Use (Unopened) Refrigerated
In-Use (Opened)
3 mL HUMULIN R U-500 KwikPen
(prefilled)
Until expiration date
28 days, room temperature.
Do not refrigerate.
20 mL multiple dose vial
Until expiration date
40 days, refrigerated or room temperature
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
Patients should be counseled that HUMULIN R U-500 is a 5-times concentrated insulin product. Extreme caution must be
observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening
hypoglycemia. Accidental mix-ups between HUMULIN R U-500 and other insulins have been reported. To avoid medication errors
between HUMULIN R U-500 and other insulins, patients should be instructed to always check the insulin label before each injection
[see Warnings and Precautions (5.1)].
If using the HUMULIN R U-500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of
insulin (no dose conversion is required) [see Dosage and Administration (2.3)].
When using HUMULIN R U-500 from a vial, patients should be counseled to use only a U-500 insulin syringe and be
informed that no dose conversion is required [see Dosage and Administration (2.4)].
Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and
management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN R U-500 therapy. Patients must be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped
insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Refer patients to the
HUMULIN R U-500 Patient Information Leaflet for additional information [see Warnings and Precautions (5)].
Women with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Never use HUMULIN R U-500 if it has become viscous (thickened) or cloudy; use it only if
it is clear and colorless.
HUMULIN R U-500 should not be used after the printed expiration date.
Do not dilute or mix HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].
Literature Revised: July 2016
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, 2016, Eli Lilly and Company. All rights reserved.
Reference ID: 3956468
1
Patient Information
Humulin® (HU-mu-lin) R U-500
insulin human injection
(500 units per mL)
Do not share your Humulin R U-500 KwikPen or U-500 insulin syringes with other people, even if the needle
has been changed. You may give other people a serious infection or get a serious infection from them.
What is Humulin R U-500?
•
Humulin R U-500 is a man-made insulin that is used to control high blood sugar in adults and children with diabetes
mellitus who need more than 200 units of insulin in a day.
•
Humulin R U-500 contains 5 times as much insulin (500 units/mL) in 1 mL as standard insulin (100 units/mL).
•
It is not known if Humulin R U-500 is safe and effective when used in combination with other insulins.
•
It is not known if Humulin R U-500 is safe and effective when given by continuous subcutaneous infusion.
•
It is not known if Humulin R U-500 is safe and effective in children.
Who should not take Humulin R U-500?
Do not take Humulin R U-500 if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to human insulin or any of the ingredients in Humulin R U-500. See the end of this Patient
Information leaflet for a complete list of ingredients in Humulin R U-500.
What should I tell my healthcare provider before using Humulin R U-500?
Before using Humulin R U-500, tell your healthcare provider about all your medical conditions including, if you:
•
have liver or kidney problems.
•
take other medicines, especially ones called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with
Humulin R U-500.
•
are pregnant, planning to become pregnant, or breast-feeding. It is not known if Humulin R U-500 will harm your
unborn or breastfeeding baby.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, or herbal supplements.
Before you start using Humulin R U-500, talk to your healthcare provider about low blood sugar and how to
manage it.
How should I use Humulin R U-500?
•
Read the detailed Instructions for Use that come with your Humulin R U-500.
•
Use Humulin R U-500 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how
much Humulin R U-500 to use and when to use it.
•
Know the dose of Humulin R U-500 you use. Do not change the dose of Humulin R U-500 you use unless your
healthcare provider tells you to.
•
Check your insulin label each time you give your injection to make sure you are using the correct insulin.
•
When using the Humulin R U-500 KwikPen: The Humulin R U-500 KwikPen is specially made to dial and deliver
doses of Humulin R U-500 insulin. Do not use any syringe to remove Humulin R U-500 from your Humulin R U-500
KwikPen. The markings on certain syringes will not measure your dose correctly. A severe overdose can happen,
causing low blood sugar, which may put your life in danger.
•
When using the Humulin R U-500 vial: There is a special U-500 insulin syringe to measure Humulin R U-500.
Use only a U-500 insulin syringe to draw up and inject your Humulin R U-500. If you do not use the right
syringe type, you may take the wrong dose of Humulin R U-500. This can cause you to have too low blood sugar
(hypoglycemia) or too high blood sugar (hyperglycemia). Your healthcare provider should show you how to draw up
Humulin R U-500.
•
Use Humulin R U-500 30 minutes before eating a meal.
•
Inject Humulin R U-500 under your skin (subcutaneously). Do not use Humulin R U-500 in an insulin pump or inject
Humulin R U-500 into your vein (intravenously) or your muscle (intramuscularly).
•
Do not mix Humulin R U-500 in the KwikPen or vial with any other type of insulin or liquid medicine.
•
Change (rotate) your injection site with each dose.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you
should check your blood sugar levels.
Keep Humulin R U-500 and all medicines out of reach of children.
Reference ID: 3956468
B3.0LINR500-0003-PPI-YYYYMMDD
2
Your dose of Humulin R U-500 may need to change because of:
•
change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or
because of other medicines you take.
What should I avoid while using Humulin R U-500?
While using Humulin R U-500 do not:
•
drive or operate heavy machinery, until you know how Humulin R U-500 affects you.
•
drink alcohol or use over-the-counter medicines that contain alcohol.
What are the possible side effects of Humulin R U-500?
Humulin R U-500 may cause serious side effects that can lead to death, including:
•
low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:
-
dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast
heartbeat, anxiety, irritability or mood changes, hunger.
-
your healthcare provider may prescribe a glucagon emergency kit so that others can give you an injection if your
blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.
•
severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or
symptoms of a severe allergic reaction:
-
a rash over your whole body, have trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with Humulin R U-500 may cause
heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If
you already have heart failure, it may get worse while you take TZDs with Humulin R U-500. Your healthcare
provider should monitor you closely while you are taking TZDs with Humulin R U-500. Tell your healthcare provider
if you have any new or worse symptoms of heart failure including:
-
shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and Humulin R U-500 may need to be adjusted or stopped by your healthcare provider if you
have new or worse heart failure.
Get emergency medical help if you have:
•
severe hypoglycemia needing hospitalization or emergency room care, and be sure to tell the hospital staff the units
of Humulin R U-500 that your healthcare provider has prescribed for you.
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme
drowsiness, dizziness, confusion.
The most common side effects of Humulin R U-500 include:
•
low blood sugar (hypoglycemia), allergic reactions including reactions at your injection site, skin thickening or pits at
the injection site (lipodystrophy), itching, and rash.
These are not all of the possible side effects of Humulin R U-500. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
General Information about the safe and effective use of Humulin R U-500
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
Humulin R U-500 for a condition for which it was not prescribed. Do not give Humulin R U-500 to other people, even if
they have the same symptoms you have. It may harm them.
This Patient Information leaflet summarizes the most important information about Humulin R U-500. If you would like
more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information
about Humulin R U-500 that is written for healthcare professionals. For more information go to www.humulin.com or call
1-800-545-5979.
What are the ingredients in Humulin R U-500?
Active ingredient: human insulin
Inactive ingredients: glycerin, metacresol, zinc oxide, water for injection, sodium hydroxide and hydrochloric acid
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
For more information about Humulin R U-500 go to www.humulin.com.
Copyright © 2015, 2016 Eli Lilly and Company. All rights reserved.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: July 2016
Reference ID: 3956468
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Instructions for Use
HUMULIN® R U-500 KwikPen®
insulin human injection U-500 (500 units/mL, 3 mL pen) usage illustration
Important:
•
Know your dose of HUMULIN R U-500 insulin. The Pen delivers your dose in insulin units. Insulin
units may not be the same as syringe markings. Ask your health care provider what your dose
should be for your Pen.
•
Your HUMULIN® R U-500 KwikPen® (Pen) works differently from other pens. It dials 5 insulin units
with each click. Do not count clicks of the dose knob to select your dose. You may not get
enough insulin or you may get too much insulin.
•
HUMULIN R U-500 is a concentrated insulin. Do not transfer HUMULIN R U-500 insulin from
your Pen into a syringe. A severe overdose can happen, causing very low blood sugar, which
may put your life in danger. usage illustration
DO NOT TRANSFER TO A SYRINGE
SEVERE OVERDOSE CAN RESULT
Read the Instructions for Use before you start taking HUMULIN R U-500 and each time you get another Pen.
There may be new information. This information does not take the place of talking to your healthcare provider
about your medical condition or your treatment.
Do not share your HUMULIN R U-500 Pen with other people, even if the needle has been changed. You
may give other people a serious infection or get a serious infection from them.
HUMULIN R U-500 KwikPen (“Pen”) is a disposable prefilled pen containing 1500 units of HUMULIN R. You can
give yourself more than 1 dose from the Pen. Each turn (click) of the Dose Knob dials 5 units of insulin. You can
give from 5 to 300 units in a single injection. The plunger only moves a little with each injection, and you may not
notice that it moves. The plunger will only reach the end of the cartridge when you have used all 1500 units in the
Pen.
This Pen is not recommended for use by the blind or visually impaired without the help of someone
trained to use the Pen.
Reference ID: 3956468
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2
KwikPen Parts
Pen Cap
Cartridge Holder
Label
Dose Indicator usage illustration
Cap Clip
Rubber Seal
Plunger
Pen Body
Dose
Window
Dose
Knob
Pen Needle Parts
(Needles Not Included)
Needle
Dose Knob
Raised ridges
on end usage illustration
Outer Needle
Inner Needle
Paper Tab
Shield
Shield
How to recognize your HUMULIN R U 500 KwikPen
• Pen color:
Aqua
• Dose Knob:
Aqua with raised ridges on the end
• Label:
HUMULIN R U-500 and 500 units/mL in a green box
Supplies needed to give your injection
•
HUMULIN R U-500 KwikPen
•
KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended)
•
Alcohol swab
Preparing your Pen
•
Wash your hands with soap and water.
•
Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use
more than 1 type of insulin.
•
Do not use your Pen past the expiration date printed on the Label or for more than 28 days after you first start
using the Pen.
•
Always use a new Needle for each injection to help prevent infections and blocked Needles. Do not
reuse or share your needles with other people. You may give other people a serious infection or get a
serious infection from them.
Reference ID: 3956468
3
Step 1:
•
Pull the Pen Cap straight off.
– Do not remove the KwikPen Label.
•
Wipe the Rubber Seal with an alcohol swab.
HUMULIN R U-500 should look clear and
colorless. Do not use if it is cloudy, colored, or has
particles or clumps in it. usage illustration
Step 2:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer Needle
Shield. usage illustration
Step 3:
•
Push the capped Needle straight onto the Pen
and twist the Needle on until it is tight. usage illustration
Step 4:
•
Pull off the Outer Needle Shield. Do not throw
it away.
•
Pull off the Inner Needle Shield and throw it
away. usage illustration
Priming your Pen
Prime before each injection.
•
Priming your Pen means removing the air from the Needle and Cartridge that may collect during normal use
and ensures that the Pen is working correctly.
•
If you do not prime before each injection, you may get too much or too little insulin.
Step 5:
•
To prime your pen, turn the Dose Knob to
select 5 units. usage illustration
Step 6:
•
Hold your Pen with the Needle pointing up.
Tap the Cartridge Holder gently to collect air
bubbles at the top. usage illustration
Reference ID: 3956468
4
Step 7:
•
Continue holding your Pen with Needle
pointing up. Push the Dose Knob in until it
stops, and “0” is seen in the Dose Window.
Hold the Dose Knob in and count to 5 slowly.
You should see insulin at the tip of the Needle.
– If you do not see insulin, repeat priming
steps 5 to 7, no more than 8 times.
– If you still do not see insulin, change the
Needle and repeat priming steps 5 to 7.
Small air bubbles are normal and will not affect
your dose. usage illustration
Selecting your dose
This Pen has been made to deliver the dose in insulin units that is shown in the Dose W indow. Ask your
healthcare provider what your dose should be for this Pen.
•
You can give from 5 to 300 units in a single injection.
•
If your dose is more than 300 units, you will need to give more than 1 injection.
– If you need help with dividing up your dose the right way, ask your healthcare provider.
– You must use a new Needle for each injection and repeat the priming step.
Reference ID: 3956468
5
Step 8:
•
Turn the Dose Knob to select the number of
units you need to inject. The Dose Indicator
should line up with your dose.
– The Dose Knob clicks as you turn it. Each
click of the Dose Knob dials 5 insulin
units at a time.
– Do not dial your dose by counting the
clicks. You may dial the wrong dose.
This may lead to you getting too much
insulin or not enough insulin.
– The dose can be corrected by turning the
Dose Knob in either direction until the
correct dose lines up with the Dose
Indicator.
– The even numbers (for example, 80) are
printed on the dial.
– The odd numbers (for example, 125) are
shown as lines between the even
numbers.
•
Always check the number in the Dose
Window to make sure you have dialed the
correct dose. usage illustration
Example: 80 units
shown in Dose W indow
Example: 125 units
shown in Dose W indow usage illustration
•
The Pen will not let you dial more than the number of units left in the Pen.
•
If your dose is more than the number of units left in the Pen, you may either:
– inject the amount left in your Pen and then use a new Pen to give the rest of your dose,
or
– get a new Pen and inject your full dose.
•
It is normal to see a small amount of insulin left in the Pen that you cannot inject. Do not transfer this to a
syringe. Severe overdose can happen.
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Giving your injection
•
Inject your insulin as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
•
Do not try to change your dose while injecting.
Step 9:
•
Choose your injection site.
HUMULIN is injected under the skin
(subcutaneously) of your stomach area,
buttocks, upper legs or upper arms.
•
Wipe your skin with an alcohol swab, and let
your skin dry before you inject your dose. usage illustration
Step 10:
•
Insert the Needle into your skin.
•
Push the Dose Knob all the way in.
•
Continue to hold the Dose
Knob in and slowly count to 5
before removing the Needle. usage illustration
5sec
Do not try to inject your insulin by turning the Dose
Knob. You will not receive your insulin by turning
the Dose Knob. usage illustration
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Step 11:
•
Pull the Needle out of your skin.
– A drop of insulin at the Needle tip is
normal. It will not affect your dose.
•
Check the number in the Dose W indow.
– If you see “0” in the Dose Window, you
have received the full amount you dialed.
– If you do not see “0” in the Dose W indow,
do not redial. Insert the Needle into your
skin and finish your injection.
– If you still do not think you received the full
amount you dialed for your injection, do
not start over or repeat your injection.
Monitor your blood glucose as instructed
by your healthcare provider.
The Plunger only moves a little with each injection,
and you may not notice that it moves.
If you see blood after you take the Needle out of
your skin, press the injection site lightly with a
piece of gauze or an alcohol swab. Do not rub the
area. usage illustration
After your injection
Step 12:
•
Carefully replace the Outer Needle Shield. usage illustration
Step 13:
•
Unscrew the capped Needle and throw it away
(see Disposing of Pens and Needles
section).
•
Do not store the Pen with the Needle attached
to prevent leaking, blocking the Needle, and air
from entering the Pen. usage illustration
Step 14:
•
Replace the Pen Cap by lining up the Cap Clip
with the Dose Indicator and pushing straight
on. usage illustration
Disposing of Pens and Needles
•
Put your used Needles in a FDA-cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose Needles in your household trash.
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•
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
– made of a heavy-duty plastic,
– can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
– upright and stable during use,
– leak-resistant, and
– properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community guidelines for the
right way to dispose of your sharps disposal container. There may be state or local laws about how you
should throw away used needles and syringes. For more information about safe sharps disposal, and for
specific information about sharps disposal in the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal
•
Do not dispose of your used sharps disposal container in your household trash unless your community
guidelines permit this. Do not recycle your used sharps disposal container.
•
The used Pen may be discarded in your household trash after you have removed the needle.
Storing your Pen
Unused Pens
•
Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
•
Do not freeze HUMULIN R U-500. Do not use if it has been frozen.
•
Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the
refrigerator.
In-use Pen
•
Store the Pen you are currently using at room temperature up to 86°F (30°C). Keep away from heat and light.
•
Throw away the Pen you are using after 28 days, even if it still has insulin left in it.
What you should know if you are switching to HUMULIN R U 500 KwikPen
Ask your healthcare provider what your dose should be for your Pen in insulin units. Always follow your
healthcare provider’s instructions for dosing.
If you are:
It is important to know:
Switching from
HUMULIN R U-500 vial
(and syringe)
Your Pen may measure your dose differently. The markings in the Dose
Window may not be the same as the markings on the syringe you used in
the past.
Ask your healthcare provider what dose in insulin units you should
dial on your Pen.
Switching from another
type of insulin device or
pen.
The HUMULIN R U-500 KwikPen is different from other pens. It dials 5
insulin units with each click of the Dose Knob.
Do not select your dose by counting clicks. You may not get enough
insulin or you may get too much insulin.
General information about the safe and effective use of your Pen
•
Keep your Pen and Needles out of the sight and reach of children.
•
Do not use your Pen if any part looks broken or damaged.
•
Always carry an extra Pen in case yours is lost or damaged.
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Troubleshooting
•
If you cannot remove the Pen Cap, gently twist the cap back and forth, and then pull the cap straight off.
•
If it is hard to push the Dose Knob:
–
Pushing the Dose Knob more slowly will make it easier to inject.
–
Your Needle may be blocked. Put on a new Needle and prime the Pen.
–
You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen.
If you have any questions or problems with your HUMULIN R U-500 KwikPen, contact Lilly at 1-800-LillyRx
(1-800-545-5979) or call your healthcare provider for help. For more information on HUMULIN R U-500 KwikPen
and insulin, go to www.humulin.com.
Scan this code to launch
www.humulin.com
These Instructions for Use have been approved by the U.S. Food and Drug Administration.
HUMULIN® and HUMULIN® KwikPen® are trademarks of Eli Lilly and Company.
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2015, Eli Lilly and Company. All rights reserved.
HUMULIN R U-500 KwikPen meets the current dose accuracy and functional requirements of ISO 11608-1:2014.
Document revision date: December 29, 2015
Lilly (red script)
Reference ID: 3956468
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Instructions for Use
Humulin® R U-500
insulin human injection (500 units/mL, 20 mL vial)
Please read these instructions before use.
Warnings
• For your safety, always inject Humulin® R U-500 insulin with a U-500 syringe.
• If you use another kind of syringe, you may get a dangerous overdose.
Needle Shield
(green)
Needle
Plunger
Syringe
Body
U-500 Symbol
(green)
85 units shown
at Plunger Tip
Plunger Rod
U-500 syringe – for single injection only
The U-500 syringe has a green U-500 symbol and a green Needle Shield on the syringe.
Important Information
• Humulin R U-500 is a concentrated insulin.
• Know your dose. Your health care provider will tell you the number of insulin units that you
should take.
• Always inject Humulin R U-500 insulin with a U-500 syringe. Other syringes will not
measure your dose correctly.
• If you use the wrong syringe, you can give yourself a severe overdose. This can cause
very low blood sugar, which may put your life in danger. For example, using a U-100
syringe can give you a 5 times overdose.
• If you do not have a U-500 syringe, you should contact your health care provider or pharmacist.
Additional Safety Information
• Each line on the U-500 syringe measures 5 units of U-500 insulin.
• You can give from 5 to 250 units in one injection.
• If your dose is more than 250 units, you will need to give more than 1 injection.
• Make sure you know how to draw up your dose with a U-500 syringe. If you need help, call your
health care provider.
• Do not reuse your U-500 syringe.
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• Do not share your U-500 syringes with other people. You may give other people a serious
infection or get a serious infection from them.
• Do not mix Humulin R U-500 with other insulins in the same syringe.
• You can get more instructions by calling Lilly at 1-800-LillyRx (1-800-545-5979).
Supplies
Protective Cap
• Humulin R U-500 vial
Rubber Stopper
• U-500 Syringe
(under Cap)
(BD [Becton, Dickinson
and Company] syringes
recommended)
• 2 alcohol swabs
Green 500 units/mL
• 1 sharps container
symbol
Before You Start
• Check your vial. Make sure it says Humulin R U-500.
• Check the expiration date on the vial. Do not use it if it is expired. Throw away the opened vial
after 40 days, even if there is still insulin left in the vial.
• See if the insulin in the vial is clear. Do not use if it is thick, cloudy, or colored or has solid
particles.
• Make sure you have a new U-500 Syringe. Check for the green U-500 symbol and green Needle
Shield.
• Check your supply. Make sure you have enough Humulin R U-500 insulin and U-500 syringes for
several injections. Always reorder before you run out.
• Check with your health care provider if you have any questions.
Use only a U-500 syringe to inject Humulin R U-500 insulin
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Prepare
• Wash your hands with soap and water.
• Always use a new syringe for each injection to help prevent infections and blocked needles.
Step 1:
Find the line on the U-500 syringe that
matches your prescribed dose. This is your
Dose Line.
Each line is 5 units.
Step 2:
If you are using a new vial, pull off the plastic
Protective Cap.
Do not remove the Rubber Stopper.
Step 3:
Wipe the Rubber Stopper with an alcohol
swab.
Step 4:
Hold the syringe with the Needle pointing up.
Pull down on the Plunger Rod until the Plunger
Tip reaches your Dose Line.
Step 5:
Push the Needle through the Rubber Stopper
of the vial.
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Step 6:
Push the Plunger all the way in. This puts air
into the vial.
Step 7:
Turn the vial and syringe upside down and
slowly pull the Plunger down until the Plunger
Tip is past your Dose Line.
If there are air bubbles, tap the syringe gently
a few times. This lets the air bubbles rise to the
top.
Step 8:
Slowly push the Plunger up until the Plunger
Tip reaches your Dose Line.
Check the syringe to make sure that you have
the right dose.
Step 9:
Pull the syringe out of the vial’s Rubber
Stopper.
Inject
• Inject your insulin exactly as your healthcare provider has shown you.
• Change (rotate) your injection site for each injection.
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5
Step 10:
Choose your injection site.
Humulin R U-500 is injected under the skin
(subcutaneously). You may inject into your
stomach area, buttocks, upper legs, or upper
arms.
Wipe the skin with an alcohol swab. Let the
injection site dry before you inject your dose.
Step 11:
Insert the Needle into your skin.
Step 12:
Push down on the Plunger to inject your dose.
Then keep the Needle in your skin for at least
5 seconds, to make sure you have injected all
of your dose.
Step 13:
Pull the Needle out of your skin.
• You may see blood after you take the
Needle out of your skin. This is normal.
Press the injection site lightly with a piece of
gauze or an alcohol swab. Do not rub the
area.
• Do not put the Needle Shield back on the
Needle, because you may get a needle stick
injury.
Disposal of used syringes
• Put your used syringes in a FDA-cleared sharps disposal container right away after use. Do
not throw away (dispose of) syringes in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
- made of a heavy-duty plastic,
- can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come
out,
- upright and stable during use,
- leak-resistant, and
Reference ID: 3956468
6
- properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to
follow your community guidelines for the right way to dispose of your
sharps disposal container. There may be state or local laws about
how you should throw away used needles and syringes. For more
information about safe sharps disposal, and for specific information
about sharps disposal in the state that you live in, go to the FDA’s
website at: http://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your
household trash unless your community guidelines permit this. Do not recycle your used
sharps disposal container. usage illustration
Storage and Handling
• Keep away from heat and out of direct light.
• Do not shake the vial.
Unopened vials:
• Store unopened vials in the refrigerator.
• Do not freeze Humulin R U-500. If it has been frozen, do not use it.
• If unopened vials have been stored in the refrigerator, you may use them until the expiration
date.
After the vial has been opened:
• Store opened vials in the refrigerator or at room temperature (less than 86°F [30°C]) for up to 40
days.
• Throw away the opened vial after 40 days, even if there is still insulin left in the vial.
General Information usage illustration
• Always use a U-500 syringe to inject Humulin R U-500 insulin.
• Never use other syringes. The lines and numbers on other syringes will not measure your
dose correctly.
• You can give yourself the wrong dose if you use any other syringe, such as a U-100,
tuberculin or allergy syringe.
For example, a U-100 syringe is made to measure U-100 insulin. If you use a U-100 Syringe
for your U-500 dose, you can give yourself a 5 times overdose.
• Do not make any changes to your dose or the type of insulin you use unless you are told to do
so by your health care provider.
• Keep your vials and syringes out of the sight and reach of children.
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Frequently Asked Questions
• Why do I need to use a U-500 syringe?
Humulin R U-500 insulin and a U-500 syringe work together to help you inject the correct dose.
Using any other syringe may result in dosing mistakes. This may put your life in danger.
• Do I have to convert my Humulin R U-500 insulin dose when I use the U-500 syringe?
No, you do not have to convert your dose. Your health care provider should tell you how much
Humulin R U-500 insulin to take in units and when to take it. Your health care provider should
show you how to draw up your dose using the U-500 syringe.
• What should I do if I run out of U-500 syringes?
If you run out of U-500 syringes, do not use any other syringe to inject Humulin R U-500 insulin.
Call your health care provider or pharmacist for help. You may also call Lilly at 1-800-Lilly-Rx
(1-800-545-5979).
Where to get more information and help
• If you have any questions about Humulin R U-500 insulin or U-500 syringes, contact Lilly at
1-800-Lilly-Rx (1-800-545-5979).
• You can also call your health care provider or pharmacist.
• For more information on Humulin R U-500 insulin, go to www.humulin.com
Scan this code to launch the humulin.com website
These Instructions for Use have been approved by the U.S. Food and Drug
Administration.
Humulin® is a trademark of Eli Lilly and Company.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1996, 2016, Eli Lilly and Company. All rights reserved.
Literature issued: July 2016
Lilly (red script)
Reference ID: 3956468
| custom-source | 2025-02-12T13:43:19.755469 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018780s153lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 153} |
1,074 |
A3.03 NL 5990 AMP
INFORMATION FOR THE PHYSICIAN
HUMULIN® R
REGULAR
INSULIN HUMAN INJECTION, USP,
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
DESCRIPTION
Humulin® R U-100 is a polypeptide hormone structurally identical to human insulin
synthesized through rDNA technology in a special non-disease-producing laboratory strain of
Escherichia coli bacteria. Humulin R U-100 has the empirical formula C257H383N65O77S6 and a
molecular weight of 5808.
Humulin R U-100 is a sterile, clear, aqueous, and colorless solution that contains human
insulin (rDNA origin) 100 units/mL, glycerin 16 mg/mL and metacresol 2.5 mg/mL, endogenous
zinc (approximately 0.015 mg/100 units) and water for injection. The pH is 7.0 to 7.8. Sodium
hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.
Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates,
proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur
and thus to prevent the production of ketone bodies by the liver. Some patients develop severe
insulin resistance such that daily doses of several hundred units of insulin or more are required.
CLINICAL PHARMACOLOGY
Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood
glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting
hepatic glucose production. Insulins inhibit lipolysis, proteolysis, and gluconeogenesis, and
enhance protein synthesis and conversion of excess glucose into fat.
Administered insulin, including Humulin R U-100, substitutes for inadequate endogenous
insulin secretion and partially corrects the disordered metabolism and inappropriate
hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the
biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals
to patients with diabetes mellitus, Humulin R U-100 restores their ability to metabolize
carbohydrates, proteins and fats.
As with all insulin preparations, the duration of action of Humulin R U-100 is dependent on
dose, site of injection, blood supply, temperature, and physical activity.
Humulin R U-100 is human insulin with a short duration of action. With subcutaneous use, the
pharmacologic effect of Humulin R U-100 begins approximately 30 minutes (range: 10 to 75
minutes) after administration of doses in the 0.05 to 0.4 units/kg range. The effect is maximal at
approximately 3 hours (range: 20 minutes to 7 hours) and terminates after approximately 8 hours
(range: 3 to 14 hours). With intravenous use, the pharmacologic effect of Humulin R U-100
begins at approximately 10 to 15 minutes and terminates at a median time of approximately 4
hours (range: 2 to 6 hours) after administration of doses in the range of 0.1 to 0.2 units/kg. The
time course of action of any insulin may vary considerably in different individuals or at different
times in the same individual.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL STUDIES
Subcutaneous use of Humulin R U-100
A 48-month multicenter, open-label, single-arm study was conducted in insulin-naïve patients
with type 1 or type 2 diabetes (N=129) to assess the safety and efficacy of Humulin R U-100.
Humulin R U-100 and Humulin® N (alone or in combination) were administered by
subcutaneous injection. Eighty-four percent of patients were Caucasian. Fifty-seven percent of
the patients were male. The mean age was 45 years (range: 4 to 83 years). The average weight
was 72 kg.
Total mean (± SD) glycohemoglobin improved from baseline to endpoint (baseline: 14.3 ±
3.1%, endpoint: 10.1 ± 2.8%). Hemoglobin A1c was not measured in this study. At baseline,
patients weighed 72 ± 23 kg; at endpoint mean weight was 80 ± 22 kg. At endpoint, mean (± SD)
total daily insulin doses for Humulin R U-100 were 0.18 ± 0.17 units/kg. At 48 months, 16
patients (21%) reported hypoglycemia. During the study, 4 patients experienced diabetic
ketoacidosis.
Intravenous use of Humulin R U-100
The intravenous administration of Humulin R U-100 was tested in 21 patients with type 1
diabetes. The patients’ usual doses of insulin were temporarily held, and blood glucose
concentrations were maintained at a range of 200 – 260 mg/dL for one to three hours during a
run-in phase of intravenous Humulin R U-100 followed by a 6-hour assessment phase. During
the assessment phase patients received intravenous Humulin R at an initial dose of 0.5 U/h,
adjusted to maintain blood glucose concentrations near normoglycemia (100 to 160 mg/dL).
The mean blood glucose levels during the assessment phase for patients on Humulin R U-100
therapy are summarized below in Table 1. All patients achieved near normoglycemia during the
6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160
mg/dL) for 20 of 21 patients treated with Humulin R U-100. The average time (± SE) required to
attain near normoglycemia was 161 ± 14 minutes for Humulin R U-100.
Table 1: Mean Blood Blood Glucose Concentrations (mg/dL)
during Intravenous Infusions of Humulin R U-100
Time from Start of Infusion (min)
Mean Blood Glucose (mg/dL) Intravenousa
0
220 ± 11
30
204 ± 17
60
193 ± 18
120
172 ± 28
180
153 ± 30
240
139 ± 24
300
131 ± 22
360
128 ± 18
a Results shown as mean ± Standard Deviation.
INDICATIONS AND USAGE
Humulin R U-100 is indicated as an adjunct to diet and exercise to improve glycemic control in
adults and children with type 1 and type 2 diabetes mellitus.
Humulin R U-100 may be administered intravenously under proper medical supervision in a
clinical setting for glycemic control (see DOSAGE AND ADMINISTRATION and Storage).
CONTRAINDICATIONS
Humulin R U-100 is contraindicated during episodes of hypoglycemia and in patients
hypersensitive to Humulin R U-100 or any of its excipients.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Any change in insulin should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species,
or method of administration may result in the need for a change in dosage.
PRECAUTIONS
Hypoglycemia
Hypoglycemia is the most common adverse reaction of all insulin therapies, including
Humulin R U-100. Severe hypoglycemia may lead to unconsciousness and/or convulsions and
may result in temporary or permanent impairment of brain function or death. Severe
hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or
glucagon administration has been observed in clinical trials with insulin, including trials with
Humulin R U-100.
As with all insulin preparations, the time course of Humulin R U-100 action may vary in
different individuals or at different times in the same individual and is dependent on dose, site of
injection, blood supply, temperature, and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity
or their usual meal plan. Insulin requirements may be altered during illness, emotional
disturbances, or other stresses. Concomitant antihyperglycemic agents may need to be adjusted.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of
meals), injection site, exercise, and concomitant medications may also alter the risk of
hypoglycemia (See PRECAUTIONS, Drug Interactions).
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients
who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or
have erratic food intake). The patient’s ability to concentrate and react may be impaired as a
result of hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery.
Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Non-Ketotic Syndrome
Hyperglycemia, diabetic ketoacidosis, or hyperosmolar coma may develop if the patient takes
less Humulin R U-100 than needed to control blood glucose levels. This could be due to
increases in insulin demand during illness or infection, neglect of diet, omission or improper
administration of prescribed insulin doses or use of drugs that affect glucose metabolism or
insulin sensitivity. Early signs of diabetic ketoacidosis include glycosuria and ketonuria.
Polydipsia, polyuria, loss of appetite, fatigue, dry skin, abdominal pain, nausea and vomiting and
compensatory tachypnea come on gradually, usually over a period of some hours or days, in
conjunction with hyperglycemia and ketonemia. Severe sustained hyperglycemia may result in
hyperosmolar coma or death.
Hypokalemia
Insulin stimulates potassium movement into the cells, possibly leading to hypokalemia, that
left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Since
intravenously administered insulin has a rapid onset of action, increased attention to
hypokalemia is necessary. Therefore, potassium levels must be monitored closely when Humulin
R U-100 or any other insulin is administered intravenously. Use caution in patients who may be
at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations).
Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including Humulin R U-100 (see ADVERSE REACTIONS).
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Localized reactions and generalized myalgias have been reported with the use of metacresol as
an injectable excipient.
Renal or Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal
or hepatic impairment.
Drug Interactions
Some medications may alter insulin requirements and the risk for hypoglycemia and
hyperglycemia (see ADVERSE REACTIONS, Drug Interactions).
Use in Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, miscarriage, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and is decreased with good glucose control. It is
important for patients to maintain good control of diabetes before conception and during
pregnancy. Special attention should be paid to diet, exercise and insulin regimens. Insulin
requirements may decrease during the first trimester, usually increase during the second and third
trimesters, and rapidly decline after delivery. Careful monitoring is essential in these patients.
Female patients should be advised to tell their physician if they intend to become, or if they
become pregnant.
Studies show that endogenous insulin only crosses the placenta in minimal amounts. While
there are no adequate and well-controlled studies in pregnant women, an extensive body of
published literature demonstrates the maternal and fetal benefits of insulin treatment in patients
with diabetes during pregnancy. Humulin R is a recombinant human insulin that is identical to
the endogenous hormone; therefore, reproduction and fertility studies were not performed in
animals.
Labor and Delivery
Careful glucose monitoring and management of patients with diabetes during labor and
delivery are required.
Nursing Mothers
Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the
gastrointestinal tract. No adverse reactions have been associated with infant exposure to insulin
through the consumption of human milk. In a study of eight preterm infants between 26 to 30
weeks gestation, enteral administration of Humulin R did not result in hypoglycemia. Good
glucose control supports lactation in patients with diabetes. Patients with diabetes who are
lactating may require adjustments in insulin dose and/or diet.
ADVERSE REACTIONS
Hypoglycemia
Hypoglycemia is one of the most frequent adverse events experienced by insulin users.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
Reference ID: 2923994
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• coma
• death
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, autonomic diabetic neuropathy, use of medications
such as beta-adrenergic blockers, changing insulin preparations, or intensified control (3 or more
insulin injections per day) of diabetes.
Without recognition of early warning symptoms, the patient may not be able to take steps to
avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning
symptoms should monitor their blood glucose more frequently, especially prior to activities such
as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that
contain sugar. Patients should always carry a quick source of sugar, such as hard candy, non-diet
carbohydrate-containing drinks or glucose tablets.
Hypokalemia
See Precautions
Lipodystrophy
Administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or
lipohypertrophy (enlargement or thickening of tissue).
Allergy
Local Allergy – Patients occasionally experience erythema, local edema, and pruritus at the site
of injection. This condition usually is self-limiting. In some instances, this condition may be
related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection
technique.
Systemic Allergy – Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be
life threatening.
Weight Gain
Weight gain can occur with some insulin therapies and has been attributed to the anabolic
effects of insulin and the decrease in glycosuria.
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
Drug Interactions
A number of substances affect glucose metabolism and may require insulin dose adjustment
and particularly close monitoring.
Drugs that may increase the blood-glucose-lowering effect of Humulin R U-100 and
susceptibility to hypoglycemia:
• Oral antihyperglycemic agents, salicylates, sulfa antibiotics, certain antidepressants
(monoamine oxidase inhibitors, selective serotonin reuptake inhibitors [SSRIs]),
pramlintide, disopyramide, fibrates, fluoxetine, propoxyphene, pentoxifylline, ACE
inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors
of pancreatic function (e.g., octreotide), and alcohol.
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Drugs that may reduce the blood-glucose-lowering effect:
• Corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral
contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents,
somatropin, atypical antipsychotics, glucagon, protease inhibitors and thyroid
replacement therapy.
Drugs that may increase or decrease blood-glucose-lowering effect:
• Beta-adrenergic blockers, clonidine, lithium salts, and alcohol.
• Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
Drugs that may mask the signs of hypoglycemia:
• Beta-adrenergic blockers, clonidine, guanethidine, and reserpine.
OVERDOSAGE
Excess insulin may cause hypoglycemia and hypokalemia, particularly after intravenous
administration. Hypoglycemia may occur as a result of an excess of insulin relative to food
intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with
oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
DOSAGE AND ADMINISTRATION
Humulin R U-100, when used subcutaneously, is usually given three or more times daily
before meals. The dosage and timing of Humulin R U-100 should be individualized and
determined, based on the physician’s advice, in accordance with the needs of the patient.
Humulin R U-100 may also be used in combination with oral antihyperglycemic agents or
longer-acting insulin products to suit the needs of the individual patients with diabetes. The
injection of Humulin R U-100 should be followed by a meal within approximately 30 minutes of
administration.
The average range of total daily insulin requirement for maintenance therapy in insulin-treated
patients without severe insulin resistance lies between 0.5 and 1 unit/kg/day. However, in pre
pubertal children it usually varies from 0.7 to 1 unit/kg/day, but can be much lower during the
period of partial remission. In situations of insulin resistance, e.g. during puberty or due to
obesity, the daily insulin requirement may be substantially higher. Initial dosages for patients
with diabetes are often lower, e.g., 0.2 to 0.4 units/kg/day.
Humulin R U-100 may be administered by subcutaneous injection in the abdominal wall, the
thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall
ensures a faster absorption than from other injection sites. Injection into a lifted skin fold
minimizes the risk of intramuscular injection. Injection sites should be rotated within the same
region. As with all insulin, the duration of action will vary according to the dose, injection site,
blood flow, temperature, and level of physical activity.
Intravenous administration of Humulin R U-100 is possible under medical supervision with
close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia.
For intravenous use, Humulin R U-100 should be used at concentrations from 0.1 unit/mL to 1
unit/mL in infusion systems with the infusion fluids 0.9% sodium chloride using polyvinyl
chloride infusion bags.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use Humulin R U-100 if
Reference ID: 2923994
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A3.03 NL 5990 AMP
it has become viscous (thickened) or cloudy; use it only if it is clear and colorless. Humulin R
U-100 should not be used after the printed expiration date.
Mixing of Insulins
• Humulin R U-100 should only be mixed as directed by the physician
• Humulin R U-100 is short-acting and is often used in combination with intermediate- or
long-acting insulins.
• The order of mixing and brand or model of syringe should be specified by the physician. A
U-100 insulin syringe should always be used. Failure to use the correct syringe can lead to
dosage errors.
• In general, when an intermediate-acting insulin (e.g., NPH insulin isophane suspension) is
mixed with short-acting soluble insulin (e.g., regular), the short-acting insulin should be drawn
into the syringe first.
Storage
Not in-use (unopened): Humulin R U-100 vials not in-use should be stored in a refrigerator
(2° to 8°C [36° to 46°F]), but not in the freezer.
In-use (opened): The Humulin R U-100 vial currently in-use can be kept unrefrigerated as
long as it is kept as cool as possible [below 30°C (86°F)] away from heat and light. In-use vials
must be used within 31 days or be discarded, even if they still contain Humulin R U-100.
Admixture: Infusion bags prepared with Humulin R U-100 as indicated under DOSAGE AND
ADMINISTRATION are stable when stored in a refrigerator (2° to 8°C [36° to 46°F]) for 48
hours and then may be used at room temperature for up to an additional 48 hours.
Do not use Humulin R U-100 after the expiration date stamped on the label or if it has
been frozen.
HOW SUPPLIED
Humulin R U-100, Regular, insulin human injection, USP (rDNA origin), 100 units/mL, is
supplied as follows:
10 mL vials
NDC 0002-8215-01 (HI-210)
3 mL vials
NDC 0002-8215-17 (HI-213)
Literature issued March, 2011
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
www.lilly.com
Copyright © 2011, Eli Lilly and Company. All rights reserved.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A0.02 NL 5692 AMP
PATIENT INFORMATION
HUMULIN® R
REGULARINSULIN HUMAN INJECTION, USP (rDNA ORIGIN) 100
UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE
INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN
PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE
MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER,
TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF
MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY
REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF
AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR
DURING THE FIRST SEVERAL WEEKS OR MONTHS.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood regularly for
glucose. Studies have shown that some chronic complications of diabetes such as eye disease,
kidney disease, and nerve disease can be significantly reduced if the blood sugar is maintained as
close to normal as possible. Proper control of your diabetes requires close and constant
cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat
a balanced diet, exercise regularly, and take your insulin injections as prescribed by your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
REGULAR HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
bacteria that has been genetically altered to produce human insulin. Humulin R [Regular insulin
human injection, USP (rDNA origin)] consists of zinc-insulin crystals dissolved in a clear fluid.
It takes effect within 30 minutes and has a duration of activity of approximately 4 to 12 hours.
The time course of action of any insulin may vary considerably in different individuals or at
different times in the same individual. As with all insulin preparations, the duration of action of
Humulin R is dependent on dose, site of injection, blood supply, temperature, and physical
Reference ID: 2923994
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activity. Humulin R is a sterile solution and is for subcutaneous injection. It should not be used
intramuscularly. The concentration of Humulin R is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
Always check the carton and the bottle label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor. There
are two Humulin R formulations: Humulin R U-100 and Humulin R U-500. Make sure that you
have the formulation prescribed by your doctor.
Always check the appearance of your bottle of Humulin R before withdrawing each dose.
Humulin R is a clear and colorless liquid with a water-like appearance and consistency. Do not
use Humulin R:
•
if it appears cloudy, thickened, or slightly colored, or
•
if solid particles are visible.
If you see anything unusual in the appearance of Humulin R solution in your bottle or notice
your insulin requirements changing, talk to your doctor.
Storage
Not in-use (unopened): Humulin R U-100 bottles not in-use should be stored in a refrigerator
(36° to 46°F [2° to 8°C]), but not in the freezer.
In-use (opened): The Humulin R U-100 bottle you are currently using can be kept
unrefrigerated as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and
light. In-use bottles must be used within 31 days or be thrown out, even if they still contain
Humulin R U-100.
Do not use Humulin R after the expiration date stamped on the label or if it has been
frozen.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin R may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin R dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
Reference ID: 2923994
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sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your Health Care Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2. Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5. A change in the body’s need for insulin.
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• dizziness
• palpitation
• tremor
• hunger
• restlessness
• tingling in the hands, feet, lips, or
tongue
• lightheadedness
• drowsiness
• sleep disturbances
• anxiety
• blurred vision
• slurred speech
• depressed mood
• irritability
• abnormal behavior
Reference ID: 2923994
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• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from
animal-source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking
sugar-containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2. Eating significantly more than your meal plan suggests.
3. Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
Reference ID: 2923994
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A0.02 NL 5692 AMP
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Patient Information revised March 2011
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, 2011, Eli Lilly and Company. All rights reserved.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A0.01 NL 8270 AMP
INSTRUCTIONS FOR INSULIN VIAL USE
NEVER SHARE NEEDLES AND SYRINGES.
Correct Syringe Type
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
With Humulin R, it is important to use a syringe that is marked for U-100 insulin preparations.
Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for
you, such as a blood glucose level that is too low or too high.
Syringe Use
To help avoid contamination and possible infection, follow these instructions exactly.
Disposable syringes and needles should be used only once and then discarded by placing the
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
resistant container as directed by your Health Care Professional.
Preparing the Dose
1. Wash your hands.
2. Inspect the insulin. Humulin R solution should look clear and colorless. Do not use
Humulin R if it appears cloudy, thickened, or slightly colored, or if you see particles in the
solution. Do not use Humulin R if you notice anything unusual in its appearance.
3. If using a new Humulin R bottle, flip off the plastic protective cap, but do not remove the
stopper. Wipe the top of the bottle with an alcohol swab.
4. If you are mixing insulins, refer to the “Mixing Humulin R with Longer-Acting Human
Insulins” section below.
5. Draw an amount of air into the syringe that is equal to the Humulin R dose. Put the needle
through rubber top of the Humulin R bottle and inject the air into the bottle.
6. Turn the Humulin R bottle and syringe upside down. Hold the bottle and syringe firmly in
one hand.
7. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
of Humulin R into the syringe.
8. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
10. If you do not need to mix your Humulin R with a longer-acting insulin, go to the
“Injection Instructions” section below and follow the directions.
Mixing Humulin R with Longer-Acting Human Insulins
1. Humulin R should be mixed with longer-acting human insulins only on the advice of your
doctor.
2. Draw an amount of air into the syringe that is equal to the amount of longer-acting insulin
you are taking. Insert the needle into the longer-acting insulin bottle and inject the air.
Withdraw the needle.
3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are
taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw
the needle.
4. Turn the Humulin R bottle and syringe upside down.
5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
of Humulin R into the syringe.
6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
Reference ID: 2923994
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A0.01 NL 8270 AMP
7. Remove the syringe with the needle from the Humulin R bottle and insert it into the
longer-acting insulin bottle. Turn the longer-acting insulin bottle and syringe upside
down. Hold the bottle and syringe firmly in one hand and shake gently. Making sure the
tip of the needle is in the longer-acting insulin, withdraw the correct dose of longer-acting
insulin.
8. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
9. Follow the directions under “Injection Instructions” section below.
Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before
giving your injection. It is important to be consistent in your method.
Syringes from different manufacturers may vary in the amount of space between the bottom
line and the needle. Because of this, do not change:
• the sequence of mixing, or
• the model and brand of syringe or needle that your doctor has prescribed.
Injection Instructions
1.
To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
2. Cleanse the skin with alcohol where the injection is to be made.
3. With one hand, stabilize the skin by spreading it or pinching up a large area.
4. Insert the needle as instructed by your doctor.
5. Push the plunger in as far as it will go.
6. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
7. Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your Health Care Professional.
Patient Instruction for Use revised March 2011
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, 2011, Eli Lilly and Company. All rights reserved.
Reference ID: 2923994
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A1.08 NL 3053 AMP
1
INFORMATION FOR THE PHYSICIAN
HUMULIN® R
REGULAR
U-500 (CONCENTRATED)
INSULIN HUMAN INJECTION, USP
(rDNA ORIGIN)
DESCRIPTION
Humulin R® U-500 is a polypeptide hormone structurally identical to human insulin
synthesized through rDNA technology in a special non-disease-producing laboratory strain of
Escherichia coli bacteria. Humulin R U-500 has the empirical formula C257H383N65O77S6 and a
molecular weight of 5808.
Humulin R U-500 is a sterile, clear, aqueous and colorless solution that contains human insulin
(rDNA origin) 500 units/mL, glycerin 16 mg/mL, metacresol 2.5 mg/mL and zinc oxide to
supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and water
for injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added
during manufacture to adjust the pH.
Humulin R U-500 is for subcutaneous injection only. It should not be used intravenously or
intramuscularly. Humulin R U-500 contains 500 units of insulin in each milliliter (5-times
more concentrated than Humulin R U-100 [see DOSAGE AND ADMINISTRATION]). It
also contains 16 mg glycerin, 2.5 mg metacresol as a preservative, and zinc-oxide calculated to
supplement endogenous zinc to obtain a total zinc content of 0.017 mg/100 units and water for
injection. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to
adjust the pH.
Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates,
proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur
and thus to prevent the production of ketone bodies by the liver. Some patients might develop
severe insulin resistance such that daily doses of several hundred units of insulin or more are
required.
CLINICAL PHARMACOLOGY
Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood
glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting
hepatic glucose production. Insulins inhibit lipolysis, proteolysis, and gluconeogenesis, and
enhance protein synthesis and conversion of excess glucose into fat.
Administered insulin, including Humulin R U-500, substitutes for inadequate endogenous
insulin secretion and partially corrects the disordered metabolism and inappropriate
hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the
biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals
to patients with diabetes mellitus, Humulin R U-500 restores their ability to metabolize
carbohydrates, proteins and fats.
As with all insulin preparations, the duration of action of Humulin R U-500 is dependent on
dose, site of injection, blood supply, temperature, and physical activity.
Humulin R U-500 is unmodified by any agent that might prolong its action. Clinical
experience has shown that it frequently has time action characteristics reflecting both prandial
and basal activity. It takes effect within 30 minutes, has a peak similar to that observed with U
100 regular human insulin and has a relatively long duration of activity following a single dose
(up to 24 hours) as compared with U-100 regular insulins. This effect has been credited to the
Reference ID: 2923994
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2
high concentration of the preparation. The time course of action of any insulin may vary
considerably in different individuals or at different times in the same individual.
INDICATIONS AND USAGE
Humulin R U-500 is indicated as an adjunct to diet and exercise to improve glycemic control in
adults and children with type 1 and type 2 diabetes mellitus.
Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes
requiring daily doses of more than 200 units, since a large dose may be administered
subcutaneously in a reasonable volume.
CONTRAINDICATIONS
Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients
hypersensitive to Humulin R U-500 or any of its excipients.
WARNINGS
Any change of insulin should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species,
or method of administration may result in the need for a change in dosage.
Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more
concentrated than Humulin R U-100). For Humulin R U-500, extreme caution must be
observed in the measurement of dosage because inadvertent overdose may result in serious
adverse reaction or life-threatening hypoglycemia.
PRECAUTIONS
Dosing Confusion/Dosing Errors
Medication errors associated with Humulin R U-500 have occurred and resulted in patients
experiencing hyperglycemia, hypoglycemia or death. The majority of errors occurred due to
errors in dispensing, prescribing or administration. Attention to the following details may
prevent:
• Dispensing errors
The Humulin R U-500 vial, which contains 20 mL, versus the Humulin R U-100 vial, which
contains 10 mL – is marked with a band of diagonal brown strips to distinguish it from the U-100
vial, which has no stripes. “U-500” is also highlighted in red on the label.
• Prescribing errors (see DOSAGE AND ADMINISTRATION)
The prescribed dose of Humulin R U-500 should always be expressed in actual units of
Humulin R U-500 along with corresponding markings on the syringe the patient is using (i.e., a
U-100 insulin syringe or tuberculin syringe [see DOSAGE AND ADMINISTRATION]).
• Administration errors (see DOSAGE AND ADMINISTRATION)
A majority of these errors occurred due to dosing confusion when the Humulin R U-500 dose
was prescribed in units or volume corresponding to a U-100 syringe or tuberculin syringe
markings, respectively, or the prescribed dose was administered without recognizing that the
markings on the syringe used do not directly correspond to U-500 dose. Instructions for use
should always be read and followed before use.
Instruct the patient to inform hospital or emergency department staff of the dose of Humulin R
U-500 prescribed, in the event of a future hospitalization or visit to the Emergency Department.
A conversion chart is provided and should always be used when administering Humulin R
U-500 doses with U-100 insulin syringes or tuberculin syringes.
Hypoglycemia
Hypoglycemia is the most common adverse reaction of all insulin therapies, including
Humulin R U-500. Severe hypoglycemia may lead to unconsciousness and/or convulsions and
may result in temporary or permanent impairment of brain function or death. Severe
hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or
glucagon administration has been observed in clinical trials with insulin, including trials with
Humulin R U-500.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
As with all insulin preparations, the time course of Humulin R U-500 action may vary in
different individuals or at different times in the same individual and is dependent on dose, site of
injection, blood supply, temperature, and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity
or their usual meal plan. Insulin requirements may be altered during illness, emotional
disturbances, or other stresses. Concomitant oral antidiabetic treatment may need to be adjusted.
Any patient who requires Humulin R U-500 for control of diabetes should be under close
observation until appropriate dosage is established. The response will vary among patients. Most
patients will require 2 or 3 injections per day.
Insulin resistance, in some patients is transitory; after several weeks or months during which
high dosage is required, responsiveness to the pharmacologic effect of insulin may be regained
and dosage can be reduced.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of
meals), injection site, exercise, and concomitant medications may also alter the risk of
hypoglycemia (see PRECAUTIONS, Drug Interactions).
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients
who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or
have erratic food intake). The patient’s ability to concentrate and react may be impaired as a
result of hypoglycemia. This may prevent a risk in situations where these abilities are especially
important, such as driving or operating other machinery.
Severe hypoglycemia may develop 18 to 24 hours after the original injection of Humulin R
U-500.
Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Non-Ketotic Syndrome
Hyperglycemia, diabetic ketoacidosis, or hyperosmolar coma may develop if the patient takes
less Humulin R U-500 than needed to control blood glucose levels. This could be due to
increases in insulin demand during illness or infection, neglect of diet, omission or improper
administration of prescribed insulin doses or use of drugs that affect glucose metabolism or
insulin sensitivity. Early signs of diabetic ketoacidosis include glycosuria and ketonuria.
Polydipsia, polyuria, loss of appetite, fatigue, dry skin, abdominal pain, nausea and vomiting and
compensatory tachypnea come on gradually, usually over a period of some hours or days, in
conjunction with hyperglycemia and ketonemia. Severe sustained hyperglycemia may result in
hyperosmolar coma or death.
Hypokalemia
Insulin stimulates potassium movement into the cells, possibly leading to hypokalemia, that
left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in
patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering
medications, patients taking medications sensitive to serum potassium concentrations).
Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including Humulin R U-500 (see ADVERSE REACTIONS).
Localized reactions and generalized myalgias have been reported with the use of metacresol as
an injectable excipient.
Renal or Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal
or hepatic impairment.
Drug Interactions
Some medications may alter insulin requirements and the risk for hypoglycemia and
hyperglycemia (see ADVERSE REACTIONS, Drug Interactions).
Reference ID: 2923994
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Use in Pregnancy
Pregnancy Category B - All pregnancies have background risk of birth defects, miscarriage, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and is decreased with good glucose control. It is
important for patients to maintain good control of diabetes before conception and during
pregnancy. Special attention should be paid to diet, exercise and insulin regimens. Insulin
requirements may decrease during the first trimester, usually increase during the second and third
trimesters and rapidly decline after delivery. Careful glucose monitoring is essential in these
patients. Female patients should be advised to tell their physician if they intend to become, or if
they become pregnant.
Studies show that endogenous insulin only crosses the placenta in minimal amounts. While
there are no adequate and well-controlled studies in pregnant women, an extensive body of
published literature demonstrates the maternal and fetal benefits of insulin treatment in patients
with diabetes during pregnancy. Humulin R U-500 is a recombinant human insulin that is
identical to the endogenous hormone; therefore, reproduction and fertility studies were not
performed in animals.
Labor and Delivery
Careful glucose monitoring and management of patients with diabetes during labor and
delivery are required.
Nursing Mothers
Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the
gastrointestinal tract. In lactating infants, no adverse reactions have been associated with
maternal use of insulin. In a study of eight preterm infants between 26 to 30 weeks gestation,
enteral administration of Humulin R did not result in hypoglycemia. Good glucose control
supports lactation in patients with diabetes. Patients with diabetes who are lactating may require
adjustments in insulin dose and/or diet.
Pediatric Use
There are no well-controlled studies of use of Humulin R U-500 in children.
ADVERSE REACTIONS
Hypoglycemia
Hypoglycemia is one of the most frequent adverse events experienced by insulin users.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• coma
• death
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, autonomic diabetic neuropathy, use of medications
such as beta-adrenergic blockers, changing insulin preparations, or intensified control (3 or more
insulin injections per day) of diabetes.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Without recognition of early warning symptoms, the patient may not be able to take steps to
avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning
symptoms should monitor their blood glucose more frequently, especially prior to activities such
as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that
contain sugar. Patients should always carry a quick source of sugar, such as hard candy, non-diet
carbohydrate-containing drinks or glucose tablets.
Hypoglycemia when using Humulin R U-500 can be prolonged and severe.
Hypokalemia
See Precautions
Lipodystrophy
Administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or
lipohypertrophy (enlargement or thickening of tissue).
Allergy
Local Allergy — Patients occasionally experience erythema, local edema, and pruritus at the
site of injection. This condition usually is self-limiting. In some instances, this condition may be
related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection
technique.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be
life threatening.
Weight gain
Weight gain can occur with some insulin therapies and has been attributed to the anabolic
effects of insulin and the decrease in glycosuria.
Peripheral Edema
Insulin man cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
Drug Interactions
The concurrent use of oral antihyperglycemic diabetes agents with Humulin R U-500 is not
recommended since there are limited data to support such use.
A number of substances affect glucose metabolism and may require insulin dose adjustment
and particularly close monitoring.
Drugs that may increase the blood-glucose-lowering effect of Humulin R U-500 and
susceptibility to hypoglycemia:
• Oral antihyperglycemic diabetes agents, salicylates, sulfa antibiotics, certain
antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors
[SSRIs]), pramlintide, disopyramide, fibrates, fluoxetine, propoxyphene,
pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, beta-adrenergic
blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol.
Drugs that may reduce the blood-glucose-lowering effect:
• Corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral
contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents,
somatropin, atypical antipsychotics, glucagon, protease inhibitors and thyroid
replacement therapy.
Drugs that may increase or decrease blood-glucose-lowering effect:
• Beta-adrenergic blockers, clonidine, lithium salts, and alcohol.
• Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
Drugs that may mask the signs of hypoglycemia:
• Beta-adrenergic blockers, clonidine, guanethidine, and reserpine.
Reference ID: 2923994
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
OVERDOSAGE
Excess insulin may cause hypoglycemia and hypokalemia. Hypoglycemia may occur as a
result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes
of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal
patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic
impairment may be treated with intramuscular/subcutaneous glucagon or concentrated
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected
appropriately.
DOSAGE AND ADMINISTRATION
Humulin R U-500 is usually given two or three times daily before meals. The dosage and time
of Humulin R U-500 should be individualized and determined, based on the physician’s advice,
in accordance with the needs of the patient. The injection of Humulin R U-500 should be
followed by a meal within approximately 30 minutes of administration.
The average range of total daily insulin requirement for maintenance therapy in insulin-treated
patients without severe insulin resistance lies between 0.5 and 1.0 unit/kg/day. However, in pre
pubertal children it usually varies from 0.7 to 1.0 unit/kg/day, but can be much lower during the
period of partial remission. In situations of insulin resistance, e.g., during puberty or due to
obesity, the daily insulin requirement may be substantially higher. Initial dosages for type 2
diabetes patients are often lower, e.g., 0.2 to 0.4 units/kg/day.
Humulin R U-500 is useful for the treatment of insulin resistant patients with diabetes
requiring daily doses of more than 200 units, since a large dose may be administered
subcutaneously in a reasonable volume.
Humulin R U-500 may be administered by subcutaneous injection in the abdominal wall, the
thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall
ensures a faster absorption than from other injection sites. Injection into a lifted skin fold
minimizes the risk of intramuscular injection. Injection sites should be rotated within the same
region. As with all insulin, the duration of action will vary according to the dose, injection site,
blood flow, temperature, and level of physical activity.
Humulin R U-500 should only be administered subcutaneously. Do not administer Humulin R
U-500 intravenously or intramuscularly.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use Humulin R U-500 if
it has become viscous (thickened) or cloudy; use it only if it is clear and colorless. Humulin R
U-500 should not be used after the printed expiration date.
Do not mix Humulin R U-500 with other insulins, as there are no data to support such
use.
When administering Humulin R U-500
If U-100 insulin syringes are used, since their markings are in units and are designed and
intended for use with the less concentrated U-100 insulin products, it is extremely important to
explain the amount of Humulin R U-500 insulin to be administered in both actual dose and with
specification of “unit markings” on the U-100 syringe.
If tuberculin syringes are used, since their markings are in volume (mL), the actual amount of
Humulin R U-500 should be explained in both actual dose and with specification of volume
(mL). Table 1 contains conversion information using both U-100 insulin and tuberculin syringes
to help avoid dose confusion.
Reference ID: 2923994
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3053 AMP
7
Table 1: Conversion Information for Humulin R U-500 Insulin Dose
When Using a U-100 Insulin Syringe or a Tuberculin Syringe
Humulin R U-500
dose (units)
U-100 insulin syringe
(unit markings)
Tuberculin syringe
(volume in mL)
25
5
0.05
50
10
0.1
75
15
0.15
100
20
0.2
125
25
0.25
150
30
0.3
175
35
0.35
200
40
0.4
225
45
0.45
250
50
0.5
275
55
0.55
300
60
0.6
325
65
0.65
350
70
0.7
375
75
0.75
400
80
0.8
425
85
0.85
450
90
0.9
475
95
0.95
500
100
1.0
Dose (actual Humulin R
U-500 units)
Divide dose (actual Humulin R
U-500 units) by 5
Divide dose (actual Humulin R
U-500 units) by 500
For doses other than those listed above refer to the following formulas:
U-100 insulin syringe
Divide prescribed Dose (actual units) by 5 = Unit markings in a U-100 insulin syringe.
Tuberculin syringe
Divide prescribed Dose (actual units) by 500 = Volume (mL) in a tuberculin syringe
Storage
Not in-use (unopened): Humulin R U-500 vials not in-use should be stored in a refrigerator,
(2° to 8°C [36° to 46°F]), but not in the freezer.
In-use (opened): The Humulin R U-500 vial currently in-use can be kept unrefrigerated as
long as it is kept as cool as possible (below 30°C [86°F]) away from heat and light. In-use vials
must be used within 31 days or be discarded, even if they still contain Humulin R U-500.
Do not use Humulin R U-500 after the expiration date stamped on the label or if it has
been frozen.
HOW SUPPLIED
Vials, 500 units/mL, 20 mL (HI-500) (1s), NDC 0002-8501-01
Literature revised March 2011
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1996, 2011, Eli Lilly and Company. All rights reserved.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A0.16 NL 8900 AMP
1
PATIENT INFORMATION
Humulin® (HU-mu-lin) R
Regular
U-500 (Concentrated)
insulin human injection, (rDNA origin)
Read the Patient Information that comes with Humulin R U-500 before you start taking it and
each time you get a refill. There may be new information. This leaflet does not take the place of
talking with your healthcare provider about your diabetes or treatment.
What is the most important information I should know about Humulin R U-500?
Humulin R U-500 (500 units/mL) contains 5 times as much insulin in 1 mL as standard U
100 (100 units/mL) insulin. This means that it is more concentrated than standard U-100
insulin.
Know your insulin. Make sure you know the strength, dose and type of insulin that is prescribed
for you. Do not change the strength, dose or type of insulin you use unless told to do so by your
healthcare provider.
It is important that you take the right dose of Humulin R U-500. Taking too much Humulin
R U-500 can cause life-threatening low blood sugar (hypoglycemia) or death. Taking too
little Humulin R U-500 can cause high blood sugar (hyperglycemia).
There are no special syringes to measure Humulin R U-500. It is important that you use only the
syringes that your healthcare provider tells you to use. Your healthcare provider should tell you
how much Humulin R U-500 to take and when to take it. Your healthcare provider should show
you how to draw up Humulin R U-500. The amount of Humulin R U-500 will be less than the
amount of standard U-100 insulin which would be drawn up into the syringe. See the section,
“How should I take Humulin R U-500?”
What is Humulin R U-500?
Humulin R U-500 is a prescription medicine used to treat high blood sugar in people with
diabetes mellitus. Humulin R U-500 is a man-made insulin that is similar to the insulin produced
by the human pancreas. Humulin R U-500 is used along with diet and exercise to lower blood
sugar in people with:
• type 1 diabetes.
• type 2 diabetes whose blood sugars are not controlled well with diabetes medicine taken by
mouth.
Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes who need
more than 200 units of insulin a day.
It is not known if Humulin R U-500 is safe and effective in children.
Who should not take Humulin R U-500?
Reference ID: 2923994
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2
Do not take Humulin R U-500 if:
• your blood sugar is too low (hypoglycemia). See the section, “What are the possible side
effects of Humulin R U-500?” for more information on low blood sugar.
• you are allergic to any of the ingredients in Humulin R U-500. See the end of this leaflet for a
complete list of ingredients in Humulin R U-500.
What should I tell my healthcare provider before taking Humulin R U-500?
Before you take Humulin R U-500, tell your healthcare provider if you:
• have liver or kidney problems
• any other medical conditions. Certain medical conditions can affect your insulin needs and
your dose of Humulin R U-500.
• are pregnant, plan to become pregnant, or are breast-feeding. It is not known if Humulin
R U-500 will harm your unborn baby or breast-feeding child. You and your healthcare
provider should talk about the best way to manage your diabetes while you are pregnant or
breast-feeding. It is especially important to keep good control of your blood sugar during
pregnancy.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. Many medicines can affect your
blood sugar levels and your insulin needs. Your Humulin R U-500 dose may need to change if
you take other medicines. Especially tell your healthcare provider if you take other medicines to
treat your diabetes.
Know the medicines you take. Keep a list of your medicines with you and show it to your
healthcare provider and pharmacist when you get a new medicine.
How should I take Humulin R U-500?
• Take Humulin R U-500 exactly as prescribed.
• Do not make any changes to your strength, dose or type of insulin unless you are told to
do so by your healthcare provider.
• Check the label carefully to make sure you have the right type and strength of insulin
prescribed for you.
•Your healthcare provider should show you how to prepare and inject Humulin R U-500 before
you start taking it.
• Humulin R U-500 should look clear and colorless. Do not use Humulin R U-500 if it
does not look clear, colorless or has particles in it. Talk with your pharmacist or
healthcare provider if you have any questions.
• Follow your healthcare provider’s instructions about how often you should check your blood
sugar level for hypoglycemia (too low blood sugar) and hyperglycemia (too high blood
sugar).
• Humulin R U-500 starts working about 30 minutes after injection. The effects of Humulin R
U-500 may last up to 24 hours.
• You should eat a meal within 30 minutes of injecting Humulin R U-500.
• Choose an injection area (upper arm, abdomen, buttocks, or thigh). Change injection sites
within the area you choose for each dose. Do not inject into the exact same spot for each
injection. Never inject Humulin U-500 into a vein or muscle.
• Inject Humulin R U-500 under your skin (subcutaneous), as shown to you by your healthcare
provider.
• Your healthcare provider should regularly check your diabetes with blood tests, including
your blood sugar levels and hemoglobin A1C.
Reference ID: 2923994
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3
• If you take too much Humulin R U-500, your blood sugar may fall too low (hypoglycemia).
You can treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary
right away. Always carry a quick source of sugar, such as hard candy, fruit juice or glucose
tablets.
• Your healthcare provider may prescribe a glucagon emergency kit so that others can give you
an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take
sugar by mouth.
There are no special syringes to measure Humulin R U-500. It is important that you use only the
syringes that your healthcare provider tells you to use to give your injections of Humulin R U
500. You should use either a U-100 insulin syringe or tuberculin syringe as instructed by your
healthcare provider.
• If you are using U-100 insulin syringes, your healthcare provider should explain how to use
this syringe to give the prescribed dose with the unit markings on the syringe.
• If you are using tuberculin syringes, your healthcare provider should explain how to use this
syringe to give the prescribed dose with volume markings on the syringe.
If you do not use the right syringe type, you may take the wrong dose of Humulin R U-500. This
can cause you to have too low blood sugar (hypoglycemia) or too high blood sugar
(hyperglycemia).
Make sure you know:
• your prescribed dose of Humulin R U-500.
• which syringe to use and how to draw up your prescribed dose.
If you do not understand your dose, talk with your healthcare provider about how much insulin
to take.
If you are hospitalized or go to an emergency room, make sure to tell the hospital staff the actual
dose of Humulin R U-500 that your healthcare provider has prescribed for you.
Your healthcare provider may change your dose of Humulin R U-500 because of:
• illness
• change in diet
• stress
• change in physical activity or exercise
• other medicines you take
• travel
Check your blood sugar and stay on the diet and exercise plan as prescribed by your healthcare
provider.
• Do not share needles or syringes with others.
• Place used needles and syringes in a closable, puncture-resistant container. You may use a
sharps container (such as a red biohazard container) or a hard plastic container (such as a
detergent bottle) or a metal container (such as an empty coffee can). Ask your healthcare
provider for instructions on the right way to throw away the container. There may be state
and local laws about how you should throw away used needles and syringes.
• Do not throw the container in household trash and do not recycle.
What should I avoid while taking Humulin R U-500?
Reference ID: 2923994
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4
• Alcohol. Drinking alcohol may affect your blood sugar when you take Humulin R U-500
• Driving and operating machinery. You may have trouble paying attention or reacting if
you have low blood sugar (hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is all right for you to drive if you have:
• Low blood sugar (hypoglycemia)
• Decreased or no warning signs of low blood sugar
What are the possible side effects of Humulin R U-500?
Humulin R U-500 can cause serious side effects, including:
See the section “What is the most important information I should know about Humulin R U
500?”
• Low blood sugar (hypoglycemia).
Symptoms of low blood sugar may happen suddenly with Humulin R U-500. Symptoms
of mild or moderate low blood sugar may include:
• sweating
• drowsiness
• dizziness
• trouble sleeping
• fast heart beat
• feeling anxious
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips or tongue
• feeling irritable
• lightheadedness
• abnormal behavior
• trouble concentrating
• walking unsteady
• headache
• personality changes
Humulin R U-500 can cause low blood sugar (hypoglycemia) that is severe and that can
last a long time.
• Severe low blood sugar can cause you to become confused, pass out (become
unconscious), have seizures or coma, and could cause death.
Talk to your healthcare provider about how to tell if you have low blood sugar and what to
do if this happens while taking Humulin R U-500. Know your symptoms of low blood sugar.
Follow your healthcare provider’s instructions for treating your low blood sugar.
Tell your healthcare provider if low blood sugar is a problem for you. Your healthcare
provider may need to change the amount of Humulin R U-500 that you take, change your
meal plans or your exercise program to help you avoid low blood sugar.
• Serious allergic reactions. Get medical help right away if you have any of these
symptoms of a severe allergic reaction:
• rash all over your body
• shortness of breath
• trouble breathing (wheezing)
• fast heart beat
• sweating
• feel faint
Reference ID: 2923994
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
• Low potassium (hypokalemia) in your blood. Your healthcare provider may do blood tests
to check you for low potassium.
Common side effects of Humulin R U-500 include:
• Skin thickening or pits at the injection site (lipodystrophy). Change (rotate) where you inject
your insulin to help prevent these skin changes from happening. Do not inject insulin into
this type of skin. Do not inject into the exact same spot for each injection.
• Injection site reactions (local allergic reaction). Symptoms may include: redness, swelling
and itching at the injection site. Tell your healthcare provider if you have skin reactions that
do not go away.
• Weight gain
• Swelling due to fluid retention
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
These are not all of the possible side effect of Humulin R U-500. For more information, ask your
healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store Humulin R U-500?
Unopened vials of Humulin R U-500:
• Keep unopened vials of Humulin R U-500 in a refrigerator at 36°F to 46°F (2°C to 8°C).
• Do not freeze. Do not use Humulin R U-500 if it has been frozen.
• Do not use Humulin R U-500 after the expiration date stamped on the label.
Opened (in-use) vial of Humulin R U-500:
• Keep opened vial of Humulin R U-500 in the refrigerator or at room temperature below 86°F
(30°C).
• Keep Humulin R U-500 away from heat and direct sunlight.
• The opened vial must be used within 31 days of opening. Throw away any opened vial after
31 days of use, even if there is insulin left in the vial.
• Do not use Humulin R U-500 after the expiration date stamped on the label.
Keep Humulin R U-500 and all medicines out of the reach of children.
General Information about Humulin R U-500
Medicines are sometimes prescribed for purposes other than those listed in patient information
leaflets. Do not use Humulin R U-500 for a condition for which it was not prescribed. Do not
give Humulin R U-500 to other people, even if they have the same symptoms you have. It may
harm them.
This leaflet summarizes the most important information about Humulin R U-500. If you would
like more information, talk with your healthcare provider. You can ask your healthcare provider
or pharmacist for information about Humulin R U-500 that is written for healthcare
professionals.
For more information about Humulin R U-500 call 1-800-545-5979 or go to www.lilly.com.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A0.16 NL 8900 AMP
6
What are the ingredients in Humulin R U-500?
Active ingredient: human insulin rDNA origin
Inactive ingredients: glycerin, metacresol, zinc oxide, water for injection, sodium hydroxide or
hydrochloric acid.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Issued March/2011.
Reference ID: 2923994
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:19.837218 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018780s120lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 120} |
1,082 |
1
A3.0 NL 3680 AMP
1
INFORMATION FOR THE PATIENT
2
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
3
HUMULIN® N Pen
4
NPH
5
HUMAN INSULIN
6
(rDNA ORIGIN) ISOPHANE SUSPENSION
7
100 UNITS PER ML (U-100)
8
WARNINGS
9
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-
10
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
11
INSULIN PRODUCED BY YOUR BODY'S PANCREAS AND BECAUSE OF ITS
12
UNIQUE MANUFACTURING PROCESS.
13
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
14
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
15
MANUFACTURER, TYPE (E.G., REGULAR, NPH, LENTE, ETC), SPECIES
16
(BEEF, PORK, BEEF-PORK, HUMAN), OR METHOD OF MANUFACTURE
17
(rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED
18
FOR A CHANGE IN DOSAGE.
19
SOME PATIENTS TAKING HUMULIN (HUMAN INSULIN, rDNA ORIGIN)
20
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH
21
ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY
22
OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS
23
OR MONTHS.
24
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW
25
THE “DISPOSABLE INSULIN DELIVERY DEVICE USER MANUAL” AND
26
THIS INFORMATION FOR THE PATIENT INSERT BEFORE USING THIS
27
PRODUCT. BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A
28
NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE.
29
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES
30
OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR
31
THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL
32
USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE A WRONG DOSE (see also
33
INSTRUCTIONS FOR PEN USE section).
34
DIABETES
35
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
36
hormone is necessary for the body's correct use of food, especially sugar. Diabetes occurs when
37
the pancreas does not make enough insulin to meet your body's needs.
38
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
39
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
40
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
41
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
42
sugar is maintained as close to normal as possible. The American Diabetes Association
43
recommends that if your premeal glucose levels are consistently above 130 mg/dL or your
44
hemoglobin A1c (HbA1c) is more than 7%, consult your doctor. A change in your diabetes
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
therapy may be needed. If your blood tests consistently show below-normal glucose levels, you
46
should also let your doctor know. Proper control of your diabetes requires close and constant
47
cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat
48
a balanced diet, exercise regularly, and take your insulin injections as prescribed.
49
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
50
wear diabetic identification so that appropriate treatment can be given if complications occur
51
away from home.
52
NPH HUMAN INSULIN
53
Description
54
Humulin is synthesized in a non-disease-producing special laboratory strain of Escherichia
55
coli bacteria that has been genetically altered by the addition of the human gene for insulin
56
production. Humulin N (human insulin [rDNA origin] isophane suspension) is a crystalline
57
suspension of human insulin with protamine and zinc providing an intermediate-acting insulin
58
with a slower onset of action and a longer duration of activity (up to 24 hours) than that of
59
regular insulin. The time course of action of any insulin may vary considerably in different
60
individuals or at different times in the same individual. As with all insulin preparations, the
61
duration of action of Humulin N is dependent on dose, site of injection, blood supply,
62
temperature, and physical activity. Humulin N is a sterile suspension and is for subcutaneous
63
injection only. It should not be used intravenously or intramuscularly. The concentration of
64
Humulin N in Humulin N Pen is 100 units/mL (U-100).
65
Identification
66
Humulin disposable insulin delivery devices, manufactured by Eli Lilly and Company, are
67
available in 2 formulations NPH and 70/30.
68
Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT
69
USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION.
70
The Humulin N Pen is available in boxes of 5 disposable insulin delivery devices (“insulin
71
Pens”). The Humulin N Pen is not designed to allow any other insulin to be mixed in its
72
cartridge, or for the cartridge to be removed.
73
Always examine the appearance of Humulin N suspension in the insulin Pen before
74
administering a dose. A cartridge of Humulin N contains a small glass bead to assist in mixing.
75
Humulin N Pen must be rolled between the palms 10 times and inverted 180° 10 times before
76
each injection so that the contents are uniformly mixed (see Figures 1 and 2). Inspect the
77
Humulin N suspension for uniform mixing and repeat the above steps as necessary.
78
Figure 1.
Figure 2.
79
80
Humulin N should look uniformly cloudy or milky after mixing. Do not use if the insulin
81
substance (the white material) remains visibly separated from the liquid after mixing. Do not use
82
the Humulin N Pen if there are clumps in the insulin after mixing. Do not use the Humulin N Pen
83
if solid white particles stick to the walls of the cartridge, giving it a frosted appearance.
84
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Always check the appearance of the Humulin N suspension in the insulin Pen before using,
85
and if you note anything unusual in the appearance of Humulin N suspension or notice your
86
insulin requirements changing markedly, consult your doctor.
87
Never attempt to remove the cartridge from the Humulin N Pen. Inspect the cartridge through
88
the clear cartridge holder.
89
Storage
90
Not in-use (unopened): Humulin N Pens not in-use should be stored in a refrigerator but not
91
in the freezer. Do not use Humulin N Pen if it has been frozen.
92
In-use: Humulin N Pens in-use should NOT be refrigerated but should be kept at room
93
temperature (below 86°F [30°C]) away from direct heat and light. Humulin N Pens in-use must
94
be discarded after 2 weeks, even if they still contain Humulin N.
95
Do not use Humulin N Pens after the expiration date stamped on the label.
96
INSTRUCTIONS FOR PEN USE
97
It is important to read, understand, and follow the instructions in the “Disposable Insulin
98
Delivery Device User Manual” before using. Failure to follow instructions may result in a
99
wrong insulin dose. The Pen must be primed before each injection to make sure the Pen is
100
ready to dose. Performing the priming step is important to confirm that insulin comes out
101
when you push the injection button, and to remove air that may collect in the insulin
102
cartridge during normal use.
103
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
104
PREPARING THE INSULIN PEN FOR INJECTION
105
1.
Always check the appearance of the Humulin N suspension in the insulin Pen before
106
using.
107
2.
Roll the Humulin N Pen between the palms 10 times (see Figure 1 above).
108
3.
Holding the Humulin N Pen by one end, invert it 180° slowly 10 times to allow the glass
109
bead to travel the full length of the cartridge with each inversion (see Figure 2 above).
110
The cartridge is contained in the clear cartridge holder of the Humulin N Pen.
111
4.
Inspect the appearance of the Humulin N suspension to make sure the contents look
112
uniformly cloudy or milky. If not, repeat the above steps until the contents are mixed. Do
113
not use a Humulin N Pen if there are clumps in the insulin or if solid white particles stick
114
to the walls of the cartridge.
115
5.
Follow the instructions in the “Disposable Insulin Delivery Device User Manual” for
116
these steps:
117
• Preparing the Pen
118
• Attaching the Needle
119
• Priming the Pen. The Pen must be primed before each injection to make sure the
120
Pen is ready to dose. Performing the priming step is important to confirm that insulin
121
comes out when you push the injection button, and to remove air that may collect in the
122
insulin cartridge during normal use.
123
• Setting a Dose
124
• Injecting a Dose
125
• Following an Injection
126
PREPARING FOR INJECTION
127
1.
Wash your hands.
128
2.
To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
129
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
130
3.
Cleanse the skin with alcohol where the injection is to be made.
131
4.
With one hand, stabilize the skin by spreading it or pinching up a large area.
132
5.
Inject the dose as instructed by your doctor.
133
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
6.
After dispensing a dose, pull the needle out and apply gentle pressure over the injection
134
site for several seconds. Do not rub the area.
135
7.
Immediately after an injection, remove the needle from the Humulin N Pen. Doing so will
136
guard against contamination, leakage, reentry of air, and needle clogs. Do not reuse
137
needles. Place the used needle in a puncture-resistant disposable container and properly
138
dispose of it as directed by your Health Care Professional.
139
DOSAGE
140
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
141
Because each patient's case of diabetes is different, this schedule has been individualized for you.
142
Your usual insulin dose may be affected by changes in your food, activity, or work schedule.
143
Carefully follow your doctor's instructions to allow for these changes. Other things that may
144
affect your insulin dose are:
145
Illness
146
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
147
Even if you are not eating, you will still require insulin. You and your doctor should establish a
148
sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine
149
glucose and ketones frequently and call your doctor as instructed.
150
Pregnancy
151
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
152
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
153
are nursing a baby, consult your doctor.
154
Medication
155
Insulin requirements may be increased if you are taking other drugs with hyperglycemic
156
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
157
requirements may be reduced in the presence of drugs with hypoglycemic activity, such as oral
158
hypoglycemics, salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
159
Always discuss any medications you are taking with your doctor.
160
Exercise
161
Exercise may lower your body's need for insulin during and for some time after the activity.
162
Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the
163
area of injection site (for example, the leg should not be used for injection just prior to running).
164
Discuss with your doctor how you should adjust your regimen to accommodate exercise.
165
Travel
166
Persons traveling across more than 2 time zones should consult their doctor concerning
167
adjustments in their insulin schedule.
168
COMMON PROBLEMS OF DIABETES
169
Hypoglycemia (Insulin Reaction)
170
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
171
experienced by insulin users. It can be brought about by:
172
1.
Taking too much insulin
173
2.
Missing or delaying meals
174
3.
Exercising or working more than usual
175
4.
An infection or illness (especially with diarrhea or vomiting)
176
5.
A change in the body's need for insulin
177
6.
Diseases of the adrenal, pituitary or thyroid gland, or progression of kidney or liver
178
disease
179
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
7.
Interactions with other drugs that lower blood glucose, such as oral hypoglycemics,
180
salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants
181
8.
Consumption of alcoholic beverages
182
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
183
• sweating
• drowsiness
184
• dizziness
• sleep disturbances
185
• palpitation
• anxiety
186
• tremor
• blurred vision
187
• hunger
• slurred speech
188
• restlessness
• depressed mood
189
• tingling in the hands, feet, lips, or tongue
• irritability
190
• lightheadedness
• abnormal behavior
191
• inability to concentrate
• unsteady movement
192
• headache
• personality changes
193
Signs of severe hypoglycemia can include:
194
• disorientation
• seizures
195
• unconsciousness
• death
196
Therefore, it is important that assistance be obtained immediately.
197
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
198
conditions, such as long duration of diabetes, diabetic nerve disease, medications such as beta-
199
blockers, change in insulin preparations, or intensified control (3 or more insulin injections per
200
day) of diabetes.
201
A few patients who have experienced hypoglycemic reactions after transfer from animal-
202
source insulin to human insulin have reported that the early warning symptoms of
203
hypoglycemia were less pronounced or different from those experienced with their
204
previous insulin.
205
Without recognition of early warning symptoms, you may not be able to take steps to avoid
206
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
207
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
208
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
209
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
210
containing foods to treat your hypoglycemia.
211
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
212
Patients should always carry a quick source of sugar, such as candy mints or glucose tablets.
213
More severe hypoglycemia may require the assistance of another person. Patients who are unable
214
to take sugar orally or who are unconscious require an injection of glucagon or should be treated
215
with intravenous administration of glucose at a medical facility.
216
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
217
about these symptoms, you should monitor your blood glucose frequently to help you learn to
218
recognize the symptoms that you experience with hypoglycemia.
219
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
220
symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans,
221
and/or exercise programs to help you avoid hypoglycemia.
222
Hyperglycemia and Diabetic Acidosis
223
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
224
Hyperglycemia can be brought about by:
225
1.
Omitting your insulin or taking less than the doctor has prescribed
226
2.
Eating significantly more than your meal plan suggests
227
3.
Developing a fever, infection, or other significant stressful situation
228
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
In patients with insulin-dependent diabetes, prolonged hyperglycemia can result in diabetic
229
acidosis. The first symptoms of diabetic acidosis usually come on gradually, over a period of
230
hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor
231
on the breath. With acidosis, urine tests show large amounts of glucose and acetone. Heavy
232
breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia
233
or diabetic acidosis can lead to nausea, vomiting, dehydration, loss of consciousness or death.
234
Therefore, it is important that you obtain medical assistance immediately.
235
Lipodystrophy
236
Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the
237
skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these
238
conditions, consult your doctor. A change in your injection technique may help alleviate the
239
problem.
240
Allergy to Insulin
241
Local Allergy Patients occasionally experience redness, swelling, and itching at the site of
242
injection of insulin. This condition, called local allergy, usually clears up in a few days to a few
243
weeks. In some instances, this condition may be related to factors other than insulin, such as
244
irritants in the skin cleansing agent or poor injection technique. If you have local reactions,
245
contact your doctor.
246
Systemic Allergy Less common, but potentially more serious, is generalized allergy to
247
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
248
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
249
threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor
250
immediately.
251
ADDITIONAL INFORMATION
252
Additional information about diabetes may be obtained from your diabetes educator.
253
DIABETES FORECAST is a national magazine designed especially for patients with
254
diabetes and their families and is available on subscription from the American Diabetes
255
Association, National Service Center, 1660 Duke Street, Alexandria, Virginia 22314,
256
1-800-DIABETES (1-800-342-2383).
257
Another publication, DIABETES COUNTDOWN, is available from the Juvenile Diabetes
258
Foundation, 120 Wall Street 19th Floor, New York, New York 10005-4001, 1-800-JDF-CURE
259
(1-800-533-2873).
260
Additional information about Humulin and Humulin N Pen can be obtained by calling
261
1-888-88-LILLY (1-888-885-4559).
262
Literature issued XXX 2003
263
Eli Lilly and Company, Indianapolis, IN 46285, USA
264
265
A3.0 NL 3680 AMP
PRINTED IN USA
266
267
Copyright 1998, 2003, Eli Lilly and Company. All rights reserved.
268
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A3.0 NL 3730 AMP
____________________________________________________________________________
Lilly
Disposable Insulin Delivery Device
User Manual
____________________________________________________________________________
Instructions for Use
Read and follow these step by step instructions carefully. Failure to follow these instructions
completely, including the priming step, may result in a wrong insulin dose. Also, read the
Information for the Patient insert enclosed in your Pen box.
Pen Features
• A multiple dose, disposable insulin delivery device
(“insulin Pen”) containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
___________________________________________________________________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Table of Contents
______________________________________________________________________
Pen Parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Important Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Preparing the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Attaching the Needle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Priming the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Setting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Injecting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Following an Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
________________________________________________________________________
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Pen Parts
3
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Important Notes
•
Please read these instructions carefully before using your Pen. Failure to follow these
instructions completely, including the priming step, may result in a wrong dose.
•
Use a new needle for each injection.
•
Be sure a needle is attached to the Pen before priming, setting (dialing) the dose and injecting
your insulin.
•
The Pen must be primed before each injection to make sure the Pen is ready to dose.
Performing the priming step is important to confirm that insulin comes out when you push the
injection button, and to remove air that may collect in the insulin cartridge during normal use.
See Section III. Priming the Pen, pages 10-13.
•
If you do not prime, you may receive a wrong dose.
•
The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
•
Do not share your Pen.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Important Notes
(Continued)
•
Keep your Pen out of the reach of children.
•
Pens that have not been used should be stored in a refrigerator but not in a freezer. Do not use
a Pen if it has been frozen. Refer to the Information for the Patient insert for complete storage
instructions.
•
After a Pen is used for the first time, it should NOT be refrigerated but should be kept at
room temperature [below 86°F (30°C)] and away from direct heat and light.
•
An unrefrigerated Pen should be discarded according to the time specified in the Information
for the Patient insert, even if it still contains insulin.
•
Never use a Pen after the expiration date stamped on the label.
•
Do not store your Pen with the needle attached. Doing so may allow insulin to leak from the
Pen and air bubbles to form in the cartridge. Additionally, with suspension (cloudy) insulins,
crystals may clog the needle.
•
Always carry an extra Pen in case yours is lost or damaged.
•
Dispose of empty Pens as instructed by your Health Care Professional and without the needle
attached.
•
This Pen is not recommended for use by blind or visually impaired persons without the
assistance of a person trained in the proper use of the product.
•
Any changes in insulin should be made cautiously and only under medical supervision.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
I. Preparing the Pen
1. Before proceeding, refer to the Information for the Patient insert for instructions on
checking the appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has been
prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges contain
a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal on the
end of the Pen.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen needles.
1. Always use a new needle for each injection. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
2. Remove the paper tab from the outer needle shield.
3. Attach the capped needle onto the end of the Pen by turning
it clockwise until tight.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle pointing up and remove the
outer needle shield. Keep it to use during needle
removal.
5. Remove the inner needle shield and discard.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
III. Priming the Pen
•
Always use a new needle for each injection.
•
The Pen must be primed before each injection to make sure the Pen is ready to dose.
Performing the priming step is important to confirm that insulin comes out when you push the
injection button, and to remove air that may collect in the insulin cartridge during normal use.
•
If you do not prime, you may receive a wrong dose.
1.
You cannot prime your Pen until you can see the arrow
(→) in the dose window. If a number or a blank space is
in the dose window, push in the injection button
completely until a diamond (♦) or arrow (→) is seen.
When diamonds (♦) can be seen in the dose window, turn
the dose knob clockwise until the arrow (→) is seen and
the notches on the Pen and dose knob are in line.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
III. Priming the Pen
(Continued)
2. With the arrow in the dose window, pull the dose knob
out in the direction of the arrow until a “0” is seen in the
dose window.
3. Turn the dose knob clockwise until the number “2” is
seen in the dose window. If the number you have dialed
is too high, simply turn the dose knob backward until the
number 2 is seen in the dose window.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
III. Priming the Pen
(Continued)
4. Hold your Pen with the needle pointing up. Tap the
clear cartridge holder gently with your finger so any air
bubbles collect near the top. Using your thumb, if
possible, push in the injection button completely and
maintain pressure until the insulin flow stops. You
should see either a drop or a stream of insulin come out
of the tip of the needle. If insulin does not come out of
the tip of the needle, repeat steps 1 through 4. If after
several attempts insulin does not come out of the tip of
the needle, refer to the “Questions and Answers”
section at the end of this manual.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
III. Priming the Pen
(Continued)
5.
At the completion of the priming step, a diamond
(♦) must be seen in the dose window.
Note: A small air bubble may remain in the cartridge after the completion of the priming
step. If you have properly primed the Pen, this small air bubble will not affect your
insulin dose.
6. Now you are ready to set your dose. See next page.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
IV. Setting a Dose
•
Always use a new needle for each injection. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
•
Caution: Do not push in the injection button while setting your dose. Failure to follow
these instructions carefully may result in an inaccurate insulin dose.*
1. Pen has been primed and a diamond (♦) can be seen in the dose window.
2. Turn the dose knob clockwise until the arrow (→)
is seen in the dose window and the notches on the
Pen and dose knob are in line.
* See Page 16.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
IV. Setting a Dose
(Continued)
3. With the arrow (→) in the dose window, pull the
dose knob out in the direction of the arrow until a
“0” is seen in the dose window. A dose cannot be
dialed until the dose knob is pulled out.
4. Turn the dose knob clockwise until your dose is
seen in the dose window. If the dose you have
dialed is too high, simply turn the dose knob
backward until the correct dose is seen in the
dose window.
5. If you cannot dial a full dose, see the “Questions and Answers” section at the end
of this manual.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
V. Injecting a Dose
•
Always use a new needle for each injection. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
•
Caution: Do not attempt to change the dose after you begin to push in the injection
button. Failure to follow these instructions carefully may result in an inaccurate insulin
dose.*
•
The effort needed to push in the injection button may increase while you are injecting
your insulin dose. If you cannot completely push in the injection button, refer to the
“Questions and Answers” section at the end of this manual.
*
If you have set (dialed) a dose and pushed in the injection button without a needle attached or
if no insulin comes out of the needle, see the “Questions and Answers” section.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
V. Injecting a Dose
(Continued)
1.
Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
Inject the insulin by using your thumb, if
possible, to completely push in the injection
button. When the injection button has been
completely pushed in (a diamond (♦) or arrow
(→) must be seen in the dose window to
indicate that the injection button has been
completely pushed in), continue to hold it down
and count slowly to 5. After dispensing a dose,
pull the needle out and apply gentle pressure over
the injection site for several seconds. Do not rub
the area.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
VI. Following an Injection
Do not store or dispose of the Pen with a needle attached. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
1.
Check that the injection button has been
completely pushed in and you can see a
diamond (♦) or arrow (→) in the dose window.
If a diamond (♦) or arrow (→) cannot be seen in
the dose window, your full dose has not been
delivered. Contact your Health Care
Professional immediately for additional
instructions.
2.
Carefully replace the outer needle shield.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
VI. Following an Injection
(Continued)
3.
Remove the capped needle by turning it
counterclockwise and dispose of it as directed
by your Health Care Professional. Place the
used needle in a puncture-resistant disposable
container and properly dispose of it as directed
by your Health Care Professional.
4.
Replace the cap on the Pen.
5. The Pen that you are using should NOT be refrigerated but kept at room temperature [below
86°F (30°C)] and away from direct heat and light. It should be discarded according to the
time specified in the Information for the Patient insert, even if it still contains insulin.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Questions and Answers
Problem
Action
Dose dialed and injection button
pushed in without a needle
attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely (even if a
“0” is seen in the window) until a diamond (♦) or
arrow (→) is seen in the dose window.
3) Prime the Pen.
Insulin does not come out of the
needle.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely (even if a
“0” is seen in the window) until a diamond (♦) or
arrow (→) is seen in the dose window.
3) Prime the Pen.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Questions and Answers
(Continued)
Problem
Action
Wrong dose (too high or too low)
dialed.
If you have not pushed in the injection button, simply
turn the dose knob backward or forward to correct the
dose.
Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing down. The
scale (20 units between marks) on the clear cartridge
holder shows an estimate of the number of units
remaining. These numbers should not be used for
measuring an insulin dose.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Questions and Answers
(Continued)
Problem
Action
Full dose cannot be dialed.
The Pen will not allow you to dial a dose greater than
the number of insulin units remaining in the cartridge.
For example, if you need 31 units and only 25 units
remain in the Pen, you will not be able to dial past 25.
Do not attempt to dial past this point. (The insulin that
remains is unusable and not part of the 300 units.) If a
partial dose remains in the Pen you may either:
1) Give the partial dose and then give the remaining
dose using a new Pen, or
2) Give the full dose with a new Pen.
A small amount of insulin
remains in the cartridge but a
dose cannot be dialed.
The Pen design prevents the cartridge from being
completely emptied. The Pen has delivered 300 units of
usable insulin.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Questions and Answers
(Continued)
Problem
Action
Cannot completely push in the
injection button when priming the
Pen or injecting a dose.
1) Needle is not attached or is clogged.
a. Attach a new needle.
b. Push in the injection button completely (even if
a “0” is seen in the window) until a diamond (♦)
or arrow (→) is seen in the dose window.
c. Prime the Pen.
2) If you are sure insulin is coming out of the needle,
push in the injection button more slowly to reduce
the effort needed and maintain a constant pressure
until the injection button is completely pushed in.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
For additional information call,
1-888-88-LILLY
Literature issued XXX 2003
Eli Lilly and Company, Indianapolis, IN 46285, USA
A3.0 NL 3730 AMP
PRINTED IN USA
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
W W 9 1 9 0 A M X
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C-1004
C-1004
C-1004
If the seal is broken before first use, contact pharmacist
If the seal is broken before first use, contact pharmacist
FC 2491 AMS
FC 2491 AMS
FC 2491 AMS
NDC 0002-8730-01
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:19.969401 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18781scm074_humulin_lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 74} |
1,077 |
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN R U-500 safely and effectively. See full prescribing
information for HUMULIN R U-500.
HUMULIN R U-500 (insulin human injection), for subcutaneous use
Initial U.S. Approval: 1994
--------------------------- RECENT MAJOR CHANGES -------------------------
Dosage and Administration:
Delivery of HUMULIN R U-500 from HUMULIN R U-500 KwikPen (2.3)
12/2015
Warnings and Precautions:
Never Share a HUMULIN R U-500 KwikPen or Syringes Between Patients
(5.2)
12/2015
----------------------------INDICATIONS AND USAGE --------------------------
HUMULIN® R U-500 is a concentrated human insulin indicated to improve
glycemic control in adults and children with diabetes mellitus requiring more
than 200 units of insulin per day. (1)
Limitation of Use: The safety and efficacy of HUMULIN R U-500 used in
combination with other insulins has not been determined. The safety and
efficacy of HUMULIN R U-500 delivered by continuous subcutaneous
infusion has not been determined. (1.1)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
•
Adhere to administration instructions to reduce the risk of dosing errors.
(2.1, 2.3, 2.4, 5.1)
•
Individualize dose of HUMULIN R U-500 based on metabolic needs,
blood glucose monitoring results and glycemic control goal. (2.2)
•
Administer HUMULIN R U-500 subcutaneously two or three times
daily 30 minutes before a meal. Rotate injection sites to reduce the risk
of lipodystrophy. (2.1, 2.2)
•
Do NOT mix HUMULIN R U-500 with other insulins. (2.1)
•
Do NOT administer HUMULIN R U-500 intravenously or
intramuscularly.
•
Do NOT perform dose conversion when using the HUMULIN R U-500
KwikPen. The dose window of the HUMULIN R U-500 KwikPen
shows the number of units of HUMULIN R U-500 to be injected and
NO dose conversion is required. Do NOT transfer HUMULIN R U-500
from the HUMULIN R U-500 KwikPen into a syringe. (2.3)
•
CONVERT the prescribed dose of HUMULIN R U-500 into a “unit” or
“volume” mark when using the vial presentation and a U-100 or a
tuberculin syringe device to deliver HUMULIN R U-500. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS --------------------
HUMULIN R U-500 (500 units per mL) is available in a colorless solution as:
(3)
•
3 mL HUMULIN® R U-500 KwikPen® (prefilled, 1,500 units of insulin)
•
20 mL vial (containing 10,000 units of insulin)
-------------------------------CONTRAINDICATIONS-----------------------------
•
Do not use during episodes of hypoglycemia. (4)
•
Do not use in patients with hypersensitivity to HUMULIN R U-500 or
any of its excipients. (4)
------------------------ WARNINGS AND PRECAUTIONS ----------------------
•
Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial
Presentation: Can be life-threatening. Overdose has occurred as a result
of dispensing, prescribing or administration errors. Attention to details at
all levels is required to prevent these errors. (2.1, 2.3, 2.4, 5.1)
•
Never share a HUMULIN R U-500 KwikPen or syringe between
patients, even if the needle is changed. (5.2)
•
Hyper- or Hypoglycemia with Changes in Insulin Regimen: Carry out
under close medical supervision and increase frequency of blood glucose
monitoring. (5.3)
•
Hypoglycemia: May be life-threatening. Increase monitoring with
changes to: insulin dosage, co-administered glucose lowering
medications, meal pattern, physical activity; and in patients with renal
impairment or hepatic impairment or hypoglycemia unawareness. (5.4)
•
Hypersensitivity Reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur. Discontinue HUMULIN R U-500,
monitor, and treat if indicated. (5.5)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk for hypokalemia and treat if indicated. (5.6)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure
occurs. (5.7)
-------------------------------ADVERSE REACTIONS -----------------------------
Adverse reactions associated with HUMULIN R U-500 include
hypoglycemia, allergic reactions, injection site reactions, lipodystrophy,
pruritus, and rash. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -----------------------------
•
Certain drugs may affect glucose metabolism and may necessitate
insulin dose adjustment. (7.1, 7.2, 7.3)
•
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine). (7.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 12/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Limitation of Use
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Dosing Instructions
2.3
Delivery of HUMULIN R U-500 using the HUMULIN R U-500
Disposable Prefilled KwikPen Device
2.4
Delivery of HUMULIN R U-500 using a U-100 Insulin Syringe
or a Tuberculin Syringe
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hyperglycemia, Hypoglycemia or Death due to Dosing Errors
with the Vial Presentation
5.2
Never Share a HUMULIN R U-500 KwikPen or Syringe
Between Patients
5.3
Hyperglycemia or Hypoglycemia with Changes in Insulin
Regimen
5.4
Hypoglycemia
5.5
Hypersensitivity and Allergic Reactions
5.6
Hypokalemia
5.7
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect
of HUMULIN R U-500
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN R U-500
7.4
Drugs That May Affect Signs and Symptoms of Hypoglycemia
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients
with diabetes mellitus requiring more than 200 units of insulin per day.
1.1
Limitation of Use
The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined.
The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
•
Prescribe HUMULIN R U-500 ONLY to patients who require more than 200 units of insulin per day.
•
Train patients on proper use and injection technique before initiating HUMULIN R U-500. Training reduces the risk of
administration errors such as needle sticks and dosing errors.
•
To avoid serious dosing errors for patients using the vial presentation, determine the type of syringe that the patient will
use to deliver the prescribed dose of HUMULIN R U-500, instruct the patient on how to correctly draw the prescribed
dose of HUMULIN R U-500 into the particular syringe, and confirm that the patient has understood these instructions and
can correctly draw the prescribed dose of HUMULIN R U-500 with their syringe [see Dosage and Administration (2.4)
and Warnings and Precautions (5.1)].
•
Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being
used [see Warnings and Precautions (5.1)].
•
Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the
solution appears clear and colorless.
•
Instruct patients to inject HUMULIN R U-500 subcutaneously into the thigh, upper arm, abdomen, or buttocks.
•
Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy [see
Adverse Reactions (6)].
•
DO NOT administer HUMULIN R U-500 intravenously or intramuscularly.
•
DO NOT dilute or mix HUMULIN R U-500 with any other insulin products or solutions.
2.2
Dosing Instructions
•
Instruct patients to inject HUMULIN R U-500 subcutaneously usually two or three times daily approximately 30 minutes
before meals.
•
Individualize and titrate the dosage of HUMULIN R U-500 based on the patient’s metabolic needs, blood glucose
monitoring results, and glycemic control goal.
•
Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient
content or timing of food intake), changes in renal or hepatic function, changes in medications or during acute illness to
minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.3)].
2.3
Delivery of HUMULIN R U-500 using the HUMULIN R U-500 Disposable Prefilled KwikPen Device
•
DO NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the
HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected and NO dose
conversion is required.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
DO NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into a syringe for administration as
overdose and severe hypoglycemia can occur [see Warnings and Precautions (5.4)].
•
The HUMULIN R U-500 KwikPen is for single patient use only [see Warnings and Precautions (5.2)].
2.4
Delivery of HUMULIN R U-500 using a U-100 Insulin Syringe or a Tuberculin Syringe
•
U-100 insulin and tuberculin syringes are not scaled to measure HUMULIN R U-500 insulin. When using a U-100 insulin
syringe or a tuberculin syringe to deliver HUMULIN U-500, a conversion step is REQUIRED to ensure the correct
amount of HUMULIN R U-500 is drawn up in the syringe. Failure to follow this conversion step will result in failure
to draw up the correct amount of HUMULIN R U-500 in the syringe and will result in serious dosing errors [see
Warnings and Precautions (5.1)].
•
Markings on the U-100 syringe refer to units of less concentrated insulin products (i.e., U-100 insulin products) and NOT
units of HUMULIN R U-500. If U-100 insulin syringes are used, prescribers or healthcare workers MUST CONVERT
the prescribed dose of HUMULIN R U-500 into a U-100 insulin syringe “unit marking” to determine the correct amount
of HUMULIN R U-500 to draw up in the syringe. Prescribers or healthcare workers MUST DETERMINE that patients
can draw up the correct amount of HUMULIN R U-500 in the syringe before prescribing and dispensing.
•
To convert from the HUMULIN R U-500 prescribed dose to a U-100 insulin syringe “unit marking”, divide the
prescribed dose of HUMULIN R U-500 by 5. The resulting number is the “unit marking” on a U-100 insulin syringe
to which the patient should draw up HUMULIN R U-500. For example, if a patient is prescribed 100 units of
HUMULIN R U-500, then the patient should draw up HUMULIN R U-500 to the 20 “unit mark” on a U-100 insulin
syringe (i.e., 100 divided by 5).
•
Markings on the tuberculin syringe refer to volume (mL) and NOT units of HUMULIN R U-500. If tuberculin syringes
are used, prescribers or healthcare workers MUST CONVERT the prescribed dose of HUMULIN R U-500 into a
tuberculin syringe “volume marking” in mL to determine the correct amount of HUMULIN R U-500 to draw up in the
syringe. Prescribers or healthcare workers MUST DETERMINE that patients can draw up the correct amount of
HUMULIN R U-500 in the syringe before prescribing and dispensing.
•
To convert from the HUMULIN R U-500 prescribed dose to a tuberculin syringe “volume marking” in mL, divide
the prescribed dose of HUMULIN R U-500 by 500. The resulting number is the “volume (mL) marking” on a tuberculin
syringe to which the patient should draw up HUMULIN R U-500. For example, if a patient is prescribed 100 units of
HUMULIN R U-500, then the patient should draw up HUMULIN R U-500 to the 0.2 mL “volume mark” on a tuberculin
syringe (i.e., 100 divided by 500).
Table 1: Examples of prescribed doses of HUMULIN R U-500 converted to amount of HUMULIN R U-500 to draw up in a U
100 insulin syringe or a tuberculin syringe for delivery of HUMULIN R U-500 using these devices
HUMULIN R U-500
dose prescribed (units of insulin)
Delivery Using a U-100 insulin syringe
Amount of HUMULIN R U-500 to
draw up in the syringe in “unit
marking”
Delivery Using a Tuberculin syringe
Amount of HUMULIN R U-500 to draw
up in the syringe in “volume marking”
Conversion: Divide prescribed dose by 5
Conversion: Divide prescribed dose by
500
25 Units
Draw to the 5 unit mark on syringe
Draw to the 0.05 mL mark on syringe
50 Units
Draw to the 10 unit mark on syringe
Draw to the 0.1 mL mark on syringe
75 Units
Draw to the 15 unit mark on syringe
Draw to the 0.15 mL mark on syringe
100 Units
Draw to the 20 unit mark on syringe
Draw to the 0.2 mL mark on syringe
125 Units
Draw to the 25 unit mark on syringe
Draw to the 0.25 mL mark on syringe
150 Units
Draw to the 30 unit mark on syringe
Draw to the 0.3 mL mark on syringe
175 Units
Draw to the 35 unit mark on syringe
Draw to the 0.35 mL mark on syringe
200 Units
Draw to the 40 unit mark on syringe
Draw to the 0.4 mL mark on syringe
225 Units
Draw to the 45 unit mark on syringe
Draw to the 0.45 mL mark on syringe
250 Units
Draw to the 50 unit mark on syringe
Draw to the 0.5 mL mark on syringe
…
…
…
500 Units
Draw to the 100 unit mark on syringe
Draw to the 1.0 mL mark on syringe
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
DOSAGE FORMS AND STRENGTHS
HUMULIN R U-500 (500 units per mL) is available in a colorless solution as:
•
3 mL HUMULIN R U-500 KwikPen (prefilled, 1,500 units of insulin)
•
20 mL vial (containing 10,000 units of insulin)
4
CONTRAINDICATIONS
HUMULIN R U-500 is contraindicated:
•
During episodes of hypoglycemia
•
In patients who are hypersensitive to HUMULIN R U-500 or any of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with the Vial Presentation
Medication errors associated with the HUMULIN R U-500 vial presentation have occurred and resulted in patients
experiencing hyperglycemia, hypoglycemia or death. The majority of errors occurred due to errors in dispensing, prescribing or
administration. Attention to details at all levels may prevent these errors.
Dispensing Errors
Instruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct insulin
brand and concentration.
The HUMULIN R U-500 vial, which contains 20 mL, has a band of diagonal brown stripes. “U-500” is also highlighted in red
on the HUMULIN R U-500 vial label.
Prescribing Errors
When using a U-100 insulin syringe or tuberculin syringe, express the prescribed dose of HUMULIN R U-500 in units of
insulin along with the appropriate corresponding markings on the syringe the patient is using [see Dosage and Administration (2.4)].
Administration Errors
Instruct patients to always check the insulin label before each injection.
A majority of the medication errors with HUMULIN R U-500 vial presentation occurred due to dosing confusion when the
HUMULIN R U-500 dose was prescribed in units or volume corresponding to a U-100 syringe or tuberculin syringe markings,
respectively, or the prescribed dose was administered without recognizing that the markings on the syringe used do not directly
correspond to U-500 dose. Adhere to administration and conversion instructions [see Dosage and Administration (2.1, 2.4)].
Instruct the patient to inform hospital or emergency department staff of the dose of HUMULIN R U-500 prescribed, in the
event of a future hospitalization or visit to the Emergency Department.
Conversion instructions are provided and should always be used when administering HUMULIN R U-500 doses with U-100
insulin syringes or 1 mL tuberculin syringes [see Dosage and Administration (2.4)].
5.2
Never Share a HUMULIN R U-500 KwikPen or Syringe Between Patients
HUMULIN R U-500 KwikPens should never be shared between patients, even if the needle is changed. Patients using
HUMULIN R U-500 vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-
borne pathogens.
5.3
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in insulin, manufacturer, type, or method of administration may affect glycemic control and predispose to
hypoglycemia or hyperglycemia. These changes should be made cautiously and only under medical supervision and the frequency of
blood glucose monitoring should be increased. For patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic
treatment may be needed.
5.4
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulin, including HUMULIN R U-500. Severe
hypoglycemia can cause seizures, may be life-threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours
after an injection of HUMULIN R U-500. Hypoglycemia can impair concentration ability and reaction time; this may place an
individual and others at risk in situations where these abilities are important (e.g., driving, or operating other machinery).
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic
nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions
(7.3, 7.4)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulin
preparations, the glucose lowering effect time course of HUMULIN R U-500 may vary in different individuals or at different times in
the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and
temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content
or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7.1, 7.2,
7.3, 7.4)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6,
8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an
essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have
reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. To minimize
the risk of hypoglycemia do not administer HUMULIN R U-500 intravenously, intramuscularly or in an insulin pump or dilute or mix
HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].
5.5
Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMULIN R
U-500 [see Adverse Reactions (6)]. If hypersensitivity reactions occur, discontinue HUMULIN R U-500; treat per standard of care
and monitor until symptoms and signs resolve [See Adverse Reactions (6)].
5.6
Hypokalemia
All insulin products, including HUMULIN R U-500, cause a shift in potassium from the extracellular to intracellular space,
possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use
caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations).
5.7
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-
related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.
Patients treated with insulin, including HUMULIN R U-500, and a PPAR-gamma agonist should be observed for signs and symptoms
of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose
reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
•
Hypoglycemia [see Warnings and Precautions (5.4)].
•
Hypokalemia [see Warnings and Precautions (5.6)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or to establish a causal relationship to drug exposure.
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMULIN R U-500 [see
Warnings and Precautions (5.4)].
Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, rash, angioedema,
bronchospasm, hypotension, and shock may occur with any insulin, including HUMULIN R U-500 and may be life threatening [see
Warnings and Precautions (5.5)].
Lipodystrophy
Long-term use of insulin, including HUMULIN R U-500, can cause lipodystrophy at the site of repeated insulin injections.
Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
insulin absorption. Rotate insulin injections sites within the same region to reduce the risk of lipodystrophy [see Dosage and
Administration (2.1)].
Injection Site Reactions
Patients taking HUMULIN R U-500 may experience injection site reactions, including injection site hematoma, pain,
hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass.
Weight Gain
Weight gain can occur with insulin therapy, including HUMULIN R U-500, and has been attributed to the anabolic effects of
insulin.
Peripheral Edema
Insulin, including HUMULIN R U-500, may cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
Immunogenicity
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The presence of antibodies
that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper- or hypoglycemia.
The incidence of antibody formation with HUMULIN R U-500 is unknown.
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN R U-500 use may be increased with antidiabetic agents, ACE inhibitors,
angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide,
propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased
frequency of glucose monitoring may be required when HUMULIN R U-500 is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN R U-500
The glucose lowering effect of HUMULIN R U-500 may be decreased when co-administered with atypical antipsychotics
(e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives,
phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol,
epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required
when HUMULIN R U-500 is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN R U-500
The glucose lowering effect of HUMULIN R U-500 may be increased or decreased when co-administered with alcohol, beta-
blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN R U-500 is co-administered with
these drugs.
7.4
Drugs That May Affect Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)] may be blunted when beta-blockers,
clonidine, guanethidine, and reserpine are co-administered with HUMULIN R U-500.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This
background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is
essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. In patients with diabetes or gestational diabetes, insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they
become pregnant while taking HUMULIN R U-500.
Human Data
While there are no adequate and well-controlled studies in pregnant women, evidence from published literature suggests that
good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal benefits.
Animal Data
Reproduction and fertility studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the gastrointestinal tract. No adverse
reactions associated with infant exposure to insulin through the consumption of human milk have been reported. In a study of eight
preterm infants between 26 to 30 weeks gestation, enteral administration of biosynthetic human insulin did not result in hypoglycemia.
Good glucose control supports lactation in patients with diabetes. Women with diabetes who are lactating may require adjustments in
their insulin dose.
8.4
Pediatric Use
There are no well-controlled studies of use of HUMULIN R U-500 in children. Standard precautions as applied to use of
HUMULIN R U-500 in adults are appropriate for use in children. As in adults, the dosage of HUMULIN R U-500 in pediatric patients
must be individualized based on metabolic needs and results of frequent monitoring of blood glucose.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution
should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial
dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.
8.6
Renal Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.
8.7
Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma,
seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery.
Hypokalemia must be corrected appropriately.
11
DESCRIPTION
HUMULIN R U-500 (insulin human injection, USP) is a human insulin solution used to lower blood glucose. Human insulin
is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. HUMULIN R has the
empirical formula C257H383N65O77S6 with a molecular weight of 5808.
HUMULIN R U-500 is a sterile, aqueous, and colorless solution. HUMULIN R U-500 contains 500 units of insulin in each
milliliter. Each milliliter of HUMULIN R U-500 also contains glycerin 16 mg, metacresol 2.5 mg, zinc oxide to supplement the
endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric
acid may be added during manufacture to adjust the pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. Insulins lower blood
glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins
inhibit lipolysis and proteolysis, and enhance protein synthesis.
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12.2
Pharmacodynamics
In a euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m2), single doses of HUMULIN R U-500 at
50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both
doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal
activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.
Figure 1 should be considered a representative example since the time course of action of insulin may vary in different
individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected
by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)]. graph
Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 in
Healthy Obese Subjects
12.3
Pharmacokinetics
Absorption — In a euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between 4
hours (50 unit dose) and 8 hours (100 unit dose) with a range of 0.5-8 hours.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the
liver being the major organ involved in the clearance of insulin.
Elimination — Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy
obese subjects (N≥21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN R U-500.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
graph
Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of a 100 U Dose of HUMULIN R
U-500 Healthy Obese Subjects
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed with HUMULIN R U-500 in animals. Biosynthetic human insulin
was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis
assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN R U-500 (500 units per mL) is available as:
2 x 3 mL HUMULIN R U-500 KwikPen (prefilled)
20 mL vials
NDC 0002-8824-27
NDC 0002-8501-01
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use HUMULIN R U-500 after the expiration date printed on the label or if it
has been frozen. Do not shake the vial.
Not In Use (Unopened) HUMULIN R U-500 KwikPen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 28 days.
In-Use (Opened) HUMULIN R U-500 KwikPen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 28 days, even if the pen still contains
HUMULIN R U-500. See storage table below:
Not In Use (Unopened) HUMULIN R U-500 Vials
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A6.0-LINR500-0001-USPI-20151229
17
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 40 days.
In-Use (Opened) HUMULIN R U-500 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must be used
within 40 days or be discarded, even if they still contain HUMULIN R U-500.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 40 days, even if the vial still contains
HUMULIN R U-500. See storage table below:
Not In-Use (Unopened) Refrigerated
In-Use (Opened)
3 mL HUMULIN R U-500 KwikPen
(prefilled)
Until expiration date
28 days, room temperature.
Do not refrigerate.
20 mL vial
Until expiration date
40 days, refrigerated or room temperature
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
Patients should be counseled that HUMULIN R U-500 is a 5-times concentrated insulin product. Extreme caution must be
observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening
hypoglycemia. Accidental mix-ups between HUMULIN R U-500 and other insulins have been reported. To avoid medication errors
between HUMULIN R U-500 and other insulins, patients should be instructed to always check the insulin label before each injection
[see Warnings and Precautions (5.1)].
If using the HUMULIN R U-500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of
insulin (no dose conversion is required) [see Dosage and Administration (2.3)].
When using HUMULIN R U-500 from a vial, patients should be counseled to calculate the conversion and measure the
amount of delivered insulin using the unit of measurement that corresponds to the type of syringe being used [see Dosage and
Administration (2.4)].
Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and
management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN R U-500 therapy. Patients must be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped
insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Refer patients to the
HUMULIN R U-500 Patient Information Leaflet for additional information [see Warnings and Precautions (5)].
Women with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Never use HUMULIN R U-500 if it has become viscous (thickened) or cloudy; use it only if
it is clear and colorless.
HUMULIN R U-500 should not be used after the printed expiration date.
Do not dilute or mix HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].
Literature Revised: December 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, 2015, Eli Lilly and Company. All rights reserved.
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Patient Information
Humulin® (HU-mu-lin) R U-500
insulin human injection
(500 units per mL)
Do not share your Humulin R U-500 KwikPen or syringes with other people, even if the needle has been
changed. You may give other people a serious infection or get a serious infection from them.
What is Humulin R U-500?
•
Humulin R U-500 is a man-made insulin that is used to control high blood sugar in adults and children with diabetes
mellitus who need more than 200 units of insulin in a day.
•
Humulin R U-500 contains 5 times as much insulin (500 units/mL) in 1 mL as standard insulin (100 units/mL).
•
It is not known if Humulin R U-500 is safe and effective in children.
Who should not take Humulin R U-500?
Do not take Humulin R U-500 if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to human insulin or any of the ingredients in Humulin R U-500. See the end of this Patient
Information leaflet for a complete list of ingredients in Humulin R U-500.
What should I tell my healthcare provider before using Humulin R U-500?
Before using Humulin R U-500, tell your healthcare provider about all your medical conditions including, if you:
•
have liver or kidney problems.
•
take other medicines, especially ones called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with
Humulin R U-500.
•
are pregnant, planning to become pregnant, or breast-feeding. It is not known if Humulin R U-500 will harm your
unborn or breastfeeding baby.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, or herbal supplements.
Before you start using Humulin R U-500, talk to your healthcare provider about low blood sugar and how to
manage it.
How should I use Humulin R U-500?
•
Read the detailed Instructions for Use that come with your Humulin R U-500.
•
Use Humulin R U-500 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how
much Humulin R U-500 to use and when to use it.
•
Know the amount of Humulin R U-500 you use. Do not change the amount of Humulin R U-500 you use unless your
healthcare provider tells you to.
•
Check your insulin label each time you give your injection to make sure you are using the correct insulin.
•
When using the Humulin R U-500 KwikPen: The Humulin R U-500 KwikPen is specially made to dial and deliver
doses of Humulin R U-500 insulin. Do not use a syringe to remove Humulin R U-500 from your Humulin R U-500
KwikPen. The markings on a syringe will not measure your dose correctly. A severe overdose can happen, causing
low blood sugar, which may put your life in danger.
•
When using the Humulin R U-500 vial: There are no special syringes to measure Humulin R U-500. Use a U-100
insulin syringe or tuberculin syringe as instructed by your healthcare provider. It is important that you use only the
syringes that your healthcare provider tells you to use. If you do not use the right syringe type, you may take the
wrong dose of Humulin R U-500. This can cause you to have too low blood sugar (hypoglycemia) or too high blood
sugar (hyperglycemia). Your healthcare provider should show you how to draw up Humulin R U-500. The amount of
Humulin R U-500 will be less than the amount of standard U-100 insulin drawn up into the syringe.
-
For U-100 insulin syringes, your healthcare provider should explain how to use this syringe to give the
prescribed dose with the unit markings on the syringe.
-
For tuberculin syringes, your healthcare provider should explain how to use this syringe to give the prescribed
dose with volume markings on the syringe.
•
Use Humulin R U-500 30 minutes before eating a meal.
•
Inject Humulin R U-500 under your skin (subcutaneously). Do not use Humulin R U-500 in an insulin pump or inject
Humulin R U-500 into your vein (intravenously) or your muscle (intramuscularly).
•
Do not mix Humulin R U-500 in the KwikPen or vial with any other type of insulin or liquid medicine.
•
Change (rotate) your injection site with each dose.
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you
should check your blood sugar levels.
Keep Humulin R U-500 and all medicines out of reach of children.
Your dose of Humulin R U-500 may need to change because of:
•
change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or
because of other medicines you take.
What should I avoid while using Humulin R U-500?
While using Humulin R U-500 do not:
•
drive or operate heavy machinery, until you know how Humulin R U-500 affects you.
•
drink alcohol or use over-the-counter medicines that contain alcohol.
What are the possible side effects of Humulin R U-500?
Humulin R U-500 may cause serious side effects that can lead to death, including:
•
low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:
-
dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast
heartbeat, anxiety, irritability or mood changes, hunger.
-
your healthcare provider may prescribe a glucagon emergency kit so that others can give you an injection if your
blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.
•
severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or
symptoms of a severe allergic reaction:
-
a rash over your whole body, have trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with Humulin R U-500 may cause
heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If
you already have heart failure, it may get worse while you take TZDs with Humulin R U-500. Your healthcare
provider should monitor you closely while you are taking TZDs with Humulin R U-500. Tell your healthcare provider
if you have any new or worse symptoms of heart failure including:
-
shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and Humulin R U-500 may need to be adjusted or stopped by your healthcare provider if you
have new or worse heart failure.
Get emergency medical help if you have:
•
severe hypoglycemia needing hospitalization or emergency room care, and be sure to tell the hospital staff the units
of Humulin R U-500 that your healthcare provider has prescribed for you.
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme
drowsiness, dizziness, confusion.
The most common side effects of Humulin R U-500 include:
•
low blood sugar (hypoglycemia), allergic reactions including reactions at your injection site, skin thickening or pits at
the injection site (lipodystrophy), itching, and rash.
These are not all of the possible side effects of Humulin R U-500. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0-LINR500-0001-PPI-YYYYMMDD
3
General Information about the safe and effective use of Humulin R U-500
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
Humulin R U-500 for a condition for which it was not prescribed. Do not give Humulin R U-500 to other people, even if
they have the same symptoms you have. It may harm them.
This Patient Information leaflet summarizes the most important information about Humulin R U-500. If you would like
more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information
about Humulin R U-500 that is written for healthcare professionals. For more information go to www.humulin.com or call
1-800-545-5979.
What are the ingredients in Humulin R U-500?
Active ingredient: human insulin
Inactive ingredients: glycerin, metacresol, zinc oxide, water for injection, sodium hydroxide and hydrochloric acid
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
For more information about Humulin R U-500 go to www.humulin.com.
Copyright © 2015, Eli Lilly and Company. All rights reserved.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: December 2015
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Instructions for Use
HUMULIN® R U-500 KwikPen®
insulin human injection U-500 (500 units/mL, 3 mL pen) usage illustration
Important:
•
Know your dose of HUMULIN R U-500 insulin. The Pen delivers your dose in insulin units. Insulin
units may not be the same as syringe markings. Ask your health care provider what your dose
should be for your Pen.
•
Your HUMULIN® R U-500 KwikPen® (Pen) works differently from other pens. It dials 5 insulin units
with each click. Do not count clicks of the dose knob to select your dose. You may not get
enough insulin or you may get too much insulin.
•
HUMULIN R U-500 is a concentrated insulin. Do not transfer HUMULIN R U-500 insulin from
your Pen into a syringe. A severe overdose can happen, causing very low blood sugar, which
may put your life in danger.
DO NOT TRANSFER TO A SYRINGE
SEVERE OVERDOSE CAN RESULT
Read the Instructions for Use before you start taking HUMULIN R U-500 and each time you get another Pen.
There may be new information. This information does not take the place of talking to your healthcare provider
about your medical condition or your treatment.
Do not share your HUMULIN R U-500 Pen with other people, even if the needle has been changed. You
may give other people a serious infection or get a serious infection from them.
HUMULIN R U-500 KwikPen (“Pen”) is a disposable prefilled pen containing 1500 units of HUMULIN R. You can
give yourself more than 1 dose from the Pen. Each turn (click) of the Dose Knob dials 5 units of insulin. You can
give from 5 to 300 units in a single injection. The plunger only moves a little with each injection, and you may not
notice that it moves. The plunger will only reach the end of the cartridge when you have used all 1500 units in the
Pen.
This Pen is not recommended for use by the blind or visually impaired without the help of someone
trained to use the Pen.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
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e
i
l
l
u
s
t
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a
t
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-
2
KwikPen Parts
Outer Needle
Inner Needle
Paper Tab
Shield
Shield
How to recognize your HUMULIN R U 500 KwikPen
• Pen color:
Aqua
• Dose Knob:
Aqua with raised ridges on the end
• Label:
HUMULIN R U-500 and 500 units/mL in a green box
Supplies needed to give your injection
•
HUMULIN R U-500 KwikPen
•
KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended)
•
Alcohol swab
Preparing your Pen
•
Wash your hands with soap and water.
•
Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use
more than 1 type of insulin.
•
Do not use your Pen past the expiration date printed on the Label or for more than 28 days after you first start
using the Pen.
•
Always use a new Needle for each injection to help prevent infections and blocked Needles. Do not
reuse or share your needles with other people. You may give other people a serious infection or get a
serious infection from them.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Step 1:
•
Pull the Pen Cap straight off.
– Do not remove the KwikPen Label.
•
Wipe the Rubber Seal with an alcohol swab.
HUMULIN R U-500 should look clear and
colorless. Do not use if it is cloudy, colored, or has
particles or clumps in it. usage illustration
Step 2:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer Needle
Shield. usage illustration
Step 3:
•
Push the capped Needle straight onto the Pen
and twist the Needle on until it is tight. usage illustration
Step 4:
•
Pull off the Outer Needle Shield. Do not throw
it away.
•
Pull off the Inner Needle Shield and throw it
away. usage illustration
Priming your Pen
Prime before each injection.
•
Priming your Pen means removing the air from the Needle and Cartridge that may collect during normal use
and ensures that the Pen is working correctly.
•
If you do not prime before each injection, you may get too much or too little insulin.
Step 5:
•
To prime your pen, turn the Dose Knob to
select 5 units. usage illustration
Step 6:
•
Hold your Pen with the Needle pointing up.
Tap the Cartridge Holder gently to collect air
bubbles at the top. usage illustration
Reference ID: 3866564
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4
Step 7:
•
Continue holding your Pen with Needle
pointing up. Push the Dose Knob in until it
stops, and “0” is seen in the Dose Window.
Hold the Dose Knob in and count to 5 slowly.
You should see insulin at the tip of the Needle.
– If you do not see insulin, repeat priming
steps 5 to 7, no more than 8 times.
– If you still do not see insulin, change the
Needle and repeat priming steps 5 to 7.
Small air bubbles are normal and will not affect
your dose. usage illustration
Selecting your dose
This Pen has been made to deliver the dose in insulin units that is shown in the Dose W indow. Ask your
healthcare provider what your dose should be for this Pen.
•
You can give from 5 to 300 units in a single injection.
•
If your dose is more than 300 units, you will need to give more than 1 injection.
– If you need help with dividing up your dose the right way, ask your healthcare provider.
– You must use a new Needle for each injection and repeat the priming step.
Reference ID: 3866564
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5
Step 8:
•
Turn the Dose Knob to select the number of
units you need to inject. The Dose Indicator
should line up with your dose.
– The Dose Knob clicks as you turn it. Each
click of the Dose Knob dials 5 insulin
units at a time.
– Do not dial your dose by counting the
clicks. You may dial the wrong dose.
This may lead to you getting too much
insulin or not enough insulin.
– The dose can be corrected by turning the
Dose Knob in either direction until the
correct dose lines up with the Dose
Indicator.
– The even numbers (for example, 80) are
printed on the dial.
– The odd numbers (for example, 125) are
shown as lines between the even
numbers.
•
Always check the number in the Dose
Window to make sure you have dialed the
correct dose. usage illustration
Example: 80 units
shown in Dose W indow
Example: 125 units
shown in Dose W indow usage illustration
•
The Pen will not let you dial more than the number of units left in the Pen.
•
If your dose is more than the number of units left in the Pen, you may either:
– inject the amount left in your Pen and then use a new Pen to give the rest of your dose,
or
– get a new Pen and inject your full dose.
•
It is normal to see a small amount of insulin left in the Pen that you cannot inject. Do not transfer this to a
syringe. Severe overdose can happen.
Reference ID: 3866564
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6
Giving your injection
•
Inject your insulin as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
•
Do not try to change your dose while injecting.
Step 9:
•
Choose your injection site.
HUMULIN is injected under the skin
(subcutaneously) of your stomach area,
buttocks, upper legs or upper arms.
•
Wipe your skin with an alcohol swab, and let
your skin dry before you inject your dose. usage illustration
Step 10:
•
Insert the Needle into your skin.
•
Push the Dose Knob all the way in.
•
Continue to hold the Dose
Knob in and slowly count to 5
before removing the Needle. usage illustration
5sec
Do not try to inject your insulin by turning the Dose
Knob. You will not receive your insulin by turning
the Dose Knob. usage illustration
Reference ID: 3866564
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7
Step 11:
•
Pull the Needle out of your skin.
– A drop of insulin at the Needle tip is
normal. It will not affect your dose.
•
Check the number in the Dose W indow.
– If you see “0” in the Dose Window, you
have received the full amount you dialed.
– If you do not see “0” in the Dose W indow,
do not redial. Insert the Needle into your
skin and finish your injection.
– If you still do not think you received the full
amount you dialed for your injection, do
not start over or repeat your injection.
Monitor your blood glucose as instructed
by your healthcare provider.
The Plunger only moves a little with each injection,
and you may not notice that it moves.
If you see blood after you take the Needle out of
your skin, press the injection site lightly with a
piece of gauze or an alcohol swab. Do not rub the
area. usage illustration
After your injection
Step 12:
•
Carefully replace the Outer Needle Shield. usage illustration
Step 13:
•
Unscrew the capped Needle and throw it away
(see Disposing of Pens and Needles
section).
•
Do not store the Pen with the Needle attached
to prevent leaking, blocking the Needle, and air
from entering the Pen. usage illustration
Step 14:
•
Replace the Pen Cap by lining up the Cap Clip
with the Dose Indicator and pushing straight
on. usage illustration
Disposing of Pens and Needles
•
Put your used Needles in a FDA-cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose Needles in your household trash.
Reference ID: 3866564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
-
8
•
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
– made of a heavy-duty plastic,
– can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
– upright and stable during use,
– leak-resistant, and
– properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community guidelines for the
right way to dispose of your sharps disposal container. There may be state or local laws about how you
should throw away used needles and syringes. For more information about safe sharps disposal, and for
specific information about sharps disposal in the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal
•
Do not dispose of your used sharps disposal container in your household trash unless your community
guidelines permit this. Do not recycle your used sharps disposal container.
•
The used Pen may be discarded in your household trash after you have removed the needle.
Storing your Pen
Unused Pens
•
Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
•
Do not freeze HUMULIN R U-500. Do not use if it has been frozen.
•
Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the
refrigerator.
In-use Pen
•
Store the Pen you are currently using at room temperature up to 86°F (30°C). Keep away from heat and light.
•
Throw away the Pen you are using after 28 days, even if it still has insulin left in it.
What you should know if you are switching to HUMULIN R U 500 KwikPen
Ask your healthcare provider what your dose should be for your Pen in insulin units. Always follow your
healthcare provider’s instructions for dosing.
If you are:
It is important to know:
Switching from
HUMULIN R U-500 vial
(and syringe)
Your Pen may measure your dose differently. The markings in the Dose
Window may not be the same as the markings on the syringe you used in
the past.
Ask your healthcare provider what dose in insulin units you should
dial on your Pen.
Switching from another
type of insulin device or
pen.
The HUMULIN R U-500 KwikPen is different from other pens. It dials 5
insulin units with each click of the Dose Knob.
Do not select your dose by counting clicks. You may not get enough
insulin or you may get too much insulin.
General information about the safe and effective use of your Pen
•
Keep your Pen and Needles out of the sight and reach of children.
•
Do not use your Pen if any part looks broken or damaged.
•
Always carry an extra Pen in case yours is lost or damaged.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A4.0-LINRU500-0000-IFU-20151229
9
Troubleshooting
•
If you cannot remove the Pen Cap, gently twist the cap back and forth, and then pull the cap straight off.
•
If it is hard to push the Dose Knob:
–
Pushing the Dose Knob more slowly will make it easier to inject.
–
Your Needle may be blocked. Put on a new Needle and prime the Pen.
–
You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen.
If you have any questions or problems with your HUMULIN R U-500 KwikPen, contact Lilly at 1-800-LillyRx
(1-800-545-5979) or call your healthcare provider for help. For more information on HUMULIN R U-500 KwikPen
and insulin, go to www.humulin.com.
Scan this code to launch
www.humulin.com
These Instructions for Use have been approved by the U.S. Food and Drug Administration.
HUMULIN® and HUMULIN® KwikPen® are trademarks of Eli Lilly and Company.
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2015, Eli Lilly and Company. All rights reserved.
HUMULIN R U-500 KwikPen meets the current dose accuracy and functional requirements of ISO 11608-1:2014.
Document revision date: December 29, 2015
Lilly (red script)
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
INSTRUCTIONS FOR INSULIN VIAL USE
HUMULIN® (HU-mu-lin) R U-500
insulin human injection (500 units/mL, 20 mL vial)
Read the Instructions for Use before you start taking HUMULIN R U-500 and each time you get a new
HUMULIN R U-500 vial. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
Do not share your syringes with other people, even if the needle has been changed. You may give
other people a serious infection or get a serious infection from them.
Correct Syringe Type
It is important that you use only the syringes that your healthcare provider tells you to use to give your
injections of HUMULIN R U-500. You should use either a U-100 insulin syringe or tuberculin syringe as
instructed by your healthcare provider. Your healthcare provider should show you how to draw up
HUMULIN R U-500 the right way.
• If you are using U-100 insulin syringes, your healthcare provider should explain how to use this
syringe to give the prescribed dose with the unit markings on the syringe.
• If you are using tuberculin syringes, your healthcare provider should explain how to use this
syringe to give the prescribed dose with volume markings on the syringe.
It is important to remember that the markings on the syringe do not match the HUMULIN R U-500
insulin dose. HUMULIN R U-500 (500 units/mL) is 5 times more concentrated than standard insulin
(100 units/mL).
If you do not use the right syringe type, you may take the wrong dose of HUMULIN R U-500. This can
cause you to have too low blood sugar (hypoglycemia) or too high blood sugar (hyperglycemia).
Make sure you know:
• your prescribed dose of HUMULIN R U-500.
• which syringe to use and how to draw up the insulin to your prescribed dose.
If you do not understand your dose, talk with your healthcare provider about the right way to measure and
take your insulin dose.
Supplies need to give your injection
• a HUMULIN R U-500 vial
• a U-100 insulin syringe or a tuberculin syringe
• 2 alcohol swabs
• 1 sharps container for throwing away used needles and syringes. See “Disposing of used
needles and syringes” at the end of these instructions.
Reference ID: 3866564
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2
usage illus
trat
ion
Preparing the Dose
• Wash your hands with soap and water.
• Check the HUMULIN R U-500 label to make sure you are taking the right type of insulin.
This is especially important if you use more than 1 type of insulin.•
Do not use
HUMULIN R U-500 past the expiration date printed on the label or 40 days after you first use it.
• Always use a new syringe or needle for each injection to help make sure the syringe needle
is sterile and to prevent blocked needles. Do not reuse or share your syringes or needles
with other people. You may give other people a serious infection or get a serious infection
from them.
Step 1:
Check the insulin. HUMULIN R U-500 solution should look clear
and colorless. Do not use HUMULIN R U-500 if it looks cloudy,
thick, slightly colored, or if you see particles in the solution. Do
not shake.
Step 2:
If you are using a new HUMULIN R U-500 vial, flip off the plastic
protective cap, but do not remove the rubber stopper. usage illustration
Step 3:
Wipe the rubber stopper of the vial with an alcohol swab. usage illustration
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Step 4:
Hold the syringe with the needle pointing up. Pull down on the
plunger until the tip of the plunger reaches the line for the number
of unit markings or volume markings (mL) for your prescribed
HUMULIN R U-500 dose. usage illustration
Plunger is shown at the 20 unit
marking
(U-100 insulin syringe)
Step 5:
Push the needle through the rubber stopper of the HUMULIN R
U-500 vial and push the plunger all the way in. This puts air into
the vial. usage illustration
Step 6:
Turn the HUMULIN R U-500 vial and syringe upside down. Hold
the vial and syringe firmly in one hand. Slowly pull the plunger
down until the tip of the plunger is a few markings past the line for
the number of unit markings or volume markings (mL)] for your
prescribed dose. usage illustration
Plunger is shown at the 24 unit
marking.
(U-100 insulin syringe)
Step 7:
If there are air bubbles in the syringe, tap the syringe gently a few
times to let any air bubbles rise to the top. usage illustration
Step 8:
Slowly push the plunger up until the tip reaches the line for your
prescribed dose.
Check to make sure that you have the right dose. usage illustration
Plunger is shown at the 20 unit
marking
(U-100 insulin syringe)
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Step 9:
Pull the syringe out of the vial’s rubber stopper. usage illustration
Giving your HUMULIN R U-500 Injection
• Inject your insulin exactly as your healthcare provider has shown you
• Change (rotate) your injection site for each injection
Step 10:
Choose your injection site.
HUMULIN R U-500 is injected under the skin (subcutaneously) of
your stomach area (abdomen), buttocks, upper legs, or upper
arms.
To avoid tissue damage, choose a site for each injection that is at
least 1/2 inch from the previous injection site.
Wipe the skin at the injection site with an alcohol swab. Let the
injection site dry before you inject your dose. usage illustration
Step 11:
Insert the needle into your skin. usage illustration
Step 12:
Push down on the plunger to inject your dose. The needle should
stay in your skin for at least 5 seconds to make sure you have
injected all of your insulin dose. usage illustration
Step 13:
Pull the needle out of your skin.
• If you see blood after you take the needle out of your skin,
press the injection site with a piece of gauze or an alcohol
swab. Do not rub the area.
• Do not recap the used needle. Recapping the needle can
lead to a needle stick injury. usage illustration
Disposing of used needles and syringes:
• Put your used needles and syringes in a FDA-cleared sharps disposal container right away after
use. Do not throw away (dispose of) loose needles and syringes in your household trash.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
• If you do not have a FDA-cleared sharps disposal container, you may use a household container
that is:
• Made of a heavy-duty plastic,
• Can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
• Upright and stable during use,
• Leak resistant, and
• Properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be state or
local laws about how you should throw away used needles and syringes. For more information
about safe sharps disposal, and for specific information about sharps disposal in the state that you
live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
How should I store HUMULIN R U-500?
All unopened HUMULIN R U-500 vials:
• Store all unopened vials in the refrigerator between 36° to 46°F (2° to 8°C).
• Do not freeze. Do not use if it has been frozen.
• Keep away from heat and out of direct light.
• Do not shake the vial.
• Unopened vials can be used until the expiration date on the carton and label, if they have been
stored in the refrigerator.
• Unopened vials should be thrown away after 40 days if they are stored at room temperature
After HUMULIN R U-500 vials have been opened:
• Store opened vials in a refrigerator or at room temperature below 86°F (30°C) for up to 40 days.
• Keep away from heat and out of direct light.
• Do not shake the vial.
• Throw away all opened vials after 40 days, even if there is still insulin left in the vial.
General information about the safe and effective use of HUMULIN R U-500.
• Keep HUMULIN R U-500 vials, syringes, needles, and all medicines out of the reach of children.
• Always use a new syringe or needle for each injection.
• Do not reuse or share your syringes or needles with other people. You may give other
people a serious infection or get a serious infection from them.
If you have any questions or problems with HUMULIN R U-500, contact Lilly at 1-800-Lilly-Rx
(1-800-545-5979) or call your healthcare provider for help. For more information on HUMULIN and insulin,
go to www.humulin.com.
Scan this code to launch the humulin.com website
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A4.0LINR500VL- 8540-IFU-20151229
6
HUMULIN ® is a trademark of Eli Lilly and Company.
Instructions for Use revised: December 29, 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 2015, Eli Lilly and Company. All rights reserved.
Reference ID: 3866564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.081784 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018780s135s152lbl.pdf', 'application_number': 18780, 'submission_type': 'SUPPL ', 'submission_number': 135} |
1,083 |
5.01 PA 9135 FSAMP
1
INFORMATION FOR THE PATIENT
2
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
3
HUMULIN® N Pen
4
NPH
5
HUMAN INSULIN
6
(rDNA ORIGIN) ISOPHANE SUSPENSION
7
100 UNITS PER ML (U-100)
8
WARNINGS
9
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-
10
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
11
INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF
12
ITS UNIQUE MANUFACTURING PROCESS.
13
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND
14
ONLY UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
15
MANUFACTURER, TYPE (E.G., REGULAR, NPH, LENTE, ETC), SPECIES
16
(BEEF, PORK, BEEF-PORK, HUMAN), OR METHOD OF MANUFACTURE
17
(rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED
18
FOR A CHANGE IN DOSAGE.
19
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
20
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH
21
ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY
22
OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL
23
WEEKS OR MONTHS.
24
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW
25
THE “DISPOSABLE INSULIN DELIVERY DEVICE USER MANUAL” AND
26
THIS “INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS
27
PRODUCT.
28
BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A
29
NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE.
30
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES
31
OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR
32
THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL
33
USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE TOO MUCH OR TOO
34
LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN USE section).
35
DIABETES
36
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
37
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
38
the pancreas does not make enough insulin to meet your body’s needs.
39
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
40
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
41
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
42
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
43
is maintained as close to normal as possible. The American Diabetes Association recommends
44
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
45
(HbA1c) is more than 7%, consult your doctor. A change in your diabetes therapy may be needed.
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If your blood tests consistently show below-normal glucose levels, you should also let your
47
doctor know. Proper control of your diabetes requires close and constant cooperation with your
48
doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
49
exercise regularly, and take your insulin injections as prescribed.
50
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
51
wear diabetic identification so that appropriate treatment can be given if complications occur
52
away from home.
53
NPH HUMAN INSULIN
54
Description
55
Humulin is synthesized in a non-disease-producing special laboratory strain of Escherichia coli
56
bacteria that has been genetically altered by the addition of the human gene for insulin
57
production. Humulin® N (human insulin [rDNA origin] isophane suspension) is a crystalline
58
suspension of human insulin with protamine and zinc providing an intermediate-acting insulin
59
with a slower onset of action and a longer duration of activity (up to 24 hours) than that of
60
regular insulin. The time course of action of any insulin may vary considerably in different
61
individuals or at different times in the same individual. As with all insulin preparations, the
62
duration of action of Humulin N is dependent on dose, site of injection, blood supply,
63
temperature, and physical activity. Humulin N is a sterile suspension and is for subcutaneous
64
injection only. It should not be used intravenously or intramuscularly. The concentration of
65
Humulin N in Humulin N Pen is 100 units/mL (U-100).
66
Identification
67
Humulin disposable insulin delivery devices, by Eli Lilly and Company, are available in
68
2 formulations NPH and 70/30.
69
Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT
70
USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION.
71
The Humulin N Pen is available in boxes of 5 disposable insulin delivery devices (“insulin
72
Pens”). The Humulin N Pen is not designed to allow any other insulin to be mixed in its
73
cartridge, or for the cartridge to be removed.
74
Always examine the appearance of Humulin N suspension in the insulin Pen before
75
administering a dose. A cartridge of Humulin N contains a small glass bead to assist in mixing.
76
Humulin N Pen must be rolled between the palms 10 times and inverted 180° 10 times before
77
each injection so that the contents are uniformly mixed (see Figures 1 and 2). Inspect the
78
Humulin N suspension for uniform mixing and repeat the above steps as necessary.
79
Figure 1.
Figure 2.
80
Humulin N should look uniformly cloudy or milky after mixing. Do not use if the insulin
81
substance (the white material) remains visibly separated from the liquid after mixing. Do not use
82
the Humulin N Pen if there are clumps in the insulin after mixing. Do not use the Humulin N Pen
83
if solid white particles stick to the walls of the cartridge, giving it a frosted appearance.
84
Always check the appearance of the Humulin N suspension in the insulin Pen before using, and
85
if you note anything unusual in the appearance of Humulin N suspension or notice your insulin
86
requirements changing markedly, consult your doctor.
87
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Never attempt to remove the cartridge from the Humulin N Pen. Inspect the cartridge through
88
the clear cartridge holder.
89
Storage
90
Not in-use (unopened): Humulin N Pens not in-use should be stored in a refrigerator but not
91
in the freezer. Do not use a Humulin N Pen if it has been frozen.
92
In-use: Humulin N Pens in-use should NOT be refrigerated but should be kept at room
93
temperature (below 86°F [30°C]) away from direct heat and light. Humulin N Pens in-use must
94
be discarded after 2 weeks, even if they still contain Humulin N.
95
Do not use Humulin N Pens after the expiration date stamped on the label.
96
INSTRUCTIONS FOR INSULIN PEN USE
97
It is important to read, understand, and follow the instructions in the “Disposable Insulin
98
Delivery Device User Manual” before using. Failure to follow instructions may result in
99
getting too much or too little insulin. The needle must be changed and the Pen must be
100
primed before each injection to make sure the Pen is ready to dose. Performing these steps
101
before each injection is important to confirm that insulin comes out when you push the
102
injection button, and to remove air that may collect in the insulin cartridge during normal
103
use.
104
Every time you inject:
105
• Use a new needle.
106
• Prime to make sure the Pen is ready to dose.
107
• Make sure you got your full dose.
108
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
109
PREPARING THE INSULIN PEN FOR INJECTION
110
1. Always check the appearance of the Humulin N suspension in the insulin Pen before
111
using.
112
2. Roll the Humulin N Pen between the palms 10 times (see Figure 1).
113
3. Holding the Humulin N Pen by one end, invert it 180° slowly 10 times to allow the small
114
glass bead to travel the full length of the cartridge with each inversion (see Figure 2). The
115
cartridge is contained in the clear cartridge holder of the Humulin N Pen.
116
4. Inspect the appearance of the Humulin N suspension to make sure the contents look
117
uniformly cloudy or milky. If not, repeat the above steps until the contents are mixed. Do
118
not use a Humulin N Pen if there are clumps in the insulin or if solid white particles stick
119
to the walls of the cartridge.
120
5. Follow the instructions in the “Disposable Insulin Delivery Device User Manual” for these
121
steps:
122
• Preparing the Pen
123
• Attaching the Needle. Use a new needle for each injection.
124
• Priming the Pen. The Pen must be primed before each injection to make sure the
125
Pen is ready to dose. Performing the priming step is important to confirm that insulin
126
comes out when you push the injection button, and to remove air that may collect in the
127
insulin cartridge during normal use.
128
• Setting a Dose
129
• Injecting a Dose. To make sure you have received your full dose, you must push the
130
injection button all the way down until you see a diamond (N) or an arrow (→) in
131
the center of the dose window.
132
• Following an Injection
133
PREPARING FOR INJECTION
134
1. Wash your hands.
135
2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
136
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
137
3. Cleanse the skin with alcohol where the injection is to be made.
138
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4. With one hand, stabilize the skin by spreading it or pinching up a large area.
139
5. Inject the dose as instructed by your doctor. Hold the needle under the skin for at least
140
5 seconds after injecting.
141
6. After injecting a dose, pull the needle out and apply gentle pressure over the injection site
142
for several seconds. Do not rub the area.
143
7. Immediately after an injection, remove the needle from the Humulin N Pen. Doing so will
144
guard against contamination, leakage, reentry of air, and needle clogs. Do not reuse
145
needles. Place the used needle in a puncture-resistant disposable container and properly
146
dispose of it as directed by your Health Care Professional.
147
DOSAGE
148
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
149
Because each patient’s case of diabetes is different, this schedule has been individualized for you.
150
Your usual Humulin N dose may be affected by changes in your food, activity, or work
151
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things that
152
may affect your Humulin N dose are:
153
Illness
154
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
155
Even if you are not eating, you will still require insulin. You and your doctor should establish a
156
sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine
157
glucose and ketones frequently and call your doctor as instructed.
158
Pregnancy
159
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
160
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
161
are nursing a baby, consult your doctor.
162
Medication
163
Insulin requirements may be increased if you are taking other drugs with hyperglycemic
164
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
165
requirements may be reduced in the presence of drugs with blood-glucose-lowering activity, such
166
as oral antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, and
167
certain antidepressants. Always discuss any medications you are taking with your doctor.
168
Exercise
169
Exercise may lower your body’s need for insulin during and for some time after the physical
170
activity. Exercise may also speed up the effect of a Humulin N dose, especially if the exercise
171
involves the area of injection site (for example, the leg should not be used for injection just prior
172
to running). Discuss with your doctor how you should adjust your regimen to accommodate
173
exercise.
174
Travel
175
Persons traveling across more than 2 time zones should consult their doctor concerning
176
adjustments in their insulin schedule.
177
COMMON PROBLEMS OF DIABETES
178
Hypoglycemia (Low Blood Sugar)
179
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
180
experienced by insulin users. It can be brought about by:
181
1. Taking too much insulin.
182
2. Missing or delaying meals.
183
3. Exercising or working more than usual.
184
4. An infection or illness (especially with diarrhea or vomiting).
185
5. A change in the body's need for insulin.
186
6. Diseases of the adrenal, pituitary or thyroid gland, or progression of kidney or liver
187
disease.
188
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7. Interactions with other drugs that lower blood glucose, such as oral antidiabetic agents,
189
salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
190
8. Consumption of alcoholic beverages.
191
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
192
• sweating
• drowsiness
193
• dizziness
• sleep disturbances
194
• palpitation
• anxiety
195
• tremor
• blurred vision
196
• hunger
• slurred speech
197
• restlessness
• depressed mood
198
• tingling in the hands, feet, lips, or tongue
• irritability
199
• lightheadedness
• abnormal behavior
200
• inability to concentrate
• unsteady movement
201
• headache
• personality changes
202
Signs of severe hypoglycemia can include:
203
• disorientation
• seizures
204
• unconsciousness
• death
205
Therefore, it is important that assistance be obtained immediately.
206
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
207
conditions, such as long duration of diabetes, diabetic nerve disease, medications such as beta-
208
blockers, change in insulin preparations, or intensified control (3 or more insulin injections per
209
day) of diabetes.
210
A few patients who have experienced hypoglycemic reactions after transfer from animal-
211
source insulin to human insulin have reported that the early warning symptoms of
212
hypoglycemia were less pronounced or different from those experienced with their
213
previous insulin.
214
Without recognition of early warning symptoms, you may not be able to take steps to avoid
215
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
216
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
217
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
218
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
219
containing foods to treat your hypoglycemia.
220
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
221
Patients should always carry a quick source of sugar, such as candy mints or glucose tablets.
222
More severe hypoglycemia may require the assistance of another person. Patients who are unable
223
to take sugar orally or who are unconscious require an injection of glucagon or should be treated
224
with intravenous administration of glucose at a medical facility.
225
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about
226
these symptoms, you should monitor your blood glucose frequently to help you learn to recognize
227
the symptoms that you experience with hypoglycemia.
228
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
229
symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans,
230
and/or exercise programs to help you avoid hypoglycemia.
231
Hyperglycemia and Diabetic Ketoacidosis (DKA)
232
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
233
Hyperglycemia can be brought about by:
234
1. Omitting your insulin or taking less than the doctor has prescribed.
235
2. Eating significantly more than your meal plan suggests.
236
3. Developing a fever, infection, or other significant stressful situation.
237
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
238
DKA. The first symptoms of DKA usually come on gradually, over a period of hours or days,
239
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and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath.
240
With DKA, urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid
241
pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to
242
nausea, vomiting, stomach pains, dehydration, loss of consciousness or death. Therefore, it is
243
important that you obtain medical assistance immediately.
244
Lipodystrophy
245
Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the
246
skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these
247
conditions, consult your doctor. A change in your injection technique may help alleviate the
248
problem.
249
Allergy to Insulin
250
Local Allergy Patients occasionally experience redness, swelling, and itching at the site of
251
injection of insulin. This condition, called local allergy, usually clears up in a few days to a few
252
weeks. In some instances, this condition may be related to factors other than insulin, such as
253
irritants in the skin cleansing agent or poor injection technique. If you have local reactions,
254
contact your doctor.
255
Systemic Allergy Less common, but potentially more serious, is generalized allergy to
256
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
257
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
258
threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor
259
immediately.
260
ADDITIONAL INFORMATION
261
Additional information about diabetes may be obtained from your diabetes educator.
262
DIABETES FORECAST is a magazine designed especially for people with diabetes and their
263
families. It is available by subscription from the American Diabetes Association (ADA), P.O.
264
Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383).
265
Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research
266
Foundation International (JDRFI), 120 Wall Street 19th Floor, New York, NY 10005,
267
1-800-533-CURE (1-800-533-2873).
268
Additional information about Humulin and Humulin N Pens can be obtained by calling The
269
Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).
270
Literature revised XXX, 2004
271
Manufactured by Lilly France S.A.S.
272
F-67640 Fegersheim, France
273
for Eli Lilly and Company
274
Indianapolis, IN 46285, USA
275
Copyright © 1998, 2004, Eli Lilly and Company. All rights reserved.
276
5.01 PA 9135 FSAMP
277
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
5.01 PA 9115 FSAMP
Lilly
Disposable Insulin Delivery Device
User Manual
Instructions for Use
Read and follow all of these instructions carefully. If you
do not follow these instructions completely, you may
get too much or too little insulin.
Every time you inject:
• Use a new needle
• Prime to make sure the Pen is ready to
dose
• Make sure you got your full dose (see
page 18)
Also, read the Information for the Patient insert
enclosed in your Pen box.
Pen Features
• A multiple dose, disposable insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Table of Contents
_______________________________________________________________
Pen Parts............................................................................................................ 3
Important Notes..................................................................................................4
Preparing the Pen ..............................................................................................6
Attaching the Needle..........................................................................................8
Priming the Pen................................................................................................10
Setting a Dose..................................................................................................14
Injecting a Dose................................................................................................16
Following an Injection.......................................................................................18
Questions and Answers ...................................................................................20
_______________________________________________________________
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
3
Pen Parts
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Important Notes
• Read and follow all of these instructions carefully. If you do not follow these
instructions completely, you may get too much or too little insulin.
• Use a new needle for each injection.
• Be sure a needle is completely attached to the Pen before priming, setting
the dose and injecting your insulin.
• Prime every time.
• The Pen must be primed before each injection to make sure the Pen is
ready to dose. Performing the priming step is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect
in the insulin cartridge during normal use. See Section III. “Priming the Pen”,
pages 10-13.
• If you do not prime, you may get too much or too little insulin.
• Make sure you get your full dose.
• To make sure you get your full dose, you must push the injection button all the
way down until you see a diamond (♦) or an arrow (→) in the center of the dose
window. See “Following an Injection”, page 18.
• The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
• Do not share your Pen.
• Keep your Pen out of the reach of children.
• Pens that have not been used (unopened) should be stored in a refrigerator but not
in a freezer. Do not use a Pen if it has been frozen. Refer to the INFORMATION
FOR THE PATIENT insert for complete storage instructions.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Important Notes
(Continued)
• After a Pen is used for the first time, it should NOT be refrigerated but should be
kept at room temperature [below 86°F (30°C)] and away from direct heat and light.
• An unrefrigerated Pen should be discarded according to the time specified in the
Information for the Patient insert, even if it still contains insulin.
• Never use a Pen after the expiration date stamped on the label.
• Do not store your Pen with the needle attached. Doing so may allow insulin to leak
from the Pen and air bubbles to form in the cartridge. Additionally, with suspension
(cloudy) insulins, crystals may clog the needle.
• Always carry an extra Pen in case yours is lost or damaged.
• Dispose of empty Pens as instructed by your Health Care Professional and without
the needle attached.
• This Pen is not recommended for use by blind or visually impaired persons without
the assistance of a person trained in the proper use of the product.
• The directions regarding needle handling are not intended to replace local, Health
Care Professional, or institutional policies.
• Any changes in insulin should be made cautiously and only under medical
supervision.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
I. Preparing the Pen
1. Before proceeding, refer to the INFORMATION FOR THE PATIENT insert for
instructions on checking the appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has
been prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down
10 times until the insulin is evenly
mixed.
Note: Suspension (cloudy) insulin
cartridges contain a small glass bead to
assist in mixing.
6. Use an alcohol swab to wipe the rubber seal
on the end of the Pen.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen
needles.
1. Always use a new needle for each injection. Do not push injection button
without a needle attached. Storing the Pen with the needle attached may allow
insulin to leak from the Pen and air bubbles to form in the cartridge.
2. Remove the paper tab from the outer needle
shield.
3. Attach the capped needle onto the end of the
Pen by turning it clockwise until tight.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle pointing up and
remove the outer needle shield. Keep it to
use during needle removal.
5. Remove the inner needle shield and discard.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
III. Priming the Pen
• The Pen must be primed before each injection to make sure the Pen is ready
to dose. Performing the priming step is important to confirm that insulin comes out
when you push the injection button, and to remove air that may collect in the insulin
cartridge during normal use.
• If you do not prime, you may get too much or too little insulin.
• Always use a new needle for each injection.
1. Make sure the arrow is in the center of the
dose window as shown.
2. If you do not see the arrow in the center of the
dose window, push in the injection button fully
and turn the dose knob until the arrow is seen
in the center of the dose window.
Correct
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
III. Priming the Pen
(Continued)
3. With the arrow in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window.
4. Turn the dose knob clockwise until the number
“2” is seen in the dose window. If the number
you have dialed is too high, simply turn the
dose knob backward until the number 2 is seen
in the dose window.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
III. Priming the Pen
(Continued)
5. Hold your Pen with the needle pointing up. Tap
the clear cartridge holder gently with your
finger so any air bubbles collect near the top.
Using your thumb, if possible, push in the
injection button completely. Keep pressing and
continue to hold the injection button firmly
while counting slowly to 5. You should see
either a drop or a stream of insulin come out of
the tip of the needle.
If insulin does not come out of the tip of the
needle, repeat steps 1 through 5. If after
several attempts insulin does not come out of
the tip of the needle, change the needle and
repeat the priming steps.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
III. Priming the Pen
(Continued)
6. At the completion of the priming step, a
diamond (♦) must be seen in the center of the
dose window. If a diamond (♦) is not seen in
the center of the dose window, continue
pushing on the injection button until you see a
diamond (♦) in the center of the dose window.
Correct
Note: A small air bubble may remain in the cartridge after the completion of
the priming step. If you have properly primed the Pen, this small air bubble
will not affect your insulin dose.
7. Now you are ready to set your dose. See next page.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
IV. Setting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not push in the injection button while setting your dose. Failure to
follow these instructions carefully may result in getting too much or too little
insulin. If you accidentally push the injection button while setting your dose,
you must prime the Pen again before injecting your dose. See Section III.
“Priming the Pen”, pages 10-13.
1. A diamond must be seen in the center of the dose window before setting your dose.
If you do not see a diamond in the center of the dose
window, the Pen has not been primed correctly and
you are not ready to set your dose. Before continuing,
repeat the priming steps.
Correct
2. Turn the dose knob clockwise until the arrow
(→) is seen in the center of the dose window
and the notches on the Pen and dose knob are
in line.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
IV. Setting a Dose
(Continued)
3. With the arrow (→) in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window. A dose cannot be dialed until the dose
knob is pulled out.
4. Turn the dose knob clockwise until your dose
is seen in the dose window. If the dose you
have dialed is too high, simply turn the dose
knob backward until the correct dose is seen in
the dose window.
5. If you cannot dial your full dose, see the “Questions and Answers” section, Question
5, at the end of this manual.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
V. Injecting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not attempt to change the dose after you begin to push in the
injection button. Failure to follow these instructions carefully may result in
getting too much or too little insulin.
• The effort needed to push in the injection button may increase while you are
injecting your insulin dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers” section, Question 7, at the end
of this manual.
• Do not inject a dose unless the Pen is primed, just before injection, or you may get
too much or too little insulin.
•
If you have set a dose and pushed in the injection button without a needle attached
or if no insulin comes out of the needle, see the “Questions and Answers” section,
Questions 1 and 2.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
V. Injecting a Dose
(Continued)
1. Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2. Insert the needle into your skin. Inject the
insulin by using your thumb, if possible, to
push in the injection button completely.
3. Keep pressing and continue to hold the
injection button firmly while counting
slowly to 5.
4. When the injection is done, a diamond (♦) or
arrow (→) must be seen in the center of the dose
window. This means your full dose has been
delivered. If you do not see the diamond or
arrow in the center of the dose window, you
did not get a full dose. Contact your Health
Care Professional for additional instruction.
Correct
Correct
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
VI. Following an Injection
1. Make sure you got your full dose by checking
that the injection button has been completely
pushed in and you can see a diamond (♦) or
arrow (→) in the center of the dose window. If
you do not see the diamond (♦) or arrow (→)
in the center of the dose window, you have not
received your full dose. Contact your Health
Care Professional for additional instructions.
2. Carefully replace the outer needle shield as
instructed by your Health Care Professional.
18
Outer
Needle
Shield
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
VI. Following an Injection
(Continued)
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly throw it away as directed by your
Health Care Professional.
4. Replace the cap on the Pen.
5. The Pen that you are currently using should be kept at a temperature below 86°F
(30°C) and away from heat and light. It should be discarded according to the time
specified in the INFORMATION FOR THE PATIENT insert, even if it still contains
insulin.
Do not store or dispose of the Pen with a needle attached. Storing the Pen with
the needle attached may allow insulin to leak from the Pen and air bubbles to
form in the cartridge.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Questions and Answers
Problem
Action
1. Dose dialed and injection
button pushed in without a
needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or arrow (→) is seen in
the center of the dose window.
3) Prime the Pen.
2. Insulin does not come out
of the needle.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or arrow (→) is seen in
the center of the dose window.
3) Prime the Pen. See Section III. “Priming
the Pen”, pages 10-13.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Questions and Answers
(Continued)
Problem
Action
3. Wrong dose (too high or
too low) dialed.
If you have not pushed in the injection
button, simply turn the dose knob backward
or forward to correct the dose.
4. Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing
down. The scale (20 units between marks)
on the clear cartridge holder shows an
estimate of the number of units remaining.
These numbers should not be used for
measuring an insulin dose.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Questions and Answers
(Continued)
Problem
Action
5. Full dose cannot be dialed.
The Pen will not allow you to dial a dose
greater than the number of insulin units
remaining in the cartridge.
For example, if you need 31 units and only
25 units remain in the Pen you will not be
able to dial past 25. Do not attempt to dial
past this point. (The insulin that remains is
unusable and not part of the 300 units.) If a
partial dose remains in the Pen you may
either:
1) Give the partial dose and then give the
remaining dose using a new Pen, or
2) Give the full dose with a new Pen.
6. A small amount of insulin
remains in the cartridge but
a dose cannot be dialed.
The Pen design prevents the cartridge from
being completely emptied. The Pen has
delivered 300 units of usable insulin.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Questions and Answers
(Continued)
Problem
Action
7. Cannot completely push in the
injection button when priming
the Pen or injecting a dose.
1)
Needle is not attached or is
clogged.
a. Attach a new needle.
b. Push in the injection button
completely (even if a “0” is seen
in the window) until a diamond
(♦) or arrow (→) is seen in the
center of the dose window.
c. Prime the Pen.
2)
If you are sure insulin is coming out
of the needle, push in the injection
button more slowly to reduce the
effort needed and maintain a
constant pressure until the injection
button is completely pushed in.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
For additional information call,
1-800-LILLY-RX (1-800-545-5979)
Revised XX, 2004
Manufactured by Lilly France S.A.S.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
PA 9115 FSAMP
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.185797 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18781slr076_humulin_lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 76} |
1,085 | This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.188077 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/18780s086,18781s080lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 80} |
1,087 |
1
1
2
INFORMATION FOR THE PATIENT
3
10 mL Vial (1000 Units per vial)
4
HUMULIN® N
5
NPH
6
HUMAN INSULIN (rDNA ORIGIN)
7
ISOPHANE SUSPENSION
8
100 UNITS PER ML (U-100)
9
WARNINGS
10
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL
11
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
12
INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF
13
ITS UNIQUE MANUFACTURING PROCESS.
14
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
15
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
16
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
17
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
18
CHANGE IN DOSAGE.
19
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN,
20
rDNA ORIGIN) MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED
21
WITH OTHER INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY
22
OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL
23
WEEKS OR MONTHS.
24
DIABETES
25
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
26
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
27
the pancreas does not make enough insulin to meet your body’s needs.
28
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
29
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
30
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
31
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
32
is maintained as close to normal as possible. The American Diabetes Association recommends
33
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
34
(HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may
35
be needed. If your blood tests consistently show below-normal glucose levels, you should also let
36
your doctor know. Proper control of your diabetes requires close and constant cooperation with
37
your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
38
exercise regularly, and take your insulin injections as prescribed by your doctor.
39
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
40
wear diabetic identification so that appropriate treatment can be given if complications occur
41
away from home.
42
NPH HUMAN INSULIN
43
Description
44
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
45
bacteria that has been genetically altered to produce human insulin. Humulin N [Human insulin
46
(rDNA origin) isophane suspension] is a crystalline suspension of human insulin with protamine
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
47
and zinc providing an intermediate-acting insulin with a slower onset of action and a longer
48
duration of activity (up to 24 hours) than that of Regular human insulin. The time course of
49
action of any insulin may vary considerably in different individuals or at different times in the
50
same individual. As with all insulin preparations, the duration of action of Humulin N is
51
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N
52
is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously
53
or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100).
54
Identification
55
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
56
prescribed the type of insulin that he/she believes is best for you.
57
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
58
DIRECTION.
59
Always check the carton and the bottle label for the name and letter designation of the insulin
60
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
61
Always check the appearance of your bottle of Humulin N before withdrawing each dose.
62
Before each injection the Humulin N bottle must be carefully shaken or rotated several times to
63
completely mix the insulin. Humulin N suspension should look uniformly cloudy or milky after
64
mixing. If not, repeat the above steps until contents are mixed.
65
Do not use Humulin N:
66
• if the insulin substance (the white material) remains at the bottom of the bottle after mixing
67
or
68
• if there are clumps in the insulin after mixing, or
69
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance.
70
If you see anything unusual in the appearance of Humulin N suspension in your bottle or notice
71
your insulin requirements changing, talk to your doctor.
72
Storage
73
Not in-use (unopened): Humulin N bottles not in-use should be stored in a refrigerator, but
74
not in the freezer.
75
In-use (opened): The Humulin N bottle you are currently using can be kept unrefrigerated as
76
long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
77
Do not use Humulin N after the expiration date stamped on the label or if it has been
78
frozen.
79
INSTRUCTIONS FOR INSULIN VIAL USE
80
NEVER SHARE NEEDLES AND SYRINGES.
81
Correct Syringe Type
82
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
83
With Humulin N, it is important to use a syringe that is marked for U-100 insulin preparations.
84
Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for
85
you, such as a blood glucose level that is too low or too high.
86
Syringe Use
87
To help avoid contamination and possible infection, follow these instructions exactly.
88
Disposable syringes and needles should be used only once and then discarded by placing the
89
used needle in a puncture-resistant disposable container. Properly dispose of the puncture
90
resistant container as directed by your Health Care Professional.
91
Preparing the Dose
92
1. Wash your hands.
93
2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
94
3. Inspect the insulin. Humulin N suspension should look uniformly cloudy or milky. Do not
95
use Humulin N if you notice anything unusual in its appearance.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
96
4.
If using a new Humulin N bottle, flip off the plastic protective cap, but do not remove the
97
stopper. Wipe the top of the bottle with an alcohol swab.
98
5. If you are mixing insulins, refer to the “Mixing Humulin N and Regular Human Insulin”
99
section below.
100
6. Draw an amount of air into the syringe that is equal to the Humulin N dose. Put the needle
101
through rubber top of the Humulin N bottle and inject the air into the bottle.
102
7. Turn the Humulin N bottle and syringe upside down. Hold the bottle and syringe firmly in
103
one hand and shake gently.
104
8.
Making sure the tip of the needle is in the Humulin N suspension, withdraw the correct
105
dose of Humulin N into the syringe.
106
9. Before removing the needle from the Humulin N bottle, check the syringe for air bubbles.
107
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
108
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
109
10. Remove the needle from the bottle and lay the syringe down so that the needle does not
110
touch anything.
111
11. If you do not need to mix your Humulin N with Regular human insulin, go to the
112
“Injection Instructions” section below and follow the directions.
113
Mixing Humulin N and Regular Human Insulin (Humulin R)
114
1. Humulin N should be mixed with Humulin R only on the advice of your doctor.
115
2. Draw an amount of air into the syringe that is equal to the amount of Humulin N you are
116
taking. Insert the needle into the Humulin N bottle and inject the air. Withdraw the needle.
117
3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are
118
taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw
119
the needle.
120
4. Turn the Humulin R bottle and syringe upside down.
121
5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
122
of Humulin R into the syringe.
123
6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
124
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
125
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
126
7. Remove the syringe with the needle from the Humulin R bottle and insert it into the
127
Humulin N bottle. Turn the Humulin N bottle and syringe upside down. Hold the bottle
128
and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in
129
the Humulin N, withdraw the correct dose of Humulin N.
130
8. Remove the needle from the bottle and lay the syringe down so that the needle does not
131
touch anything.
132
9. Follow the directions under “Injection Instructions” section below.
133
Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before
134
giving your injection. It is important to be consistent in your method.
135
Syringes from different manufacturers may vary in the amount of space between the bottom
136
line and the needle. Because of this, do not change:
137
• the sequence of mixing, or
138
• the model and brand of syringe or needle that your doctor has prescribed.
139
Injection Instructions
140
1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
141
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
142
2. Cleanse the skin with alcohol where the injection is to be made.
143
3.
With one hand, stabilize the skin by spreading it or pinching up a large area.
144
4.
Insert the needle as instructed by your doctor.
145
5. Push the plunger in as far as it will go.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
146
6.
Pull the needle out and apply gentle pressure over the injection site for several seconds.
147
Do not rub the area.
148
7.
Place the used needle in a puncture-resistant disposable container and properly dispose of
149
the puncture-resistant container as directed by your Health Care Professional.
150
DOSAGE
151
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
152
Because each patient’s diabetes is different, this schedule has been individualized for you.
153
Your usual dose of Humulin N may be affected by changes in your diet, activity, or work
154
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
155
that may affect your Humulin N dose are:
156
Illness
157
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
158
Even if you are not eating, you will still require insulin. You and your doctor should establish a
159
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
160
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
161
Pregnancy
162
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
163
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
164
are nursing a baby, talk to your doctor.
165
Medication
166
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
167
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
168
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
169
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
170
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
171
Your Health Care Professional may be aware of other medications that may affect your diabetes
172
control. Therefore, always discuss any medications you are taking with your doctor.
173
Exercise
174
Exercise may lower your body’s need for insulin during and for some time after the physical
175
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
176
involves the area of injection site (for example, the leg should not be used for injection just prior
177
to running). Discuss with your doctor how you should adjust your insulin regimen to
178
accommodate exercise.
179
Travel
180
When traveling across more than 2 time zones, you should talk to your doctor concerning
181
adjustments in your insulin schedule.
182
COMMON PROBLEMS OF DIABETES
183
Hypoglycemia (Low Blood Sugar)
184
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
185
experienced by insulin users. It can be brought about by:
186
1. Missing or delaying meals.
187
2.
Taking too much insulin.
188
3. Exercising or working more than usual.
189
4. An infection or illness associated with diarrhea or vomiting.
190
5.
A change in the body’s need for insulin.
191
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
192
disease.
193
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
194
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
195
medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
196
8. Consumption of alcoholic beverages.
197
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
198
• sweating
199
• dizziness
200
• palpitation
201
• tremor
202
• hunger
203
• restlessness
204
• tingling in the hands, feet, lips, or tongue
205
• lightheadedness
206
• inability to concentrate
207
• headache
208
Signs of severe hypoglycemia can include:
209
• disorientation
210
• unconsciousness
• drowsiness
• sleep disturbances
• anxiety
• blurred vision
• slurred speech
• depressed mood
• irritability
• abnormal behavior
• unsteady movement
• personality changes
• seizures
• death
211
Therefore, it is important that assistance be obtained immediately.
212
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
213
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
214
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
215
per day) of diabetes.
216
A few patients who have experienced hypoglycemic reactions after transfer from animal
217
source insulin to human insulin have reported that the early warning symptoms of
218
hypoglycemia were less pronounced or different from those experienced with their
219
previous insulin.
220
Without recognition of early warning symptoms, you may not be able to take steps to avoid
221
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
222
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
223
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
224
glucose is below your normal fasting glucose, you should consider eating or drinking sugar
225
containing foods to treat your hypoglycemia.
226
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
227
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
228
severe hypoglycemia may require the assistance of another person. Patients who are unable to
229
take sugar orally or who are unconscious require an injection of glucagon or should be treated
230
with intravenous administration of glucose at a medical facility.
231
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
232
about these symptoms, you should monitor your blood glucose frequently to help you learn to
233
recognize the symptoms that you experience with hypoglycemia.
234
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
235
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
236
and/or exercise programs to help you avoid hypoglycemia.
237
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
238
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
239
Hyperglycemia can be brought about by any of the following:
240
1. Omitting your insulin or taking less than your doctor has prescribed.
241
2.
Eating significantly more than your meal plan suggests.
242
3.
Developing a fever, infection, or other significant stressful situation.
243
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
244
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
245
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
246
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
247
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
248
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
249
of consciousness, or death. Therefore, it is important that you obtain medical assistance
250
immediately.
251
Lipodystrophy
252
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
253
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
254
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
255
the problem.
256
Allergy
257
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
258
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
259
some instances, this condition may be related to factors other than insulin, such as irritants in the
260
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
261
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
262
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
263
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
264
threatening. If you think you are having a generalized allergic reaction to insulin, call your
265
doctor immediately.
266
ADDITIONAL INFORMATION
267
Information about diabetes may be obtained from your diabetes educator.
268
Additional information about diabetes and Humulin can be obtained by calling The Lilly
269
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
270
Patient Information revised Month dd, yyyy
271
Vials manufactured by
272
Eli Lilly and Company, Indianapolis, IN 46285, USA
273
274
for Wal-Mart Stores, Inc.
275
276
Copyright © XXXX, Eli Lilly and Company. All rights reserved.
277
PRINTED IN USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.417590 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018781s114lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 114} |
1,086 | Instructions for Use
Read and follow all of these instructions
carefully. If you do not follow these
instructions completely, you may get
too much or too little insulin.
Every time you inject:
• Use a new needle
• Prime to make sure the Pen is
ready to dose
• Make sure you got a full dose
(see page 18)
Also, read the Information for
the Patient insert enclosed in
your Pen box.
Pen Features
• A multiple dose, disposable insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100 insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
Disposable Insulin Delivery Device
User Manual
PV 3734 AMP
This label may not be the latest approved by FDA.
t labeling information, please visit https://www.fda.gov/
2
Pen Parts ............................................................ 3
Important Notes .................................................. 4
Preparing the Pen ................................................ 6
Attaching the Needle .......................................... 8
Priming the Pen ....................................................10
Setting a Dose......................................................14
Injecting a Dose....................................................16
Following an Injection ..........................................18
Questions and Answers ........................................20
Table of Contents
This label may not be the latest approved by FDA.
t labeling information, please visit https://www.fda.gov/
3
Pen Parts
Dose Knob
Raised Notch
Raised Notch
Label
Dose Window
Pen Cap
Outer Needle Shield
Inner Needle Shield
Needle
Rubber Seal
Clear Cartridge Holder
Insulin Cartridge
Injection Button
Paper
Tab
This label may not be the latest approved by FDA.
t labeling information, please visit https://www.fda.gov/
4
Important Notes
• Read and follow all of these instructions carefully. If you
do not follow these instructions completely, you may get
too much or too little insulin.
• Use a new needle for each injection.
• Be sure a needle is completely attached to the Pen
before priming, setting (dialing) the dose and
injecting your insulin.
• Prime every time.
• The Pen must be primed before each injection to make
sure the Pen is ready to dose. Performing the priming
step is important to confirm that insulin comes out when
you push the injection button, and to remove air that
may collect in the insulin cartridge during normal use.
See Section III. “Priming the Pen”, pages 10-13.
• If you do not prime, you may get too much or too
little insulin.
• Make sure you get a full dose.
• To make sure you get a full dose, you must push the
injection button all the way down until you see a
diamond (N) or arrow (©) in the center of the dose
window. See “Following an Injection”, page 18.
• The numbers on the clear cartridge holder give an estimate
of the amount of insulin remaining in the cartridge. Do not
use these numbers for measuring an insulin dose.
• Do not share your Pen.
This label may not be the latest approved by FDA.
t labeling information, please visit https://www.fda.gov/
5
•
•
•
•
•
•
•
•
•
•
•
Keep your Pen out of the reach of children.
Pens that have not been used should be stored in a refrigerator
but not in a freezer. Do not use a Pen if it has been frozen.
Refer to the Information for the Patient insert for complete
storage instructions.
After a Pen is used for the first time, it should NOT be
refrigerated but should be kept at room temperature [below
86°F (30°C)] and away from direct heat and light.
An unrefrigerated Pen should be discarded according to the
time specified in the Information for the Patient insert, even if
it still contains insulin.
Never use a Pen after the expiration date stamped on the label.
Do not store your Pen with the needle attached. Doing so may
allow insulin to leak from the Pen and air bubbles to form in the
cartridge. Additionally, with suspension (cloudy) insulins,
crystals may clog the needle.
Always carry an extra Pen in case yours is lost or damaged.
Dispose of empty Pens as instructed by your Health Care
Professional and without the needle attached.
This Pen is not recommended for use by blind or visually
impaired persons without the assistance of a person trained in
the proper use of the product.
The directions regarding needle handling are not intended to
replace local, Health Care Professional or institutional policies.
Any changes in insulin should be made cautiously and only
under medical supervision.
Important Notes
(Continued)
This label may not be the latest approved by FDA.
t labeling information, please visit https://www.fda.gov/
6
I. Preparing the Pen
1. Before proceeding, refer to the Information for the
Patient insert for instructions on checking the
appearance of your insulin.
2. Check the label on the Pen to be sure the Pen
contains the type of insulin that has been
prescribed for you.
3. Always wash your hands before preparing your
Pen for use.
4. Pull the Pen cap to remove.
Pen Cap
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7
5. If your insulin is a suspension
(cloudy):
a. Roll the Pen back and
forth 10 times then
perform step b.
b. Gently turn the Pen up
and down 10 times until
the insulin is evenly
mixed.
Note: Suspension (cloudy)
insulin cartridges contain
a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe
the rubber seal on the end of
the Pen.
I. Preparing the Pen
(Continued)
Glass
Bead
Glass
Bead
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This device is suitable for use with Becton Dickinson
and Company’s insulin pen needles.
1. Always use a new needle for each injection. Do
not push injection button without a needle
attached. Storing the Pen with the needle
attached may allow insulin to leak from the Pen
and air bubbles to form in the cartridge.
2. Remove the paper tab from
the outer needle shield.
3. Attach the capped needle
onto the end of the Pen by
turning it clockwise until
tight.
II. Attaching the Needle
Outer Needle
Shield
Paper Tab
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II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle
pointing up and remove the
outer needle shield. Keep it
to use during needle
removal.
5. Remove the inner needle shield and discard.
Outer Needle
Shield (Keep)
Inner Needle
Shield
(Discard)
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• The Pen must be primed before each injection to
make sure the Pen is ready to dose. Performing the
priming step is important to confirm that insulin
comes out when you push the injection button, and to
remove air that may collect in the insulin cartridge
during normal use.
• If you do not prime, you may get too much or too
little insulin.
• Always use a new needle for each injection.
1. Make sure the arrow is in the
center of the dose window as
shown.
2. If you do not see the
arrow in the center of
the dose window,
push in the injection
button fully and turn
the dose knob until the arrow is seen in the center
of the dose window.
III. Priming the Pen
Correct
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3. With the arrow in the center
of the dose window, pull the
dose knob out in the direction
of the arrow until a “0” is
seen in the dose window.
4. Turn the dose knob clockwise
until the number “2” is seen
in the dose window. If the
number you have dialed is too
high, simply turn the dose knob
backward until the number 2
is seen in the dose window.
III. Priming the Pen
(Continued)
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5. Hold your Pen with the
needle pointing up. Tap the
clear cartridge holder gently
with your finger so any air
bubbles collect near the top.
Using your thumb, if
possible, push in the
injection button completely. Keep pressing and
continue to hold the injection button firmly while
counting slowly to 5. You should see either a
drop or a stream of insulin come out of the tip of
the needle.
If insulin does not come out of the tip of the
needle, repeat steps 1 through 5. If after several
attempts insulin does not come out of the tip of
the needle, change the needle and repeat the
priming steps.
III. Priming the Pen
(Continued)
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6. At the completion of the
priming step, a diamond (N)
must be seen in the center of
the dose window. If a
diamond (N) is not seen in
the center of the dose
window, continue
pushing on the
injection button until
you see a diamond (N)
in the center of the
dose window.
Note: A small air bubble may remain in the cartridge
after the completion of the priming step. If you have
properly primed the Pen, this small air bubble will
not affect your insulin dose.
7. Now you are ready to set your dose. See next
page.
III. Priming the Pen
(Continued)
Correct
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• Always use a new needle for each injection.
Storing the Pen with the needle attached may
allow insulin to leak from the Pen and air
bubbles to form in the cartridge.
• Caution: Do not push in the injection button while
setting your dose. Failure to follow these
instructions carefully may result in getting too
much or too little insulin. If you accidentally push
the injection button while setting your dose, you
must prime the pen again before injecting your
dose. See Section III. “Priming the Pen”,
pages 10-13.
1. A diamond must be seen in the center of the dose
window before setting your dose.
If you do not see a
diamond in the center
of the dose window,
the pen has not been
primed correctly and
you are not ready to set your dose. Before continuing,
repeat the priming steps.
IV. Setting a Dose
Correct
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2. Turn the dose knob clockwise
until the arrow (©) is seen in the
center of the dose window and
the notches on the Pen and dose
knob are in line.
3. With the arrow (©) in the center
of the dose window, pull the
dose knob out in the direction
of the arrow until a “0” is seen
in the dose window. A dose
cannot be dialed until the dose
knob is pulled out.
4. Turn the dose knob clockwise
until your dose is seen in the
dose window. If the dose you
have dialed is too high, simply
turn the dose knob backward
until the correct dose is seen in
the dose window.
5. If you cannot dial a full dose, see the “Questions and
Answers” section, Question 5, at the end of this
manual.
IV. Setting a Dose
(Continued)
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V. Injecting a Dose
•
• Caution: Do not attempt to change the dose after
you begin to push in the injection button. Failure to
follow these instructions carefully may result in
getting too much or too little insulin.
•
may increase while you are injecting your insulin
dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers”
section, Question 7, at the end of this manual.
• Do not inject a dose unless the pen is primed,
just before injection, or you may get too much
or too little insulin.
• If you have set (dialed) a dose and pushed in the
injection button without a needle attached or if no
insulin comes out of the needle, see the “Questions
and Answers” section, Questions 1 and 2.
1. Wash hands. Prepare the skin and use the
injection technique recommended by your Health
Care Professional.
Always use a new needle for each injection.
Storing the Pen with the needle attached may
allow insulin to leak from the Pen and air
bubbles to form in the cartridge.
The effort needed to push in the injection button
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V. Injecting a Dose
(Continued)
Insert the needle into your skin.
Inject the insulin by using your
thumb, if possible, to push in
the injection button completely.
3.
2.
Keep pressing and continue to
hold the injection button firmly
while counting slowly to 5.
4. When the injection is
done, a diamond (N)
or arrow (©) must be
seen in the center of
the dose window. This
means your full dose
has been delivered.
If you do not see the
diamond or arrow in
the center of the dose
window, you did not get a full dose. Contact your
Health Care Professional for additional instruction.
Correct
Correct
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VI.Following an Injection
1. Make sure you got a full
dose by checking that the
injection button has been
completely pushed in and
you can see a diamond (N)
or arrow (©) in the center
of the dose window. If you
do not see the diamond (N) or arrow (©) in the
center of the dose window, you have not received
a full dose. Contact your Health Care Professional
for additional instructions.
2. Carefully replace the outer
needle shield as instructed
by your Health Care
Professional.
220
180
140
100
60
20
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3. Remove the capped needle
by turning it counterclockwise
and throw it away. Place the
used needle in a puncture-
resistant disposable container
and properly dispose of it
as directed by your Health
Care Professional.
4. Replace the cap on the Pen.
5. The Pen that you are using should NOT be
refrigerated but kept at a room temperature
below 86°F (30°C) and away from direct heat and
light. It should be discarded according to the
time specified in the Information for the Patient
insert, even if it still contains insulin.
Do not store or dispose of the Pen with a needle
attached. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air
bubbles to form in the cartridge.
220
180
140
100
60
20
VI. Following an Injection
(Continued)
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1. Dose dialed
and injection
button
pushed in
without a
needle
attached.
Problem
Action
2. Insulin does
not come out
of the needle.
To obtain an accurate dose you
must:
1) Attach a new needle.
2) Push in the injection button
completely (even if a “0” is seen
in the window) until a diamond
(N) or arrow (©) is seen in the
center of the dose window.
3) Prime the Pen.
To obtain an accurate dose you
must:
1) Attach a new needle.
2) Push in the injection button
completely (even if a “0” is seen
in the window) until a diamond
(N) or arrow (©) is seen in the
center of the dose window.
3) Prime the Pen. See Section III.
“Priming the Pen”, pages 10-13.
Questions and Answers
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21
Questions and Answers
(Continued)
3. Wrong dose
(too high or
too low)
dialed.
Problem
Action
4. Not sure
how much
insulin
remains
in the
cartridge.
If you have not pushed in the
injection button, simply turn the
dose knob backward or forward
to correct the dose.
Hold the Pen with the needle end
pointing down. The scale
(20 units between marks) on the
clear cartridge holder shows an
estimate of the number of units
remaining. These numbers should
not be used for measuring an
insulin dose.
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Questions and Answers
(Continued)
5. Full dose cannot
be dialed.
6. A small amount
of insulin
remains in the
cartridge but a
dose cannot be
dialed.
The Pen design prevents the
cartridge from being completely
emptied. The Pen has delivered
300 units of usable insulin.
Problem
Action
The Pen will not allow you to dial a
dose greater than the number of
insulin units remaining in the
cartridge.
For example, if you need
31 units and only 25 units remain in
the Pen, you will not be able to dial
past 25. Do not attempt to dial past
this point. (The insulin that remains is
unusable and not part of the
300 units.) If a partial dose remains
in the Pen you may either:
1) Give the partial dose and then give
the remaining dose using a new
Pen, or
2) Give the full dose with a new Pen.
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Questions and Answers
(Continued)
7. Cannot
completely
push in the
injection
button when
priming the
Pen or
injecting a
dose.
Problem
Action
1) Needle is not attached or is
clogged.
a. Attach a new needle.
b. Push in the injection button
completely (even if a “0” is
seen in the window) until a
diamond (N) or arrow (©) is
seen in the center of the
dose window.
c. Prime the Pen.
2) If you are sure insulin is
coming out of the needle, push
in the injection button more
slowly to reduce the effort
needed and maintain a
constant pressure until the
injection button is completely
pushed in.
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For additional information call,
1-888-88-LILLY
Literature revised May 2, 2005
Eli Lilly and Company
Indianapolis, IN 46285, USA
PV 3734 AMP
PRINTED IN USA
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| custom-source | 2025-02-12T13:43:20.479873 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018781s025,060,065,085lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 85} |
1,088 | 1
A3.0NL 5712 AMP
INFORMATION FOR THE PATIENT
10 mL Vial (1000 Units per vial)
HUMULIN® N
NPH
HUMAN INSULIN (rDNA ORIGIN)
ISOPHANE SUSPENSION
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF
ITS UNIQUE MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
Humulin N may cause serious side effects, including:
•
swelling of your hands and feet
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with
Humulin N may cause heart failure in some people. This can happen even if you have
never had heart failure or heart problems before. If you already have heart failure it may
get worse while you take TZDs with Humulin N. Your healthcare provider should
monitor you closely while you are taking TZDs with Humulin N. Tell your healthcare
provider if you have any new or worse symptoms of heart failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and Humulin N may need to be adjusted or stopped by your healthcare
provider if you have new or worse heart failure.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
is maintained as close to normal as possible. The American Diabetes Association recommends
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
(HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may
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be needed. If your blood tests consistently show below-normal glucose levels, you should also let
your doctor know. Proper control of your diabetes requires close and constant cooperation with
your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
exercise regularly, and take your insulin injections as prescribed by your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
NPH HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
bacteria that has been genetically altered to produce human insulin. Humulin N [Human insulin
(rDNA origin) isophane suspension] is a crystalline suspension of human insulin with protamine
and zinc providing an intermediate-acting insulin with a slower onset of action and a longer
duration of activity (up to 24 hours) than that of Regular human insulin. The time course of
action of any insulin may vary considerably in different individuals or at different times in the
same individual. As with all insulin preparations, the duration of action of Humulin N is
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N
is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously
or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
Always check the carton and the bottle label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of your bottle of Humulin N before withdrawing each dose.
Before each injection the Humulin N bottle must be carefully shaken or rotated several times to
completely mix the insulin. Humulin N suspension should look uniformly cloudy or milky after
mixing. If not, repeat the above steps until contents are mixed.
Do not use Humulin N:
• if the insulin substance (the white material) remains at the bottom of the bottle after mixing
or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance.
If you see anything unusual in the appearance of Humulin N suspension in your bottle or notice
your insulin requirements changing, talk to your doctor.
Storage
Not in-use (unopened): Humulin N bottles not in-use should be stored in a refrigerator, but
not in the freezer.
In-use (opened): The Humulin N bottle you are currently using can be kept unrefrigerated as
long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
Do not use Humulin N after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN VIAL USE
NEVER SHARE NEEDLES AND SYRINGES.
Correct Syringe Type
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
With Humulin N, it is important to use a syringe that is marked for U-100 insulin preparations.
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Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for
you, such as a blood glucose level that is too low or too high.
Syringe Use
To help avoid contamination and possible infection, follow these instructions exactly.
Disposable syringes and needles should be used only once and then discarded by placing the
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
resistant container as directed by your healthcare provider.
Preparing the Dose
1. Wash your hands.
2.
Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
3. Inspect the insulin. Humulin N suspension should look uniformly cloudy or milky. Do not
use Humulin N if you notice anything unusual in its appearance.
4.
If using a new Humulin N bottle, flip off the plastic protective cap, but do not remove the
stopper. Wipe the top of the bottle with an alcohol swab.
5. If you are mixing insulins, refer to the “Mixing Humulin N and Regular Human Insulin”
section below.
6. Draw an amount of air into the syringe that is equal to the Humulin N dose. Put the needle
through rubber top of the Humulin N bottle and inject the air into the bottle.
7. Turn the Humulin N bottle and syringe upside down. Hold the bottle and syringe firmly in
one hand and shake gently.
8.
Making sure the tip of the needle is in the Humulin N suspension, withdraw the correct
dose of Humulin N into the syringe.
9. Before removing the needle from the Humulin N bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
10. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
11. If you do not need to mix your Humulin N with Regular human insulin, go to the
“Injection Instructions” section below and follow the directions.
Mixing Humulin N and Regular Human Insulin (Humulin R)
1.
Humulin N should be mixed with Humulin R only on the advice of your doctor.
2. Draw an amount of air into the syringe that is equal to the amount of Humulin N you are
taking. Insert the needle into the Humulin N bottle and inject the air. Withdraw the needle.
3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are
taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw
the needle.
4. Turn the Humulin R bottle and syringe upside down.
5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
of Humulin R into the syringe.
6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
7. Remove the syringe with the needle from the Humulin R bottle and insert it into the
Humulin N bottle. Turn the Humulin N bottle and syringe upside down. Hold the bottle
and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in
the Humulin N, withdraw the correct dose of Humulin N.
8. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
9. Follow the directions under “Injection Instructions” section below.
Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before
giving your injection. It is important to be consistent in your method.
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Syringes from different manufacturers may vary in the amount of space between the bottom
line and the needle. Because of this, do not change:
• the sequence of mixing, or
• the model and brand of syringe or needle that your doctor has prescribed.
Injection Instructions
1.
To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
2. Cleanse the skin with alcohol where the injection is to be made.
3.
With one hand, stabilize the skin by spreading it or pinching up a large area.
4.
Insert the needle as instructed by your doctor.
5. Push the plunger in as far as it will go.
6.
Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
7.
Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your healthcare provider.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin N may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin N dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your healthcare provider may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Before you use Humulin N, tell your healthcare provider if you:
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with Humulin N.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
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COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2.
Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5.
A change in the body’s need for insulin.
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from
animal-source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2.
Eating significantly more than your meal plan suggests.
3.
Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, yyyy, Eli Lilly and Company. All rights reserved.
A3.0NL 5712 AMP
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A3.0NL 9135 FSAMP
INFORMATION FOR THE PATIENT
3 ML PREFILLED INSULIN DELIVERY DEVICE
HUMULIN® N Pen
NPH
HUMAN INSULIN
(rDNA ORIGIN) ISOPHANE SUSPENSION
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE
INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN
PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE
MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER,
TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF
MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY
REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF
AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR
DURING THE FIRST SEVERAL WEEKS OR MONTHS.
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW THE
INSULIN DELIVERY DEVICE USER MANUAL AND THIS “INFORMATION FOR
THE PATIENT” INSERT BEFORE USING THIS PRODUCT.
THE PEN MUST BE PRIMED TO A STREAM OF INSULIN (NOT JUST A FEW
DROPS) BEFORE EACH INJECTION TO MAKE SURE THE PEN IS READY TO
DOSE. YOU MAY NEED TO PRIME A NEW PEN UP TO SIX TIMES BEFORE A
STREAM OF INSULIN APPEARS.
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES OUT
WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR THAT MAY
COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL USE. IF YOU DO NOT
PRIME, YOU MAY RECEIVE TOO MUCH OR TOO LITTLE INSULIN (see also
INSTRUCTIONS FOR INSULIN PEN USE section).
Humulin N may cause serious side effects, including:
•
swelling of your hands and feet
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with
Humulin N may cause heart failure in some people. This can happen even if you have
never had heart failure or heart problems before. If you already have heart failure it may
get worse while you take TZDs with Humulin N. Your healthcare provider should
monitor you closely while you are taking TZDs with Humulin N. Tell your healthcare
provider if you have any new or worse symptoms of heart failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and Humulin N may need to be adjusted or stopped by your healthcare
provider if you have new or worse heart failure.
Reference ID: 3273554
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2
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
is maintained as close to normal as possible. The American Diabetes Association recommends
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
(HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may
be needed. If your blood tests consistently show below-normal glucose levels, you should also let
your doctor know. Proper control of your diabetes requires close and constant cooperation with
your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
exercise regularly, and take your insulin injections as prescribed by your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
NPH HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
bacteria that has been genetically altered to produce human insulin. Humulin N [Human insulin
(rDNA origin) isophane suspension] is a crystalline suspension of human insulin with protamine
and zinc providing an intermediate-acting insulin with a slower onset of action and a longer
duration of activity (up to 24 hours) than that of Regular human insulin. The time course of
action of any insulin may vary considerably in different individuals or at different times in the
same individual. As with all insulin preparations, the duration of action of Humulin N is
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N
is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously
or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
The Humulin N Pen is available in boxes of 5 prefilled insulin delivery devices (“insulin
Pens”). The Humulin N Pen is not designed to allow any other insulin to be mixed in its
cartridge, or for the cartridge to be removed.
Always check the carton and the Pen label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Reference ID: 3273554
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3
Always check the appearance of Humulin N suspension in your insulin Pen before using. A
cartridge of Humulin N contains a small glass bead to assist in mixing. Roll the Pen back and
forth between the palms 10 times (see Figure 1). Gently turn the Pen up and down 10 times until
the insulin is evenly mixed (see Figure 2). If not evenly mixed, repeat the above steps until
contents are mixed. Pens containing Humulin N suspension should be examined frequently.
Do not use Humulin N:
• if the insulin substance (the white material) remains visibly separated from the liquid after
mixing or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the walls of the cartridge, giving a frosted appearance.
If you see anything unusual in the appearance of the Humulin N suspension in your Pen or
notice your insulin requirements changing, talk to your doctor.
Never attempt to remove the cartridge from the Humulin N Pen. Inspect the cartridge through
the clear cartridge holder.
Storage
Not in-use (unopened): Humulin N Pens not in-use should be stored in a refrigerator, but not
in the freezer.
In-use (opened): Humulin N Pens in-use should NOT be refrigerated but should be kept at
room temperature [below 86°F (30°C)] away from direct heat and light. The Humulin N Pen you
are currently using must be discarded 2 weeks after the first use, even if it still contains Humulin
N.
Do not use Humulin N after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN PEN USE
It is important to read, understand, and follow the instructions in the Insulin Delivery
Device User Manual before using. Failure to follow instructions may result in getting too
much or too little insulin. The needle must be changed and the Pen must be primed to a
stream of insulin (not just a few drops) before each injection to make sure the Pen is ready
to dose. You may need to prime a new Pen up to six times before a stream of insulin
appears. Performing these steps before each injection is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect in the
insulin cartridge during normal use.
Every time you inject:
• Use a new needle.
• Prime to a stream of insulin (not just a few drops) to make sure the Pen is ready to dose.
• Make sure you got your full dose.
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
PREPARING FOR INJECTION
1. Wash your hands.
2.
To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
3. Follow the instructions in your Insulin Delivery Device User Manual to prepare for
injection.
4.
After injecting the dose, pull the needle out and apply gentle pressure over the injection
site for several seconds. Do not rub the area.
5. After the injection, remove the needle from the Humulin N Pen. Do not reuse needles.
6.
Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your healthcare provider.
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4
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin N may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin N dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your healthcare provider may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Before you use Humulin N, tell your healthcare provider if you:
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with Humulin N.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2.
Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5.
A change in the body’s need for insulin.
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Reference ID: 3273554
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5
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from animal-
source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2.
Eating significantly more than your meal plan suggests.
3.
Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
Reference ID: 3273554
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1998, yyyy, Eli Lilly and Company. All rights reserved.
A3.0NL 9135 FSAMP
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Lilly
Prefilled Insulin Delivery Device
User Manual
Instructions for Use
Read and follow all of these instructions carefully. If you
do not follow these instructions completely, you may
get too much or too little insulin.
Every time you inject:
• Use a new needle
• Prime to make sure the Pen is ready to dose
• Make sure you got your full dose (see page
18)
Also, read the “Patient Information” enclosed
in your Pen box.
Pen Features
• A multiple dose, prefilled insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
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2
Table of Contents
_______________________________________________________________
Pen Parts ..........................................................................................................3
Important Notes................................................................................................ 4
Preparing the Pen ............................................................................................ 6
Attaching the Needle........................................................................................ 8
Priming the Pen.............................................................................................. 10
Setting a Dose................................................................................................ 14
Injecting a Dose ............................................................................................. 16
Following an Injection..................................................................................... 18
Questions and Answers ................................................................................. 20
_______________________________________________________________
2
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3
Pen Parts
3
3
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
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Important Notes
• Read and follow all of these instructions carefully. If you do not follow these
instructions completely, you may get too much or too little insulin.
• Use a new needle for each injection.
• Be sure a needle is completely attached to the Pen before priming, setting
the dose and injecting your insulin.
• Prime every time.
• The Pen must be primed before each injection to make sure the Pen is
ready to dose. Performing the priming step is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect
in the insulin cartridge during normal use. See Section III. “Priming the Pen”,
pages 10-13.
• If you do not prime, you may get too much or too little insulin.
• Make sure you get your full dose.
• To make sure you get your full dose, you must push the injection button all the
way down until you see a diamond (♦) or an arrow (
) in the center of the dose
window. See “Following an Injection”, page 18.
• The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
• Do not share your Pen or needles.
• Keep your Pen and needles out of the reach of children.
• Pens that have not been used should be stored in a refrigerator but not in a freezer.
Do not use a Pen if it has been frozen. Refer to the “Patient Information” for
complete storage instructions.
4
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5
Important Notes
(Continued)
• After a Pen is used for the first time, it should NOT be refrigerated but should be
kept at room temperature [below 86°F (30°C)] and away from direct heat and light.
• An unrefrigerated Pen should be discarded according to the time specified in the
“Patient Information”, even if it still contains insulin.
• Never use a Pen after the expiration date stamped on the label.
• Do not store your Pen with the needle attached. Doing so may allow insulin to leak
from the Pen and air bubbles to form in the cartridge. Additionally, with suspension
(cloudy) insulins, crystals may clog the needle.
• Always carry an extra Pen in case yours is lost or damaged.
• Follow your Health Care Professional’s instruction for safe handling of needles and
disposal of empty pens.
• This Pen is not recommended for use by blind or visually impaired persons without
the assistance of a person trained in the proper use of the product.
• The directions regarding needle handling are not intended to replace local, Health
Care Professional, or institutional policies.
• Any changes in insulin should be made cautiously and only under medical
supervision.
5
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I. Preparing the Pen
1. Before proceeding, refer to the “Patient Information” for instructions on checking the
appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has
been prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
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I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges
contain a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal
on the end of the Pen.
7
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II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen
needles.
1. Always use a new needle for each injection. Do not push injection button
without a needle attached. Storing the Pen with the needle attached may allow
insulin to leak from the Pen and air bubbles to form in the cartridge.
2. Remove the paper tab from the outer needle
shield.
3. Attach the capped needle onto the end of the
Pen by turning it clockwise until tight.
8
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9
II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle pointing up and
remove the outer needle shield. Keep it to
use during needle removal.
5. Remove the inner needle shield and discard.
9
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III. Priming the Pen
• Prime every time. The Pen must be primed to a stream of insulin (not just a few
drops) before each injection to make sure the Pen is ready to dose.
• You may need to prime a new Pen up to six times before a stream of insulin
appears.
• If you do not prime, you may get too much or too little insulin.
• Always use a new needle for each injection.
1. Make sure the arrow (
) is in the center of the
dose window as shown.
2. If you do not see the arrow in the center of the
dose window, push in the injection button fully
and turn the dose knob until the arrow is seen
in the center of the dose window.
Correct
10
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III. Priming the Pen
(Continued)
3. With the arrow in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window.
4. Turn the dose knob clockwise until the number
“2” is seen in the dose window. If the number
you have dialed is too high, simply turn the
dose knob backward until the number “2” is
seen in the dose window.
11
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III. Priming the Pen
(Continued)
5. Hold your Pen with the needle pointing straight
up. Tap the clear cartridge holder gently with
your finger so any air bubbles collect near the
top.
Using your thumb, if possible, push in the
injection button completely. Keep pressing and
continue to hold the injection button firmly
while counting slowly to 5. You should see a
stream of insulin come out of the tip of the
needle.
If a stream of insulin does not come out of the
tip of the needle, repeat steps 1 through 5. If
after six attempts a stream of insulin does not
come out of the tip of the needle, change the
needle. Repeat steps 1 through 5 up to two
more times. If you are still unable to get insulin
flowing out of the needle, do NOT use the
Pen. Contact your Health Care Professional or
Lilly.
12
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13
III. Priming the Pen
(Continued)
6. At the completion of the priming step, a
diamond (♦) must be seen in the center of the
dose window. If a diamond (♦) is not seen in
the center of the dose window, continue
pushing on the injection button until you see a
diamond (♦) in the center of the dose window.
Correct
Note: A small air bubble may remain in the cartridge after the completion of
the priming step. If you have properly primed the Pen, this small air bubble
will not affect your insulin dose.
7. Now you are ready to set your dose. See next page.
13
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
IV. Setting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not push in the injection button while setting your dose. Failure to
follow these instructions carefully may result in getting too much or too little
insulin. If you accidentally push the injection button while setting your dose,
you must prime the Pen again before injecting your dose. See Section III.
“Priming the Pen”, pages 10-13.
1. A diamond must be seen in the center of the dose window before setting your dose.
If you do not see a diamond in the center of the dose
window, the Pen has not been primed correctly and
you are not ready to set your dose. Before continuing,
repeat the priming steps.
Correct
2. Turn the dose knob clockwise until the arrow
(
) is seen in the center of the dose window
and the notches on the Pen and dose knob are
in line.
14
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
IV. Setting a Dose
(Continued)
3. With the arrow (
) in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window. A dose cannot be dialed until the dose
knob is pulled out.
4. Turn the dose knob clockwise until your dose
is seen in the dose window. If the dose you
have dialed is too high, simply turn the dose
knob backward until the correct dose is seen in
the dose window.
5. If you cannot dial your full dose, see the “Questions and Answers” section,
Question 5, at the end of this manual.
15
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
V. Injecting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not attempt to change the dose after you begin to push in the
injection button. Failure to follow these instructions carefully may result in
getting too much or too little insulin.
• The effort needed to push in the injection button may increase while you are
injecting your insulin dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers” section, Question 7, at the end
of this manual.
• Do not inject a dose unless the Pen is primed, just before injection, or you may get
too much or too little insulin.
•
If you have set a dose and pushed in the injection button without a needle attached
or if no insulin comes out of the needle, see the “Questions and Answers” section,
Questions 1 and 2.
16
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
V. Injecting a Dose
(Continued)
1. Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2. Insert the needle into your skin. Inject the
insulin by using your thumb, if possible, to
push in the injection button completely.
3. Keep pressing and continue to hold the
injection button firmly while counting
slowly to 5.
4. When the injection is done, a diamond (♦) or an
arrow (
) must be seen in the center of the dose
window. This means your full dose has been
delivered. If you do not see a diamond or an
arrow in the center of the dose window, you
did not get your full dose. Contact your Health
Care Professional for additional instructions.
Correct
Correct
17
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
VI. Following an Injection
1. Make sure you got your full dose by checking
that the injection button has been completely
pushed in and you can see a diamond (♦) or
an arrow (
) in the center of the dose window.
If you do not see a diamond (♦) or an arrow
(
) in the center of the dose window, you
have not received your full dose. Contact your
Health Care Professional for additional
instructions.
2. Carefully replace the outer needle shield as
instructed by your Health Care Professional.
18
Outer
Needle
Shield
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
VI. Following an Injection
(Continued)
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly throw it away as directed by your
Health Care Professional.
4. Replace the cap on the Pen.
5. The Pen that you are using should NOT be refrigerated but should be kept at room
temperature [below 86°F (30°C)] and away from direct heat and light. It should be
discarded according to the time specified in the “Patient Information”, even if it still
contains insulin.
Do not store or dispose of the Pen with a needle attached. Storing the Pen with
the needle attached may allow insulin to leak from the Pen and air bubbles to
form in the cartridge.
19
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Questions and Answers
Problem
Action
1. Dose dialed and injection
button pushed in without a
needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen.
2. Insulin does not come out
of the needle.
Note: You may need to prime
a new pen up to six times
before a stream of insulin
appears.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen. See Section III. “Priming
the Pen”, pages 10-13.
20
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Questions and Answers
(Continued)
Problem
Action
3. Why do I need to prime a
new pen up to six times?
The first time you use a new pen, priming up
to six times may be needed to see a stream
of insulin come out of the tip of the needle. If
you do not prime until you see a stream of
insulin, you may get too much or too little
insulin.
4. Wrong dose (too high or
too low) dialed.
If you have not pushed in the injection
button, simply turn the dose knob backward
or forward to correct the dose.
5. Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing
down. The scale (20 units between marks)
on the clear cartridge holder shows an
estimate of the number of units remaining.
These numbers should not be used for
measuring an insulin dose.
21
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Questions and Answers
(Continued)
Problem
Action
6. Full dose cannot be dialed.
The Pen will not allow you to dial a dose
greater than the number of insulin units
remaining in the cartridge. For example, if
you need 31 units and only 25 units remain
in the Pen, you will not be able to dial past
25. Do not attempt to dial past this point.
(The insulin that remains is unusable and
not part of the 300 units.) If a partial dose
remains in the Pen you may either:
1) Give the partial dose and then give the
remaining dose using a new Pen, or
2) Give the full dose with a new Pen.
7. A small amount of insulin
remains in the cartridge but
a dose cannot be dialed.
The Pen design prevents the cartridge from
being completely emptied. The Pen has
delivered 300 units of usable insulin.
22
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Questions and Answers
(Continued)
Problem
Action
8. Cannot completely push in
the injection button when
priming the Pen or injecting
a dose.
1) Needle is not attached or is clogged.
a. Attach a new needle.
b. Push in the injection button
completely (even if a “0” is seen in
the window) until a diamond (♦) or an
arrow (
) is seen in the center of the
dose window.
c. Prime the Pen.
2)
If you are sure insulin is coming out of
the needle, push in the injection button
more slowly to reduce the effort needed
and maintain a constant pressure until
the injection button is completely
pushed in.
23
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
For additional information call,
1-800-LILLY-RX (1-800-545-5979),
or visit our website at www.Humalog.com
Revised XXX xx, 200x
Manufactured by Lilly France S.A.S.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
24
Reference ID: 3273554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.584929 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018781s121lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 121} |
1,089 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN N safely and effectively. See full prescribing information for
HUMULIN N.
HUMULIN® N (human insulin [rDNA origin]) isophane suspension),
injectable suspension, for subcutaneous use
Initial U.S. Approval: 1982
--------------------------- RECENT MAJOR CHANGES -------------------------
Warnings and Precautions (5.5)
03/2013
----------------------------INDICATIONS AND USAGE --------------------------
HUMULIN N is an intermediate-acting human insulin indicated to improve
glycemic control in adult and pediatric patients with diabetes mellitus. (1)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
•
Only administer subcutaneously (in abdominal wall, thigh, upper arm, or
buttocks). (2.2)
•
Individualize and adjust dosage based on metabolic needs, blood glucose
monitoring results and glycemic control goal. (2.3)
•
See Full Prescribing Information for dosage adjustments due to drug
interactions and patients with renal and hepatic impairment. (2.3, 2.4)
•
May use with a meal-time insulin if indicated. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS --------------------
Injectable suspension 100 units per mL (U-100) available as 10 mL vials or 3
mL prefilled pens. (3)
-------------------------------CONTRAINDICATIONS -----------------------------
•
During episodes of hypoglycemia. (4)
•
In patients with hypersensitivity to HUMULIN N or any of its
excipients. (4)
------------------------WARNINGS AND PRECAUTIONS ----------------------
•
Changes in Insulin Regimen: Carry out under close medical supervision
and increase frequency of blood glucose monitoring. (5.1)
•
Hypoglycemia: May be life-threatening. Monitor blood glucose and
increase monitoring frequency with changes to insulin dosage, use of
glucose lowering medications, meal pattern, physical activity; in patients
with renal or hepatic impairment; and in patients with hypoglycemia
unawareness. (5.2, 7, 8.6, 8.7)
•
Hypersensitivity Reactions: May be life-threatening. Discontinue
HUMULIN N, monitor and treat if indicated. (5.3)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk of hypokalemia and treat if indicated. (5.4)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure
occurs. (5.5)
-------------------------------ADVERSE REACTIONS -----------------------------
Adverse reactions observed with HUMULIN N include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight
gain, and edema. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545 5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -----------------------------
•
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage
may be needed. (7.1, 7.2, 7.3)
•
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (5.2, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 11/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Route of Administration
2.3
Dosage Information
2.4
Dosage Adjustment due to Drug Interactions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Changes in Insulin Regimen
5.2
Hypoglycemia
5.3
Hypersensitivity Reactions
5.4
Hypokalemia
5.5
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect
of HUMULIN N
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN N
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
HUMULIN N is an intermediate-acting recombinant human insulin indicated to improve glycemic control in adults and
pediatric patients with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inspect HUMULIN N visually before use. It should not contain particulate matter and should appear uniformly cloudy after
mixing. Do not use HUMULIN N if particulate matter is seen.
2.2
Route of Administration
HUMULIN N should only be administered subcutaneously.
Administer in the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of
lipodystrophy, rotate the injection site within the same region from one injection to the next [see Adverse Reactions (6)].
Do not administer HUMULIN N intravenously or intramuscularly and do not use HUMULIN N in an insulin infusion pump.
2.3
Dosage Information
Individualize and adjust the dosage of HUMULIN N based on the individual’s metabolic needs, blood glucose monitoring
results and glycemic control goal.
Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or
timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.1, 5.2), and Use
in Specific Populations (8.6, 8.7)].
2.4
Dosage Adjustment due to Drug Interactions
Dosage adjustment may be needed when HUMULIN N is coadministered with certain drugs [see Drug Interactions (7)].
Dosage adjustment may be needed when switching from another insulin to HUMULIN N [see Warnings and Precautions
(5.1)].
Instructions for Mixing with Other Insulins
HUMULIN N may be used with a prandial insulin if indicated. HUMULIN N may be mixed with HUMULIN R or
HUMALOG before injection.
•
If HUMULIN N is mixed with HUMULIN R, HUMULIN R should be drawn into the syringe first. Injection should
occur immediately after mixing.
•
If HUMULIN N is mixed with HUMALOG, HUMALOG should be drawn into the syringe first. Injection should occur
immediately after mixing.
3
DOSAGE FORMS AND STRENGTHS
HUMULIN N injectable suspension: 100 units per mL (U-100) is available as:
•
10 mL vials
•
3 mL prefilled pens
4
CONTRAINDICATIONS
HUMULIN N is contraindicated:
•
During episodes of hypoglycemia [see Warnings and Precautions (5.2)], and
•
In patients who have had hypersensitivity reactions to HUMULIN N or any of its excipients [see Warnings and
Precautions (5.3)].
5
WARNINGS AND PRECAUTIONS
5.1
Changes in Insulin Regimen
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to
hypoglycemia [see Warnings and Precautions (5.2)] or hyperglycemia. These changes should be made cautiously and under close
medical supervision and the frequency of blood glucose monitoring should be increased.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN N. Severe hypoglycemia
can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may
place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic
nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions
(7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when
the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of
HUMULIN N may vary in different individuals or at different times in the same individual and depends on many conditions,
including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other
factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals),
changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or
hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an
essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have
reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
5.3
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMULIN N.
If hypersensitivity reactions occur, discontinue HUMULIN N; treat per standard of care and monitor until symptoms and signs resolve
[see Adverse Reactions (6)]. HUMULIN N is contraindicated in patients who have had hypersensitivity reactions to HUMULIN N or
any of its excipients [see Contraindications (4)].
5.4
Hypokalemia
All insulin products, including HUMULIN N, cause a shift in potassium from the extracellular to intracellular space, possibly
leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium
levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications
sensitive to serum potassium concentrations).
5.5
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-
related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.
Patients treated with insulin, including HUMULIN N, and a PPAR-gamma agonist should be observed for signs and symptoms of
heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose
reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.2)].
•
Hypokalemia [see Warnings and Precautions (5.4)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN N. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to
establish a causal relationship to drug exposure.
Allergic Reactions
Some patients taking HUMULIN N have experienced erythema, local edema, and pruritus at the site of injection. These
conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and
Precautions (5.3)].
Peripheral Edema
Some patients taking HUMULIN N have experienced sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
Lipodystrophy
Administration of insulin subcutaneously, including HUMULIN N, has resulted in lipoatrophy (depression in the skin) or
lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] in some patients.
Weight gain
Weight gain has occurred with some insulin therapies including HUMULIN N and has been attributed to the anabolic effects
of insulin and the decrease in glycosuria.
Immunogenicity
Development of antibodies that react with human insulin have been observed with all insulin, including HUMULIN N.
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN N use may be increased when co-administered with antidiabetic agents,
salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, disopyramide, fibrates, propoxyphene, pentoxifylline,
ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide). Dose adjustment and increased
frequency of glucose monitoring may be required when HUMULIN N is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN N
The glucose lowering effect of HUMULIN N may be decreased when co-administered with corticosteroids, isoniazid, niacin,
estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline),
somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones. Dose adjustment and increased frequency of
glucose monitoring may be required when HUMULIN N is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN N
The glucose lowering effect of HUMULIN N may be increased or decreased when co-administered with beta-blockers,
clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN N is co-administered with these
drugs.
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.2)] may be blunted when beta-blockers,
clonidine, guanethidine, and reserpine are co-administered with HUMULIN N.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This
background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is
essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. In patients with diabetes or gestational diabetes, insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is
essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they
become pregnant while taking HUMULIN N.
Human Data
While there are no adequate and well-controlled studies of HUMULIN N in pregnant women, evidence from published
literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal
benefits.
Animal Data
Reproduction and fertility toxicity studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk; it is unknown whether HUMULIN N is present in human milk. Insulin orally
ingested is degraded in the gastrointestinal tract. No adverse reactions associated with infant exposure to insulin through the
consumption of human milk have been reported. Good glucose control supports lactation in patients with diabetes. Women with
diabetes who are lactating may require adjustments in their insulin dose.
8.4
Pediatric Use
HUMULIN N has not been studied in pediatric patients. As in adults, the dosage of HUMULIN N in pediatric patients must
be individualized based on metabolic needs, treatment goal and blood glucose monitoring results.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN N has not been studied [see Clinical
Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN N, may be at increased risk of
hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.2)].
8.6
Renal Impairment
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN N has not been studied [see
Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent
HUMULIN N dose adjustment and more frequent blood glucose monitoring.
8.7
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN N has not been studied [see
Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent
HUMULIN N dose adjustment and more frequent blood glucose monitoring.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.2, 5.4)]. Mild
episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or physical activity level may
be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
HUMULIN N (human insulin [rDNA origin] isophane suspension) is a human insulin suspension. Human insulin is produced
by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. HUMULIN N is a suspension of
crystals produced from combining human insulin and protamine sulfate under appropriate conditions for crystal formation. The amino
acid sequence of HUMULIN N is identical to human insulin and has the empirical formula C257H383N65O77S6 with a molecular weight
of 5808.
HUMULIN N is a sterile white suspension. Each milliliter of HUMULIN N contains 100 units of insulin human, 0.35 mg of
protamine sulfate, 16 mg of glycerin, 3.78 mg of dibasic sodium phosphate, 1.6 mg of metacresol, 0.65 mg of phenol, zinc oxide
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.5. Sodium hydroxide and/or hydrochloric
acid may be added during manufacture to adjust the pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
HUMULIN N lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting
hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.
12.2
Pharmacodynamics
HUMULIN N is an intermediate-acting insulin with a slower onset of action and a longer duration of activity than that of
regular human insulin. In a study in which healthy subjects (n=16) received subcutaneous injections of HUMULIN N (0.4 unit/kg) on
4 occasions, the median maximum effect occurred at 6.5 hours (range: 2.8 to 13 hours). In this study, insulin activity was measured by
the rate of glucose infusions.
The time course of action of insulin, such as HUMULIN N may vary in different individuals or within the same individual.
The parameters of HUMULIN N activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only
as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of
injection, physical activity level, and other variables [see Warnings and Precautions (5.2)]. graph
Figure 1: Mean Insulin Activity Versus Time Profile After Subcutaneous Injection of HUMULIN N (0.4 unit/kg) in Healthy
Subjects.
12.3
Pharmacokinetics
Absorption — In healthy subjects given subcutaneous doses of HUMULIN N (0.4 unit/kg), median peak serum concentration
of insulin occurred at approximately 4 hours (range: 1 to 12 hours) after dosing.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the
liver being the major organ involved in the clearance of insulin.
Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be accurately
estimated from the terminal slope of the concentration versus time curve. In healthy subjects given subcutaneous doses of
HUMULIN N (0.4 unit/kg), the mean apparent half-life was approximately 4.4 hours (range: 1-84 hours).
Specific Populations
The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN N have not been
studied.
Careful glucose monitoring and dose adjustments of insulin, including HUMULIN N, may be necessary in patients with renal
or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic in the in
vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN N 100 units per mL (U-100) is available as:
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
10 mL vials
NDC 0002-8315-01 (HI-310)
5 x 3 mL prefilled pen
NDC 0002-8730-59 (HP-8730)
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use after the expiration date.
Not In-Use (Unopened) HUMULIN N Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31days.
In-Use (Opened) HUMULIN N Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must be used
within 31 days or be discarded, even if they still contain HUMULIN N.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31 days, even if the vial still contains
HUMULIN N.
Not In-Use (Unopened) HUMULIN N Pen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 14 days.
In-Use (Opened) HUMULIN N Pen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 14 days, even if the pen still contains
HUMULIN N. See storage table below:
Not In-Use (Unopened)
Refrigerated
Not In-Use (Unopened)
Room Temperature
In-Use (Opened)
10 mL vial
Until expiration date
31 days
31 days, refrigerated/room
temperature
3 mL pen
Until expiration date
14 days
14 days, room temperature.
Do not refrigerate.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management
of hypoglycemia and hyperglycemia especially at initiation of HUMULIN N therapy. Instruct patients on handling of special
situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent
administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of
hypoglycemia.
Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who
have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery
[see Warnings and Precautions (5.2)].
Inform patients that accidental mix-ups between HUMULIN N and other insulins have been reported. Instruct patients to
always carefully check that they are administering the correct insulin (e.g., by checking the insulin label before each injection) to
avoid medication errors between HUMULIN N and other insulins.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with HUMULIN N. Inform patients on the symptoms of
hypersensitivity reactions [see Warnings and Precautions (5.3)].
Females with Reproductive Potential
Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are contemplating
pregnancy [see Use in Specific Populations (8.1)].
Visual Inspection Prior to Use
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A6.0NL 8480 AMP
Instruct patients to visually inspect HUMULIN N before use and to use HUMULIN N only if it contains no particulate matter
and appears uniformly cloudy after mixing [see Dosage and Administration (2.1)].
Expiration Date
Instruct patients not to use HUMULIN N after the printed expiration date.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, 2013, Eli Lilly and Company. All rights reserved.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
B4.0NL 5714 AMP
PATIENT INFORMATION
HUMULIN® (HU-mu-lin) N
(human insulin [rDNA origin] isophane suspension)
What is HUMULIN N?
•
HUMULIN N is a man-made insulin that is used to control high blood sugar in adults and children with
diabetes mellitus.
Who should not use HUMULIN N?
Do not use HUMULIN N if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to HUMULIN N or any of the ingredients in HUMULIN N.
Before using HUMULIN N, tell your healthcare provider about all your medical conditions
including, if you:
•
have liver or kidney problems.
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse while you take
TZDs with HUMULIN N.
•
are pregnant, planning to become pregnant, or are breastfeeding.
•
are taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.
Before you start using HUMULIN N, talk to your healthcare provider about low blood sugar and
how to manage it.
How should I use HUMULIN N?
•
Read the Instructions for Use that come with your HUMULIN N.
•
Use HUMULIN N exactly as your healthcare provider tells you to.
•
Know the type and strength of insulin you use. Do not change the type of insulin you use unless your
healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin
may need to change if you use different types of insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and
when you should check your blood sugar levels.
Your HUMULIN N dose may need to change because of:
•
change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in
diet.
What should I avoid while using HUMULIN N?
While using HUMULIN N do not:
•
Drive or operate heavy machinery, until you know how HUMULIN N affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of HUMULIN N?
HUMULIN N may cause serious side effects that can lead to death, including:
•
low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
•
dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech,
shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger.
•
serious allergic reaction (whole body reaction). Get medical help right away, if you have
any of these symptoms of an allergic reaction:
•
a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with HUMULIN N may
cause heart failure in some people. This can happen even if you have never had heart failure or heart
problems before. If you already have heart failure it may get worse while you take TZDs with
HUMULIN N. Your healthcare provider should monitor you closely while you are taking TZDs with
HUMULIN N. Tell your healthcare provider if you have any new or worse symptoms of heart failure
including:
•
shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and HUMULIN N may need to be adjusted or stopped by your healthcare
provider if you have new or worse heart failure.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat,
sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of HUMULIN N include:
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
B4.0NL 5714 AMP
•
low blood sugar (hypoglycemia), allergic reactions including reactions at the injection site, skin
thickening or pits at the injection site (lipodystrophy), itching, rash, weight gain, and swelling of your
hands and feet.
These are not all the possible side effects of HUMULIN N. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of HUMULIN N:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
You can ask your pharmacist or healthcare provider for information about HUMULIN N that is written for
health professionals. Do not use HUMULIN N for a condition for which it was not prescribed. Do not give
HUMULIN N to other people, even if they have the same symptoms that you have. It may harm them.
What are the ingredients in HUMULIN N?
Active Ingredient: insulin human (rDNA origin)
Inactive Ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol, phenol, zinc
oxide, water for injection, hydrochloric acid or sodium hydroxide
For more information, call 1-800-545-5979 or go to www.humulin.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: Month DD, YYYY
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, yyyy, Eli Lilly and Company. All rights reserved.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL8530AMP
Instructions for Use
HUMULIN® (HU-mu-lin) N
(human insulin [rDNA origin] isophane suspension)
vial (100 Units/mL, U-100)
Read the Instructions for Use before you start taking HUMULIN N and each time
you get a new HUMULIN N vial. There may be new information. This information
does not take the place of talking to your healthcare provider about your medical
condition or your treatment.
Do not share your syringes or needles with anyone else. You may give an
infection to them or get an infection from them.
Supplies needed to give your injection:
• a HUMULIN N vial
• a U-100 insulin syringe and needle
• 2 alcohol swabs
• 1 sharps container for throwing away used needles and syringes. See
“Disposing of used needles and syringes” at the end of these
instructions.
usage illus
trat
ion
Preparing your HUMULIN N dose:
• Wash your hands with soap and water.
• Check the HUMULIN N label to make sure you are taking the right
type of insulin. This is especially important if you use more than 1
type of insulin.
• Do not use HUMULIN N past the expiration date printed on the label or 31
days after you first use it.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Always use a new needle for each injection to help ensure sterility and
prevent blocked needles.
Step 1:
Gently roll the vial between the palms of your
hands at least 10 times.
Step 2:
Invert the vial at least 10 times.
Do not shake.
Mixing is important to make sure you get the
right dose. Humulin N should look white and
cloudy after mixing. Do not use it if it looks clear
or contains any lumps or particles.
Step 3:
If you are using a new vial, pull off the plastic
Protective Cap, but do not remove the Rubber
Stopper.
Step 4:
Wipe the Rubber Stopper with an alcohol swab.
Step 5:
Hold the syringe with the needle pointing up. Pull
down on the Plunger until the tip of the Plunger
reaches the line for the number of units for your
prescribed dose.
(Example Dose: 20 units shown)
Step 6:
Push the needle through the Rubber Stopper of the
vial.
usage illustrationusage illustrationusage illustrationusage illustrationusage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 7:
Push the plunger all the way in. This puts air into
the vial.
Step 8:
Turn the vial and syringe upside down and slowly
pull the Plunger down until the tip is a few units
past the line for your prescribed dose.
(Example Dose: 20 units
Plunger is shown at 24 units)
If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top.
Step 9:
Slowly push the Plunger up until the tip reaches
the line for your prescribed dose.
Check the syringe to make sure that you have the
right dose.
(Example Dose: 20 units shown)
Step 10:
Pull the syringe out of the vial’s Rubber Stopper.
usage illustrationusage illustration
Giving your HUMULIN N injection:
•
Inject your insulin exactly as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 11:
Choose your injection site.
HUMULIN N is injected under the skin
(subcutaneously) of your stomach area (abdomen),
buttocks, upper legs or upper arms.
Wipe the skin with an alcohol swab. Let the
injection site dry before you inject your dose.
Step 12:
Insert the needle into your skin.
Step 13:
Push down on the Plunger to inject your dose.
The needle should stay in your skin for at least 5
seconds to make sure you have injected all of your
insulin dose.
Step 14:
Pull the needle out of your skin.
•
If you see blood after you take the needle
out of your skin, press the injection site with
a piece of gauze or an alcohol swab. Do not
rub the area.
•
Do not recap the needle. Recapping the
needle can lead to a needle stick injury.
Disposing of used needles and syringes:
• Put your used needles and syringes in a FDA-cleared sharps disposal container
usage illustrationusage illustrationusage illustrationusage illustration
right away after use. Do not throw away (dispose of) loose needles and
syringes in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
o made of a heavy-duty plastic,
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
o upright and stable during use,
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
logo
o leak-resistant, and
o properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
• Do not recycle the container.
How should I store HUMULIN N?
All unopened HUMULIN N vials:
• Store all unopened vials in the refrigerator.
• Do not freeze. Do not use if it has been frozen.
• Keep away from heat and out of direct light.
• Unopened vials can be used until the expiration date on the carton and label, if
they have been stored in the refrigerator.
• Unopened vials should be thrown away after 31 days, if they are stored at room
temperature.
After HUMULIN N vials have been opened:
• Store opened vials in the refrigerator or at room temperature below 86°F (30°C)
for up to 31 days.
• Keep away from heat and out of direct light.
• Throw away all opened vials after 31 days of use, even if there is still insulin left
in the vial.
General information about the safe and effective use of HUMULIN N.
Keep HUMULIN N vials, syringes, needles, and all medicines out of the reach of
children.
If you have any questions or problems with your HUMULIN, contact Lilly at 1-800
Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more
information on HUMULIN and insulin, go to www.humulin.com.
Scan this code to launch the humulin.com website
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL8530AMP
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
Revised: 11/2013
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3.0 NL 9540 AMP
Instructions for Use
HUMULIN® N KwikPen™
(human insulin [rDNA origin] isophane suspension) usage illustration
Read the Instructions for Use before you start taking HUMULIN N and each time you
get another HUMULIN® N KwikPen™. There may be new information. This information
does not take the place of talking to your healthcare provider about your medical
condition or your treatment.
HUMULIN N KwikPen (“Pen”) is a disposable pen containing 3 mL (300 units) of U
100 HUMULIN® N (human insulin isophane suspension [rDNA origin]) insulin. You can
inject from 1 to 60 units in a single injection.
HUMULIN N KwikPen has a blue and light green Label with a matching light green
Dose Knob (See the KwikPen Parts diagram below).
Do not share your HUMULIN N KwikPen or needles with another person. You
may give an infection to them or get an infection from them.
This Pen is not recommended for use by the blind or visually impaired
without the assistance of a person trained in the proper use of the product. usage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Supplies you will need to give your HUMULIN N injection:
• HUMULIN N KwikPen
• KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles
recommended)
• alcohol swab
Preparing HUMULIN N KwikPen:
• Wash your hands with soap and water.
• Check the HUMULIN N KwikPen Label to make sure you are taking the
right type of insulin. This is especially important if you use more than
1 type of insulin.
• Do not use HUMULIN N past the expiration date printed on the Label or 14
days after you start using the Pen.
• Always use a new needle for each injection to help ensure sterility and
prevent blocked needles.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 1:
•
Pull the Pen Cap straight off.
•
Wipe the Rubber Seal with an
alcohol swab.
- Do not twist the cap.
-
Do not remove the HUMULIN N
KwikPen Label.
- Do not attach the Needle
before mixing.
Step 2:
•
Gently roll the Pen between your
hands 10 times.
Step 3:
•
Move the Pen up and down (invert)
the Pen 10 times.
Mixing by rolling and inverting the
Pen is important to make sure you
get the right dose.
Step 4:
•
Check the liquid in the Pen.
HUMULIN N should look white and
cloudy after mixing. Do not use if it
looks clear or has any lumps or
particles in it.
usage illustrationusage illustrationusage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer
Needle Shield.
Step 6:
•
Push the capped Needle straight onto
the Pen and twist the Needle on until
it is tight.
Step 7:
•
Pull off the Outer Needle Shield. Do
not throw it away.
•
Pull off the Inner Needle Shield and
throw it away.
usage illustrationusage illustrationusage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 8:
•
Turn the Dose Knob to select 2 units.
Step 9:
•
Hold the Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top.
Step 10:
•
Hold the Pen with Needle pointing up.
Push the Dose Knob in until it stops,
and “0” is seen in the Dose Window.
•
Hold the Dose Knob in and count
to 5 slowly.
A stream of insulin should be seen
from the needle.
- If you do not see a stream of
insulin, repeat steps 8 to 10, no
more than 4 times.
- If you still do not see a stream of
insulin, change the needle and
repeat steps 8 to 10.
Priming the HUMULIN N KwikPen:
Prime the HUMULIN N KwikPen before each injection. Priming ensures the Pen
is ready to dose and removes air that may collect in the cartridge during normal use.
If you do not prime before each injection, you may get too much or too little insulin. usage illustrationusage illustrationusage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Selecting your dose:
Step 11:
•
Turn the Dose Knob to select the
number of units you need to inject.
The Dose Indicator should line up with
your dose.
The dose can be corrected by turning
the Dose Knob in either direction until
the correct dose lines up with the
Dose Indicator.
-
The even numbers are printed on
the dial.
(Example: 10 units shown)
-
The odd numbers, after the
number 1, are shown as full lines.
(Example: 15 units shown)
• The HUMULIN N KwikPen will not let you dial more than the number of units
left in the Pen.
• If your dose is more than the number of units left in the Pen, you may either:
-
inject the amount left in your Pen and then use a new Pen to give the rest
of your dose, or
-
get a new Pen and inject the full dose.
• The Pen is designed to deliver a total of 300 units of insulin. The cartridge
contains an additional small amount of insulin that cannot be delivered.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Giving your HUMULIN N injection:
•
Inject your HUMULIN N exactly as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
•
Do not try to change your dose while injecting HUMULIN N.
Step 12:
•
Choose your injection site.
HUMULIN N is injected under the skin
(subcutaneously) of your stomach
area, buttocks, upper legs or upper
arms.
•
Wipe the skin with an alcohol swab,
and let the injection site dry before
you inject your dose.
Step 13:
•
Insert the Needle into your skin.
Step 14:
•
Put your thumb on the Dose Knob
and push the Dose Knob in until it
stops.
•
Hold the Dose Knob in and slowly
count to 5.
usage illustrationusage illustrationusage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 15:
•
Pull the Needle out of your skin.
You should see “0” in the Dose
Window. If you do not see “0” in the
Dose Window, you did not receive
your full dose.
- If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
- A drop of insulin at the needle tip
is normal. It will not affect your
dose.
- If you do not think you
received your full dose, do not
take another dose. Call Lilly at
1-800-LillyRx (1-800-545-5979) or
your healthcare provider for help.
Step 16:
•
Carefully replace the Outer Needle
Shield.
Step 17:
•
Unscrew the capped Needle and throw
it away.
•
Do not store the Pen with the Needle
attached to prevent leaking, blocking
of the Needle, and air from entering
the Pen.
company logousage illustrationusage illustration
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 18:
•
Replace the Pen Cap by lining up the
Cap Clip with the Dose Indicator and
pushing straight on.
usage illustration
After your injection:
• Put your used needles and pens in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and pens in
your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store my HUMULIN N KwikPen?
• Store unused HUMULIN N KwikPens in the refrigerator at 36°F to 46°F (2°C to
8°C). The Pen you are currently using should be stored at room temperature,
below 86°F (30°C).
• Do not freeze HUMULIN N. Do not use HUMULIN N if it has been frozen.
• Unused Pens may be used until the expiration date printed on the Label, if kept
in the refrigerator.
• The HUMULIN N Pen you are using should be thrown away after 14 days, even
if it still has insulin left in it.
• Keep HUMULIN N away from heat and out of the light.
General information about the safe and effective use of HUMULIN N
KwikPen.
• Keep HUMULIN N KwikPen and needles out of the reach of children.
• Do not use the Pen if any part looks broken or damaged.
• Always carry an extra Pen in case yours is lost or damaged.
• If you cannot remove the Pen Cap, gently twist the Pen Cap back and forth,
and then pull the Pen Cap straight off.
• If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and
get a new one.
-
It may help to push the Dose Knob more slowly during your injection.
• Use the space below to keep track of how long you should use each HUMULIN
N KwikPen.
-
Write down the date you start using your HUMULIN N KwikPen. Count
forward 14 days.
- Write down the date you should throw it away.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HUMULIN N KwikPen meets the current dose accuracy and functional requirements
of ISO 11608-1:2000.
Issued: Month Day, Year
3.0 NL 9540 AMP
Example:
First used on _______ + 14 days = Throw out on ______
Date
Date
Pen 1 - First used on _______ Throw out on _______
Date
Date
Pen 2 - First used on _______ Throw out on _______
Date
Date
Pen 3 - First used on _______ Throw out on _______
Date
Date
Pen 4 - First used on _______ Throw out on _______
Date
Date
Pen 5 - First used on _______ Throw out on _______
Date
Date
If you have any questions or problems with your HUMULIN N KwikPen, contact Lilly at
1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help. For more
information on HUMULIN N KwikPen and insulin, go to www.lilly.com.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
HUMULIN® and HUMULIN® KwikPen™ are trademarks of Eli Lilly and Company.
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © YYYY, Eli Lilly and Company. All rights reserved.
Reference ID: 3403614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.728227 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018781s118s122lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 122} |
1,527 | This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
10/3/02 01:25:51 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:20.897244 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19717s41lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 41} |
1,090 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN N safely and effectively. See full prescribing
information for HUMULIN N.
HUMULIN® N (human insulin [rDNA origin] isophane suspension),
injectable suspension, for subcutaneous use
Initial U.S. Approval: 1982
--------------------------- RECENT MAJOR CHANGES -------------------------
Warnings and Precautions
Never Share a HUMULIN N Pen, HUMULIN N KwikPen, or
Syringe Between Patients (5.1)
02/2015
---------------------------- INDICATIONS AND USAGE --------------------------
HUMULIN N is an intermediate-acting human insulin indicated to
improve glycemic control in adult and pediatric patients with diabetes
mellitus. (1)
------------------------DOSAGE AND ADMINISTRATION ----------------------
•
Only administer subcutaneously (in abdominal wall, thigh, upper
arm, or buttocks). (2.2)
•
Individualize and adjust dosage based on metabolic needs, blood
glucose monitoring results and glycemic control goal. (2.3)
•
See Full Prescribing Information for dosage adjustments due to
drug interactions and patients with renal and hepatic impairment.
(2.3, 2.4)
•
May use with a meal-time insulin if indicated. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
Injectable suspension 100 units per mL (U-100) available as 10 mL
vials, 3 mL vials, 3 mL prefilled pens and 3 mL HUMULIN® N KwikPen®
(prefilled). (3)
------------------------------- CONTRAINDICATIONS -----------------------------
•
During episodes of hypoglycemia. (4)
•
In patients with hypersensitivity to HUMULIN N or any of its
excipients. (4)
------------------------ WARNINGS AND PRECAUTIONS ----------------------
•
Never share a HUMULIN N pen, HUMULIN N KwikPen, or
syringe between patients, even if the needle is changed. (5.1)
•
Changes in Insulin Regimen: Carry out under close medical
supervision and increase frequency of blood glucose monitoring.
(5.2)
•
Hypoglycemia: May be life-threatening. Monitor blood glucose
and increase monitoring frequency with changes to insulin
dosage, use of glucose lowering medications, meal pattern,
physical activity; in patients with renal or hepatic impairment; and
in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7)
•
Hypersensitivity Reactions: May be life-threatening. Discontinue
HUMULIN N, monitor and treat if indicated. (5.4)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk of hypokalemia and treat if indicated. (5.5)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of
heart failure; consider dosage reduction or discontinuation if heart
failure occurs. (5.6)
-------------------------------ADVERSE REACTIONS -----------------------------
Adverse reactions observed with HUMULIN N include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, rash,
weight gain, and edema. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
and Company at 1-800-LillyRx (1-800-545-5979) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -----------------------------
•
Drugs that Affect Glucose Metabolism: Adjustment of insulin
dosage may be needed. (7.1, 7.2, 7.3)
•
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine,
guanethidine, and reserpine): Signs and symptoms of
hypoglycemia may be reduced or absent. (5.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 02/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Route of Administration
2.3
Dosage Information
2.4
Dosage Adjustment due to Drug Interactions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a HUMULIN N Pen, HUMULIN N KwikPen,
or Syringe Between Patients
5.2
Changes in Insulin Regimen
5.3
Hypoglycemia
5.4
Hypersensitivity Reactions
5.5
Hypokalemia
5.6
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering
Effect of HUMULIN N
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN N
7.4
Drugs That May Blunt Signs and Symptoms of
Hypoglycemia
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
Reference ID: 3722216
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
HUMULIN N is an intermediate-acting recombinant human insulin indicated to improve glycemic control in adults
and pediatric patients with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
Inspect HUMULIN N visually before use. It should not contain particulate matter and should appear uniformly
cloudy after mixing. Do not use HUMULIN N if particulate matter is seen.
2.2
Route of Administration
HUMULIN N should only be administered subcutaneously.
Administer in the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of
lipodystrophy, rotate the injection site within the same region from one injection to the next [see Adverse Reactions (6)].
Do not administer HUMULIN N intravenously or intramuscularly and do not use HUMULIN N in an insulin infusion
pump.
2.3
Dosage Information
Individualize and adjust the dosage of HUMULIN N based on the individual’s metabolic needs, blood glucose
monitoring results and glycemic control goal.
Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e.,
macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings
and Precautions (5.2, 5.3), and Use in Specific Populations (8.6, 8.7)].
2.4
Dosage Adjustment due to Drug Interactions
Dosage adjustment may be needed when HUMULIN N is coadministered with certain drugs [see Drug Interactions
(7)].
Dosage adjustment may be needed when switching from another insulin to HUMULIN N [see Warnings and
Precautions (5.2)].
Instructions for Mixing with Other Insulins
HUMULIN N may be used with a prandial insulin if indicated. HUMULIN N may be mixed with HUMULIN R or
HUMALOG before injection.
•
If HUMULIN N is mixed with HUMULIN R, HUMULIN R should be drawn into the syringe first. Injection should
occur immediately after mixing.
•
If HUMULIN N is mixed with HUMALOG, HUMALOG should be drawn into the syringe first. Injection should
occur immediately after mixing.
3
DOSAGE FORMS AND STRENGTHS
HUMULIN N injectable suspension: 100 units per mL (U-100) is available as:
•
10 mL vials
•
3 mL vials
•
3 mL prefilled pens
•
3 mL HUMULIN N KwikPen (prefilled)
4
CONTRAINDICATIONS
HUMULIN N is contraindicated:
•
During episodes of hypoglycemia [see Warnings and Precautions (5.3)], and
•
In patients who have had hypersensitivity reactions to HUMULIN N or any of its excipients [see Warnings and
Precautions (5.4)].
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a HUMULIN N Pen, HUMULIN N KwikPen, or Syringe Between Patients
HUMULIN N pens and HUMULIN N KwikPens must never be shared between patients, even if the needle is
changed. Patients using HUMULIN N vials must never share needles or syringes with another person. Sharing poses a
risk for transmission of blood-borne pathogens.
5.2
Changes in Insulin Regimen
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and
predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. These changes should be made
cautiously and under close medical supervision and the frequency of blood glucose monitoring should be increased.
5.3
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN N. Severe
hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability
and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g.,
driving or operating other machinery).
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the
same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding
diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system
(e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is
highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering
effect time course of HUMULIN N may vary in different individuals or at different times in the same individual and depends
on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical
Pharmacology (12.2)]. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g.,
macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication
[see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in
Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood
glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for
hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood
glucose monitoring is recommended.
5.4
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including
HUMULIN N. If hypersensitivity reactions occur, discontinue HUMULIN N; treat per standard of care and monitor until
symptoms and signs resolve [see Adverse Reactions (6)]. HUMULIN N is contraindicated in patients who have had
hypersensitivity reactions to HUMULIN N or any of its excipients [see Contraindications (4)].
5.5
Hypokalemia
All insulin products, including HUMULIN N, cause a shift in potassium from the extracellular to intracellular space,
possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and
death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering
medications, patients taking medications sensitive to serum potassium concentrations).
5.6
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can
cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or
exacerbate heart failure. Patients treated with insulin, including HUMULIN N, and a PPAR-gamma agonist should be
observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.3)].
•
Hypokalemia [see Warnings and Precautions (5.5)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN N. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or to establish a causal relationship to drug exposure.
Allergic Reactions
Some patients taking HUMULIN N have experienced erythema, local edema, and pruritus at the site of injection.
These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see
Warnings and Precautions (5.4)].
Peripheral Edema
Some patients taking HUMULIN N have experienced sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Lipodystrophy
Administration of insulin subcutaneously, including HUMULIN N, has resulted in lipoatrophy (depression in the
skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] in some patients.
Weight gain
Weight gain has occurred with some insulin therapies including HUMULIN N and has been attributed to the
anabolic effects of insulin and the decrease in glycosuria.
Immunogenicity
Development of antibodies that react with human insulin have been observed with all insulin, including
HUMULIN N.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN N use may be increased when co-administered with
antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, disopyramide, fibrates,
propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g.,
octreotide). Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN N is co
administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN N
The glucose lowering effect of HUMULIN N may be decreased when co-administered with corticosteroids,
isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid
hormones. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN N is co
administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN N
The glucose lowering effect of HUMULIN N may be increased or decreased when co-administered with beta-
blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN N is
co-administered with these drugs.
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)] may be blunted when beta-
blockers, clonidine, guanethidine, and reserpine are co-administered with HUMULIN N.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug
exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with
good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. In patients with diabetes or gestational diabetes, insulin
requirements may decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female
patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking
HUMULIN N.
Human Data
While there are no adequate and well-controlled studies of HUMULIN N in pregnant women, evidence from
published literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant
maternal and fetal benefits.
Animal Data
Reproduction and fertility toxicity studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk; it is unknown whether HUMULIN N is present in human milk. Insulin
orally ingested is degraded in the gastrointestinal tract. No adverse reactions associated with infant exposure to insulin
through the consumption of human milk have been reported. Good glucose control supports lactation in patients with
diabetes. Women with diabetes who are lactating may require adjustments in their insulin dose.
8.4
Pediatric Use
HUMULIN N has not been studied in pediatric patients. As in adults, the dosage of HUMULIN N in pediatric
patients must be individualized based on metabolic needs, treatment goal and blood glucose monitoring results.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN N has not been studied [see
Clinical Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN N, may be at increased
risk of hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.3)].
8.6
Renal Impairment
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN N has not been
studied [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may
require more frequent HUMULIN N dose adjustment and more frequent blood glucose monitoring.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
8.7
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN N has not been
studied [see Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia and
may require more frequent HUMULIN N dose adjustment and more frequent blood glucose monitoring.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3,
5.5)]. Mild episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or
physical activity level may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated
with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and
observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be
corrected appropriately.
11
DESCRIPTION
HUMULIN N (human insulin [rDNA origin] isophane suspension) is a human insulin suspension. Human insulin is
produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. HUMULIN N is
a suspension of crystals produced from combining human insulin and protamine sulfate under appropriate conditions for
crystal formation. The amino acid sequence of HUMULIN N is identical to human insulin and has the empirical formula
C257H383N65O77S6 with a molecular weight of 5808.
HUMULIN N is a sterile white suspension. Each milliliter of HUMULIN N contains 100 units of insulin human,
0.35 mg of protamine sulfate, 16 mg of glycerin, 3.78 mg of dibasic sodium phosphate, 1.6 mg of metacresol, 0.65 mg of
phenol, zinc oxide content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.5. Sodium
hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
HUMULIN N lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by
inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.
12.2
Pharmacodynamics
HUMULIN N is an intermediate-acting insulin with a slower onset of action and a longer duration of activity than
that of regular human insulin. In a study in which healthy subjects (n=16) received subcutaneous injections of
HUMULIN N (0.4 unit/kg) on 4 occasions, the median maximum effect occurred at 6.5 hours (range: 2.8 to 13 hours). In
this study, insulin activity was measured by the rate of glucose infusions.
The time course of action of insulin, such as HUMULIN N may vary in different individuals or within the same
individual. The parameters of HUMULIN N activity (time of onset, peak time, and duration) as designated in Figure 1
should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is
known to be affected by the site of injection, physical activity level, and other variables [see Warnings and Precautions
(5.3)]. graph
Figure 1: Mean Insulin Activity Versus Time Profile After Subcutaneous Injection of HUMULIN N (0.4 unit/kg) in
Healthy Subjects.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
12.3
Pharmacokinetics
Absorption — In healthy subjects given subcutaneous doses of HUMULIN N (0.4 unit/kg), median peak serum
concentration of insulin occurred at approximately 4 hours (range: 1 to 12 hours) after dosing.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and
adipocytes, with the liver being the major organ involved in the clearance of insulin.
Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be
accurately estimated from the terminal slope of the concentration versus time curve. In healthy subjects given
subcutaneous doses of HUMULIN N (0.4 unit/kg), the mean apparent half-life was approximately 4.4 hours (range: 1-84
hours).
Specific Populations
The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN N have not
been studied.
Careful glucose monitoring and dose adjustments of insulin, including HUMULIN N, may be necessary in patients
with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic
in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN N 100 units per mL (U-100) is available as:
10 mL vials
NDC 0002-8315-01 (HI-310)
3 mL vials
NDC 0002-8315-17 (HI-313)
5 x 3 mL prefilled pen
NDC 0002-8730-59 (HP-8730)
5 x 3 mL HUMULIN N KwikPen (prefilled)
NDC 0002-8805-59 (HP-8805)
Each prefilled HUMULIN N pen and HUMULIN N KwikPen is for use by a single patient. HUMULIN N pens and
HUMULIN N KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMULIN
N vials must never share needles or syringes with another person.
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use after the expiration date.
Not In-Use (Unopened) HUMULIN N Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31days.
In-Use (Opened) HUMULIN N Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must
be used within 31 days or be discarded, even if they still contain HUMULIN N.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31 days, even if the vial still
contains HUMULIN N.
Not In-Use (Unopened) HUMULIN N Pen and KwikPen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 14 days.
In-Use (Opened) HUMULIN N Pen and KwikPen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 14 days, even if the pen still
contains HUMULIN N. See storage table below:
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
____________
A2.01-LINN-8480-USPI-YYYYMMDD
7
Not In-Use (Unopened)
Refrigerated
Not In-Use (Unopened)
Room Temperature
In-Use (Opened)
10 mL vial
3 mL vial
Until expiration date
31 days
31 days, refrigerated/room
temperature
3 mL pen
3 mL HUMULIN N
KwikPen (prefilled)
Until expiration date
14 days
14 days, room
temperature.
Do not refrigerate.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Never Share a HUMULIN N Pen, HUMULIN N KwikPen, or Syringe Between Patients
Advise patients that they must never share a HUMULIN N pen or HUMULIN N KwikPen with another person, even
if the needle is changed. Advise patients using HUMULIN N vials not to share needles or syringes with another person.
Sharing poses a risk for transmission of blood-borne pathogens.
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and
management of hypoglycemia and hyperglycemia especially at initiation of HUMULIN N therapy. Instruct patients on
handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or
skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals.
Instruct patients on the management of hypoglycemia.
Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise
patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when
driving or operating machinery [see Warnings and Precautions (5.3)].
Inform patients that accidental mix-ups between HUMULIN N and other insulins have been reported. Instruct
patients to always carefully check that they are administering the correct insulin (e.g., by checking the insulin label before
each injection) to avoid medication errors between HUMULIN N and other insulins.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with HUMULIN N. Inform patients on the symptoms
of hypersensitivity reactions [see Warnings and Precautions (5.4)].
Females with Reproductive Potential
Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are
contemplating pregnancy [see Use in Specific Populations (8.1)].
Visual Inspection Prior to Use
Instruct patients to visually inspect HUMULIN N before use and to use HUMULIN N only if it contains no particulate
matter and appears uniformly cloudy after mixing [see Dosage and Administration (2.1)].
Expiration Date
Instruct patients not to use HUMULIN N after the printed expiration date.
HUMULIN® and HUMULIN® N KwikPen® are trademarks of Eli Lilly and Company.
Literature revised February 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, YYYY, Eli Lilly and Company. All rights reserved.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
PATIENT INFORMATION
HUMULIN® (HU-mu-lin) N
(human insulin [rDNA origin] isophane suspension)
Do not share your HUMULIN N Pen, HUMULIN N KwikPen, or syringes with other
people, even if the needle has been changed. You may give other people a
serious infection or get a serious infection from them.
What is HUMULIN N?
• HUMULIN N is a man-made insulin that is used to control high blood sugar in adults
and children with diabetes mellitus.
Who should not use HUMULIN N?
Do not use HUMULIN N if you:
• are having an episode of low blood sugar (hypoglycemia).
• have an allergy to HUMULIN N or any of the ingredients in HUMULIN N.
Before using HUMULIN N, tell your healthcare provider about all your medical
conditions including, if you:
• have liver or kidney problems.
• take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
• have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with HUMULIN N.
• are pregnant, planning to become pregnant, or are breastfeeding.
• are taking new prescription or over-the-counter medicines, vitamins, or herbal
supplements.
Before you start using HUMULIN N, talk to your healthcare provider about low
blood sugar and how to manage it.
How should I use HUMULIN N?
• Read the Instructions for Use that come with your HUMULIN N.
• Use HUMULIN N exactly as your healthcare provider tells you to.
• Know the type and strength of insulin you use. Do not change the type of insulin you
use unless your healthcare provider tells you to. The amount of insulin and the best
time for you to take your insulin may need to change if you use different types of
insulin.
• Check your blood sugar levels. Ask your healthcare provider what your blood
sugars should be and when you should check your blood sugar levels.
• Do not share your HUMULIN N Pen, HUMULIN N KwikPen, or syringes with
other people, even if the needle has been changed. You may give other people
a serious infection or get a serious infection from them.
Your HUMULIN N dose may need to change because of:
• change in level of physical activity or exercise, weight gain or loss, increased stress,
illness, change in diet.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
What should I avoid while using HUMULIN N?
While using HUMULIN N do not:
• Drive or operate heavy machinery, until you know how HUMULIN N affects you.
• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of HUMULIN N?
HUMULIN N may cause serious side effects that can lead to death, including:
• low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood
sugar include:
• dizziness or light-headedness, sweating, confusion, headache, blurred vision,
slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes,
hunger.
• serious allergic reaction (whole body reaction). Get medical help right away, if
you have any of these symptoms of an allergic reaction:
• a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
• low potassium in your blood (hypokalemia).
• heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with
HUMULIN N may cause heart failure in some people. This can happen even if you
have never had heart failure or heart problems before. If you already have heart
failure it may get worse while you take TZDs with HUMULIN N. Your healthcare
provider should monitor you closely while you are taking TZDs with HUMULIN N.
Tell your healthcare provider if you have any new or worse symptoms of heart failure
including:
• shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and HUMULIN N may need to be adjusted or stopped by your
healthcare provider if you have new or worse heart failure.
Get emergency medical help if you have:
• trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue,
or throat, sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of HUMULIN N include:
• low blood sugar (hypoglycemia), allergic reactions including reactions at the injection
site, skin thickening or pits at the injection site (lipodystrophy), itching, rash, weight
gain, and swelling of your hands and feet.
These are not all the possible side effects of HUMULIN N. Call your doctor for medical
advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of HUMULIN N:
Medicines are sometimes prescribed for purposes other than those listed in a Patient
Information leaflet. You can ask your pharmacist or healthcare provider for information
about HUMULIN N that is written for health professionals. Do not use HUMULIN N for a
condition for which it was not prescribed. Do not give HUMULIN N to other people, even
if they have the same symptoms that you have. It may harm them.
What are the ingredients in HUMULIN N?
Active Ingredient: insulin human (rDNA origin)
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
A1.01-LINN-5715-PIL-YYYYMMDD
Inactive Ingredients: protamine sulfate, glycerin, dibasic sodium phosphate,
metacresol, phenol, zinc oxide, water for injection, hydrochloric acid or sodium
hydroxide
For more information, call 1-800-545-5979 or go to www.humulin.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Patient Information revised February 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1997, YYYY, Eli Lilly and Company. All rights reserved.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Instructions for Use
HUMULIN® N KwikPen®
(human insulin [rDNA origin] isophane suspension) usage illustration
Read the Instructions for Use before you start taking HUMULIN N and each time you get another
HUMULIN® N KwikPen®. There may be new information. This information does not take the place
of talking to your healthcare provider about your medical condition or your treatment.
Do not share your HUMULIN N KwikPen with other people, even if the needle has been
changed. You may give other people a serious infection or get a serious infection from
them.
HUMULIN N KwikPen (“Pen”) is a disposable pen containing 3 mL (300 units) of U-100
HUMULIN® N (human insulin isophane suspension [rDNA origin]) insulin. You can inject from 1 to
60 units in a single injection.
HUMULIN N KwikPen has a blue and light green Label with a matching light green Dose Knob
(See the KwikPen Parts diagram below).
This Pen is not recommended for use by the blind or visually impaired without the
assistance of a person trained in the proper use of the product. usage illustration
Supplies you will need to give your HUMULIN N injection:
• HUMULIN N KwikPen
• KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles
recommended)
• alcohol swab
Preparing HUMULIN N KwikPen:
• Wash your hands with soap and water.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
u
s
a
g
e illustration
• Check the HUMULIN N KwikPen Label to make sure you are taking the right type of
insulin. This is especially important if you use more than 1 type of insulin.
• Do not use HUMULIN N past the expiration date printed on the Label or 14 days after you
start using the Pen.
• Always use a new needle for each injection to help ensure sterility and prevent
blocked needles. Do not reuse or share your needles with other people. You may
give other people a serious infection or get a serious infection from them.
Step 1:
•
Pull the Pen Cap straight off.
•
Wipe the Rubber Seal with an alcohol
swab.
-
Do not twist the cap.
-
Do not remove the HUMULIN N
KwikPen Label.
-
Do not attach the Needle before
mixing.
Step 2:
•
Gently roll the Pen between your
hands 10 times.
Step 3:
•
Move the Pen up and down (invert) 10
times.
Mixing by rolling and inverting the
Pen is important to make sure you
get the right dose.
Step 4:
•
Check the liquid in the Pen.
HUMULIN N should look white and
cloudy after mixing. Do not use if it
looks clear or has any lumps or
particles in it.
Step 5:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer
Needle Shield.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
us
a
ge illustration
u
s
a
g
e illustration
Step 6:
•
Push the capped Needle straight onto
the Pen and twist the Needle on until it
is tight.
Step 7:
•
Pull off the Outer Needle Shield. Do
not throw it away.
•
Pull off the Inner Needle Shield and
throw it away.
Priming the HUMULIN N KwikPen:
Prime the HUMULIN N KwikPen before each injection. Priming ensures the Pen is ready to
dose and removes air that may collect in the cartridge during normal use. If you do not prime
before each injection, you may get too much or too little insulin.
Step 8:
•
Turn the Dose Knob to select 2 units.
Step 9:
•
Hold the Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top.
Step 10:
•
Hold the Pen with Needle pointing up.
Push the Dose Knob in until it stops,
and “0” is seen in the Dose Window.
•
Hold the Dose Knob i n and count to
5 slowly.
A stream of insulin should be seen
from the needle.
-
If you do not see a stream of
insulin, repeat steps 8 to 10, no
more than 4 times.
-
If you still do not see a stream of
insulin, change the needle and
repeat steps 8 to 10.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Selecting your dose:
Step 11:
•
Turn the Dose Knob to select the
number of units you need to inject. The
Dose Indicator should line up with your
dose.
The dose can be corrected by turning
the Dose Knob in either direction until
the correct dose lines up with the Dose
Indicator.
-
The even numbers are printed on
the dial.
-
The odd numbers, after the
number 1, are shown as full lines.
(Example: 10 units shown)
(Example: 15 units shown)
• The HUMULIN N KwikPen will not let you dial more than the number of units left in the
Pen.
• If your dose is more than the number of units left in the Pen, you may either:
-
inject the amount left in your Pen and then use a new Pen to give the rest of your
dose, or
-
get a new Pen and inject the full dose.
• The Pen is designed to deliver a total of 300 units of insulin. The cartridge contains an
additional small amount of insulin that cannot be delivered.
Giving your HUMULIN N injection:
• Inject your HUMULIN N exactly as your healthcare provider has shown you.
• Change (rotate) your injection site for each injection.
• Do not try to change your dose while injecting HUMULIN N.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
u
s
a
g
e
illustration
Step 12:
•
Choose your injection site.
HUMULIN N is injected under the skin
(subcutaneously) of your stomach
area, buttocks, upper legs or upper
arms.
•
Wipe the skin with an alcohol swab,
and let the injection site dry before you
inject your dose.
Step 13:
•
Insert the Needle into your skin.
Step 14:
•
Put your thumb on the Dose Knob and
push the Dose Knob in until it stops.
•
Hold the Dose Knob in and slowly
count to 5.
Step 15:
•
Pull the Needle out of your skin.
You should see “0” in the Dose
Window. If you do not see “0” in the
Dose Window, you did not receive your
full dose.
-
If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
-
A drop of insulin at the needle tip is
normal. It will not affect your dose.
-
If you do not think you received
your full dose, do not take
another dose. Call Lilly at
1-800-LillyRx (1-800-545-5979) or
your healthcare provider for help.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
u
s
age illustration
Step 16:
•
Carefully replace the Outer Needle
Shield.
Step 17:
•
Unscrew the capped Needle and throw
it away.
•
Do not store the Pen with the Needle
attached to prevent leaking, blocking of
the Needle, and air from entering the
Pen.
Step 18:
•
Replace the Pen Cap by lining up the
Cap Clip with the Dose Indicator and
pushing straight on.
After your injection:
• Put your used needles in a FDA-cleared sharps disposal container right away after use.
Do not throw away (dispose of) loose needles in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to
come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be
state or local laws about how you should throw away used needles and syringes. For
more information about safe sharps disposal, and for specific information about sharps
disposal in the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless
your community guidelines permit this. Do not recycle your used sharps disposal
container.
• The used Pen may be discarded in your household trash after you have removed the
needle.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
How should I store my HUMULIN N KwikPen?
• Store unused HUMULIN N KwikPens in the refrigerator at 36°F to 46°F (2°C to 8°C). The
Pen you are currently using should be stored at room temperature, below 86°F (30°C).
• Do not freeze HUMULIN N. Do not use HUMULIN N if it has been frozen.
• Unused Pens may be used until the expiration date printed on the Label, if kept in the
refrigerator.
• The HUMULIN N Pen you are using should be thrown away after 14 days, even if it still
has insulin left in it.
• Keep HUMULIN N away from heat and out of the light.
General information about the safe and effective use of HUMULIN N KwikPen.
• Keep HUMULIN N KwikPen and needles out of the reach of children.
• Always use a new needle for each injection.
• Do not share your Pen or needles with other people. You may give other people a
serious infection or get a serious infection from them.
• Do not use the Pen if any part looks broken or damaged.
• Always carry an extra Pen in case yours is lost or damaged.
• If you cannot remove the Pen Cap, gently twist the Pen Cap back and forth, and then pull
the Pen Cap straight off.
• If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new
one.
-
It may help to push the Dose Knob more slowly during your injection.
• Use the space below to keep track of how long you should use each HUMULIN N
KwikPen.
-
Write down the date you start using your HUMULIN N KwikPen. Count forward 14
days.
-
Write down the date you should throw it away.
Example:
First used on _______ + 14 days = Throw out on ______
Date
Date
Pen 1 - First used on _______
Throw out on _______
Date
Date
Pen 2 - First used on _______
Throw out on _______
Date
Date
Pen 3 - First used on _______
Throw out on _______
Date
Date
Pen 4 - First used on _______
Throw out on _______
Date
Date
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
A2.01-LINN-9540-KP IFU-YYYMMDD
Pen 5 - First used on _______
Throw out on _______
Date
Date
If you have any questions or problems with your HUMULIN N KwikPen, contact Lilly at
1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help. For more information on
HUMULIN N KwikPen and insulin, go to www.lilly.com.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
HUMULIN® and HUMULIN® KwikPen® are trademarks of Eli Lilly and Company.
Revised: February 2015
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2013, YYYY, Eli Lilly and Company. All rights reserved.
HUMULIN N KwikPen meets the current dose accuracy and functional requirements of ISO
11608-1:2000.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
HUMULIN® (HU-mu-lin) N
(human insulin [rDNA origin] isophane suspension)
vial (100 Units/mL, U-100)
Read the Instructions for Use before you start taking HUMULIN N and each time you get a new
HUMULIN N vial. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
Do not share your syringes with other people, even if the needle has been changed. You
may give other people a serious infection or get a serious infection from them.
Supplies needed to give your injection:
• a HUMULIN N vial
• a U-100 insulin syringe and needle
• 2 alcohol swabs
• 1 sharps container for throwing away used needles and syringes. See “Disposing of
used needles and syringes” at the end of these instructions.
usage illus
trat
ion
Preparing your HUMULIN N dose:
• Wash your hands with soap and water.
• Check the HUMULIN N label to make sure you are taking the right type of insulin.
This is especially important if you use more than 1 type of insulin.
• Do not use HUMULIN N past the expiration date printed on the label or 31 days after
you first use it.
• Always use a new syringe or needle for each injection to help ensure sterility and
prevent blocked needles. Do not reuse or share your syringes or needles with
other people. You may give other people a serious infection or get a serious
infection from them.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
g
e
i
l
lustration
Step 1:
Gently roll the vial between the palms of your hands at
least 10 times.
Step 2:
Invert the vial at least 10 times.
Do not shake.
Mixing is important to make sure y ou get the right dose.
Humulin N should look white and cloudy after mixing. Do
not use it if it looks clear or contains any lumps or
particles.
Step 3:
If you are using a new vial, pull off the plastic Protective
Cap, but do not remove the Rubber Stopper.
Step 4:
Wipe the Rubber Stopper with an alcohol swab.
Step 5:
Hold the syringe with the needle pointing up. Pull down on
the Plunger until the tip of the Plunger reaches the line for
the number of units for your prescribed dose.
Step 6:
Push the needle through the Rubber Stopper of the vial.
(Ex
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
g
e
i
l
l
u
s
t
ration
Step 7:
Push the plunger all the way in. This puts air into the vial.
Step 8:
Turn the vial and syringe upside down and slowly pull the
Plunger down until the tip is a few units past the line for
your prescribed dose.
If there are air bubbles, tap the syringe gently a few times
to let any air bubbles rise to the top.
Step 9:
Slowly push the Plunger up until the tip reaches the line for
your prescribed dose.
Check the syringe to make sure that you have the right
(E
dose.
Step 10:
Pull the syringe out of the vial’s Rubber Stopper.
Giving your HUMULIN N injection:
• Inject your insulin exactly as your healthcare provider has shown you.
• Change (rotate) your injection site for each injection.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
ge illustration
Step 11:
Choose your injection site.
HUMULIN N is injected under the skin (subcutaneously) of
your stomach area (abdomen), buttocks, upper legs or
upper arms.
Wipe the skin with an alcohol swab. Let the injection site
dry before you inject your dose.
Step 12:
Insert the needle into your skin.
Step 13:
Push down on the Plunger to inject your dose.
The needle should stay in your skin for at least 5 seconds
to make sure you have injected all of your insulin dose.
Step 14:
Pull the needle out of your skin.
• If you see blood after you take the needle out of
your skin, press the injection site with a piece of
gauze or an alcohol swab. Do not rub the ar
ea.
• Do not recap the needle. Recapping t he needle can
lead to a needle stick injury.
Disposing of used needles and syringes:
• Put your used needles and syringes in a FDA-cleared sharps disposal container right away
after use. Do not throw away (dispose of) loose needles and syringes in your household
trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to
come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be state
or local laws about how you should throw away used needles and syringes. For more
information about safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
• Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
How should I store HUMULIN N?
All unopened HUMULIN N vials:
• Store all unopened vials in the refrigerator.
• Do not freeze. Do not use if it has been frozen.
• Keep away from heat and out of direct light.
• Unopened vials can be used until the expiration date on the carton and label, if they have
been stored in the refrigerator.
• Unopened vials should be thrown away after 31 days, if they are stored at room temperature.
After HUMULIN N vials have been opened:
• Store opened vials in the refrigerator or at room temperature below 86°F (30°C) for up to 31
days.
• Keep away from heat and out of direct light.
• Throw away all opened vials after 31 days of use, even if there is still insulin left in the vial.
General information about the safe and effective use of HUMULIN N.
• Keep HUMULIN N vials, syringes, needles, and all medicines out of the reach of children.
• Always use a new syringe or needle for each injection.
• Do not reuse or share your syringes or needles with other people. You may give other
people a serious infection or get a serious infection from them.
If you have any questions or problems with your HUMULIN, contact Lilly at 1-800-Lilly-Rx (1
800-545-5979) or call your healthcare provider for help. For more information on HUMULIN and
insulin, go to www.humulin.com.
Scan this code to launch the humulin.com website
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Humulin® is a trademark of Eli Lilly and Company.
Instructions for Use revised: February 2015
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A2.01-LINN-8530-VIAL IFU-YYYYMMDD
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, YYYY, Eli Lilly and Company. All rights reserved.
Reference ID: 3722216
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lilly
Prefilled Insulin Delivery Device
User Manual
Instructions for Use
Read and follow all of these
instructions carefully. If you do not
follow these instructions completely,
you may get too much or too little
insulin.
Every time you inject:
• Use a new needle
• Prime to make sure the Pen is ready to
dose
• Make sure you got your full dose (see page
18)
Also, read the “Patient Information” enclosed
in your Pen box.
Pen Features
• A multiple dose, prefilled insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
Do not share your Pen with other people, even if the needle has
been changed. You may give other people a serious infection or
get a serious infection from them. usage illustration
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______________________________________________________________
______________________________________________________________
Table of Contents
Pen Parts ..........................................................................................................3
Important Notes................................................................................................ 4
Preparing the Pen ............................................................................................ 6
Attaching the Needle ........................................................................................ 8
Priming the Pen.............................................................................................. 10
Setting a Dose................................................................................................ 14
Injecting a Dose ............................................................................................. 16
Following an Injection..................................................................................... 18
Questions and Answers ................................................................................. 20
2
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3
Pen Parts
usage illustratio
n
3
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Important Notes
• Read and follow all of these instructions carefully. If you do not follow these
instructions completely, you may get too much or too little insulin.
• Always use a new needle for each injection to help ensure sterility and prevent
blocked needles. Do not reuse or share your needles with other people. You
may give other people a serious infection or get a serious infection from them.
• Be sure a needle is completely attached to the Pen before priming, setting
the dose and injecting your insulin.
• Prime every time.
• The Pen must be primed before each injection to make sure the Pen is
ready to dose. Performing the priming step is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect
in the insulin cartridge during normal use. See Section III. “Priming the Pen”,
pages 10-13.
• If you do not prime, you may get too much or too little insulin.
• Make sure you get your full dose.
• To make sure you get your full dose, you must push the injection button all the
way down until you see a diamond (♦) or an arrow (
) in the center of the dose
window. See “Following an Injection”, page 18.
• The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
• Do not share your Pen with other people, even if the needle has been changed.
You may give other people a serious infection or get a serious infection from
them.
• Keep your Pen and needles out of the reach of children.
• Pens that have not been used should be stored in a refrigerator but not in a freezer.
Do not use a Pen if it has been frozen. Refer to the “Patient Information” for
complete storage instructions.
4
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Important Notes
(Continued)
• After a Pen is used for the first time, it should NOT be refrigerated but should be
kept at room temperature [below 86°F (30°C)] and away from direct heat and light.
• An unrefrigerated Pen should be discarded according to the time specified in the
“Patient Information”, even if it still contains insulin.
• Never use a Pen after the expiration date stamped on the label.
• Do not store your Pen with the needle attached. Doing so may allow insulin to leak
from the Pen and air bubbles to form in the cartridge. Additionally, with suspension
(cloudy) insulins, crystals may clog the needle.
• Always carry an extra Pen in case yours is lost or damaged.
• Follow your Health Care Professional’s instruction for safe handling of needles and
disposal of empty pens.
• This Pen is not recommended for use by blind or visually impaired persons without
the assistance of a person trained in the proper use of the product.
• The directions regarding needle handling are not intended to replace local, Health
Care Professional, or institutional policies.
• Any changes in insulin should be made cautiously and only under medical
supervision.
5
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I. Preparing the Pen
1. Before proceeding, refer to the “Patient Information” for instructions on checking the
appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has
been prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove. usage illustration
6
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I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges
contain a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal
on the end of the Pen. usage illustration
7
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II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen
needles.
Always use a new needle for each injection. Do not reuse or share your needles
with other people. You may give other people a serious infection or get a serious
infection from them.
Do not push injection button without a needle attached. Storing the Pen with the
needle attached may allow insulin to leak from the Pen and air bubbles to form in
the cartridge.
1. Remove the paper tab from the outer needle
shield. usage illustration
2. Attach the capped needle onto the end of the
Pen by turning it clockwise until tight. usage illustration
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II. Attaching the Needle
(Continued)
3. Hold the Pen with the needle pointing up and
remove the outer needle shield. Keep it to
use during needle removal. usage illustration
4. Remove the inner needle shield and discard.
9
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III. Priming the Pen
• Prime every time. The Pen must be primed to a stream of insulin (not just a few
drops) before each injection to make sure the Pen is ready to dose.
• You may need to prime a new Pen up to six times before a stream of insulin
appears.
• If you do not prime, you may get too much or too little insulin.
• Always use a new needle for each injection.
1. Make sure the arrow (
) is in the center of the
dose window as shown.
usage illustration
1. If you do not see the arrow in the center of the
dose window, push in the injection button fully
and turn the dose knob until the arrow is seen
in the center of the dose window.
10
usage illustration
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III. Priming the Pen
(Continued)
3. With the arrow in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window. usage illustration
4. Turn the dose knob clockwise until the number
“2” is seen in the dose window. If the number
you have dialed is too high, simply turn the
dose knob backward until the number “2” is
seen in the dose window. usage illustration
11
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III. Priming the Pen
(Continued)
5. Hold your Pen with the needle pointing straight
up. Tap the clear cartridge holder gently with
your finger so any air bubbles collect near the
top.
Using your thumb, if possible, push in the
injection button completely. Keep pressing and
continue to hold the injection button firmly
while counting slowly to 5. You should see a
stream of insulin come out of the tip of the
needle.
If a stream of insulin does not come out of the
tip of the needle, repeat steps 1 through 5. If
after six attempts a stream of insulin does not
come out of the tip of the needle, change the
needle. Repeat steps 1 through 5 up to two
more times. If you are still unable to get insulin
flowing out of the needle, do NOT use the
Pen. Contact your Health Care Professional or
Lilly.
12 usage illustration
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III. Priming the Pen
(Continued)
6. At the completion of the priming step, a
diamond (♦) must be seen in the center of the
dose window. If a diamond (♦) is not seen in
the center of the dose window, continue
pushing on the injection button until you see a
diamond (♦) in the center of the dose window. usage illustration
Correct
Note: A small air bubble may remain in the cartridge after the completion of
the priming step. If you have properly primed the Pen, this small air bubble
will not affect your insulin dose.
7. Now you are ready to set your dose. See next page.
13
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u
s
age illustration
IV. Setting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not push in the injection button while setting your dose. Failure to
follow these instructions carefully may result in getting too much or too little
insulin. If you accidentally push the injection button while setting your dose,
you must prime the Pen again before injecting your dose. See Section III.
“Priming the Pen”, pages 10-13.
1. A diamond must be seen in the center of the dose wind
If you do not see a diamond in the center of the dose
window, the Pen has not been primed correctly and
you are not ready to set your dose. Before continuing,
repeat the priming steps.
ow before setting your dose.
2. Turn the dose knob clockwise until the arrow (
) is seen in the center of the dose window
and the notches on the Pen and dose knob are
in line.
usage illustration
14
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IV. Setting a Dose
(Continued)
3. With the arrow (
) in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window. A dose cannot be dialed until the dose
knob is pulled out. usage illustration
4. Turn the dose knob clockwise until your dose
is seen in the dose window. If the dose you
have dialed is too high, simply turn the dose
knob backward until the correct dose is seen in
the dose window.
5. If you cannot dial your full dose, see the “Questions and Answers” section,
Question 6, at the end of this manual.
15
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V. Injecting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not attempt to change the dose after you begin to push in the
injection button. Failure to follow these instructions carefully may result in
getting too much or too little insulin.
• The effort needed to push in the injection button may increase while you are
injecting your insulin dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers” section, Question 8, at the end
of this manual.
• Do not inject a dose unless the Pen is primed, just before injection, or you may get
too much or too little insulin.
• If you have set a dose and pushed in the injection button without a needle attached
or if no insulin comes out of the needle, see the “Questions and Answers” section,
Questions 1 and 2.
16
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u
s
a
g
e illustration
V. Injecting a Dose
(Continued)
1. Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2. Insert the needle into your skin. Inject the
insulin by using your thumb, if possible, to
push in the injection button completely. usage illustration
3. Keep pressing and continue to hold the
injection button firmly while counting
slowly to 5.
4. When the injection is done, a diamond (♦) or an
arrow (
) must be seen in the center of the dose
window. This means your full dose has been
delivered. If you do not see a diamond or an
arrow in the center of the dose window, you
did not get your full dose. Contact your Health
Care Professional for additional instructions.
Correct
17
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VI. Following an Injection
1. Make sure you got your full dose by checking
that the injection button has been completely
pushed in and you can see a diamond (♦) or
an arrow (
) in the center of the dose window.
If you do not see a diamond (♦) or an arrow (
) in the center of the dose window, you have
not received your full dose. Contact your
Health Care P
rofessional for additional
instructions.
2. Carefully replace the outer needle shield as
instructed by your Health Care Professional. usage illustration
usage
illustr
ation
18
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VI. Following an Injection
(Continued)
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly throw it away as directed by your
Health Care Professional. usage illustration
4. Replace the cap on the Pen. usage illustration
5. The Pen that you are using should NOT be refrigerated but should be kept at room
temperature [below 86°F (30°C)] and away from direct heat and light. It should be
discarded according to the time specified in the “Patient Information”, even if it still
contains insulin.
Do not store or dispose of the Pen with a needle attached. Storing the Pen with
the needle attached may allow insulin to leak from the Pen and air bubbles to
form in the cartridge.
19
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Questions and Answers
Problem
Action
1. Dose dialed and injection
button pushed in without a
needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen.
2. Insulin does not come out
of the needle.
Note: You may need to prime
a new pen up to six times
before a stream of insulin
appears.
To obtain an accurate dose you must:
1) Always attach a new needle to help
ensure sterility and prevent blocked
needles.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen. See Section III. “Priming
the Pen”, pages 10-13.
20
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Questions and Answers
(Continued)
Problem
Action
3. Why do I need to prime a
The first time you use a new pen, priming up
new pen up to six times?
to six times may be needed to see a stream
of insulin come out of the tip of the needle. If
you do not prime until you see a stream of
insulin, you may get too much or too little
insulin.
4. Wrong dose (too high or
If you have not pushed in the injection
too low) dialed.
button, simply turn the dose knob backward
or forward to correct the dose.
5. Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing
down. The scale (20 units between marks)
on the clear cartridge holder shows an
estimate of the number of units remaining.
These numbers should not be used for
measuring an insulin dose.
21
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Questions and Answers
(Continued)
Problem
Action
6. Full dose cannot be dialed.
The Pen will not allow you to dial a dose
greater than the number of insulin units
remaining in the cartridge. For example, if
you need 31 units and only 25 units remain
in the Pen, you will not be able to dial past
25. Do not attempt to dial past this point.
(The insulin that remains is unusable and
not part of the 300 units.) If a partial dose
remains in the Pen you may either:
1) Give the partial dose and then give the
remaining dose using a new Pen, or
2) Give the full dose with a new Pen.
7. A small amount of insulin
The Pen design prevents the cartridge from
remains in the cartridge but
being completely emptied. The Pen has
a dose cannot be dialed.
delivered 300 units of usable insulin.
22
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Questions and Answers
(Continued)
Problem
Action
8. Cannot completely push in
1) Needle is not attached or is clogged.
the injection button when
a. Attach a new needle to help ensure
priming the Pen or injecting
sterility and prevent blocked needles.
a dose.
b. Push in the injection button
completely (even if a “0” is seen in
the window) until a diamond (♦) or an
arrow (
) is seen in the center of the
dose window.
c. Prime the Pen.
2)
If you are sure insulin is coming out of
the needle, push in the injection button
more slowly to reduce the effort needed
and maintain a constant pressure until
the injection button is completely
pushed in.
23
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A1.01-PEN-9117-IFU-YYYYMMDD
For additional information call,
1-800-LILLY-RX (1-800-545-5979),
or visit our website at www.Humalog.com
Revised February 2015
Manufactured by Lilly France S.A.S.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
24
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| custom-source | 2025-02-12T13:43:21.080403 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018781s154lbl.pdf', 'application_number': 18781, 'submission_type': 'SUPPL ', 'submission_number': 154} |
1,528 |
1
5.0 PA 9143-A FSAMP
1
INFORMATION FOR THE PATIENT
2
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
3
HUMULIN® 70/30 Pen
4
70% HUMAN INSULIN
5
ISOPHANE SUSPENSION
6
AND
7
30% HUMAN INSULIN INJECTION
8
(rDNA ORIGIN)
9
100 Units per mL (U-100)
10
WARNINGS
11
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM
12
ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL
13
TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND
14
BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS.
15
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
16
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
17
MANUFACTURER, TYPE (E.G., REGULAR, NPH, LENTE, ETC), SPECIES
18
(BEEF, PORK, BEEF-PORK, HUMAN), OR METHOD OF MANUFACTURE
19
(rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED
20
FOR A CHANGE IN DOSAGE.
21
SOME PATIENTS TAKING HUMULIN (HUMAN INSULIN, rDNA ORIGIN)
22
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH
23
ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY
24
OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS
25
OR MONTHS.
26
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW
27
THE “DISPOSABLE INSULIN DELIVERY DEVICE USER MANUAL” AND
28
THIS “INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS
29
PRODUCT.
30
BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A
31
NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE.
32
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES
33
OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR
34
THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL
35
USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE A WRONG DOSE (see also
36
INSTRUCTIONS FOR PEN USE section).
37
DIABETES
38
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
39
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
40
the pancreas does not make enough insulin to meet your body’s needs.
41
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
42
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
43
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
44
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
45
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
sugar is maintained as close to normal as possible. The American Diabetes Association
46
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
47
hemoglobin A1c (HbA1c) is more than 7%, consult your doctor. A change in your diabetes
48
therapy may be needed. If your blood tests consistently show below-normal glucose levels, you
49
should also let your doctor know. Proper control of your diabetes requires close and constant
50
cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat
51
a balanced diet, exercise regularly, and take your insulin injections as prescribed.
52
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
53
wear diabetic identification so that appropriate treatment can be given if complications occur
54
away from home.
55
70/30 HUMAN INSULIN
56
Description
57
Humulin is synthesized in a non-disease-producing special laboratory strain of
58
Escherichia coli bacteria that has been genetically altered by the addition of the human gene for
59
insulin production. Humulin 70/30 is a mixture of 70% Human Insulin Isophane Suspension
60
and 30% Human Insulin Injection, (rDNA origin). It is an intermediate-acting insulin combined
61
with the more rapid onset of action of regular insulin. The duration of activity may last up to
62
24 hours following injection. The time course of action of any insulin may vary considerably in
63
different individuals or at different times in the same individual. As with all insulin preparations,
64
the duration of action of Humulin 70/30 is dependent on dose, site of injection, blood supply,
65
temperature, and physical activity. Humulin 70/30 is a sterile suspension and is for subcutaneous
66
injection only. It should not be used intravenously or intramuscularly. The concentration of
67
Humulin 70/30 in the Humulin 70/30 Pen is 100 units/mL (U-100).
68
Identification
69
Humulin disposable insulin delivery devices, by Eli Lilly and Company, are available in
70
2 formulations — NPH and 70/30.
71
Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT
72
USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION.
73
The Humulin 70/30 Pen is available in boxes of 5 disposable insulin delivery devices (“insulin
74
Pens”). The Humulin 70/30 Pen is not designed to allow any other insulin to be mixed in its
75
cartridge, or for the cartridge to be removed.
76
Always examine the appearance of Humulin 70/30 suspension in the insulin Pen before
77
administering a dose. A cartridge of Humulin 70/30 contains a small glass bead to assist in
78
mixing. Humulin 70/30 Pen must be rolled between the palms 10 times and inverted 180°
79
10 times before each injection so that the contents are uniformly mixed (see Figures 1 and 2).
80
Inspect the Humulin 70/30 suspension for uniform mixing and repeat the above steps as
81
necessary.
82
Figure 1.
Figure 2.
83
Humulin 70/30 should look uniformly cloudy or milky after mixing. Do not use if the insulin
84
substance (the white material) remains visibly separated from the liquid after mixing. Do not use
85
the Humulin 70/30 Pen if there are clumps in the insulin after mixing. Do not use the
86
Humulin 70/30 Pen if solid white particles stick to the walls of the cartridge, giving it a frosted
87
appearance.
88
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Always check the appearance of the Humulin 70/30 suspension in the insulin Pen before using,
89
and if you note anything unusual in the appearance of Humulin 70/30 suspension or notice your
90
insulin requirements changing markedly, consult your doctor.
91
Never attempt to remove the cartridge from the Humulin 70/30 Pen. Inspect the cartridge
92
through the clear cartridge holder.
93
Storage
94
Humulin 70/30 Pens that have not beed used should be stored in a refrigerator but not in the
95
freezer. The Humulin 70/30 Pen that you are currently using should not be refrigerated but
96
should be kept as cool as possible (below 86°F [30°C]) and away from heat and light. Do not use
97
an insulin Pen if it has been frozen. Unrefrigerated Humulin 70/30 Pens must be discarded
98
after 10 days, even if they still contain insulin. Do not use Humulin 70/30 Pens after the
99
expiration date stamped on the label.
100
INSTRUCTIONS FOR PEN USE
101
It is important to read, understand, and follow the instructions in the “Disposable Insulin
102
Delivery Device User Manual” before using. Failure to follow instructions may result in a wrong
103
insulin dose. The Pen must be primed before each injection to make sure the Pen is ready to
104
dose. Performing the priming step is important to confirm that insulin comes out when you push
105
the injection button, and to remove air that may collect in the insulin cartridge during normal
106
use.
107
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
108
PREPARING THE PEN FOR INJECTION
109
1.
Always check the appearance of the Humulin 70/30 suspension in the insulin Pen before
110
using.
111
2.
Roll the Humulin 70/30 Pen between the palms 10 times (see Figure 1 above).
112
3.
Holding the Humulin 70/30 Pen by one end, invert it 180° slowly 10 times to allow the
113
glass bead to travel the full length of the cartridge with each inversion (see Figure 2
114
above). The cartridge is contained in the clear cartridge holder of the Humulin 70/30 Pen.
115
4.
Inspect the appearance of the Humulin 70/30 suspension to make sure the contents look
116
uniformly cloudy or milky. If not, repeat the above steps until the contents are mixed. Do
117
not use a Humulin 70/30 Pen if there are clumps in the insulin or if solid white particles
118
stick to the walls of the cartridge.
119
5.
Follow the instructions in the “Disposable Insulin Delivery Device User Manual” for
120
these steps:
121
• Preparing the Pen
122
• Attaching the Needle
123
• Priming the Pen. The Pen must be primed before each injection to make sure the Pen is
124
ready to dose. Performing the priming step is important to confirm that insulin comes out
125
when you push the injection button, and to remove air that may collect in the insulin
126
cartridge during normal use.
127
• Setting a Dose
128
• Injecting a Dose
129
• Following an Injection
130
PREPARING FOR INJECTION
131
1.
Wash your hands.
132
2.
To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
133
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
134
3.
Cleanse the skin with alcohol where the injection is to be made.
135
4.
With one hand, stabilize the skin by spreading it or pinching up a large area.
136
5.
Inject the dose as instructed by your doctor.
137
6.
After dispensing a dose, pull the needle out and apply gentle pressure over the injection
138
site for several seconds. Do not rub the area.
139
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
7.
Immediately after an injection, remove the needle from the Humulin 70/30 Pen. Doing so
140
will guard against contamination, leakage, reentry of air, and needle clogs. Do not reuse
141
needles. Place the used needle in a puncture-resistant disposable container and properly
142
dispose of it as directed by your Health Care Professional.
143
DOSAGE
144
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
145
Because each patient’s case of diabetes is different, this schedule has been individualized for
146
you.
147
Your usual insulin dose may be affected by changes in your food, activity, or work schedule.
148
Carefully follow your doctor’s instructions to allow for these changes. Other things that may
149
affect your insulin dose are:
150
Illness
151
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
152
Even if you are not eating, you will still require insulin. You and your doctor should establish a
153
sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine
154
glucose and ketones frequently and call your doctor as instructed.
155
Pregnancy
156
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
157
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
158
are nursing a baby, consult your doctor.
159
Medication
160
Insulin requirements may be increased if you are taking other drugs with hyperglycemic
161
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
162
requirements may be reduced in the presence of drugs with hypoglycemic activity, such as oral
163
hypoglycemics, salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
164
Always discuss any medications you are taking with your doctor.
165
Exercise
166
Exercise may lower your body’s need for insulin during and for some time after the activity.
167
Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the
168
area of injection site (for example, the leg should not be used for injection just prior to running).
169
Discuss with your doctor how you should adjust your regimen to accommodate exercise.
170
Travel
171
Persons traveling across more than 2 time zones should consult their doctor concerning
172
adjustments in their insulin schedule.
173
COMMON PROBLEMS OF DIABETES
174
Hypoglycemia (Insulin Reaction)
175
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
176
experienced by insulin users. It can be brought about by:
177
1.
Taking too much insulin.
178
2.
Missing or delaying meals.
179
3.
Exercising or working more than usual.
180
4.
An infection or illness (especially with diarrhea or vomiting).
181
5.
A change in the body’s need for insulin.
182
6.
Diseases of the adrenal, pituitary or thyroid gland, or progression of kidney or liver
183
disease.
184
7.
Interactions with other drugs that lower blood glucose, such as oral hypoglycemics,
185
salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
186
8.
Consumption of alcoholic beverages.
187
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
188
• sweating
• drowsiness
189
• dizziness
• sleep disturbances
190
• palpitation
• anxiety
191
• tremor
• blurred vision
192
• hunger
• slurred speech
193
• restlessness
• depressed mood
194
• tingling in the hands, feet, lips, or tongue
• irritability
195
• lightheadedness
• abnormal behavior
196
• inability to concentrate
• unsteady movement
197
• headache
• personality changes
198
Signs of severe hypoglycemia can include:
199
• disorientation
• seizures
200
• unconsciousness
• death
201
Therefore, it is important that assistance be obtained immediately.
202
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
203
conditions, such as long duration of diabetes, diabetic nerve disease, medications such as
204
beta-blockers, change in insulin preparations, or intensified control (3 or more insulin injections
205
per day) of diabetes.
206
A few patients who have experienced hypoglycemic reactions after transfer from
207
animal-source insulin to human insulin have reported that the early warning symptoms of
208
hypoglycemia were less pronounced or different from those experienced with their
209
previous insulin.
210
Without recognition of early warning symptoms, you may not be able to take steps to avoid
211
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
212
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
213
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
214
glucose is below your normal fasting glucose, you should consider eating or drinking
215
sugar-containing foods to treat your hypoglycemia.
216
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
217
Patients should always carry a quick source of sugar, such as candy mints or glucose tablets.
218
More severe hypoglycemia may require the assistance of another person. Patients who are unable
219
to take sugar orally or who are unconscious require an injection of glucagon or should be treated
220
with intravenous administration of glucose at a medical facility.
221
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
222
about these symptoms, you should monitor your blood glucose frequently to help you learn to
223
recognize the symptoms that you experience with hypoglycemia.
224
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
225
symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans,
226
and/or exercise programs to help you avoid hypoglycemia.
227
Hyperglycemia and Diabetic Acidosis
228
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
229
Hyperglycemia can be brought about by:
230
1.
Omitting your insulin or taking less than the doctor has prescribed.
231
2.
Eating significantly more than your meal plan suggests.
232
3.
Developing a fever, infection, or other significant stressful situation.
233
In patients with insulin-dependent diabetes, prolonged hyperglycemia can result in diabetic
234
acidosis. The first symptoms of diabetic acidosis usually come on gradually, over a period of
235
hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor
236
on the breath. With acidosis, urine tests show large amounts of glucose and acetone. Heavy
237
breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia
238
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
or diabetic acidosis can lead to nausea, vomiting, dehydration, loss of consciousness or death.
239
Therefore, it is important that you obtain medical assistance immediately.
240
Lipodystrophy
241
Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the
242
skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these
243
conditions, consult your doctor. A change in your injection technique may help alleviate the
244
problem.
245
Allergy to Insulin
246
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
247
injection of insulin. This condition, called local allergy, usually clears up in a few days to a few
248
weeks. In some instances, this condition may be related to factors other than insulin, such as
249
irritants in the skin cleansing agent or poor injection technique. If you have local reactions,
250
contact your doctor.
251
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
252
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
253
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
254
threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor
255
immediately.
256
ADDITIONAL INFORMATION
257
Additional information about diabetes may be obtained from your diabetes educator.
258
DIABETES FORECAST is a magazine designed especially for people with diabetes and their
259
families. It is available by subscription from the American Diabetes Association (ADA), P.O.
260
Box 363, Mt. Morris, IL 61054-0363. 1-800-DIABETES (1-800-342-2383).
261
Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research
262
Foundation International (JDRFI), 120 Wall Street 19th Floor, New York, NY 10005,
263
1-800-533-CURE (1-800-533-2873).
264
Additional information about Humulin and Humulin 70/30 Pens can be obtained by calling
265
The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).
266
Literature revised XXXX 2003
267
Manufactured by Lilly France S.A.S.
268
F-67640 Fegersheim, France
269
for Eli Lilly and Company
270
Indianapolis, IN 46285, USA
271
Copyright 1998, 2003, Eli Lilly and Company. All rights reserved.
272
5.0 PA 9143-A FSAMP
273
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
5.0 PA 9113-A FSAMP
Lilly
Disposable Insulin Delivery Device
User Manual
Instructions for Use
Read and follow these step by step instructions
carefully. Failure to follow these instructions
completely, including the priming step, may
result in a wrong insulin dose. Also, read
the INFORMATION FOR THE PATIENT
insert enclosed in your Pen box.
Pen Features
•
A multiple dose, disposable insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100
insulin
•
Delivers up to 60 units per dose
•
Doses can be dialed by single units
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Table of Contents
Pen Parts ......................................................................................................................3
Important Notes.............................................................................................................4
Preparing the Pen .........................................................................................................6
Attaching the Needle.....................................................................................................8
Priming the Pen...........................................................................................................10
Setting a Dose.............................................................................................................14
Injecting a Dose ..........................................................................................................16
Following an Injection..................................................................................................18
Questions and Answers ..............................................................................................20
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Pen Parts
3
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Rubber Seal
Clear Cartridge Holder
Pen Cap
Dose Window
Raised Notch
Dose Knob
Insulin Cartridge
Label
Raised Notch
Injection Button
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4
Important Notes
•
Please read these instructions carefully before using your Pen. Failure to
follow these instructions completely, including the priming step, may result in
a wrong dose.
•
Use a new needle for each injection.
•
Be sure a needle is attached to the Pen before priming, setting (dialing) the dose
and injecting your insulin.
•
The Pen must be primed before each injection to make sure the Pen is ready
to dose. Performing the priming step is important to confirm that insulin comes out
when you push the injection button, and to remove air that may collect in the insulin
cartridge during normal use. See Section III. Priming the Pen, pages 10-13.
•
If you do not prime, you may receive a wrong dose.
•
The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
•
Do not share your Pen.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Important Notes
(Continued)
•
Keep your Pen out of the reach of children.
•
Pens not being used should be stored in a refrigerator but not in a freezer. Refer to
the INFORMATION FOR THE PATIENT insert for complete storage instructions.
•
Do not store your Pen with the needle attached. Doing so may allow insulin to leak
from the Pen and air bubbles to form in the cartridge. Additionally, with suspension
(cloudy) insulins, crystals may clog the needle.
•
Always carry an extra Pen in case yours is lost or damaged.
•
Dispose of empty Pens as instructed by your Health Care Professional and without
the needle attached.
•
This Pen is not recommended for use by blind or visually impaired persons without
the assistance of a person trained in the proper use of the product.
•
Any changes in insulin should be made cautiously and only under medical
supervision.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
I. Preparing the Pen
1. Before proceeding, refer to the INFORMATION FOR THE PATIENT insert for
instructions on checking the appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has
been prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges
contain a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal
on the end of the Pen.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen
needles.
1. Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
2. Remove the paper tab from the outer needle
shield.
3. Attach the capped needle onto the end of the
Pen by turning it clockwise until tight.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle pointing up and
remove the outer needle shield. Keep it to
use during needle removal.
5. Remove the inner needle shield and discard.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
III. Priming the Pen
•
Always use a new needle for each injection.
•
The Pen must be primed before each injection to make sure the Pen is ready
to dose. Performing the priming step is important to confirm that insulin comes out
when you push the injection button, and to remove air that may collect in the insulin
cartridge during normal use.
•
If you do not prime, you may receive a wrong dose.
1. You cannot prime your Pen until you can see
the arrow (→) in the dose window. If a number
or a blank space is in the dose window, push in
the injection button completely until a
diamond (♦) or arrow (→) is seen. When
diamonds (♦) can be seen in the dose window,
turn the dose knob clockwise until the
arrow (→) is seen and the notches on the Pen
and dose knob are in line.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
III. Priming the Pen
(Continued)
2. With the arrow in the dose window, pull the
dose knob out in the direction of the arrow until
a “0” is seen in the dose window.
3. Turn the dose knob clockwise until the
number “2” is seen in the dose window. If the
number you have dialed is too high, simply turn
the dose knob backward until the number 2 is
seen in the dose window.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
III. Priming the Pen
(Continued)
4. Hold your Pen with the needle pointing up. Tap
the clear cartridge holder gently with your
finger so any air bubbles collect near the top.
Using your thumb, if possible, push in the
injection button completely and maintain
pressure until the insulin flow stops. You
should see either a drop or a stream of insulin
come out of the tip of the needle. If insulin does
not come out of the tip of the needle, repeat
steps 1 through 4. If after several attempts
insulin does not come out of the tip of the
needle, refer to the “Questions and Answers”
section at the end of this manual.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
III. Priming the Pen
(Continued)
5. At the completion of the priming step, a
diamond (♦) must be seen in the dose window.
Note: A small air bubble may remain in the cartridge after the completion of the priming
step. If you have properly primed the Pen, this small air bubble will not affect your
insulin dose.
6. Now you are ready to set your dose. See next page.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
IV. Setting a Dose
•
Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
•
Caution: Do not push in the injection button while setting your dose. Failure to
follow these instructions carefully may result in an inaccurate insulin dose.*
1. Pen has been primed and a diamond (♦) can be seen in the dose window.
2. Turn the dose knob clockwise until the
arrow (→) is seen in the dose window and the
notches on the Pen and dose knob are in line.
*See Page 16.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
IV. Setting a Dose
(Continued)
3. With the arrow (→) in the dose window, pull
the dose knob out in the direction of the
arrow until a “0” is seen in the dose window. A
dose cannot be dialed until the dose knob is
pulled out.
4. Turn the dose knob clockwise until your dose
is seen in the dose window. If the dose you
have dialed is too high, simply turn the dose
knob backward until the correct dose is seen in
the dose window.
5. If you cannot dial a full dose, see the “Questions and Answers” section at the end of
this manual.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
V. Injecting a Dose
•
Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
•
Caution: Do not attempt to change the dose after you begin to push in the
injection button. Failure to follow these instructions carefully may result in an
inaccurate insulin dose.*
•
The effort needed to push in the injection button may increase while you are
injecting your insulin dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers” section at the end of this
manual.
*
If you have set (dialed) a dose and pushed in the injection button without the needle
attached or if no insulin comes out of the needle, see the “Questions and Answers”
section.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
V. Injecting a Dose
(Continued)
1. Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2. Inject the insulin by using your thumb, if
possible, to completely push in the injection
button. When the injection button has been
completely pushed in (a diamond (♦) or
arrow (→) must be seen in the dose window
to indicate that the injection button has
been completely pushed in), continue to hold
it down and count slowly to 5. After dispensing
a dose, pull the needle out and apply gentle
pressure over the injection site for several
seconds. Do not rub the area.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
VI. Following an Injection
Do not store or dispose of the Pen with a needle attached. Storing the Pen with
the needle attached may allow insulin to leak from the Pen and air bubbles to
form in the cartridge.
1. Check that the injection button has been
completely pushed in and you can see a
diamond (♦) or arrow (→) in the dose window.
If a diamond (♦) or arrow (→) cannot be seen
in the dose window, your full dose has not
been delivered. Contact your Health Care
Professional immediately for additional
instructions.
2. Carefully replace the outer needle shield.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
VI. Following an Injection
(Continued)
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly dispose of it as directed by your
Health Care Professional.
4. Replace the cap on the Pen.
5. The Pen that you are currently using should be kept at a temperature below 86°F
(30°C) and away from heat and light. It should be discarded according to the time
specified in the INFORMATION FOR THE PATIENT insert, even if it still contains
insulin.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Questions and Answers
Problem
Action
Dose dialed and injection button pushed
in without a needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or arrow (→) is seen in
the dose window.
3) Prime the Pen.
Insulin does not come out of the needle.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or arrow (→) is seen in
the dose window.
3) Prime the Pen.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Questions and Answers
(Continued)
Problem
Action
Wrong dose (too high or too low) dialed.
If you have not pushed in the injection
button, simply turn the dose knob backward
or forward to correct the dose.
Not sure how much insulin remains in the
cartridge.
Hold the Pen with the needle end pointing
down. The scale (20 units between marks)
on the clear cartridge holder shows an
estimate of the number of units remaining.
These numbers should not be used for
measuring an insulin dose.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Questions and Answers
(Continued)
Problem
Action
Full dose cannot be dialed.
The Pen will not allow you to dial a dose
greater than the number of insulin units
remaining in the cartridge.
For example, if you need 31 units and only
25 units remain in the Pen, you will not be
able to dial past 25. Do not attempt to dial
past this point. (The insulin that remains is
unusable and not part of the 300 units.) If a
partial dose remains in the Pen you may
either:
1) Give the partial dose and then give the
remaining dose using a new Pen, or
2) Give the full dose with a new Pen.
A small amount of insulin remains in the
cartridge but a dose cannot be dialed.
The Pen design prevents the cartridge from
being completely emptied. The Pen has
delivered 300 units of usable insulin.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Questions and Answers
(Continued)
Problem
Action
Cannot completely push in the injection
button when priming the Pen or injecting
a dose.
1)
Needle is not attached or is clogged.
a. Attach a new needle.
b. Push in the injection button
completely (even if a “0” is seen in
the window) until a diamond (♦) or
arrow (→) is seen in the dose
window.
c. Prime the Pen.
2)
If you are sure insulin is coming out of
the needle, push in the injection button
more slowly to reduce the effort
needed and maintain a constant
pressure until the injection button is
completely pushed in.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
For additional information call,
1-800-LillyRx (1-800-545-5979)
Revised XXXX 2003
Manufactured by Lilly France S.A.S.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
5.0 PA 9113-A FSAMP
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.178364 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19717slr050_humilin_lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 50} |
1,529 |
1
A3.0 NL 3670 AMP
1
INFORMATION FOR THE PATIENT
2
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
3
HUMULIN 70/30 Pen
4
70% HUMAN INSULIN
5
ISOPHANE SUSPENSION
6
AND
7
30% HUMAN INSULIN INJECTION
8
(rDNA ORIGIN)
9
100 UNITS PER ML (U-100)
10
WARNINGS
11
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-
12
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
13
INSULIN PRODUCED BY YOUR BODY'S PANCREAS AND BECAUSE OF ITS
14
UNIQUE MANUFACTURING PROCESS.
15
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
16
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
17
MANUFACTURER, TYPE (E.G., REGULAR, NPH, LENTE, ETC), SPECIES
18
(BEEF, PORK, BEEF-PORK, HUMAN), OR METHOD OF MANUFACTURE
19
(rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED
20
FOR A CHANGE IN DOSAGE.
21
SOME PATIENTS TAKING HUMULIN (HUMAN INSULIN, rDNA ORIGIN)
22
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH
23
ANIMAL-SOURCE INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY
24
OCCUR WITH THE FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS
25
OR MONTHS.
26
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW
27
THE “DISPOSABLE INSULIN DELIVERY DEVICE USER MANUAL” AND
28
THIS INFORMATION FOR THE PATIENT INSERT BEFORE USING THIS
29
PRODUCT. BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A
30
NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE.
31
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES
32
OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR
33
THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL
34
USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE A WRONG DOSE (see also
35
INSTRUCTIONS FOR PEN USE section).
36
DIABETES
37
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
38
hormone is necessary for the body's correct use of food, especially sugar. Diabetes occurs when
39
the pancreas does not make enough insulin to meet your body's needs.
40
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
41
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
42
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
43
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
44
sugar is maintained as close to normal as possible. The American Diabetes Association
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
recommends that if your premeal glucose levels are consistently above 130 mg/dL or your
46
hemoglobin A1c (HbA1c) is more than 7%, consult your doctor. A change in your diabetes
47
therapy may be needed. If your blood tests consistently show below-normal glucose levels, you
48
should also let your doctor know. Proper control of your diabetes requires close and constant
49
cooperation with your doctor. Despite diabetes, you can lead an active and healthy life if you eat
50
a balanced diet, exercise regularly, and take your insulin injections as prescribed.
51
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
52
wear diabetic identification so that appropriate treatment can be given if complications occur
53
away from home.
54
70/30 HUMAN INSULIN
55
Description
56
Humulin is synthesized in a non-disease-producing special laboratory strain of Escherichia
57
coli bacteria that has been genetically altered by the addition of the human gene for insulin
58
production. Humulin 70/30 is a mixture of 70% Human Insulin Isophane Suspension and 30%
59
Human Insulin Injection, (rDNA origin). It is an intermediate-acting insulin combined with the
60
more rapid onset of action of regular insulin. The duration of activity may last up to 24 hours
61
following injection. The time course of action of any insulin may vary considerably in different
62
individuals or at different times in the same individual. As with all insulin preparations, the
63
duration of action of Humulin 70/30 is dependent on dose, site of injection, blood supply,
64
temperature, and physical activity. Humulin 70/30 is a sterile suspension and is for subcutaneous
65
injection only. It should not be used intravenously or intramuscularly. The concentration of
66
Humulin 70/30 in the Humulin 70/30 Pen is 100 units/mL (U-100).
67
Identification
68
Humulin disposable insulin delivery devices, manufactured by Eli Lilly and Company, are
69
available in 2 formulations--NPH and 70/30.
70
Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT
71
USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION.
72
The Humulin 70/30 Pen is available in boxes of 5 disposable insulin delivery devices (“insulin
73
Pens”). The Humulin 70/30 Pen is not designed to allow any other insulin to be mixed in its
74
cartridge, or for the cartridge to be removed.
75
Always examine the appearance of Humulin 70/30 suspension in the insulin Pen before
76
administering a dose. A cartridge of Humulin 70/30 contains a small glass bead to assist in
77
mixing. Humulin 70/30 Pen must be rolled between the palms 10 times and inverted 180°
78
10 times before each injection so that the contents are uniformly mixed (see Figures 1 and 2).
79
Inspect the Humulin 70/30 suspension for uniform mixing and repeat the above steps as
80
necessary.
81
Figure 1.
Figure 2.
82
Humulin 70/30 should look uniformly cloudy or milky after mixing. Do not use if the insulin
83
substance (the white material) remains visibly separated from the liquid after mixing. Do not use
84
the Humulin 70/30 Pen if there are clumps in the insulin after mixing. Do not use the
85
Humulin 70/30 Pen if solid white particles stick to the walls of the cartridge, giving it a frosted
86
appearance.
87
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Always check the appearance of the Humulin 70/30 suspension in the insulin Pen before using,
88
and if you note anything unusual in the appearance of Humulin 70/30 suspension or notice your
89
insulin requirements changing markedly, consult your doctor.
90
Never attempt to remove the cartridge from the Humulin 70/30 Pen. Inspect the cartridge
91
through the clear cartridge holder.
92
Storage
93
Not in-use (unopened): Humulin 70/30 Pens not in-use should be stored in a refrigerator but
94
not in the freezer. Do not use Humulin 70/30 Pen if it has been frozen.
95
In-use: Humulin 70/30 Pens in-use should NOT be refrigerated but should be kept at room
96
temperature (below 86°F [30°C]) away from direct heat and light. Humulin 70/30 Pens in-use
97
must be discarded after 10 days, even if they still contain Humulin 70/30.
98
Do not use Humulin 70/30 Pens after the expiration date stamped on the label.
99
INSTRUCTIONS FOR PEN USE
100
It is important to read, understand, and follow the instructions in the “Disposable Insulin
101
Delivery Device User Manual” before using. Failure to follow instructions may result in a
102
wrong insulin dose. The Pen must be primed before each injection to make sure the Pen is
103
ready to dose. Performing the priming step is important to confirm that insulin comes out
104
when you push the injection button, and to remove air that may collect in the insulin
105
cartridge during normal use.
106
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
107
PREPARING THE INSULIN PEN FOR INJECTION:
108
1.
Always check the appearance of the Humulin 70/30 suspension in the insulin Pen before
109
using.
110
2.
Roll the Humulin 70/30 Pen between the palms 10 times (see Figure 1 above).
111
3.
Holding the Humulin 70/30 Pen by one end, invert it 180° slowly 10 times to allow the
112
glass bead to travel the full length of the cartridge with each inversion (see Figure 2
113
above). The cartridge is contained in the clear cartridge holder of the Humulin 70/30 Pen.
114
4.
Inspect the appearance of the Humulin 70/30 suspension to make sure the contents look
115
uniformly cloudy or milky. If not, repeat the above steps until the contents are mixed. Do
116
not use a Humulin 70/30 Pen if there are clumps in the insulin or if solid white particles
117
stick to the walls of the cartridge.
118
5.
Follow the instructions in the “Disposable Insulin Delivery Device User Manual” for
119
these steps:
120
• Preparing the Pen
121
• Attaching the Needle
122
• Priming the Pen. The Pen must be primed before each injection to make sure the
123
Pen is ready to dose. Performing the priming step is important to confirm that insulin
124
comes out when you push the injection button, and to remove air that may collect in the
125
insulin cartridge during normal use.
126
• Setting a Dose
127
• Injecting a Dose
128
• Following an Injection
129
PREPARING FOR INJECTION:
130
1.
Wash your hands.
131
2.
To avoid tissue damage, choose a site for each injection that is at least ½ inch from the
132
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
133
3.
Cleanse the skin with alcohol where the injection is to be made.
134
4.
With one hand, stabilize the skin by spreading it or pinching up a large area.
135
5.
Inject the dose as instructed by your doctor.
136
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4
6.
After dispensing a dose, pull the needle out and apply gentle pressure over the injection
137
site for several seconds. Do not rub the area.
138
7.
Immediately after an injection, remove the needle from the Humulin 70/30 Pen. Doing so
139
will guard against contamination, leakage, reentry of air, and needle clogs. Do not reuse
140
needles. Place the used needle in a puncture-resistant disposable container and properly
141
dispose of it as directed by your Health Care Professional.
142
DOSAGE
143
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
144
Because each patient's case of diabetes is different, this schedule has been individualized for you.
145
Your usual insulin dose may be affected by changes in your food, activity, or work schedule.
146
Carefully follow your doctor's instructions to allow for these changes. Other things that may
147
affect your insulin dose are:
148
Illness
149
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
150
Even if you are not eating, you will still require insulin. You and your doctor should establish a
151
sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine
152
glucose and ketones frequently and call your doctor as instructed.
153
Pregnancy
154
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
155
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
156
are nursing a baby, consult your doctor.
157
Medication
158
Insulin requirements may be increased if you are taking other drugs with hyperglycemic
159
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
160
requirements may be reduced in the presence of drugs with hypoglycemic activity, such as oral
161
hypoglycemics, salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
162
Always discuss any medications you are taking with your doctor.
163
Exercise
164
Exercise may lower your body's need for insulin during and for some time after the activity.
165
Exercise may also speed up the effect of an insulin dose, especially if the exercise involves the
166
area of injection site (for example, the leg should not be used for injection just prior to running).
167
Discuss with your doctor how you should adjust your regimen to accommodate exercise.
168
Travel
169
Persons traveling across more than 2 time zones should consult their doctor concerning
170
adjustments in their insulin schedule.
171
COMMON PROBLEMS OF DIABETES
172
Hypoglycemia (Insulin Reaction)
173
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
174
experienced by insulin users. It can be brought about by:
175
1.
Taking too much insulin
176
2.
Missing or delaying meals
177
3.
Exercising or working more than usual
178
4.
An infection or illness (especially with diarrhea or vomiting)
179
5.
A change in the body's need for insulin
180
6.
Diseases of the adrenal, pituitary or thyroid gland, or progression of kidney or liver
181
disease
182
7.
Interactions with other drugs that lower blood glucose, such as oral hypoglycemics,
183
salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants
184
8.
Consumption of alcoholic beverages
185
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5
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
186
• sweating
• drowsiness
187
• dizziness
• sleep disturbances
188
• palpitation
• anxiety
189
• tremor
• blurred vision
190
• hunger
• slurred speech
191
• restlessness
• depressed mood
192
• tingling in the hands, feet, lips, or tongue
• irritability
193
• lightheadedness
• abnormal behavior
194
• inability to concentrate
• unsteady movement
195
• headache
• personality changes
196
Signs of severe hypoglycemia can include:
197
• disorientation
• seizures
198
• unconsciousness
• death
199
Therefore, it is important that assistance be obtained immediately.
200
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
201
conditions, such as long duration of diabetes, diabetic nerve disease, medications such as beta-
202
blockers, change in insulin preparations, or intensified control (3 or more insulin injections per
203
day) of diabetes.
204
A few patients who have experienced hypoglycemic reactions after transfer from animal-
205
source insulin to human insulin have reported that the early warning symptoms of
206
hypoglycemia were less pronounced or different from those experienced with their
207
previous insulin.
208
Without recognition of early warning symptoms, you may not be able to take steps to avoid
209
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
210
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
211
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
212
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
213
containing foods to treat your hypoglycemia.
214
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
215
Patients should always carry a quick source of sugar, such as candy mints or glucose tablets.
216
More severe hypoglycemia may require the assistance of another person. Patients who are unable
217
to take sugar orally or who are unconscious require an injection of glucagon or should be treated
218
with intravenous administration of glucose at a medical facility.
219
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
220
about these symptoms, you should monitor your blood glucose frequently to help you learn to
221
recognize the symptoms that you experience with hypoglycemia.
222
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
223
symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans,
224
and/or exercise programs to help you avoid hypoglycemia.
225
Hyperglycemia and Diabetic Acidosis
226
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
227
Hyperglycemia can be brought about by:
228
1.
Omitting your insulin or taking less than the doctor has prescribed
229
2.
Eating significantly more than your meal plan suggests
230
3.
Developing a fever, infection, or other significant stressful situation
231
In patients with insulin-dependent diabetes, prolonged hyperglycemia can result in diabetic
232
acidosis. The first symptoms of diabetic acidosis usually come on gradually, over a period of
233
hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor
234
on the breath. With acidosis, urine tests show large amounts of glucose and acetone. Heavy
235
breathing and a rapid pulse are more severe symptoms. If uncorrected, prolonged hyperglycemia
236
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6
or diabetic acidosis can lead to nausea, vomiting, dehydration, loss of consciousness or death.
237
Therefore, it is important that you obtain medical assistance immediately.
238
Lipodystrophy
239
Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the
240
skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these
241
conditions, consult your doctor. A change in your injection technique may help alleviate the
242
problem.
243
Allergy to Insulin
244
Local Allergy--Patients occasionally experience redness, swelling, and itching at the site of
245
injection of insulin. This condition, called local allergy, usually clears up in a few days to a few
246
weeks. In some instances, this condition may be related to factors other than insulin, such as
247
irritants in the skin cleansing agent or poor injection technique. If you have local reactions,
248
contact your doctor.
249
Systemic Allergy--Less common, but potentially more serious, is generalized allergy to insulin,
250
which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood
251
pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life threatening. If
252
you think you are having a generalized allergic reaction to insulin, notify a doctor immediately.
253
ADDITIONAL INFORMATION
254
Additional information about diabetes may be obtained from your diabetes educator.
255
DIABETES FORECAST is a national magazine designed especially for patients with
256
diabetes and their families and is available on subscription from the American Diabetes
257
Association, National Service Center, 1660 Duke Street, Alexandria, Virginia 22314,
258
1-800-DIABETES (1-800-342-2383).
259
Another publication, DIABETES COUNTDOWN, is available from the Juvenile Diabetes
260
Foundation, 120 Wall Street 19th Floor, New York, New York 10005-4001, 1-800-JDF-CURE
261
(1-800-533-2873).
262
Additional information about Humulin and Humulin 70/30 Pen can be obtained by calling
263
1-888-88-LILLY (1-888-885-4559).
264
Literature issued XXX 2003
265
Eli Lilly and Company, Indianapolis, IN 46285, USA
266
267
A3.0 NL 3670 AMP
PRINTED IN USA
268
269
Copyright © 1998, 2003, Eli Lilly and Company. All rights reserved.
270
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A3.0 NL 3730 AMP
____________________________________________________________________________
Lilly
Disposable Insulin Delivery Device
User Manual
____________________________________________________________________________
Instructions for Use
Read and follow these step by step instructions carefully. Failure to follow these instructions
completely, including the priming step, may result in a wrong insulin dose. Also, read the
Information for the Patient insert enclosed in your Pen box.
Pen Features
• A multiple dose, disposable insulin delivery device
(“insulin Pen”) containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
___________________________________________________________________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Table of Contents
______________________________________________________________________
Pen Parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Important Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Preparing the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Attaching the Needle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Priming the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Setting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Injecting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Following an Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
________________________________________________________________________
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Pen Parts
3
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Important Notes
•
Please read these instructions carefully before using your Pen. Failure to follow these
instructions completely, including the priming step, may result in a wrong dose.
•
Use a new needle for each injection.
•
Be sure a needle is attached to the Pen before priming, setting (dialing) the dose and injecting
your insulin.
•
The Pen must be primed before each injection to make sure the Pen is ready to dose.
Performing the priming step is important to confirm that insulin comes out when you push the
injection button, and to remove air that may collect in the insulin cartridge during normal use.
See Section III. Priming the Pen, pages 10-13.
•
If you do not prime, you may receive a wrong dose.
•
The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
•
Do not share your Pen.
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Important Notes
(Continued)
•
Keep your Pen out of the reach of children.
•
Pens that have not been used should be stored in a refrigerator but not in a freezer. Do not use
a Pen if it has been frozen. Refer to the Information for the Patient insert for complete storage
instructions.
•
After a Pen is used for the first time, it should NOT be refrigerated but should be kept at
room temperature [below 86°F (30°C)] and away from direct heat and light.
•
An unrefrigerated Pen should be discarded according to the time specified in the Information
for the Patient insert, even if it still contains insulin.
•
Never use a Pen after the expiration date stamped on the label.
•
Do not store your Pen with the needle attached. Doing so may allow insulin to leak from the
Pen and air bubbles to form in the cartridge. Additionally, with suspension (cloudy) insulins,
crystals may clog the needle.
•
Always carry an extra Pen in case yours is lost or damaged.
•
Dispose of empty Pens as instructed by your Health Care Professional and without the needle
attached.
•
This Pen is not recommended for use by blind or visually impaired persons without the
assistance of a person trained in the proper use of the product.
•
Any changes in insulin should be made cautiously and only under medical supervision.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
I. Preparing the Pen
1. Before proceeding, refer to the Information for the Patient insert for instructions on
checking the appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has been
prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7
I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges contain
a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal on the
end of the Pen.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen needles.
1. Always use a new needle for each injection. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
2. Remove the paper tab from the outer needle shield.
3. Attach the capped needle onto the end of the Pen by turning
it clockwise until tight.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle pointing up and remove the
outer needle shield. Keep it to use during needle
removal.
5. Remove the inner needle shield and discard.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
III. Priming the Pen
•
Always use a new needle for each injection.
•
The Pen must be primed before each injection to make sure the Pen is ready to dose.
Performing the priming step is important to confirm that insulin comes out when you push the
injection button, and to remove air that may collect in the insulin cartridge during normal use.
•
If you do not prime, you may receive a wrong dose.
1.
You cannot prime your Pen until you can see the arrow
(→) in the dose window. If a number or a blank space is
in the dose window, push in the injection button
completely until a diamond (♦) or arrow (→) is seen.
When diamonds (♦) can be seen in the dose window, turn
the dose knob clockwise until the arrow (→) is seen and
the notches on the Pen and dose knob are in line.
10
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11
III. Priming the Pen
(Continued)
2. With the arrow in the dose window, pull the dose knob
out in the direction of the arrow until a “0” is seen in the
dose window.
3. Turn the dose knob clockwise until the number “2” is
seen in the dose window. If the number you have dialed
is too high, simply turn the dose knob backward until the
number 2 is seen in the dose window.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
III. Priming the Pen
(Continued)
4. Hold your Pen with the needle pointing up. Tap the
clear cartridge holder gently with your finger so any air
bubbles collect near the top. Using your thumb, if
possible, push in the injection button completely and
maintain pressure until the insulin flow stops. You
should see either a drop or a stream of insulin come out
of the tip of the needle. If insulin does not come out of
the tip of the needle, repeat steps 1 through 4. If after
several attempts insulin does not come out of the tip of
the needle, refer to the “Questions and Answers”
section at the end of this manual.
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
13
III. Priming the Pen
(Continued)
5.
At the completion of the priming step, a diamond
(♦) must be seen in the dose window.
Note: A small air bubble may remain in the cartridge after the completion of the priming
step. If you have properly primed the Pen, this small air bubble will not affect your
insulin dose.
6. Now you are ready to set your dose. See next page.
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14
IV. Setting a Dose
•
Always use a new needle for each injection. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
•
Caution: Do not push in the injection button while setting your dose. Failure to follow
these instructions carefully may result in an inaccurate insulin dose.*
1. Pen has been primed and a diamond (♦) can be seen in the dose window.
2. Turn the dose knob clockwise until the arrow (→)
is seen in the dose window and the notches on the
Pen and dose knob are in line.
* See Page 16.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
IV. Setting a Dose
(Continued)
3. With the arrow (→) in the dose window, pull the
dose knob out in the direction of the arrow until a
“0” is seen in the dose window. A dose cannot be
dialed until the dose knob is pulled out.
4. Turn the dose knob clockwise until your dose is
seen in the dose window. If the dose you have
dialed is too high, simply turn the dose knob
backward until the correct dose is seen in the
dose window.
5. If you cannot dial a full dose, see the “Questions and Answers” section at the end
of this manual.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
V. Injecting a Dose
•
Always use a new needle for each injection. Storing the Pen with the needle attached
may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
•
Caution: Do not attempt to change the dose after you begin to push in the injection
button. Failure to follow these instructions carefully may result in an inaccurate insulin
dose.*
•
The effort needed to push in the injection button may increase while you are injecting
your insulin dose. If you cannot completely push in the injection button, refer to the
“Questions and Answers” section at the end of this manual.
*
If you have set (dialed) a dose and pushed in the injection button without a needle attached or
if no insulin comes out of the needle, see the “Questions and Answers” section.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
V. Injecting a Dose
(Continued)
1.
Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
Inject the insulin by using your thumb, if
possible, to completely push in the injection
button. When the injection button has been
completely pushed in (a diamond (♦) or arrow
(→) must be seen in the dose window to
indicate that the injection button has been
completely pushed in), continue to hold it down
and count slowly to 5. After dispensing a dose,
pull the needle out and apply gentle pressure over
the injection site for several seconds. Do not rub
the area.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
VI. Following an Injection
Do not store or dispose of the Pen with a needle attached. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
1.
Check that the injection button has been
completely pushed in and you can see a
diamond (♦) or arrow (→) in the dose window.
If a diamond (♦) or arrow (→) cannot be seen in
the dose window, your full dose has not been
delivered. Contact your Health Care
Professional immediately for additional
instructions.
2.
Carefully replace the outer needle shield.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
VI. Following an Injection
(Continued)
3.
Remove the capped needle by turning it
counterclockwise and dispose of it as directed
by your Health Care Professional. Place the
used needle in a puncture-resistant disposable
container and properly dispose of it as directed
by your Health Care Professional.
4.
Replace the cap on the Pen.
5. The Pen that you are using should NOT be refrigerated but kept at room temperature [below
86°F (30°C)] and away from direct heat and light. It should be discarded according to the
time specified in the Information for the Patient insert, even if it still contains insulin.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Questions and Answers
Problem
Action
Dose dialed and injection button
pushed in without a needle
attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely (even if a
“0” is seen in the window) until a diamond (♦) or
arrow (→) is seen in the dose window.
3) Prime the Pen.
Insulin does not come out of the
needle.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely (even if a
“0” is seen in the window) until a diamond (♦) or
arrow (→) is seen in the dose window.
3) Prime the Pen.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Questions and Answers
(Continued)
Problem
Action
Wrong dose (too high or too low)
dialed.
If you have not pushed in the injection button, simply
turn the dose knob backward or forward to correct the
dose.
Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing down. The
scale (20 units between marks) on the clear cartridge
holder shows an estimate of the number of units
remaining. These numbers should not be used for
measuring an insulin dose.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Questions and Answers
(Continued)
Problem
Action
Full dose cannot be dialed.
The Pen will not allow you to dial a dose greater than
the number of insulin units remaining in the cartridge.
For example, if you need 31 units and only 25 units
remain in the Pen, you will not be able to dial past 25.
Do not attempt to dial past this point. (The insulin that
remains is unusable and not part of the 300 units.) If a
partial dose remains in the Pen you may either:
1) Give the partial dose and then give the remaining
dose using a new Pen, or
2) Give the full dose with a new Pen.
A small amount of insulin
remains in the cartridge but a
dose cannot be dialed.
The Pen design prevents the cartridge from being
completely emptied. The Pen has delivered 300 units of
usable insulin.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Questions and Answers
(Continued)
Problem
Action
Cannot completely push in the
injection button when priming the
Pen or injecting a dose.
1) Needle is not attached or is clogged.
a. Attach a new needle.
b. Push in the injection button completely (even if
a “0” is seen in the window) until a diamond (♦)
or arrow (→) is seen in the dose window.
c. Prime the Pen.
2) If you are sure insulin is coming out of the needle,
push in the injection button more slowly to reduce
the effort needed and maintain a constant pressure
until the injection button is completely pushed in.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
For additional information call,
1-888-88-LILLY
Literature issued XXX 2003
Eli Lilly and Company, Indianapolis, IN 46285, USA
A3.0 NL 3730 AMP
PRINTED IN USA
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
W W 9 1 8 0 A M X
This label may not be the latest approved by FDA.
nt labeling information, please visit https://www.fda.gov/d
C-1004
C-1004
C-1004
FC 2481 AMS
FC 2481 AMS
FC 2481 AMS
If the seal is broken before first use, contact pharmacist
If the seal is broken before first use, contact pharmacist
NDC 0002-8770-01
freezing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.272133 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19717scm054_humulin_lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 54} |
1,532 |
1
A1.0 NL 5691 AMP
A1.0 NL 5681 AMP
A2.0 NL 4460 AMP
INFORMATION FOR THE PATIENT
10 mL Vial (1000 Units per vial)
HUMULIN® R
REGULAR
INSULIN HUMAN INJECTION, USP
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM
ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL
TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND
BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
sugar is maintained as close to normal as possible. The American Diabetes Association
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your
diabetes therapy may be needed. If your blood tests consistently show below-normal glucose
levels, you should also let your doctor know. Proper control of your diabetes requires close and
constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life
if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by
your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
REGULAR HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia
coli bacteria that has been genetically altered to produce human insulin. Humulin R [Regular
insulin human injection, USP (rDNA origin)] consists of zinc-insulin crystals dissolved in a clear
fluid. Humulin R has had nothing added to change the speed or length of its action. It takes effect
rapidly and has a relatively short duration of activity (4 to 12 hours) as compared with other
insulins. The time course of action of any insulin may vary considerably in different individuals
or at different times in the same individual. As with all insulin preparations, the duration of
action of Humulin R is dependent on dose, site of injection, blood supply, temperature, and
physical activity. Humulin R is a sterile solution and is for subcutaneous injection. It should not
be used intramuscularly. The concentration of Humulin R is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
Always check the carton and the bottle label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of your bottle of Humulin R before withdrawing each dose.
Humulin R is a clear and colorless liquid with a water-like appearance and consistency.
Do not use Humulin R:
• if it appears cloudy, thickened, or slightly colored, or
• if solid particles are visible.
If you see anything unusual in the appearance of Humulin R solution in your bottle or notice
your insulin requirements changing, talk to your doctor.
Storage
Not in-use (unopened): Humulin R bottles not in-use should be stored in a refrigerator, but
not in the freezer.
In-use (opened): The Humulin R bottle you are currently using can be kept unrefrigerated as
long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
Do not use Humulin R after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN VIAL USE
NEVER SHARE NEEDLES AND SYRINGES.
Correct Syringe Type
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
With Humulin R, it is important to use a syringe that is marked for U-100 insulin preparations.
Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for
you, such as a blood glucose level that is too low or too high.
Syringe Use
To help avoid contamination and possible infection, follow these instructions exactly.
Disposable syringes and needles should be used only once and then discarded by placing the
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
resistant container as directed by your Health Care Professional.
Preparing the Dose
1. Wash your hands.
2. Inspect the insulin. Humulin R solution should look clear and colorless. Do not use
Humulin R if it appears cloudy, thickened, or slightly colored, or if you see particles in
the solution. Do not use Humulin R if you notice anything unusual in its appearance.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
3. If using a new Humulin R bottle, flip off the plastic protective cap, but do not remove the
stopper. Wipe the top of the bottle with an alcohol swab.
4. If you are mixing insulins, refer to the “Mixing Humulin R with Longer-Acting Human
Insulins” section below.
5. Draw an amount of air into the syringe that is equal to the Humulin R dose. Put the needle
through rubber top of the Humulin R bottle and inject the air into the bottle.
6. Turn the Humulin R bottle and syringe upside down. Hold the bottle and syringe firmly in
one hand.
7. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
of Humulin R into the syringe.
8. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
10. If you do not need to mix your Humulin R with a longer-acting insulin, go to the
“Injection Instructions” section below and follow the directions.
Mixing Humulin R with Longer-Acting Human Insulins
1. Humulin R should be mixed with longer-acting human insulins only on the advice of your
doctor.
2. Draw an amount of air into the syringe that is equal to the amount of longer-acting insulin
you are taking. Insert the needle into the longer-acting insulin bottle and inject the air.
Withdraw the needle.
3. Draw an amount of air into the syringe that is equal to the amount of Humulin R you are
taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw
the needle.
4. Turn the Humulin R bottle and syringe upside down.
5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
of Humulin R into the syringe.
6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
7. Remove the syringe with the needle from the Humulin R bottle and insert it into the
longer-acting insulin bottle. Turn the longer-acting insulin bottle and syringe upside
down. Hold the bottle and syringe firmly in one hand and shake gently. Making sure the
tip of the needle is in the longer-acting insulin, withdraw the correct dose of longer-acting
insulin.
8. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
9. Follow the directions under “Injection Instructions” section below.
Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before
giving your injection. It is important to be consistent in your method.
Syringes from different manufacturers may vary in the amount of space between the bottom
line and the needle. Because of this, do not change:
• the sequence of mixing, or
• the model and brand of syringe or needle that your doctor has prescribed.
Injection Instructions
1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
2. Cleanse the skin with alcohol where the injection is to be made.
3. With one hand, stabilize the skin by spreading it or pinching up a large area.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
4. Insert the needle as instructed by your doctor.
5. Push the plunger in as far as it will go.
6. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
7. Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your Health Care Professional.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin R may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin R dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your Health Care Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2. Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5. A change in the body’s need for insulin.
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from
animal-source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking
sugar-containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2. Eating significantly more than your meal plan suggests.
3. Developing a fever, infection, or other significant stressful situation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Patient Information issued/revised Month dd, yyyy
Vials manufactured by
Eli Lilly and Company, Indianapolis, IN 46285, USA or
Hospira, Inc., Lake Forest, IL 60045, USA or
Lilly France, F-67640 Fegersheim, France
for Eli Lilly and Company, Indianapolis, IN 46285, USA
A1.0 NL 5691 AMP
PRINTED IN USA
A1.0 NL5681 AMP
A2.0 NL 4460 AMP
Copyright © 1997, yyyy, Eli Lilly and Company. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A1.0 NL 5711 AMP
A1.0 NL 6792 AMP
INFORMATION FOR THE PATIENT
10 mL Vial (1000 Units per vial)
HUMULIN® N
NPH
HUMAN INSULIN (rDNA ORIGIN)
ISOPHANE SUSPENSION
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM
ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL
TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND
BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
sugar is maintained as close to normal as possible. The American Diabetes Association
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your
diabetes therapy may be needed. If your blood tests consistently show below-normal glucose
levels, you should also let your doctor know. Proper control of your diabetes requires close and
constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life
if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by
your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
NPH HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia
coli bacteria that has been genetically altered to produce human insulin. Humulin N [Human
insulin (rDNA origin) isophane suspension] is a crystalline suspension of human insulin with
protamine and zinc providing an intermediate-acting insulin with a slower onset of action and a
longer duration of activity (up to 24 hours) than that of Regular human insulin. The time course
of action of any insulin may vary considerably in different individuals or at different times in the
same individual. As with all insulin preparations, the duration of action of Humulin N is
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N
is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously
or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
Always check the carton and the bottle label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of your bottle of Humulin N before withdrawing each dose.
Before each injection the Humulin N bottle must be carefully shaken or rotated several times to
completely mix the insulin. Humulin N suspension should look uniformly cloudy or milky after
mixing. If not, repeat the above steps until contents are mixed.
Do not use Humulin N:
• if the insulin substance (the white material) remains at the bottom of the bottle after
mixing or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted
appearance.
If you see anything unusual in the appearance of Humulin N suspension in your bottle or
notice your insulin requirements changing, talk to your doctor.
Storage
Not in-use (unopened): Humulin N bottles not in-use should be stored in a refrigerator, but
not in the freezer.
In-use (opened): The Humulin N bottle you are currently using can be kept unrefrigerated as
long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
Do not use Humulin N after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN VIAL USE
NEVER SHARE NEEDLES AND SYRINGES.
Correct Syringe Type
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
With Humulin N, it is important to use a syringe that is marked for U-100 insulin preparations.
Failure to use the proper syringe can lead to a mistake in dosage, causing serious problems for
you, such as a blood glucose level that is too low or too high.
Syringe Use
To help avoid contamination and possible infection, follow these instructions exactly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Disposable syringes and needles should be used only once and then discarded by placing the
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
resistant container as directed by your Health Care Professional.
Preparing the Dose
1. Wash your hands.
2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
3. Inspect the insulin. Humulin N suspension should look uniformly cloudy or milky. Do not
use Humulin N if you notice anything unusual in its appearance.
4. If using a new Humulin N bottle, flip off the plastic protective cap, but do not remove the
stopper. Wipe the top of the bottle with an alcohol swab.
5. If you are mixing insulins, refer to the “Mixing Humulin N and Regular Human Insulin”
section below.
6. Draw an amount of air into the syringe that is equal to the Humulin N dose. Put the needle
through rubber top of the Humulin N bottle and inject the air into the bottle.
7. Turn the Humulin N bottle and syringe upside down. Hold the bottle and syringe firmly in
one hand and shake gently.
8. Making sure the tip of the needle is in the Humulin N suspension, withdraw the correct
dose of Humulin N into the syringe.
9. Before removing the needle from the Humulin N bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
10. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
11. If you do not need to mix your Humulin N with Regular human insulin, go to the
“Injection Instructions” section below and follow the directions.
Mixing Humulin N and Regular Human Insulin (Humulin R)
1. Humulin N should be mixed with Humulin R only on the advice of your doctor.
2. Draw an amount of air into the syringe that is equal to the amount of Humulin N you are
taking. Insert the needle into the Humulin N bottle and inject the air. Withdraw the
needle.
3.
Draw an amount of air into the syringe that is equal to the amount of Humulin R you are
taking. Insert the needle into the Humulin R bottle and inject the air, but do not withdraw
the needle.
4. Turn the Humulin R bottle and syringe upside down.
5. Making sure the tip of the needle is in the Humulin R solution, withdraw the correct dose
of Humulin R into the syringe.
6. Before removing the needle from the Humulin R bottle, check the syringe for air bubbles.
If bubbles are present, hold the syringe straight up and tap its side until the bubbles float
to the top. Push the bubbles out with the plunger and then withdraw the correct dose.
7. Remove the syringe with the needle from the Humulin R bottle and insert it into the
Humulin N bottle. Turn the Humulin R bottle and syringe upside down. Hold the bottle
and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in
the Humulin N, withdraw the correct dose of Humulin N.
8. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
9. Follow the directions under “Injection Instructions” section below.
Follow your doctor’s instructions on whether to mix your insulins ahead of time or just before
giving your injection. It is important to be consistent in your method.
Syringes from different manufacturers may vary in the amount of space between the bottom
line and the needle. Because of this, do not change:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
• the sequence of mixing, or
• the model and brand of syringe or needle that your doctor has prescribed.
Injection Instructions
1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
2. Cleanse the skin with alcohol where the injection is to be made.
3. With one hand, stabilize the skin by spreading it or pinching up a large area.
4. Insert the needle as instructed by your doctor.
5. Push the plunger in as far as it will go.
6. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
7. Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your Health Care Professional.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin N may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin N dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your Health Care Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2. Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5. A change in the body’s need for insulin.
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from
animal-source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking
sugar-containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2. Eating significantly more than your meal plan suggests.
3. Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Patient Information issued/revised Month dd, yyyy
Vials manufactured by
Eli Lilly and Company, Indianapolis, IN 46285, USA or
Lilly France, F-67640 Fegersheim, France
for Eli Lilly and Company, Indianapolis, IN 46285, USA
A1.0 NL 5711 AMP
A1.0 NL 6792 AMP
PRINTED IN USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Copyright © 1997, yyyy, Eli Lilly and Company. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A1.0 NL 3682 AMP
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A6.0 PA 9134 FSAMP
INFORMATION FOR THE PATIENT
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
HUMULIN® N Pen
NPH
HUMAN INSULIN
(rDNA ORIGIN) ISOPHANE SUSPENSION
100 UNITS PER ML (U-100)
WARNINGS
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THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
INSULIN PRODUCED BY YOUR BODY'S PANCREAS AND BECAUSE OF ITS
UNIQUE MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW
THE INSULIN DELIVERY DEVICE USER MANUAL AND THIS
“INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS
PRODUCT.
BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A
NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE.
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES
OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR
THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL
USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE TOO MUCH OR TOO
LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN USE section).
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body's correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body's needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
sugar is maintained as close to normal as possible. The American Diabetes Association
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your
diabetes therapy may be needed. If your blood tests consistently show below-normal glucose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
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levels, you should also let your doctor know. Proper control of your diabetes requires close and
constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life
if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by
your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
NPH HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia
coli bacteria that has been genetically altered to produce human insulin. Humulin N [Human
insulin (rDNA origin) isophane suspension] is a crystalline suspension of human insulin with
protamine and zinc providing an intermediate-acting insulin with a slower onset of action and a
longer duration of activity (up to 24 hours) than that of Regular human insulin. The time course
of action of any insulin may vary considerably in different individuals or at different times in the
same individual. As with all insulin preparations, the duration of action of Humulin N is
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin N
is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously
or intramuscularly. The concentration of Humulin N is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
The Humulin N Pen is available in boxes of 5 disposable insulin delivery devices (“insulin
Pens”). The Humulin N Pen is not designed to allow any other insulin to be mixed in its
cartridge, or for the cartridge to be removed.
Always check the carton and the Pen label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of Humulin N suspension in your insulin Pen before using. A
cartridge of Humulin N contains a small glass bead to assist in mixing. Roll the Pen between the
palms 10 times (see Figure 1). Holding the Pen by one end, invert it 180° slowly 10 times to
allow the small glass bead to travel the full length with each inversion (see Figure 2).
Figure 1.
Figure 2.
Humulin N suspension should look uniformly cloudy or milky after mixing. If not, repeat the
above steps until contents are mixed. Pens containing Humulin N suspension should be
examined frequently.
Do not use Humulin N:
• if the insulin substance (the white material) remains visibly separated from the liquid
after mixing or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
• if there are clumps in the insulin after mixing, or
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• if solid white particles stick to the walls of the cartridge, giving a frosted appearance.
If you see anything unusual in the appearance of the Humulin N suspension in your Pen or
notice your insulin requirements changing, talk to your doctor.
Never attempt to remove the cartridge from the Humulin N Pen. Inspect the cartridge through
the clear cartridge holder.
Storage
Not in-use (unopened): Humulin N Pens not in-use should be stored in a refrigerator, but not
in the freezer.
In-use (opened): Humulin N Pens in-use should NOT be refrigerated but should be kept at
room temperature [below 86°F (30°C)] away from direct heat and light. The Humulin N Pen you
are currently using must be discarded 2 weeks after the first use, even if it still contains Humulin
N.
Do not use Humulin N after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN PEN USE
It is important to read, understand, and follow the instructions in the Insulin Delivery
Device User Manual before using. Failure to follow instructions may result in getting too
much or too little insulin. The needle must be changed and the Pen must be primed before
each injection to make sure the Pen is ready to dose. Performing these steps before each
injection is important to confirm that insulin comes out when you push the injection
button, and to remove air that may collect in the insulin cartridge during normal use.
Every time you inject:
• Use a new needle.
• Prime to make sure the Pen is ready to dose.
• Make sure you got your full dose.
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
PREPARING FOR INJECTION
1. Wash your hands.
2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
3. Follow the instructions in your Insulin Delivery Device User Manual to prepare for
injection.
4. After injecting the dose, pull the needle out and apply gentle pressure over the injection
site for several seconds. Do not rub the area.
5. After the injection, remove the needle from the Humulin N Pen. Do not reuse needles.
6. Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your Health Care Professional.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient's diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin N may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor's instructions to allow for these changes. Other things that
may affect your Humulin N dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Pregnancy
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Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your Health Care Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
Exercise may lower your body's need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2. Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5. A change in the body's need for insulin.
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Therefore, it is important that assistance be obtained immediately.
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Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from animal-
source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2. Eating significantly more than your meal plan suggests.
3. Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy ⎯ Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Systemic Allergy ⎯ Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
237
238
239
240
241
242
243
244
245
246
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Patient Information issued/revised Month dd, yyyy
Pens manufactured by
247
248
249
250
251
252
253
254
255
Eli Lilly and Company, Indianapolis, IN 46285, USA or
Lilly France, F-67640 Fegersheim, France
for Eli Lilly and Company, Indianapolis, IN 46285, USA
A1.0 NL 3682 AMP
PRINTED IN USA
A6.0 PA 9134 FSAMP
Copyright © 1998, yyyy, Eli Lilly and Company. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A1.0 NL 5721 AMP
A3.0 NL 3770 AMP
INFORMATION FOR THE PATIENT
10 mL Vial (1000 Units per vial)
HUMULIN® 70/30
70% HUMAN INSULIN
ISOPHANE SUSPENSION
AND
30% HUMAN INSULIN INJECTION
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM
ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL
TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND
BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
sugar is maintained as close to normal as possible. The American Diabetes Association
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your
diabetes therapy may be needed. If your blood tests consistently show below-normal glucose
levels, you should also let your doctor know. Proper control of your diabetes requires close and
constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life
if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by
your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
70/30 HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia
coli bacteria that has been genetically altered to produce human insulin. Humulin 70/30 is a
mixture of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA
origin). It is an intermediate-acting insulin combined with the more rapid onset of action of
Regular human insulin. The duration of activity may last up to 24 hours following injection. The
time course of action of any insulin may vary considerably in different individuals or at different
times in the same individual. As with all insulin preparations, the duration of action of
Humulin 70/30 is dependent on dose, site of injection, blood supply, temperature, and physical
activity. Humulin 70/30 is a sterile suspension and is for subcutaneous injection only. It should
not be used intravenously or intramuscularly. The concentration of Humulin 70/30 is
100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
Always check the carton and the bottle label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of your bottle of Humulin 70/30 before withdrawing each dose.
Before each injection the Humulin 70/30 bottle must be carefully shaken or rotated several times
to completely mix the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky
after mixing. If not, repeat the above steps until contents are mixed.
Do not use Humulin 70/30:
• if the insulin substance (the white material) remains at the bottom of the bottle after
mixing or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted
appearance.
If you see anything unusual in the appearance of Humulin 70/30 suspension in your bottle or
notice your insulin requirements changing, talk to your doctor.
Storage
Not in-use (unopened): Humulin 70/30 bottles not in-use should be stored in a refrigerator,
but not in the freezer.
In-use (opened): The Humulin 70/30 bottle you are currently using can be kept unrefrigerated
as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN VIAL USE
NEVER SHARE NEEDLES AND SYRINGES
Correct Syringe Type
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
With Humulin 70/30, it is important to use a syringe that is marked for U-100 insulin
preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious
problems for you, such as a blood glucose level that is too low or too high.
Syringe Use
To help avoid contamination and possible infection, follow these instructions exactly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Disposable syringes and needles should be used only once and then discarded by placing the
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
resistant container as directed by your Health Care Professional.
Preparing the Dose
1. Wash your hands.
2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
3. Inspect the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky. Do
not use Humulin 70/30 if you notice anything unusual in its appearance.
4. If using a new Humulin 70/30 bottle, flip off the plastic protective cap, but do not remove
the stopper. Wipe the top of the bottle with an alcohol swab.
5. Draw an amount of air into the syringe that is equal to the Humulin 70/30 dose. Put the
needle through rubber top of the Humulin 70/30 bottle and inject the air into the bottle.
6. Turn the Humulin 70/30 bottle and syringe upside down. Hold the bottle and syringe
firmly in one hand and shake gently.
7. Making sure the tip of the needle is in the Humulin 70/30 suspension, withdraw the
correct dose of Humulin 70/30 into the syringe.
8. Before removing the needle from the Humulin 70/30 bottle, check the syringe for air
bubbles. If bubbles are present, hold the syringe straight up and tap its side until the
bubbles float to the top. Push the bubbles out with the plunger and then withdraw the
correct dose.
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
Injection Instructions
1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
2. Cleanse the skin with alcohol where the injection is to be made.
3. With one hand, stabilize the skin by spreading it or pinching up a large area.
4. Insert the needle as instructed by your doctor.
5. Push the plunger in as far as it will go.
6. Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
7. Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your Health Care Professional.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin 70/30 dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your Health Care Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2. Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5. A change in the body’s need for insulin.
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from
animal-source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking
sugar-containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2. Eating significantly more than your meal plan suggests.
3. Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Patient Information issued/revised Month dd, yyyy
Vials manufactured by
Eli Lilly and Company, Indianapolis, IN 46285, USA or
Lilly France, F-67640 Fegersheim, France
for Eli Lilly and Company, Indianapolis, IN 46285, USA
A1.0 NL 5721 AMP
PRINTED IN USA
A3.0 NL 3770 AMP
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A1.0 NL 3672 AMP
A2.0 PA 9145 FSAMP
INFORMATION FOR THE PATIENT
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
HUMULIN® 70/30 Pen
70% HUMAN INSULIN
ISOPHANE SUSPENSION
AND
30% HUMAN INSULIN INJECTION
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM
ANIMAL-SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL
TO THE INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND
BECAUSE OF ITS UNIQUE MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW
THE INSULIN DELIVERY DEVICE USER MANUAL AND THIS
“INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS
PRODUCT.
BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A
NECESSARY STEP TO MAKE SURE THE PEN IS READY TO DOSE.
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES
OUT WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR
THAT MAY COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL
USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE TOO MUCH OR TOO
LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN USE section).
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
sugar is maintained as close to normal as possible. The American Diabetes Association
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your
diabetes therapy may be needed. If your blood tests consistently show below-normal glucose
levels, you should also let your doctor know. Proper control of your diabetes requires close and
constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life
if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by
your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
70/30 HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of
Escherichia coli bacteria that has been genetically altered to produce human insulin.
Humulin 70/30 is a mixture of 70% Human Insulin Isophane Suspension and 30% Human
Insulin Injection, (rDNA origin). It is an intermediate-acting insulin combined with the more
rapid onset of action of Regular human insulin. The duration of activity may last up to 24 hours
following injection. The time course of action of any insulin may vary considerably in different
individuals or at different times in the same individual. As with all insulin preparations, the
duration of action of Humulin 70/30 is dependent on dose, site of injection, blood supply,
temperature, and physical activity. Humulin 70/30 is a sterile suspension and is for subcutaneous
injection only. It should not be used intravenously or intramuscularly. The concentration of
Humulin 70/30 is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin.
Your doctor has prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE
AND DIRECTION.
The Humulin 70/30 Pen is available in boxes of 5 disposable insulin delivery devices
(“insulin Pens”). The Humulin 70/30 Pen is not designed to allow any other insulin to be
mixed in its cartridge, or for the cartridge to be removed.
Always check the carton and the Pen label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of Humulin 70/30 suspension in your insulin Pen before using. A
cartridge of Humulin 70/30 contains a small glass bead to assist in mixing. Roll the Pen between
the palms 10 times (see Figure 1). Holding the Pen by one end, invert it 180° slowly 10 times to
allow the small glass bead to travel the full length with each inversion (see Figure 2).
Figure 1.
Figure 2.
Humulin 70/30 suspension should look uniformly cloudy or milky after mixing. If not, repeat
the above steps until contents are mixed. Pens containing Humulin 70/30 suspension should be
examined frequently.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Do not use Humulin 70/30:
• if the insulin substance (the white material) remains visibly separated from the liquid
after mixing or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the walls of the cartridge, giving a frosted appearance.
If you see anything unusual in the appearance of the Humulin 70/30 suspension in your Pen or
notice your insulin requirements changing, talk to your doctor.
Never attempt to remove the cartridge from the Humulin 70/30 Pen. Inspect the cartridge
through the clear cartridge holder.
Storage
Not in-use (unopened): Humulin 70/30 Pens not in-use should be stored in a refrigerator, but
not in the freezer.
In-use (opened): Humulin 70/30 Pens in-use should NOT be refrigerated but should be kept at
room temperature [below 86ºF (30ºC)] away from direct heat and light. The Humulin 70/30 Pen
you are currently using must be discarded 10 days after the first use, even if it still contains
Humulin 70/30.
Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN PEN USE
It is important to read, understand, and follow the instructions in the Insulin Delivery
Device User Manual before using. Failure to follow instructions may result in getting too
much or too little insulin. The needle must be changed and the Pen must be primed before
each injection to make sure the Pen is ready to dose. Performing these steps before each
injection is important to confirm that insulin comes out when you push the injection
button, and to remove air that may collect in the insulin cartridge during normal use.
Every time you inject:
• Use a new needle.
• Prime to make sure the Pen is ready to dose.
• Make sure you got your full dose.
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
PREPARING FOR INJECTION
1. Wash your hands.
2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
3. Follow the instructions in your Insulin Delivery Device User Manual to prepare for
injection.
4. After injecting the dose, pull the needle out and apply gentle pressure over the injection
site for several seconds. Do not rub the area.
5. After the injection, remove the needle from the Humulin 70/30 Pen. Do not reuse
needles.
6. Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your Health Care Professional.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin 70/30 dose are:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your Health Care Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2. Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5. A change in the body’s need for insulin.
6. Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from
animal-source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking
sugar-containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2. Eating significantly more than your meal plan suggests.
3. Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Patient Information issued/revised Month dd, yyyy
Pens manufactured by
Eli Lilly and Company, Indianapolis, IN 46285, USA or
Lilly France, F-67640 Fegersheim, France
for Eli Lilly and Company, Indianapolis, IN 46285, USA
A1.0 NL 3672 AMP
PRINTED IN USA
A2.0 PA 9145 FSAMP
Copyright © 1998, yyyy, Eli Lilly and Company. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A1.0 NL 5701 AMP
1
A3.0 NL 4590 AMP
2
INFORMATION FOR THE PATIENT
3
10 mL Vial (1000 Units per vial)
4
HUMULIN® 50/50
5
50% HUMAN INSULIN
6
ISOPHANE SUSPENSION
7
AND
8
50% HUMAN INSULIN INJECTION
9
(rDNA ORIGIN)
10
100 UNITS PER ML (U-100)
11
12
WARNINGS
13
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-
14
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
15
INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS
16
UNIQUE MANUFACTURING PROCESS.
17
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
18
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
19
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
20
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
21
CHANGE IN DOSAGE.
22
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
23
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
24
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
25
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
26
DIABETES
27
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
28
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
29
the pancreas does not make enough insulin to meet your body’s needs.
30
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
31
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
32
urine regularly for glucose. Studies have shown that some chronic complications of diabetes
33
such as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood
34
sugar is maintained as close to normal as possible. The American Diabetes Association
35
recommends that if your pre-meal glucose levels are consistently above 130 mg/dL or your
36
hemoglobin A1c (HbA1c) is more than 7%, you should talk to your doctor. A change in your
37
diabetes therapy may be needed. If your blood tests consistently show below-normal glucose
38
levels, you should also let your doctor know. Proper control of your diabetes requires close and
39
constant cooperation with your doctor. Despite diabetes, you can lead an active and healthy life
40
if you eat a balanced diet, exercise regularly, and take your insulin injections as prescribed by
41
your doctor.
42
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
43
wear diabetic identification so that appropriate treatment can be given if complications occur
44
away from home.
45
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
50/50 HUMAN INSULIN
47
Description
48
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia
49
coli bacteria that has been genetically altered to produce human insulin. Humulin 50/50 is a
50
mixture of 50% Human Insulin Isophane Suspension and 50% Human Insulin Injection (rDNA
51
origin). It is an intermediate-acting insulin combined with the more rapid onset of action of
52
Regular human insulin. The duration of activity may last up to 24 hours following injection. The
53
time course of action of any insulin may vary considerably in different individuals or at different
54
times in the same individual. As with all insulin preparations, the duration of action of
55
Humulin 50/50 is dependent on dose, site of injection, blood supply, temperature, and physical
56
activity. Humulin 50/50 is a sterile suspension and is for subcutaneous injection only. It should
57
not be used intravenously or intramuscularly. The concentration of Humulin 50/50 is
58
100 units/mL (U-100).
59
Identification
60
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
61
prescribed the type of insulin that he/she believes is best for you.
62
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
63
DIRECTION.
64
Always check the carton and the bottle label for the name and letter designation of the insulin
65
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
66
Always check the appearance of your bottle of Humulin 50/50 before withdrawing each dose.
67
Before each injection the Humulin 50/50 bottle must be carefully shaken or rotated several times
68
to completely mix the insulin. Humulin 50/50 suspension should look uniformly cloudy or milky
69
after mixing. If not, repeat the above steps until contents are mixed.
70
Do not use Humulin 50/50:
71
• if the insulin substance (the white material) remains at the bottom of the bottle after
72
mixing or
73
• if there are clumps in the insulin after mixing, or
74
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted
75
appearance.
76
If you see anything unusual in the appearance of Humulin 50/50 suspension in your bottle or
77
notice your insulin requirements changing, talk to your doctor.
78
Storage
79
Not in-use (unopened): Humulin 50/50 bottles not in-use should be stored in a refrigerator,
80
but not in the freezer.
81
In-use (opened): The Humulin 50/50 bottle you are currently using can be kept unrefrigerated
82
as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
83
Do not use Humulin 50/50 after the expiration date stamped on the label or if it has been
84
frozen.
85
INSTRUCTIONS FOR INSULIN VIAL USE
86
NEVER SHARE NEEDLES AND SYRINGES.
87
Correct Syringe Type
88
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
89
With Humulin 50/50, it is important to use a syringe that is marked for U-100 insulin
90
preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious
91
problems for you, such as a blood glucose level that is too low or too high.
92
Syringe Use
93
To help avoid contamination and possible infection, follow these instructions exactly.
94
Disposable syringes and needles should be used only once and then discarded by placing the
95
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
96
resistant container as directed by your Health Care Professional.
97
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Preparing the Dose
98
1. Wash your hands.
99
2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
100
3. Inspect the insulin. Humulin 50/50 suspension should look uniformly cloudy or milky. Do
101
not use Humulin 50/50 if you notice anything unusual in its appearance.
102
4. If using a new Humulin 50/50 bottle, flip off the plastic protective cap, but do not remove
103
the stopper. Wipe the top of the bottle with an alcohol swab.
104
5. Draw an amount of air into the syringe that is equal to the Humulin 50/50 dose. Put the
105
needle through rubber top of the Humulin 50/50 bottle and inject the air into the bottle.
106
6. Turn the Humulin 50/50 bottle and syringe upside down. Hold the bottle and syringe
107
firmly in one hand and shake gently.
108
7. Making sure the tip of the needle is in the Humulin 50/50 suspension, withdraw the
109
correct dose of Humulin 50/50 into the syringe.
110
8. Before removing the needle from the Humulin 50/50 bottle, check the syringe for air
111
bubbles. If bubbles are present, hold the syringe straight up and tap its side until the
112
bubbles float to the top. Push the bubbles out with the plunger and then withdraw the
113
correct dose.
114
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
115
touch anything.
116
Injection Instructions
117
1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
118
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
119
2. Cleanse the skin with alcohol where the injection is to be made.
120
3. With one hand, stabilize the skin by spreading it or pinching up a large area.
121
4. Insert the needle as instructed by your doctor.
122
5. Push the plunger in as far as it will go.
123
6. Pull the needle out and apply gentle pressure over the injection site for several seconds.
124
Do not rub the area.
125
7. Place the used needle in a puncture-resistant disposable container and properly dispose of
126
the puncture-resistant container as directed by your Health Care Professional.
127
DOSAGE
128
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
129
Because each patient’s diabetes is different, this schedule has been individualized for you. Your
130
usual dose of Humulin 50/50 may be affected by changes in your diet, activity, or work schedule.
131
Carefully follow your doctor’s instructions to allow for these changes. Other things that may
132
affect your Humulin 50/50 dose are:
133
Illness
134
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
135
Even if you are not eating, you will still require insulin. You and your doctor should establish a
136
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
137
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
138
Pregnancy
139
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
140
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
141
are nursing a baby, talk to your doctor.
142
Medication
143
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
144
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
145
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
146
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Your Healthcare Professional may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Exercise
151
Exercise may lower your body’s need for insulin during and for some time after the physical
152
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
153
involves the area of injection site (for example, the leg should not be used for injection just prior
154
to running). Discuss with your doctor how you should adjust your insulin regimen to
155
accommodate exercise.
156
Travel
157
When traveling across more than 2 time zones, you should talk to your doctor concerning
158
adjustments in your insulin schedule.
159
COMMON PROBLEMS OF DIABETES
160
Hypoglycemia (Low Blood Sugar)
161
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
162
experienced by insulin users. It can be brought about by:
163
1. Missing or delaying meals.
164
2.
Taking too much insulin.
165
3.
Exercising or working more than usual.
166
4.
An infection or illness associated with diarrhea or vomiting.
167
5.
A change in the body’s need for insulin.
168
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
169
disease.
170
7.
Interactions with certain drugs, such as oral antidiabetic agents, salicylates
(for example, aspirin), sulfa antibiotics, certain antidepressants and some
2
kidney and blood pressure medicines.
173
8.
Consumption of alcoholic beverages.
174
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
175
• sweating
• drowsiness
176
• dizziness
• sleep disturbances
177
• palpitation
• anxiety
178
• tremor
• blurred vision
179
• hunger
• slurred speech
180
• restlessness
• depressed mood
181
• tingling in the hands, feet, lips, or tongue
• irritability
182
• lightheadedness
• abnormal behavior
183
• inability to concentrate
• unsteady movement
184
• headache
• personality changes
185
Signs of severe hypoglycemia can include:
186
• disorientation
• seizures
187
• unconsciousness
• death
188
Therefore, it is important that assistance be obtained immediately.
189
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
190
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
191
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
192
per day) of diabetes.
193
A few patients who have experienced hypoglycemic reactions after transfer from animal-
194
source insulin to human insulin have reported that the early warning symptoms of
195
hypoglycemia were less pronounced or different from those experienced with their
196
previous insulin.
197
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Without recognition of early warning symptoms, you may not be able to take steps to avoid
198
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
199
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
200
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
201
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
202
containing foods to treat your hypoglycemia.
203
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
204
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
205
severe hypoglycemia may require the assistance of another person. Patients who are unable to
206
take sugar orally or who are unconscious require an injection of glucagon or should be treated
207
with intravenous administration of glucose at a medical facility.
208
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
209
about these symptoms, you should monitor your blood glucose frequently to help you learn to
210
recognize the symptoms that you experience with hypoglycemia.
211
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
212
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
213
and/or exercise programs to help you avoid hypoglycemia.
214
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
215
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
216
Hyperglycemia can be brought about by any of the following:
217
1. Omitting your insulin or taking less than your doctor has prescribed.
218
2. Eating significantly more than your meal plan suggests.
219
3. Developing a fever, infection, or other significant stressful situation.
220
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
221
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
222
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
223
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
224
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
225
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
226
of consciousness, or death. Therefore, it is important that you obtain medical assistance
227
immediately.
228
Lipodystrophy
229
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
230
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
231
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
232
the problem.
233
Allergy
234
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
235
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
236
some instances, this condition may be related to factors other than insulin, such as irritants in the
237
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
238
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
239
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
240
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
241
threatening. If you think you are having a generalized allergic reaction to insulin, call your
242
doctor immediately.
243
ADDITIONAL INFORMATION
244
Information about diabetes may be obtained from your diabetes educator.
245
Additional information about diabetes and Humulin can be obtained by calling The Lilly
246
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
247
248
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Patient Information issued/revised Month dd, yyyy
249
Vials manufactured by
250
Eli Lilly and Company, Indianapolis, IN 46285, USA or
251
Lilly France, F-67640 Fegersheim, France
252
253
for Eli Lilly and Company, Indianapolis, IN 46285, USA
254
A1.0 NL 5701 AMP
PRINTED IN USA
255
A3.0 NL 4590 AMP
256
257
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
258
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.517342 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018780s95,018781s89,019717s69,020100s32lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 69} |
1,534 |
1
1
2
INFORMATION FOR THE PATIENT
3
10 mL Vial (1000 Units per vial)
4
HUMULIN® 70/30
5
70% HUMAN INSULIN
6
ISOPHANE SUSPENSION
7
AND
8
30% HUMAN INSULIN INJECTION
9
(rDNA ORIGIN)
10
100 UNITS PER ML (U-100)
11
WARNINGS
12
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL
13
SOURCE INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE
14
INSULIN PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF
15
ITS UNIQUE MANUFACTURING PROCESS.
16
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
17
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH,
18
MANUFACTURER, TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR
19
METHOD OF MANUFACTURE MAY RESULT IN THE NEED FOR A
20
CHANGE IN DOSAGE.
21
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN)
22
MAY REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER
23
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE
24
FIRST DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
25
DIABETES
26
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
27
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
28
the pancreas does not make enough insulin to meet your body’s needs.
29
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
30
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
31
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
32
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
33
is maintained as close to normal as possible. The American Diabetes Association recommends
34
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
35
(HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may
36
be needed. If your blood tests consistently show below-normal glucose levels, you should also let
37
your doctor know. Proper control of your diabetes requires close and constant cooperation with
38
your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
39
exercise regularly, and take your insulin injections as prescribed by your doctor.
40
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
41
wear diabetic identification so that appropriate treatment can be given if complications occur
42
away from home.
43
70/30 HUMAN INSULIN
44
Description
45
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
46
bacteria that has been genetically altered to produce human insulin. Humulin 70/30 is a mixture
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
47
of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA origin). It
48
is an intermediate-acting insulin combined with the more rapid onset of action of Regular human
49
insulin. The duration of activity may last up to 24 hours following injection. The time course of
50
action of any insulin may vary considerably in different individuals or at different times in the
51
same individual. As with all insulin preparations, the duration of action of Humulin 70/30 is
52
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin
53
70/30 is a sterile suspension and is for subcutaneous injection only. It should not be used
54
intravenously or intramuscularly. The concentration of Humulin 70/30 is 100 units/mL (U-100).
55
Identification
56
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
57
prescribed the type of insulin that he/she believes is best for you.
58
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
59
DIRECTION.
60
Always check the carton and the bottle label for the name and letter designation of the insulin
61
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
62
Always check the appearance of your bottle of Humulin 70/30 before withdrawing each dose.
63
Before each injection the Humulin 70/30 bottle must be carefully shaken or rotated several times
64
to completely mix the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky
65
after mixing. If not, repeat the above steps until contents are mixed.
66
Do not use Humulin 70/30:
67
• if the insulin substance (the white material) remains at the bottom of the bottle after mixing
68
or
69
• if there are clumps in the insulin after mixing, or
70
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance.
71
If you see anything unusual in the appearance of Humulin 70/30 suspension in your bottle or
72
notice your insulin requirements changing, talk to your doctor.
73
Storage
74
Not in-use (unopened): Humulin 70/30 bottles not in-use should be stored in a refrigerator,
75
but not in the freezer.
76
In-use (opened): The Humulin 70/30 bottle you are currently using can be kept unrefrigerated
77
as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
78
Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been
79
frozen.
80
INSTRUCTIONS FOR INSULIN VIAL USE
81
NEVER SHARE NEEDLES AND SYRINGES.
82
Correct Syringe Type
83
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
84
With Humulin 70/30, it is important to use a syringe that is marked for U-100 insulin
85
preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious
86
problems for you, such as a blood glucose level that is too low or too high.
87
Syringe Use
88
To help avoid contamination and possible infection, follow these instructions exactly.
89
Disposable syringes and needles should be used only once and then discarded by placing the
90
used needle in a puncture-resistant disposable container. Properly dispose of the puncture
91
resistant container as directed by your Health Care Professional.
92
Preparing the Dose
93
1. Wash your hands.
94
2. Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
95
3.
Inspect the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky. Do
96
not use Humulin 70/30 if you notice anything unusual in its appearance.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
97
4. If using a new Humulin 70/30 bottle, flip off the plastic protective cap, but do not remove
98
the stopper. Wipe the top of the bottle with an alcohol swab.
99
5. Draw an amount of air into the syringe that is equal to the Humulin 70/30 dose. Put the
100
needle through rubber top of the Humulin 70/30 bottle and inject the air into the bottle.
101
6.
Turn the Humulin 70/30 bottle and syringe upside down. Hold the bottle and syringe
102
firmly in one hand and shake gently.
103
7. Making sure the tip of the needle is in the Humulin 70/30 suspension, withdraw the
104
correct dose of Humulin 70/30 into the syringe.
105
8. Before removing the needle from the Humulin 70/30 bottle, check the syringe for air
106
bubbles. If bubbles are present, hold the syringe straight up and tap its side until the
107
bubbles float to the top. Push the bubbles out with the plunger and then withdraw the
108
correct dose.
109
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
110
touch anything.
111
Injection Instructions
112
1. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
113
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
114
2. Cleanse the skin with alcohol where the injection is to be made.
115
3.
With one hand, stabilize the skin by spreading it or pinching up a large area.
116
4.
Insert the needle as instructed by your doctor.
117
5. Push the plunger in as far as it will go.
118
6.
Pull the needle out and apply gentle pressure over the injection site for several seconds.
119
Do not rub the area.
120
7.
Place the used needle in a puncture-resistant disposable container and properly dispose of
121
the puncture-resistant container as directed by your Health Care Professional.
122
DOSAGE
123
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
124
Because each patient’s diabetes is different, this schedule has been individualized for you.
125
Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work
126
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
127
that may affect your Humulin 70/30 dose are:
128
Illness
129
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
130
Even if you are not eating, you will still require insulin. You and your doctor should establish a
131
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
132
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
133
Pregnancy
134
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
135
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
136
are nursing a baby, talk to your doctor.
137
Medication
138
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
139
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
140
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
141
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
142
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
143
Your Health Care Professional may be aware of other medications that may affect your diabetes
144
control. Therefore, always discuss any medications you are taking with your doctor.
145
Exercise
146
Exercise may lower your body’s need for insulin during and for some time after the physical
147
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
148
involves the area of injection site (for example, the leg should not be used for injection just prior
149
to running). Discuss with your doctor how you should adjust your insulin regimen to
150
accommodate exercise.
151
Travel
152
When traveling across more than 2 time zones, you should talk to your doctor concerning
153
adjustments in your insulin schedule.
154
COMMON PROBLEMS OF DIABETES
155
Hypoglycemia (Low Blood Sugar)
156
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
157
experienced by insulin users. It can be brought about by:
158
1. Missing or delaying meals.
159
2.
Taking too much insulin.
160
3. Exercising or working more than usual.
161
4. An infection or illness associated with diarrhea or vomiting.
162
5.
A change in the body’s need for insulin.
163
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
164
disease.
165
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
166
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
167
medicines.
168
8. Consumption of alcoholic beverages.
169
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
170
• sweating
171
• dizziness
172
• palpitation
173
• tremor
174
• hunger
175
• restlessness
176
• tingling in the hands, feet, lips, or tongue
177
• lightheadedness
178
• inability to concentrate
179
• headache
180
Signs of severe hypoglycemia can include:
181
• disorientation
182
• unconsciousness
• drowsiness
• sleep disturbances
• anxiety
• blurred vision
• slurred speech
• depressed mood
• irritability
• abnormal behavior
• unsteady movement
• personality changes
• seizures
• death
183
Therefore, it is important that assistance be obtained immediately.
184
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
185
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
186
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
187
per day) of diabetes.
188
A few patients who have experienced hypoglycemic reactions after transfer from animal
189
source insulin to human insulin have reported that the early warning symptoms of
190
hypoglycemia were less pronounced or different from those experienced with their
191
previous insulin.
192
Without recognition of early warning symptoms, you may not be able to take steps to avoid
193
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
194
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
195
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
196
glucose is below your normal fasting glucose, you should consider eating or drinking sugar
197
containing foods to treat your hypoglycemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
198
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
199
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
200
severe hypoglycemia may require the assistance of another person. Patients who are unable to
201
take sugar orally or who are unconscious require an injection of glucagon or should be treated
202
with intravenous administration of glucose at a medical facility.
203
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
204
about these symptoms, you should monitor your blood glucose frequently to help you learn to
205
recognize the symptoms that you experience with hypoglycemia.
206
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
207
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
208
and/or exercise programs to help you avoid hypoglycemia.
209
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
210
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
211
Hyperglycemia can be brought about by any of the following:
212
1. Omitting your insulin or taking less than your doctor has prescribed.
213
2.
Eating significantly more than your meal plan suggests.
214
3.
Developing a fever, infection, or other significant stressful situation.
215
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
216
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
217
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
218
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
219
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
220
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
221
of consciousness, or death. Therefore, it is important that you obtain medical assistance
222
immediately.
223
Lipodystrophy
224
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
225
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
226
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
227
the problem.
228
Allergy
229
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
230
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
231
some instances, this condition may be related to factors other than insulin, such as irritants in the
232
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
233
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
234
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
235
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
236
threatening. If you think you are having a generalized allergic reaction to insulin, call your
237
doctor immediately.
238
ADDITIONAL INFORMATION
239
Information about diabetes may be obtained from your diabetes educator.
240
Additional information about diabetes and Humulin can be obtained by calling The Lilly
241
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
242
Patient Information revised Month dd, yyyy
243
Vials manufactured by
244
Eli Lilly and Company, Indianapolis, IN 46285, USA
245
246
for Wal-Mart Stores, Inc.
247
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
248
Copyright © XXXX, Eli Lilly and Company. All rights reserved.
249
PRINTED IN USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.547561 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019717s094lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 94} |
1,530 | 2.0 PV 3672 AMP
1
INFORMATION FOR THE PATIENT
2
3 ML DISPOSABLE INSULIN DELIVERY DEVICE
3
HUMULIN® 70/30 Pen
4
70% HUMAN INSULIN
5
ISOPHANE SUSPENSION
6
AND
7
30% HUMAN INSULIN INJECTION
8
(rDNA ORIGIN)
9
100 UNITS PER ML (U-100)
10
WARNINGS
11
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE
12
INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN
13
PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE
14
MANUFACTURING PROCESS.
15
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER
16
MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER, TYPE (E.G.,
17
REGULAR, NPH, LENTE, ETC), SPECIES (BEEF, PORK, BEEF-PORK, HUMAN), OR
18
METHOD OF MANUFACTURE (rDNA VERSUS ANIMAL-SOURCE INSULIN) MAY
19
RESULT IN THE NEED FOR A CHANGE IN DOSAGE.
20
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY
21
REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH ANIMAL-SOURCE
22
INSULINS. IF AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST
23
DOSE OR DURING THE FIRST SEVERAL WEEKS OR MONTHS.
24
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW THE
25
“DISPOSABLE INSULIN DELIVERY DEVICE USER MANUAL” AND THIS
26
“INFORMATION FOR THE PATIENT” INSERT BEFORE USING THIS PRODUCT.
27
BEFORE EACH INJECTION, YOU SHOULD PRIME THE PEN, A NECESSARY STEP
28
TO MAKE SURE THE PEN IS READY TO DOSE. PRIMING THE PEN IS IMPORTANT
29
TO CONFIRM THAT INSULIN COMES OUT WHEN YOU PUSH THE INJECTION
30
BUTTON AND TO REMOVE AIR THAT MAY COLLECT IN THE INSULIN
31
CARTRIDGE DURING NORMAL USE. IF YOU DO NOT PRIME, YOU MAY RECEIVE
32
TOO MUCH OR TOO LITTLE INSULIN (see also INSTRUCTIONS FOR INSULIN PEN
33
USE section).
34
DIABETES
35
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
36
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
37
the pancreas does not make enough insulin to meet your body’s needs.
38
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
39
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
40
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
41
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar is
42
maintained as close to normal as possible. The American Diabetes Association recommends that if
43
your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c (HbA1c) is
44
more than 7%, consult your doctor. A change in your diabetes therapy may be needed. If your
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-717/S-060
Page 2
2
Submission date: August 4, 2004
blood tests consistently show below-normal glucose levels, you should also let your doctor know.
46
Proper control of your diabetes requires close and constant cooperation with your doctor. Despite
47
diabetes, you can lead an active and healthy life if you eat a balanced diet, exercise regularly, and
48
take your insulin injections as prescribed.
49
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
50
wear diabetic identification so that appropriate treatment can be given if complications occur
51
away from home.
52
70/30 HUMAN INSULIN
53
Description
54
Humulin is synthesized in a non-disease-producing special laboratory strain of Escherichia coli
55
bacteria that has been genetically altered by the addition of the human gene for insulin production.
56
Humulin 70/30 is a mixture of 70% Human Insulin Isophane Suspension and 30% Human Insulin
57
Injection, (rDNA origin). It is an intermediate-acting insulin combined with the more rapid onset
58
of action of regular insulin. The duration of activity may last up to 24 hours following injection.
59
The time course of action of any insulin may vary considerably in different individuals or at
60
different times in the same individual. As with all insulin preparations, the duration of action of
61
Humulin 70/30 is dependent on dose, site of injection, blood supply, temperature, and physical
62
activity. Humulin 70/30 is a sterile suspension and is for subcutaneous injection only. It should not
63
be used intravenously or intramuscularly. The concentration of Humulin 70/30 in the
64
Humulin 70/30 Pen is 100 units/mL (U-100).
65
Identification
66
Humulin disposable insulin delivery devices, by Eli Lilly and Company, are available in
67
2 formulations — NPH and 70/30.
68
Your doctor has prescribed the type of insulin that he/she believes is best for you. DO NOT
69
USE ANY OTHER INSULIN EXCEPT ON HIS/HER ADVICE AND DIRECTION.
70
The Humulin 70/30 Pen is available in boxes of 5 disposable insulin delivery devices (“insulin
71
Pens”). The Humulin 70/30 Pen is not designed to allow any other insulin to be mixed in its
72
cartridge, or for the cartridge to be removed.
73
Always examine the appearance of Humulin 70/30 suspension in the insulin Pen before
74
administering a dose. A cartridge of Humulin 70/30 contains a small glass bead to assist in mixing.
75
Humulin 70/30 Pen must be rolled between the palms 10 times and inverted 180° 10 times before
76
each injection so that the contents are uniformly mixed (see Figures 1 and 2). Inspect the
77
Humulin 70/30 suspension for uniform mixing and repeat the above steps as necessary.
78
Figure 1.
Figure 2.
79
Humulin 70/30 should look uniformly cloudy or milky after mixing. Do not use if the insulin
80
substance (the white material) remains visibly separated from the liquid after mixing. Do not use
81
the Humulin 70/30 Pen if there are clumps in the insulin after mixing. Do not use the
82
Humulin 70/30 Pen if solid white particles stick to the walls of the cartridge, giving it a frosted
83
appearance.
84
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-717/S-060
Page 3
3
Submission date: August 4, 2004
Always check the appearance of the Humulin 70/30 suspension in the insulin Pen before using,
85
and if you note anything unusual in the appearance of Humulin 70/30 suspension or notice your
86
insulin requirements changing markedly, consult your doctor.
87
Never attempt to remove the cartridge from the Humulin 70/30 Pen. Inspect the cartridge through
88
the clear cartridge holder.
89
Storage
90
Not in-use (unopened): Humulin 70/30 Pens not in-use should be stored in a refrigerator but not
91
in the freezer. Do not use a Humulin 70/30 Pen if it has been frozen.
92
In-use: Humulin 70/30 Pens in-use should NOT be refrigerated but should be kept at room
93
temperature (below 86ºF [30ºC]) away from direct heat and light. Humulin 70/30 Pens in-use must
94
be discarded after 10 days, even if they still contain Humulin 70/30.
95
Do not use Humulin 70/30 Pens after the expiration date stamped on the label.
96
INSTRUCTIONS FOR INSULIN PEN USE
97
It is important to read, understand, and follow the instructions in the “Disposable Insulin
98
Delivery Device User Manual” before using. Failure to follow instructions may result in
99
getting too much or too little insulin. The needle must be changed and the Pen must be
100
primed before each injection to make sure the Pen is ready to dose. Performing these steps
101
before each injection is important to confirm that insulin comes out when you push the
102
injection button, and to remove air that may collect in the insulin cartridge during normal use.
103
Every time you inject:
104
• Use a new needle.
105
• Prime to make sure the Pen is ready to dose.
106
• Make sure you got your full dose.
107
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
108
PREPARING THE INSULIN PEN FOR INJECTION
109
1. Always check the appearance of the Humulin 70/30 suspension in the insulin Pen before
110
using.
111
2. Roll the Humulin 70/30 Pen between the palms 10 times (see Figure 1).
112
3. Holding the Humulin 70/30 Pen by one end, invert it 180° slowly 10 times to allow the
113
small glass bead to travel the full length of the cartridge with each inversion (see Figure 2).
114
The cartridge is contained in the clear cartridge holder of the Humulin 70/30 Pen.
115
4. Inspect the appearance of the Humulin 70/30 suspension to make sure the contents look
116
uniformly cloudy or milky. If not, repeat the above steps until the contents are mixed. Do not
117
use a Humulin 70/30 Pen if there are clumps in the insulin or if solid white particles stick to
118
the walls of the cartridge.
119
5. Follow the instructions in the “Disposable Insulin Delivery Device User Manual” for these
120
steps:
121
• Preparing the Pen
122
• Attaching the Needle. Use a new needle for each injection.
123
• Priming the Pen. The Pen must be primed before each injection to make sure the Pen
124
is ready to dose. Performing the priming step is important to confirm that insulin comes
125
out when you push the injection button, and to remove air that may collect in the insulin
126
cartridge during normal use.
127
• Setting a Dose
128
• Injecting a Dose. To make sure you have received your full dose, you must push the
129
injection button all the way down until you see a diamond (♦) or an arrow (→) in the
130
center of the dose window.
131
• Following an Injection
132
PREPARING FOR INJECTION
133
1. Wash your hands.
134
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-717/S-060
Page 4
4
Submission date: August 4, 2004
2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
135
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
136
3. Cleanse the skin with alcohol where the injection is to be made.
137
4. With one hand, stabilize the skin by spreading it or pinching up a large area.
138
5. Inject the dose as instructed by your doctor. Hold the needle under the skin for at least
139
5 seconds after injecting.
140
6. After injecting a dose, pull the needle out and apply gentle pressure over the injection site
141
for several seconds. Do not rub the area.
142
7. Immediately after an injection, remove the needle from the Humulin 70/30 Pen. Doing so
143
will guard against contamination, leakage, reentry of air, and needle clogs. Do not reuse
144
needles. Place the used needle in a puncture-resistant disposable container and properly
145
dispose of it as directed by your Health Care Professional.
146
DOSAGE
147
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
148
Because each patient’s case of diabetes is different, this schedule has been individualized for you.
149
Your usual Humulin 70/30 dose may be affected by changes in your food, activity, or work
150
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things that
151
may affect your Humulin 70/30 dose are:
152
Illness
153
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
154
Even if you are not eating, you will still require insulin. You and your doctor should establish a
155
sick day plan for you to use in case of illness. When you are sick, test your blood glucose/urine
156
glucose and ketones frequently and call your doctor as instructed.
157
Pregnancy
158
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
159
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
160
are nursing a baby, consult your doctor.
161
Medication
162
Insulin requirements may be increased if you are taking other drugs with hyperglycemic activity,
163
such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin requirements
164
may be reduced in the presence of drugs with blood-glucose-lowering activity, such as oral
165
antidiabetic agents, salicylates (for example, aspirin), sulfa antibiotics, alcohol, and certain
166
antidepressants. Always discuss any medications you are taking with your doctor.
167
Exercise
168
Exercise may lower your body’s need for insulin during and for some time after the physical
169
activity. Exercise may also speed up the effect of a Humulin 70/30 dose, especially if the exercise
170
involves the area of injection site (for example, the leg should not be used for injection just prior
171
to running). Discuss with your doctor how you should adjust your regimen to accommodate
172
exercise.
173
Travel
174
Persons traveling across more than 2 time zones should consult their doctor concerning
175
adjustments in their insulin schedule.
176
COMMON PROBLEMS OF DIABETES
177
Hypoglycemia (Low Blood Sugar)
178
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
179
experienced by insulin users. It can be brought about by:
180
1. Taking too much insulin.
181
2. Missing or delaying meals.
182
3. Exercising or working more than usual.
183
4. An infection or illness (especially with diarrhea or vomiting).
184
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-717/S-060
Page 5
5
Submission date: August 4, 2004
5. A change in the body’s need for insulin.
185
6. Diseases of the adrenal, pituitary or thyroid gland, or progression of kidney or liver
186
disease.
187
7. Interactions with other drugs that lower blood glucose, such as oral antidiabetic agents,
188
salicylates (for example, aspirin), sulfa antibiotics, and certain antidepressants.
189
8. Consumption of alcoholic beverages.
190
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
191
• sweating
• drowsiness
192
• dizziness
• sleep disturbances
193
• palpitation
• anxiety
194
• tremor
• blurred vision
195
• hunger
• slurred speech
196
• restlessness
• depressed mood
197
• tingling in the hands, feet, lips, or tongue
• irritability
198
• lightheadedness
• abnormal behavior
199
• inability to concentrate
• unsteady movement
200
• headache
• personality changes
201
Signs of severe hypoglycemia can include:
202
• disorientation
• seizures
203
• unconsciousness
• death
204
Therefore, it is important that assistance be obtained immediately.
205
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
206
conditions, such as long duration of diabetes, diabetic nerve disease, medications such as beta-
207
blockers, change in insulin preparations, or intensified control (3 or more insulin injections per
208
day) of diabetes.
209
A few patients who have experienced hypoglycemic reactions after transfer from animal-
210
source insulin to human insulin have reported that the early warning symptoms of
211
hypoglycemia were less pronounced or different from those experienced with their previous
212
insulin.
213
Without recognition of early warning symptoms, you may not be able to take steps to avoid more
214
serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
215
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
216
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
217
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
218
containing foods to treat your hypoglycemia.
219
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
220
Patients should always carry a quick source of sugar, such as candy mints or glucose tablets. More
221
severe hypoglycemia may require the assistance of another person. Patients who are unable to take
222
sugar orally or who are unconscious require an injection of glucagon or should be treated with
223
intravenous administration of glucose at a medical facility.
224
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain about
225
these symptoms, you should monitor your blood glucose frequently to help you learn to recognize
226
the symptoms that you experience with hypoglycemia.
227
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
228
symptoms, you should consult your doctor to discuss possible changes in therapy, meal plans,
229
and/or exercise programs to help you avoid hypoglycemia.
230
Hyperglycemia and Diabetic Ketoacidosis (DKA)
231
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
232
Hyperglycemia can be brought about by:
233
1. Omitting your insulin or taking less than the doctor has prescribed.
234
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Page 6
6
Submission date: August 4, 2004
2. Eating significantly more than your meal plan suggests.
235
3. Developing a fever, infection, or other significant stressful situation.
236
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
237
DKA. The first symptoms of DKA usually come on gradually, over a period of hours or days, and
238
include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on the breath. With
239
DKA, urine tests show large amounts of glucose and ketones. Heavy breathing and a rapid pulse
240
are more severe symptoms. If uncorrected, prolonged hyperglycemia or DKA can lead to nausea,
241
vomiting, stomach pains, dehydration, loss of consciousness, or death. Therefore, it is important
242
that you obtain medical assistance immediately.
243
Lipodystrophy
244
Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the
245
skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these
246
conditions, consult your doctor. A change in your injection technique may help alleviate the
247
problem.
248
Allergy to Insulin
249
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
250
injection of insulin. This condition, called local allergy, usually clears up in a few days to a few
251
weeks. In some instances, this condition may be related to factors other than insulin, such as
252
irritants in the skin cleansing agent or poor injection technique. If you have local reactions, contact
253
your doctor.
254
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
255
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
256
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
257
threatening. If you think you are having a generalized allergic reaction to insulin, notify a doctor
258
immediately.
259
ADDITIONAL INFORMATION
260
Additional information about diabetes may be obtained from your diabetes educator.
261
DIABETES FORECAST is a magazine designed especially for people with diabetes and their
262
families. It is available by subscription from the American Diabetes Association (ADA), P.O. Box
263
363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383).
264
Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research
265
Foundation International (JDRFI), 120 Wall Street 19th Floor, New York, NY 10005,
266
1-800-533-CURE (1-800-533-2873).
267
Additional information about Humulin and Humulin 70/30 Pens can be obtained by calling The
268
Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).
269
Literature revised XX 2004
270
Eli Lilly and Company, Indianapolis, IN 46285, USA
271
272
2.0 PV 3672 AMP
PRINTED IN USA
273
274
Copyright 1998, 2004, Eli Lilly and Company. All rights reserved.
275
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-717/S-060
Page 1
Submission date: August 4, 2004
3.0 PV 3734 AMP
1
____________________________________________________________________________
2
Lilly
3
4
Disposable Insulin Delivery Device
5
User Manual
6
____________________________________________________________________________
7
8
Instructions for Use
9
Read and follow all of these instructions carefully. If you do not follow these instructions
10
completely, you may get too much or too little insulin.
11
12
Every time you inject:
13
•
Use a new needle
14
•
Prime to make sure the Pen is ready to dose
15
•
Make sure you got your full dose (see page 18)
16
17
Also, read the “INFORMATION FOR THE PATIENT” insert
18
enclosed in your Pen box.
19
20
Pen Features
21
•
A multiple dose, disposable insulin delivery device
22
(“insulin Pen”) containing 3 mL (300 units) of U-100
23
insulin
24
•
Delivers up to 60 units per dose
25
•
Doses can be dialed by single units
26
27
28
29
30
___________________________________________________________________________
31
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NDA 19-717/S-060
Page 2
Submission date: August 4, 2004
Table of Contents
32
______________________________________________________________________
33
34
Pen Parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
35
36
Important Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
37
38
Preparing the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
39
40
Attaching the Needle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
41
42
Priming the Pen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
43
44
Setting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
45
46
Injecting a Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . … 16
47
48
Following an Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . …..18
49
50
Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
51
________________________________________________________________________
52
53
2
54
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Pen Parts
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
3
93
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
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94
Important Notes
95
96
•
Read and follow all of these instructions carefully. If you do not follow these instructions
97
completely, you may get too much or too little insulin.
98
99
•
Use a new needle for each injection.
100
101
•
Be sure a needle is completely attached to the Pen before priming, setting the dose
102
and injecting your insulin.
103
104
•
Prime every time.
105
106
•
The Pen must be primed before each injection to make sure the Pen is ready to dose.
107
Performing the priming step is important to confirm that insulin comes out when you push
108
the injection button, and to remove air that may collect in the insulin cartridge during
109
normal use. See Section III. “Priming the Pen”, pages 10-13.
110
111
•
If you do not prime, you may get too much or too little insulin.
112
113
•
Make sure you get your full dose.
114
115
•
To make sure you get your full dose, you must push the injection button all the way down
116
until you see a diamond (♦) or an arrow (→) in the center of the dose window. See
117
“Following an Injection”, page 18.
118
119
•
The numbers on the clear cartridge holder give an estimate of the amount of insulin remaining
120
in the cartridge. Do not use these numbers for measuring an insulin dose.
121
122
•
Do not share your Pen.
123
124
125
4
126
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Submission date: August 4, 2004
Important Notes
127
(Continued)
128
129
•
Keep your Pen out of the reach of children.
130
131
•
Pens that have not been used (unopened) should be stored in a refrigerator but not in a freezer.
132
Do not use a Pen if it has been frozen. Refer to the “INFORMATION FOR THE PATIENT”
133
insert for complete storage instructions.
134
135
•
After a Pen is used for the first time, it should NOT be refrigerated but should be kept at room
136
temperature [below 86°F (30°C)] and away from direct heat and light.
137
138
•
An unrefrigerated Pen should be discarded according to the time specified in the
139
“INFORMATION FOR THE PATIENT” insert, even if it still contains insulin.
140
141
•
Never use a Pen after the expiration date stamped on the label.
142
143
•
Do not store your Pen with the needle attached. Doing so may allow insulin to leak from the
144
Pen and air bubbles to form in the cartridge. Additionally, with suspension (cloudy) insulins,
145
crystals may clog the needle.
146
147
•
Always carry an extra Pen in case yours is lost or damaged.
148
149
•
Dispose of empty Pens as instructed by your Health Care Professional and without the needle
150
attached.
151
152
•
This Pen is not recommended for use by blind or visually impaired patients without the
153
assistance of a person trained in the proper use of the product.
154
155
•
The directions regarding needle handling are not intended to replace local, Health Care
156
Professional, or institutional policies.
157
158
•
Any changes in insulin should be made cautiously and only under medical supervision.
159
160
161
5
162
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I. Preparing the Pen
163
164
1. Before proceeding, refer to the “INFORMATION FOR THE PATIENT” insert for
instructions on checking the appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has been
prescribed for you.
3. Always wash your hands before preparing your Pen for use.
165
4. Pull the Pen cap to remove.
166
6
167
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I. Preparing the Pen
168
(Continued)
169
170
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
171
b. Gently turn the Pen up and down 10 times until
the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges contain a
small glass bead to assist in mixing.
172
173
6. Use an alcohol swab to wipe the rubber seal on the
end of the Pen.
174
7
175
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II. Attaching the Needle
176
177
This device is suitable for use with Becton Dickinson and Company’s insulin pen needles.
178
179
180
1. Always use a new needle for each injection. Do not push injection button without a
needle attached. Storing the Pen with the needle attached may allow insulin to leak
from the Pen and air bubbles to form in the cartridge.
181
2. Remove the paper tab from the outer needle shield.
182
3. Attach the capped needle onto the end of the Pen by turning
it clockwise until tight.
183
8
184
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II. Attaching the Needle
185
(Continued)
186
187
4. Hold the Pen with the needle pointing up and remove the
outer needle shield. Keep it to use during needle
removal.
188
5. Remove the inner needle shield and discard.
189
190
9
191
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III. Priming the Pen
192
193
•
The Pen must be primed before each injection to make sure the Pen is ready to dose.
194
Performing the priming step is important to confirm that insulin comes out when you push the
195
injection button, and to remove air that may collect in the insulin cartridge during normal use.
196
197
•
If you do not prime, you may get too much or too little insulin.
198
199
•
Always use a new needle for each injection.
200
201
1. Make sure the arrow is in the center of the dose window as
shown.
202
2. If you do not see the arrow in the center of the
203
dose window, push in the injection button fully
204
and turn the dose knob until the arrow is seen in
205
the center of the dose window.
206
207
208
Correct
209
210
211
10
212
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Page 11
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III. Priming the Pen
213
(Continued)
214
215
3. With the arrow in the center of the dose window, pull the
dose knob out in the direction of the arrow until a “0” is
seen in the dose window.
216
4. Turn the dose knob clockwise until the number “2” is seen
in the dose window. If the number you have dialed is too
high, simply turn the dose knob backward until the number
“2” is seen in the dose window.
217
11
218
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Submission date: August 4, 2004
219
III. Priming the Pen
220
(Continued)
221
222
5. Hold your Pen with the needle pointing up. Tap the clear
cartridge holder gently with your finger so any air
bubbles collect near the top.
Using your thumb, if possible, push in the injection
button completely. Keep pressing and continue to hold
the injection button firmly while counting slowly to 5.
You should see either a drop or a stream of insulin come
out of the tip of the needle.
If insulin does not come out of the tip of the needle,
repeat steps 1 through 5. If after several attempts insulin
does not come out of the tip of the needle, change the
needle and repeat the priming steps.
223
224
12
225
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Page 13
Submission date: August 4, 2004
III. Priming the Pen
226
(Continued)
227
228
6. At the completion of the priming step, a diamond
(♦) must be seen in the center of the dose window.
If a diamond (♦) is not seen in the center of the
dose window, continue pushing on the injection
button until you see a diamond (♦) in the center of
the dose window.
229
230
231
232
233
234
Correct
235
Note: A small air bubble may remain in the cartridge after the completion of the priming
step. If you have properly primed the Pen, this small air bubble will not affect your insulin
dose.
7. Now you are ready to set your dose. See next page.
236
13
237
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Page 14
Submission date: August 4, 2004
238
IV. Setting a Dose
239
240
•
Always use a new needle for each injection. Storing the Pen with the needle attached may
241
allow insulin to leak from the Pen and air bubbles to form in the cartridge.
242
243
•
Caution: Do not push in the injection button while setting your dose. Failure to follow
244
these instructions carefully may result in getting too much or too little insulin. If you
245
accidentally push the injection button while setting your dose, you must prime the Pen
246
again before injecting your dose. See Section III. “Priming the Pen”, pages 10-13.
247
248
1.
A diamond must be seen in the center of the dose window before setting your dose.
If you do not see a diamond in the center
of the dose window, the Pen has not been
primed correctly and you are not ready to
set your dose. Before continuing, repeat
the priming steps.
Correct
2.
Turn the dose knob clockwise until the arrow (→)
is seen in the center of the dose window and the
notches on the Pen and dose knob are in line.
249
250
14
251
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Page 15
Submission date: August 4, 2004
IV. Setting a Dose
252
(Continued)
253
254
3. With the arrow (→) in the center of the dose
window, pull the dose knob out in the direction of
the arrow until a “0” is seen in the dose window.
A dose cannot be dialed until the dose knob is
pulled out.
255
4. Turn the dose knob clockwise until your dose is
seen in the dose window. If the dose you have
dialed is too high, simply turn the dose knob
backward until the correct dose is seen in the dose
window.
256
5. If you cannot dial your full dose, see the “Questions and Answers” section,
Question 5, at the end of this manual.
15
257
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Page 16
Submission date: August 4, 2004
V. Injecting a Dose
258
259
•
Always use a new needle for each injection. Storing the Pen with the needle attached may
260
allow insulin to leak from the Pen and air bubbles to form in the cartridge.
261
262
•
Caution: Do not attempt to change the dose after you begin to push in the injection
263
button. Failure to follow these instructions carefully may result in getting too much or
264
too little insulin.
265
266
•
The effort needed to push in the injection button may increase while you are injecting
267
your insulin dose. If you cannot completely push in the injection button, refer to the
268
“Questions and Answers” section, Question 7, at the end of this manual.
269
270
•
Do not inject a dose unless the Pen is primed, just before injection, or you may get too much or
271
too little insulin.
272
273
•
If you have set a dose and pushed in the injection button without a needle attached or if no
274
insulin comes out of the needle, see the “Questions and Answers” section, Questions 1 and 2.
275
276
16
277
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Page 17
Submission date: August 4, 2004
V. Injecting a Dose
278
(Continued)
279
280
1.
Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2.
Insert the needle into your skin. Inject the insulin
by using your thumb, if possible, to push in the
injection button completely.
281
282
3. Keep pressing and continue to hold the injection
button firmly while counting slowly to 5.
After counting to 5, pull the needle out and apply
gentle pressure over the injection site for several
seconds. Do not rub the area.
283
284
4. When the injection is done, a diamond (♦) or
285
arrow (→) must be seen in the center of the
286
dose window. This means your full dose has
287
been delivered. If you do not see the diamond
288
or arrow in the center of the dose window,
289
you did not get your full dose. Contact your Health Care Professional for additional
290
instruction.
291
292
293
294
295
296
297
17
298
Correct
Correct
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Page 18
Submission date: August 4, 2004
VI. Following an Injection
299
300
301
1. Make sure you got your full dose by checking
that the injection button has been completely
pushed in and you can see a diamond (♦) or
arrow (→) in the center of the dose window. If
you do not see the diamond (♦) or arrow (→) in
the center of the dose window, you have not
received your full dose. Contact your Health
Care Professional for additional instructions.
302
2. Carefully replace the outer needle shield as
instructed by your Health Care Professional.
303
304
305
306
18
307
Outer
Needle
Shield
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Page 19
Submission date: August 4, 2004
VI. Following an Injection
308
(Continued)
309
310
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly throw it away as directed by your
Health Care Professional.
311
4. Replace the cap on the Pen.
312
5. The Pen that you are using should NOT be refrigerated but should be kept at room
313
temperature below 86°F (30°C) and away from direct heat and light. It should be discarded
314
according to the time specified in the “INFORMATION FOR THE PATIENT” insert, even if
315
it still contains insulin.
316
317
Do not store or dispose of the Pen with a needle attached. Storing the Pen with the needle
318
attached may allow insulin to leak from the Pen and air bubbles to form in the cartridge.
319
320
321
19
322
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Page 20
Submission date: August 4, 2004
323
Questions and Answers
324
325
Problem
Action
1. Dose dialed and injection
button pushed in without a
needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely (even if a “0”
is seen in the window) until a diamond (♦) or arrow
(→) is seen in the center of the dose window.
3) Prime the Pen.
2. Insulin does not come out of
the needle.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely (even if a “0”
is seen in the window) until a diamond (♦) or arrow
(→) is seen in the center of the dose window.
3) Prime the Pen. See Section III. “Priming the Pen”,
pages 10-13.
326
20
327
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Submission date: August 4, 2004
Questions and Answers
328
(Continued)
329
330
Problem
Action
3. Wrong dose (too high or too
low) dialed.
If you have not pushed in the injection button, simply
turn the dose knob backward or forward to correct the
dose.
4. Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing down. The
scale (20 units between marks) on the clear cartridge
holder shows an estimate of the number of units
remaining. These numbers should not be used for
measuring an insulin dose.
331
332
21
333
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Page 22
Submission date: August 4, 2004
Questions and Answers
334
(Continued)
335
336
Problem
Action
5. Full dose cannot be dialed.
The Pen will not allow you to dial a dose greater than the
number of insulin units remaining in the cartridge. For
example, if you need 31 units and only 25 units remain in
the Pen, you will not be able to dial past 25. Do not
attempt to dial past this point. (The insulin that remains is
unusable and not part of the 300 units.) If a partial dose
remains in the Pen you may either:
1) Give the partial dose and then give the remaining
dose using a new Pen, or
2) Give the full dose with a new Pen.
6. A small amount of insulin
remains in the cartridge but a
dose cannot be dialed.
The Pen design prevents the cartridge from being
completely emptied. The Pen has delivered 300 units of
usable insulin.
337
338
22
339
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Page 23
Submission date: August 4, 2004
Questions and Answers
340
(Continued)
341
342
Problem
Action
7. Cannot completely push in the
injection button when priming
the Pen or injecting a dose.
1) Needle is not attached or is clogged.
a. Attach a new needle.
b. Push in the injection button completely (even if a
“0” is seen in the window) until a diamond (♦) or
arrow (→) is seen in the center of the dose
window.
c. Prime the Pen.
2) If you are sure insulin is coming out of the needle,
push in the injection button more slowly to reduce the
effort needed and maintain a constant pressure until
the injection button is completely pushed in.
343
23
344
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Page 24
Submission date: August 4, 2004
345
For additional information call,
1-800-LillyRx (1-800-545-5979)
Literature revised XX 2004
Eli Lilly and Company, Indianapolis, IN 46285, USA
3.0 PV 3734 AMP
PRINTED IN USA
346
24
347
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C-1004
C-1004
C-1004
A1.0 NL 2483 AMS
A1.0 NL 2483 AMS
A1.0 NL 2483 AMS
If the seal is broken before first use, contact pharmacist
If the seal is broken before first use, contact pharmacist
NDC 0002-8770-01
freezing.
Important
Please read updated User Manual
Every time you inject:
Use a new needle
Prime to make sure the Pen is ready to dose
Make sure you got your full dose
1-800-545-5979
Eli Lilly and Company
Indianapolis, IN 46285, USA
1-800-545-5979
1 "
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.626530 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19717s060lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 60} |
1,535 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN 70/30 safely and effectively. See full prescribing information
for HUMULIN 70/30.
HUMULIN® 70/30 (70% human insulin isophane suspension and 30%
human insulin injection [rDNA origin]) injectable suspension, for
subcutaneous use
Initial U.S. Approval: 1989
--------------------------- RECENT MAJOR CHANGES -------------------------
Warnings and Precautions (5.5)
03/2013
----------------------------INDICATIONS AND USAGE --------------------------
HUMULIN 70/30 is an insulin indicated to improve glycemic control in adult
patients with diabetes mellitus. (1)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
•
Only administer subcutaneously (in abdominal wall, thigh, upper arm, or
buttocks). (2.2)
•
Individualize and adjust dosage based on metabolic needs, blood glucose
monitoring results and glycemic control goal. (2.3)
•
See Full Prescribing Information for dosage adjustments due to drug
interactions and patients with renal and hepatic impairment. (2.3)
•
Administer approximately 30-45 minutes before a meal. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS --------------------
Injectable suspension 100 units per mL (U-100) available as 10 mL vials or
3 mL vials or 3 mL prefilled pens. (3)
-------------------------------CONTRAINDICATIONS -----------------------------
•
During episodes of hypoglycemia. (4)
•
In patients with hypersensitivity to HUMULIN 70/30 or any of its
excipients. (4)
------------------------WARNINGS AND PRECAUTIONS ----------------------
•
Changes in Insulin Regimen: Carry out under close medical supervision
and increase frequency of blood glucose monitoring. (5.1)
•
Hypoglycemia: May be life-threatening. Monitor blood glucose and
increase monitoring frequency with changes to insulin dosage, use of
glucose lowering medications, meal pattern, physical activity; in patients
with renal or hepatic impairment; and in patients with hypoglycemia
unawareness. (5.2, 7, 8.6, 8.7)
•
Hypersensitivity Reactions: May be life-threatening. Discontinue
HUMULIN 70/30, monitor and treat if indicated. (5.3)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk of hypokalemia and treat if indicated. (5.4)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure
occurs. (5.5)
-------------------------------ADVERSE REACTIONS -----------------------------
Adverse reactions observed with insulin therapy include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight
gain, and edema. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545 5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -----------------------------
•
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage
may be needed. (7.1, 7.2, 7.3)
•
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (5.2, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 11/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Route of Administration
2.3
Dosage Information
2.4
Timing of Subcutaneous Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Changes in Insulin Regimen
5.2
Hypoglycemia
5.3
Hypersensitivity Reactions
5.4
Hypokalemia
5.5
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect
of HUMULIN 70/30
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN 70/30
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
HUMULIN 70/30 is a fixed ratio premix recombinant human insulin formulation indicated to improve glycemic control in
adult patients with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inspect HUMULIN 70/30 visually before use. It should not contain particulate matter and should appear uniformly cloudy
after mixing. Do not use HUMULIN 70/30 if particulate matter is seen. Do not mix HUMULIN 70/30 with any other insulins or
diluents.
2.2
Route of Administration
HUMULIN 70/30 should only be administered subcutaneously. Administer in the subcutaneous tissue of the abdominal wall,
thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy, rotate the injection site within the same region from one injection to
the next [see Adverse Reactions (6)].
Do not administer HUMULIN 70/30 intravenously or intramuscularly and do not use HUMULIN 70/30 in an insulin infusion
pump.
2.3
Dosage Information
Individualize and adjust the dosage of HUMULIN 70/30 based on the individual’s metabolic needs, blood glucose monitoring
results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e.,
macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and
Precautions (5.1, 5.2), and Use in Specific Populations (8.6, 8.7)].
The proportion of rapid acting and long acting insulin is fixed in a premixed insulin such as HUMULIN 70/30. Independent
adjustment of the basal or prandial dose is not possible when using a premixed insulin.
Physiological factors, disease states and concomitant drugs may impact the onset and duration of action of all insulins.
HUMULIN 70/30 dose requirements may change with changes in level of physical activity, meal patterns (i.e., macronutrient content
or timing of food intake), during major illness, or with some coadministered drugs [see Warnings and Precautions (5.2), Drug
Interactions (7), and Use in Specific Populations (8.6, 8.7)].
2.4
Timing of Subcutaneous Administration
HUMULIN 70/30 should be given subcutaneously approximately 30-45 minutes before a meal.
3
DOSAGE FORMS AND STRENGTHS
HUMULIN 70/30 injectable suspension: 100 units per mL (U-100) is available as:
•
10 mL vials
•
3 mL vials
•
3 mL prefilled pens
4
CONTRAINDICATIONS
HUMULIN 70/30 is contraindicated:
•
During episodes of hypoglycemia [see Warnings and Precautions (5.2)], and
•
In patients who have had hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Warnings and
Precautions (5.3)].
5
WARNINGS AND PRECAUTIONS
5.1
Changes in Insulin Regimen
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to
hypoglycemia [see Warnings and Precautions (5.2)] or hyperglycemia. These changes should be made cautiously and under close
medical supervision and the frequency of blood glucose monitoring should be increased.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN 70/30. Severe
hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction
time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other
machinery).
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic
nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions
(7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when
the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of
HUMULIN 70/30 may vary in different individuals or at different times in the same individual and depends on many conditions,
including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other
factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals),
changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or
hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an
essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have
reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
5.3
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including
HUMULIN 70/30. If hypersensitivity reactions occur, discontinue HUMULIN 70/30; treat per standard of care and monitor until
symptoms and signs resolve [see Adverse Reactions (6)]. HUMULIN 70/30 is contraindicated in patients who have had
hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Contraindications (4)].
5.4
Hypokalemia
All insulin products, including HUMULIN 70/30, cause a shift in potassium from the extracellular to intracellular space,
possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor
potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations).
5.5
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-
related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.
Patients treated with insulin, including HUMULIN 70/30, and a PPAR-gamma agonist should be observed for signs and symptoms of
heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose
reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.2)].
•
Hypokalemia [see Warnings and Precautions (5.4)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN 70/30. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to
establish a causal relationship to drug exposure.
Allergic Reactions
Some patients taking HUMULIN 70/30 have experienced erythema, local edema, and pruritus at the site of injection. These
conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and
Precautions (5.3)].
Peripheral Edema
Some patients taking HUMULIN 70/30 have experienced sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Lipodystrophy
Administration of insulin subcutaneously, including HUMULIN 70/30, has resulted in lipoatrophy (depression in the skin) or
lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] in some patients.
Weight gain
Weight gain has occurred with some insulin therapies including HUMULIN 70/30 and has been attributed to the anabolic
effects of insulin and the decrease in glycosuria.
Immunogenicity
Development of antibodies that react with human insulin have been observed with all insulin, including HUMULIN 70/30.
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN 70/30 use may be increased when co-administered with antidiabetic
agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, disopyramide, fibrates, propoxyphene,
pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide). Dose adjustment
and increased frequency of glucose monitoring may be required when HUMULIN 70/30 is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30
The glucose lowering effect of HUMULIN 70/30 may be decreased when co-administered with corticosteroids, isoniazid,
niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol,
terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones. Dose adjustment and increased
frequency of glucose monitoring may be required when HUMULIN 70/30 is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30
The glucose lowering effect of HUMULIN 70/30 may be increased or decreased when co-administered with beta-blockers,
clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN 70/30 is co-administered with
these drugs.
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.2)] may be blunted when beta-blockers,
clonidine, guanethidine, and reserpine are co-administered with HUMULIN 70/30.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This
background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is
essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. In patients with diabetes or gestational diabetes, insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is
essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they
become pregnant while taking HUMULIN 70/30.
Human Data
While there are no adequate and well-controlled studies of HUMULIN 70/30 in pregnant women, evidence from published
literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal
benefits.
Animal Data
Reproduction and fertility toxicity studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk; it is unknown whether HUMULIN 70/30 is present in human milk. Insulin
orally ingested is degraded in the gastrointestinal tract. No adverse reactions associated with infant exposure to insulin through the
consumption of human milk have been reported. Good glucose control supports lactation in patients with diabetes. Women with
diabetes who are lactating may require adjustments in their insulin dose.
8.4
Pediatric Use
Safety and effectiveness of HUMULIN 70/30 in patients less than 18 years of age has not been established.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied [see Clinical
Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN 70/30, may be at increased risk of
hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.2)].
8.6
Renal Impairment
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied
[see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may require more
frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.
8.7
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied
[see Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more
frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.2, 5.4)] Mild
episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or physical activity level may
be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
HUMULIN 70/30 (70% human insulin isophane suspension and 30% human insulin injection [rDNA origin]) is a human
insulin suspension. Human insulin is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of
Escherichia coli. HUMULIN 70/30 is a suspension of crystals produced from combining human insulin and protamine sulfate under
appropriate conditions for crystal formation and mixing with human insulin injection. The amino acid sequence of HUMULIN 70/30
is identical to human insulin and has the empirical formula C257H383N65O77S6 with a molecular weight of 5808.
HUMULIN 70/30 is a sterile white suspension. Each milliliter of HUMULIN 70/30 contains 100 units of insulin human,
0.24 mg of protamine sulfate, 16 mg of glycerin, 3.78 mg of dibasic sodium phosphate, 1.6 mg of metacresol, 0.65 mg of phenol, zinc
oxide content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or
hydrochloric acid may be added during manufacture to adjust the pH.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
HUMULIN 70/30 lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting
hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.
12.2
Pharmacodynamics
HUMULIN 70/30 combines an intermediate-acting insulin with the more rapid onset of action of regular human insulin. In
healthy males (n=18) given HUMULIN 70/30 (0.3 unit/kg) subcutaneously, the pharmacologic effect began at approximately 50
minutes (range: 30 to 90 minutes) (see Figure 1). The effect was maximal at approximately 3.5 hours (range: 1.5 to 6.5 hours) and the
mean duration of action was relatively long (approximately 23 hours; range: 18-24 hours).
Figure 1 should be considered only as a representative example since the time course of action of insulin may vary in different
individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected
by the site of injection, physical activity level, and other variables [see Warnings and Precautions (5.2)]. graph
Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of HUMULIN 70/30 or HUMULIN® R
U-100 (0.3 unit/kg) in Healthy Subjects.
12.3
Pharmacokinetics
Absorption — In healthy male subjects given HUMULIN 70/30 (0.3 unit/kg) subcutaneously, the mean peak serum
concentration occurred at 2.2 hours (range: 1 to 5 hours) after dosing.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the
liver being the major organ involved in the clearance of insulin.
Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be accurately
estimated from the terminal slope of the concentration versus time curve.
Specific Populations
The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN 70/30 have not been
studied.
Careful glucose monitoring and dose adjustments of insulin, including HUMULIN 70/30, may be necessary in patients with
renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic in the in
vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN 70/30 100 units per mL (U-100) is available as:
10 mL vials
NDC 0002-8715-01 (HI-710)
3 mL vials
NDC 0002-8715-17 (HI-713)
5 x 3 mL prefilled pen
NDC 0002-8770-59 (HP-8770)
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use after the expiration date.
Not In-Use (Unopened) HUMULIN 70/30 Vials
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31days.
In-Use (Opened) HUMULIN 70/30 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must be used
within 31 days or be discarded, even if they still contain HUMULIN 70/30.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31 days, even if the vial still contains
HUMULIN 70/30.
Not In-Use (Unopened) HUMULIN 70/30 Pen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 10 days.
In-Use (Opened) HUMULIN 70/30 Pen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 10 days, even if the pen still contains
HUMULIN 70/30. See storage table below:
Not In-Use (Unopened)
Refrigerated
Not In-Use (Unopened)
Room Temperature
In-Use (Opened)
10 mL vial
3 mL vial
Until expiration date
31 days
31 days, refrigerated/room
temperature
3 mL pen
Until expiration date
10 days
10 days, room temperature.
Do not refrigerate.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management
of hypoglycemia and hyperglycemia especially at initiation of HUMULIN 70/30 therapy. Instruct patients on handling of special
situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent
administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of
hypoglycemia.
Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who
have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery
[see Warnings and Precautions (5.2)].
Inform patients that accidental mix-ups between HUMULIN 70/30 and other insulins have been reported. Instruct patients to
always carefully check that they are administering the correct insulin (e.g., by checking the insulin label before each injection) to
avoid medication errors between HUMULIN 70/30 and other insulins.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with HUMULIN 70/30. Inform patients on the symptoms of
hypersensitivity reactions [see Warnings and Precautions (5.3)].
Females with Reproductive Potential
Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are contemplating
pregnancy [see Use in Specific Populations (8.1)].
Visual Inspection Prior to Use
Instruct patients to visually inspect HUMULIN 70/30 before use and to use HUMULIN 70/30 only if it contains no particulate
matter and appears uniformly cloudy after mixing [see Dosage and Administration (2.1)].
Expiration Date
Instruct patients not to use HUMULIN 70/30 after the printed expiration date.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A6.0NL 8470 AMP
Copyright © 1992, 2013, Eli Lilly and Company. All rights reserved.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL 5724 AMP
PATIENT INFORMATION
HUMULIN® (HU-mu-lin) 70/30
(70% human insulin isophane suspension and
30% human insulin injection [rDNA origin])
What is HUMULIN 70/30?
•
HUMULIN 70/30 is a man-made insulin that is used to control high blood sugar in adults with
diabetes mellitus.
Who should not use HUMULIN 70/30?
Do not use HUMULIN 70/30 if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to HUMULIN 70/30 or any of the ingredients in HUMULIN 70/30.
Before using HUMULIN 70/30, tell your healthcare provider about all your medical
conditions including, if you:
•
have liver or kidney problems.
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse while
you take TZDs with HUMULIN 70/30.
•
are pregnant, planning to become pregnant, or are breastfeeding.
•
are taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.
Before you start using HUMULIN 70/30, talk to your healthcare provider about low
blood sugar and how to manage it.
How should I use HUMULIN 70/30?
•
Read the Instructions for Use that come with your HUMULIN 70/30.
•
Use HUMULIN 70/30 exactly as your healthcare provider tells you to.
•
Know the type and strength of insulin you use. Do not change the type of insulin you use
unless your healthcare provider tells you to. The amount of insulin and the best time for you to
take your insulin may need to change if you use different types of insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should
be and when you should check your blood sugar levels.
Your HUMULIN 70/30 dose may need to change because of:
•
change in level of physical activity or exercise, weight gain or loss, increased stress, illness,
change in diet.
What should I avoid while using HUMULIN 70/30?
While using HUMULIN 70/30 do not:
•
Drive or operate heavy machinery, until you know how HUMULIN 70/30 affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of HUMULIN 70/30?
HUMULIN 70/30 may cause serious side effects that can lead to death, including:
•
low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar
include:
•
dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred
speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger.
•
serious allergic reaction (whole body reaction). Get medical help right away, if you
have any of these symptoms of an allergic reaction:
•
a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with HUMULIN
70/30 may cause heart failure in some people. This can happen even if you have never had
heart failure or heart problems before. If you already have heart failure it may get worse while
you use TZDs with HUMULIN 70/30. Your healthcare provider should monitor you closely while
you are taking TZDs with HUMULIN 70/30. Tell your healthcare provider if you have any new or
worse symptoms of heart failure including:
•
shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and HUMULIN 70/30 may need to be adjusted or stopped by your
healthcare provider if you have new or worse heart failure.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL 7480 AMP
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat,
sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of HUMULIN 70/30 include:
•
low blood sugar (hypoglycemia), allergic reactions including reactions at the injection site,
skin thickening or pits at the injection site (lipodystrophy), itching, rash, weight gain, and swelling
of your hands and feet. These are not all the possible side effects of HUMULIN 70/30. Call your
doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
General information about the safe and effective use of HUMULIN 70/30:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. You can ask your pharmacist or healthcare provider for information about HUMULIN 70/30
that is written for health professionals. Do not use HUMULIN 70/30 for a condition for which it was
not prescribed. Do not give HUMULIN 70/30 to other people, even if they have the same
symptoms that you have. It may harm them.
What are the ingredients in HUMULIN 70/30?
Active Ingredient: insulin human (rDNA origin)
Inactive Ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol,
phenol, zinc oxide, water for injection, hydrochloric acid or sodium hydroxide
For more information, call 1-800-545-5979 or go to www.humulin.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: Month DD, YYYY
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL 8520 AMP
Instructions for Use
HUMULIN® (HU-mu-lin) 70/30
(70% human insulin isophane suspension and
30% human insulin injection [rDNA origin])
vial (100 Units/mL, U-100)
Read the Instructions for Use before you start taking HUMULIN 70/30 and each
time you get a new HUMULIN 70/30 vial. There may be new information. This
information does not take the place of talking to your healthcare provider about
your medical condition or your treatment.
Do not share your syringes or needles with anyone else. You may give an
infection to them or get an infection from them.
Supplies needed to give your injection:
• a HUMULIN 70/30 vial
• a U-100 insulin syringe and needle
• 2 alcohol swabs
• 1 sharps container for throwing away used needles and syringes. See
“Disposing of used needles and syringes” at the end of these
instructions.
usage illus
trat
ion
Preparing your HUMULIN 70/30 dose:
• Wash your hands with soap and water.
• Check the HUMULIN 70/30 label to make sure you are taking the
right type of insulin. This is especially important if you use more
than 1 type of insulin.
• Do not use HUMULIN 70/30 past the expiration date printed on the label or
31 days after you first use it.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(Example Dose: 20 units shown)
•
Always use a new needle for each injection to help ensure sterility and
prevent blocked needles.
Step 1:
Gently roll the vial between the palms of your
hands at least 10 times.
Step 2:
Invert the vial at least 10 times.
Do not shake.
Mixing is important to make sure you get the
right dose. Humulin 70/30 should look white and
cloudy after mixing. Do not use it if it looks clear
or contains any lumps or particles.
Step 3:
If you are using a new vial, pull off the plastic
Protective Cap, but do not remove the Rubber
Stopper.
Step 4:
Wipe the Rubber Stopper with an alcohol swab.
Step 5:
Hold the syringe with the needle pointing up. Pull
down on the Plunger until the tip of the Plunger
reaches the line for the number of units for your
prescribed dose.
Step 6:
Push the needle through the Rubber Stopper of the
vial.
usage illustrationusage illustrationusage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 7:
Push the plunger all the way in. This puts air into
the vial.
Step 8:
Turn the vial and syringe upside down and slowly
pull the Plunger down until the tip is a few units
past the line for your prescribed dose.
(Example Dose: 20 units
Plunger is shown at 24 units)
If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top.
Step 9:
Slowly push the Plunger up until the tip reaches
the line for your prescribed dose.
Check the syringe to make sure that you have the
right dose.
(Example Dose: 20 units shown)
Step 10:
Pull the syringe out of the vial’s Rubber Stopper.
usage illustrationusage illustration
Giving your HUMULIN 70/30 injection:
•
Inject your insulin exactly as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 11:
Choose your injection site.
HUMULIN 70/30 is injected under the skin
(subcutaneously) of your stomach area (abdomen),
buttocks, upper legs or upper arms.
Wipe the skin with an alcohol swab. Let the
injection site dry before you inject your dose.
Step 12:
Insert the needle into your skin.
Step 13:
Push down on the Plunger to inject your dose.
The needle should stay in your skin for at least 5
seconds to make sure you have injected all of your
insulin dose.
Step 14:
Pull the needle out of your skin.
•
If you see blood after you take the needle
out of your skin, press the injection site with
a piece of gauze or an alcohol swab. Do not
rub the area.
•
Do not recap the needle. Recapping the
needle can lead to a needle stick injury.
usage illustrationusage illustrationusage illustrationusage illustration
Disposing of used needles and syringes:
• Put your used needles and syringes in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and
syringes in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
o made of a heavy-duty plastic,
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
o upright and stable during use,
o leak-resistant, and
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
• Do not recycle the container.
How should I store HUMULIN 70/30?
All unopened HUMULIN 70/30 vials:
• Store all unopened vials in the refrigerator.
• Do not freeze. Do not use if it has been frozen.
• Keep away from heat and out of direct light.
• Unopened vials can be used until the expiration date on the carton and label, if
they have been stored in the refrigerator.
• Unopened vials should be thrown away after 31 days, if they are stored at room
temperature.
After HUMULIN 70/30 vials have been opened:
• Store opened vials in the refrigerator or at room temperature below 86°F (30°C)
for up to 31 days.
• Keep away from heat and out of direct light.
• Throw away all opened vials after 31 days of use, even if there is still insulin left
in the vial.
General information about the safe and effective use of HUMULIN 70/30.
Keep HUMULIN 70/30 vials, syringes, needles, and all medicines out of the reach of
children.
If you have any questions or problems with your HUMULIN, contact Lilly at 1-800
Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more
information on HUMULIN and insulin, go to www.humulin.com. logo
Scan this code to launch the humulin.com website
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL8520AMP
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
Revised: Month/Year
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.0 NL 9550 AMP
Instructions for Use
HUMULIN® 70/30 KwikPen™
(70% human insulin isophane suspension
30% human insulin injection [rDNA origin]) usage illustration
Read the Instructions for Use before you start taking HUMULIN 70/30 and each time
you get another HUMULIN® 70/30 KwikPen™. There may be new information. This
information does not take the place of talking to your healthcare provider about your
medical condition or your treatment.
HUMULIN 70/30 KwikPen (“Pen”) is a disposable pen containing 3 mL (300 units) of
U-100 HUMULIN® 70/30 (70% human insulin isophane suspension and 30% human
insulin injection [rDNA origin]) insulin. You can inject from 1 to 60 units in a single
injection.
HUMULIN 70/30 KwikPen has a blue and brown Label with a matching brown Dose
Knob (See the KwikPen Parts diagram below).
Do not share your HUMULIN 70/30 KwikPen or needles with another
person. You may give an infection to them or get an infection from them.
This Pen is not recommended for use by the blind or visually impaired
without the assistance of a person trained in the proper use of the product. usage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Supplies you will need to give your HUMULIN 70/30 injection:
• HUMULIN 70/30 KwikPen
• KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles
recommended)
• alcohol swab
Preparing HUMULIN 70/30 KwikPen:
• Wash your hands with soap and water.
• Check the HUMULIN 70/30 KwikPen Label to make sure you are taking
the right type of insulin. This is especially important if you use more
than 1 type of insulin.
• Do not use HUMULIN 70/30 past the expiration date printed on the Label or
10 days after you start using the Pen.
• Always use a new needle for each injection to help ensure sterility and
prevent blocked needles.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 1:
•
Pull the Pen Cap straight off.
•
Wipe the Rubber Seal with an
alcohol swab.
- Do not twist the cap.
-
Do not remove the HUMULIN
70/30 KwikPen Label.
- Do not attach the Needle
before mixing.
Step 2:
•
Gently roll the Pen between your
hands 10 times.
Step 3:
•
Move the Pen up and down (invert)
the Pen 10 times.
Mixing by rolling and inverting the
Pen is important to make sure you
get the right dose.
Step 4:
•
Check the liquid in the Pen.
HUMULIN 70/30 should look white and
cloudy after mixing. Do not use if it
looks clear or has any lumps or
particles in it.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer
Needle Shield.
Step 6:
•
Push the capped Needle straight onto
the Pen and twist the Needle on until
it is tight.
Step 7:
•
Pull off the Outer Needle Shield. Do
not throw it away.
•
Pull off the Inner Needle Shield and
throw it away.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 8:
•
Turn the Dose Knob to select 2 units.
Step 9:
•
Hold the Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top.
Step 10:
•
Hold the Pen with Needle pointing up.
Push the Dose Knob in until it stops,
and “0” is seen in the Dose Window.
•
Hold the Dose Knob in and count
to 5 slowly.
A stream of insulin should be seen
from the needle.
- If you do not see a stream of
insulin, repeat steps 8 to 10, no
more than 4 times.
- If you still do not see a stream of
insulin, change the needle and
repeat steps 8 to 10.
Priming the HUMULIN 70/30 KwikPen:
Prime the HUMULIN 70/30 KwikPen before each injection. Priming ensures the
Pen is ready to dose and removes air that may collect in the cartridge during normal
use. If you do not prime before each injection, you may get too much or too little
insulin. usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Selecting your dose:
Step 11:
•
Turn the Dose Knob to select the
number of units you need to inject.
The Dose Indicator should line up with
your dose.
The dose can be corrected by turning
the Dose Knob in either direction until
the correct dose lines up with the
Dose Indicator.
-
The even numbers are printed on
the dial.
(Example: 10 units shown)
-
The odd numbers, after the
number 1, are shown as full lines.
(Example: 15 units shown)
• The HUMULIN 70/30 KwikPen will not let you dial more than the number of
units left in the Pen.
• If your dose is more than the number of units left in the Pen, you may either:
-
inject the amount left in your Pen and then use a new Pen to give the rest
of your dose, or
-
get a new Pen and inject the full dose.
• The Pen is designed to deliver a total of 300 units of insulin. The cartridge
contains an additional small amount of insulin that cannot be delivered.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Giving your HUMULIN 70/30 injection:
• Inject your HUMULIN 70/30 exactly as your healthcare provider has shown
you.
• Change (rotate) your injection site for each injection.
• Do not try to change your dose while injecting HUMULIN 70/30.
Step 12:
•
Choose your injection site.
HUMULIN 70/30 is injected under the
skin (subcutaneously) of your
stomach area, buttocks, upper legs or
upper arms.
•
Wipe the skin with an alcohol swab,
and let the injection site dry before
you inject your dose.
Step 13:
•
Insert the Needle into your skin.
Step 14:
•
Put your thumb on the Dose Knob
and push the Dose Knob in until it
stops.
•
Hold the Dose Knob in and slowly
count to 5.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 15:
•
Pull the Needle out of your skin.
You should see “0” in the Dose
Window. If you do not see “0” in the
Dose Window, you did not receive
your full dose.
- If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
- A drop of insulin at the needle tip
is normal. It will not affect your
dose.
- If you do not think you
received your full dose, do not
take another dose. Call Lilly at
1-800-LillyRx (1-800-545-5979) or
your healthcare provider for help.
Step 16:
•
Carefully replace the Outer Needle
Shield.
Step 17:
•
Unscrew the capped Needle and throw
it away.
•
Do not store the Pen with the Needle
attached to prevent leaking, blocking
of the Needle, and air from entering
the Pen.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 18:
•
Replace the Pen Cap by lining up the
Cap Clip with the Dose Indicator and
pushing straight on.
usage illustration
After your injection:
• Put your used needles and pens in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and pens in
your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store my HUMULIN 70/30 KwikPen?
• Store unused HUMULIN 70/30 KwikPens in the refrigerator at 36°F to 46°F
(2°C to 8°C). The Pen you are currently using should be stored at room
temperature, below 86°F (30°C).
• Do not freeze HUMULIN 70/30. Do not use HUMULIN 70/30 if it has been
frozen.
• Unused Pens may be used until the expiration date printed on the Label, if kept
in the refrigerator.
• The HUMULIN 70/30 Pen you are using should be thrown away after 10 days,
even if it still has insulin left in it.
• Keep HUMULIN 70/30 away from heat and out of the light.
General information about the safe and effective use of HUMULIN 70/30
KwikPen.
• Keep HUMULIN 70/30 KwikPen and needles out of the reach of
children.
• Do not use the Pen if any part looks broken or damaged.
• Always carry an extra Pen in case yours is lost or damaged.
• If you cannot remove the Pen Cap, gently twist the Pen Cap back and forth,
and then pull the Pen Cap straight off.
• If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and
get a new one.
-
It may help to push the Dose Knob more slowly during your injection.
• Use the space below to keep track of how long you should use each HUMULIN
70/30 KwikPen.
-
Write down the date you start using your HUMULIN 70/30 KwikPen. Count
forward 10 days.
- Write down the date you should throw it away.
Example:
First used on _______ + 10 days = Throw out on ______
Date
Date
Pen 1 - First used on _______ Throw out on _______
Date
Date
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.0 NL 9550 AMP
Pen 2 - First used on _______ Throw out on _______
Date
Date
Pen 3 - First used on _______ Throw out on _______
Date
Date
Pen 4 - First used on _______ Throw out on _______
Date
Date
Pen 5 - First used on _______ Throw out on _______
Date
Date
If you have any questions or problems with your HUMULIN 70/30 KwikPen, contact
Lilly at 1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help. For
more information on HUMULIN 70/30 KwikPen and insulin, go to www.lilly.com.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
HUMULIN® and HUMULIN® KwikPen™ are trademarks of Eli Lilly and Company.
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © YYYY, Eli Lilly and Company. All rights reserved.
HUMULIN 70/30 KwikPen meets the current dose accuracy and functional
requirements of ISO 11608-1:2000.
Issued: Month Day, Year
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.837852 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019717s098s101lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 98} |
1,536 | 1
A3.0NL 5723 AMP
INFORMATION FOR THE PATIENT
10 mL Vial (1000 Units per vial)
3 mL Vial (300 Units per vial)
HUMULIN® 70/30
70% HUMAN INSULIN
ISOPHANE SUSPENSION
AND
30% HUMAN INSULIN INJECTION
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE
INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN
PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE
MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER,
TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF
MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY
REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF
AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR
DURING THE FIRST SEVERAL WEEKS OR MONTHS.
Humulin 70/30 may cause serious side effects, including:
•
swelling of your hands and feet
• heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with
Humulin 70/30 may cause heart failure in some people. This can happen even if you have
never had heart failure or heart problems before. If you already have heart failure it may get
worse while you take TZDs with Humulin 70/30. Your healthcare provider should monitor
you closely while you are taking TZDs with Humulin 70/30. Tell your healthcare provider
if you have any new or worse symptoms of heart failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and Humulin 70/30 may need to be adjusted or stopped by your
healthcare provider if you have new or worse heart failure.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
is maintained as close to normal as possible. The American Diabetes Association recommends
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
(HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may
be needed. If your blood tests consistently show below-normal glucose levels, you should also let
your doctor know. Proper control of your diabetes requires close and constant cooperation with
your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
exercise regularly, and take your insulin injections as prescribed by your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
70/30 HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
bacteria that has been genetically altered to produce human insulin. Humulin 70/30 is a mixture
of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA origin). It
is an intermediate-acting insulin combined with the more rapid onset of action of Regular human
insulin. The duration of activity may last up to 24 hours following injection. The time course of
action of any insulin may vary considerably in different individuals or at different times in the
same individual. As with all insulin preparations, the duration of action of Humulin 70/30 is
dependent on dose, site of injection, blood supply, temperature, and physical activity. Humulin
70/30 is a sterile suspension and is for subcutaneous injection only. It should not be used
intravenously or intramuscularly. The concentration of Humulin 70/30 is 100 units/mL (U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin. Your doctor has
prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
Always check the carton and the bottle label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Always check the appearance of your bottle of Humulin 70/30 before withdrawing each dose.
Before each injection the Humulin 70/30 bottle must be carefully shaken or rotated several times
to completely mix the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky
after mixing. If not, repeat the above steps until contents are mixed.
Do not use Humulin 70/30:
• if the insulin substance (the white material) remains at the bottom of the bottle after mixing
or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the bottom or wall of the bottle, giving a frosted appearance.
If you see anything unusual in the appearance of Humulin 70/30 suspension in your bottle or
notice your insulin requirements changing, talk to your doctor.
Storage
Not in-use (unopened): Humulin 70/30 bottles not in-use should be stored in a refrigerator,
but not in the freezer.
In-use (opened): The Humulin 70/30 bottle you are currently using can be kept unrefrigerated
as long as it is kept as cool as possible [below 86°F (30°C)] away from heat and light.
Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN VIAL USE
NEVER SHARE NEEDLES AND SYRINGES
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Correct Syringe Type
Doses of insulin are measured in units. U-100 insulin contains 100 units/mL (1 mL=1 cc).
With Humulin 70/30, it is important to use a syringe that is marked for U-100 insulin
preparations. Failure to use the proper syringe can lead to a mistake in dosage, causing serious
problems for you, such as a blood glucose level that is too low or too high.
Syringe Use
To help avoid contamination and possible infection, follow these instructions exactly.
Disposable syringes and needles should be used only once and then discarded by placing the
used needle in a puncture-resistant disposable container. Properly dispose of the puncture-
resistant container as directed by your healthcare provider.
Preparing the Dose
1. Wash your hands.
2.
Carefully shake or rotate the bottle of insulin several times to completely mix the insulin.
3.
Inspect the insulin. Humulin 70/30 suspension should look uniformly cloudy or milky. Do
not use Humulin 70/30 if you notice anything unusual in its appearance.
4. If using a new Humulin 70/30 bottle, flip off the plastic protective cap, but do not remove
the stopper. Wipe the top of the bottle with an alcohol swab.
5. Draw an amount of air into the syringe that is equal to the Humulin 70/30 dose. Put the
needle through rubber top of the Humulin 70/30 bottle and inject the air into the bottle.
6.
Turn the Humulin 70/30 bottle and syringe upside down. Hold the bottle and syringe
firmly in one hand and shake gently.
7. Making sure the tip of the needle is in the Humulin 70/30 suspension, withdraw the
correct dose of Humulin 70/30 into the syringe.
8.
Before removing the needle from the Humulin 70/30 bottle, check the syringe for air
bubbles. If bubbles are present, hold the syringe straight up and tap its side until the
bubbles float to the top. Push the bubbles out with the plunger and then withdraw the
correct dose.
9. Remove the needle from the bottle and lay the syringe down so that the needle does not
touch anything.
Injection Instructions
1.
To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
2. Cleanse the skin with alcohol where the injection is to be made.
3.
With one hand, stabilize the skin by spreading it or pinching up a large area.
4.
Insert the needle as instructed by your doctor.
5. Push the plunger in as far as it will go.
6.
Pull the needle out and apply gentle pressure over the injection site for several seconds.
Do not rub the area.
7.
Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your healthcare provider.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin 70/30 dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your healthcare provider may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Before you use Humulin 70/30, tell your healthcare provider if you:
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with Humulin 70/30.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2.
Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5.
A change in the body’s need for insulin.
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from animal-
source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2.
Eating significantly more than your meal plan suggests.
3.
Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
A3.0NL 5723 AMP
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A3.0PA 9147 FSAMP
INFORMATION FOR THE PATIENT
3 ML PREFILLED INSULIN DELIVERY DEVICE
HUMULIN® 70/30 Pen
70% HUMAN INSULIN
ISOPHANE SUSPENSION
AND
30% HUMAN INSULIN INJECTION
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
WARNINGS
THIS LILLY HUMAN INSULIN PRODUCT DIFFERS FROM ANIMAL-SOURCE
INSULINS BECAUSE IT IS STRUCTURALLY IDENTICAL TO THE INSULIN
PRODUCED BY YOUR BODY’S PANCREAS AND BECAUSE OF ITS UNIQUE
MANUFACTURING PROCESS.
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY
UNDER MEDICAL SUPERVISION. CHANGES IN STRENGTH, MANUFACTURER,
TYPE (E.G., REGULAR, NPH, ANALOG), SPECIES, OR METHOD OF
MANUFACTURE MAY RESULT IN THE NEED FOR A CHANGE IN DOSAGE.
SOME PATIENTS TAKING HUMULIN® (HUMAN INSULIN, rDNA ORIGIN) MAY
REQUIRE A CHANGE IN DOSAGE FROM THAT USED WITH OTHER INSULINS. IF
AN ADJUSTMENT IS NEEDED, IT MAY OCCUR WITH THE FIRST DOSE OR
DURING THE FIRST SEVERAL WEEKS OR MONTHS.
TO OBTAIN AN ACCURATE DOSE, CAREFULLY READ AND FOLLOW THE
INSULIN DELIVERY DEVICE USER MANUAL AND THIS “INFORMATION FOR
THE PATIENT” INSERT BEFORE USING THIS PRODUCT.
THE PEN MUST BE PRIMED TO A STREAM OF INSULIN (NOT JUST A FEW
DROPS) BEFORE EACH INJECTION TO MAKE SURE THE PEN IS READY TO
DOSE. YOU MAY NEED TO PRIME A NEW PEN UP TO SIX TIMES BEFORE A
STREAM OF INSULIN APPEARS.
PRIMING THE PEN IS IMPORTANT TO CONFIRM THAT INSULIN COMES OUT
WHEN YOU PUSH THE INJECTION BUTTON AND TO REMOVE AIR THAT MAY
COLLECT IN THE INSULIN CARTRIDGE DURING NORMAL USE. IF YOU DO NOT
PRIME, YOU MAY RECEIVE TOO MUCH OR TOO LITTLE INSULIN (see also
INSTRUCTIONS FOR INSULIN PEN USE section).
Humulin 70/30 may cause serious side effects, including:
•
swelling of your hands and feet
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with
Humulin 70/30 may cause heart failure in some people. This can happen even if you have
never had heart failure or heart problems before. If you already have heart failure it may
get worse while you take TZDs with Humulin 70/30. Your healthcare provider should
monitor you closely while you are taking TZDs with Humulin 70/30. Tell your healthcare
provider if you have any new or worse symptoms of heart failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Treatment with TZDs and Humulin 70/30 may need to be adjusted or stopped by your
healthcare provider if you have new or worse heart failure.
DIABETES
Insulin is a hormone produced by the pancreas, a large gland that lies near the stomach. This
hormone is necessary for the body’s correct use of food, especially sugar. Diabetes occurs when
the pancreas does not make enough insulin to meet your body’s needs.
To control your diabetes, your doctor has prescribed injections of insulin products to keep your
blood glucose at a near-normal level. You have been instructed to test your blood and/or your
urine regularly for glucose. Studies have shown that some chronic complications of diabetes such
as eye disease, kidney disease, and nerve disease can be significantly reduced if the blood sugar
is maintained as close to normal as possible. The American Diabetes Association recommends
that if your pre-meal glucose levels are consistently above 130 mg/dL or your hemoglobin A1c
(HbA1c) is more than 7%, you should talk to your doctor. A change in your diabetes therapy may
be needed. If your blood tests consistently show below-normal glucose levels, you should also let
your doctor know. Proper control of your diabetes requires close and constant cooperation with
your doctor. Despite diabetes, you can lead an active and healthy life if you eat a balanced diet,
exercise regularly, and take your insulin injections as prescribed by your doctor.
Always keep an extra supply of insulin as well as a spare syringe and needle on hand. Always
wear diabetic identification so that appropriate treatment can be given if complications occur
away from home.
70/30 HUMAN INSULIN
Description
Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli
bacteria that has been genetically altered to produce human insulin. Humulin 70/30 is a mixture
of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection, (rDNA origin).
It is an intermediate-acting insulin combined with the more rapid onset of action of Regular
human insulin. The duration of activity may last up to 24 hours following injection. The time
course of action of any insulin may vary considerably in different individuals or at different
times in the same individual. As with all insulin preparations, the duration of action of Humulin
70/30 is dependent on dose, site of injection, blood supply, temperature, and physical activity.
Humulin 70/30 is a sterile suspension and is for subcutaneous injection only. It should not be
used intravenously or intramuscularly. The concentration of Humulin 70/30 is 100 units/mL
(U-100).
Identification
Human insulin from Eli Lilly and Company has the trademark Humulin.
Your doctor has prescribed the type of insulin that he/she believes is best for you.
DO NOT USE ANY OTHER INSULIN EXCEPT ON YOUR DOCTOR’S ADVICE AND
DIRECTION.
The Humulin 70/30 Pen is available in boxes of 5 prefilled insulin delivery devices
(“insulin Pens”). The Humulin 70/30 Pen is not designed to allow any other insulin to be
mixed in its cartridge, or for the cartridge to be removed.
Always check the carton and the Pen label for the name and letter designation of the insulin
you receive from your pharmacy to make sure it is the same as prescribed by your doctor.
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Always check the appearance of Humulin 70/30 suspension in your insulin Pen before using. A
cartridge of Humulin 70/30 contains a small glass bead to assist in mixing. Roll the Pen back and
forth between the palms 10 times (see Figure 1). Gently turn the Pen up and down 10 times until
the insulin is evenly mixed (see Figure 2). If not evenly mixed, repeat the above steps until
contents are mixed. Pens containing Humulin 70/30 suspension should be examined frequently.
Do not use Humulin 70/30:
• if the insulin substance (the white material) remains visibly separated from the liquid after
mixing or
• if there are clumps in the insulin after mixing, or
• if solid white particles stick to the walls of the cartridge, giving a frosted appearance.
If you see anything unusual in the appearance of the Humulin 70/30 suspension in your Pen or
notice your insulin requirements changing, talk to your doctor.
Never attempt to remove the cartridge from the Humulin 70/30 Pen. Inspect the cartridge
through the clear cartridge holder.
Storage
Not in-use (unopened): Humulin 70/30 Pens not in-use should be stored in a refrigerator, but
not in the freezer.
In-use (opened): Humulin 70/30 Pens in-use should NOT be refrigerated but should be kept at
room temperature [below 86°F (30°C)] away from direct heat and light. The Humulin 70/30 Pen
you are currently using must be discarded 10 days after the first use, even if it still contains
Humulin 70/30.
Do not use Humulin 70/30 after the expiration date stamped on the label or if it has been
frozen.
INSTRUCTIONS FOR INSULIN PEN USE
It is important to read, understand, and follow the instructions in the Insulin Delivery
Device User Manual before using. Failure to follow instructions may result in getting too
much or too little insulin. The needle must be changed and the Pen must be primed to a
stream of insulin (not just a few drops) before each injection to make sure the Pen is ready
to dose. You may need to prime a new Pen up to six times before a stream of insulin
appears. Performing these steps before each injection is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect in the
insulin cartridge during normal use.
Every time you inject:
• Use a new needle.
• Prime to a stream of insulin (not just a few drops) to make sure the Pen is ready to dose.
• Make sure you got your full dose.
NEVER SHARE INSULIN PENS, CARTRIDGES, OR NEEDLES.
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
PREPARING FOR INJECTION
1. Wash your hands.
2. To avoid tissue damage, choose a site for each injection that is at least 1/2 inch from the
previous injection site. The usual sites of injection are abdomen, thighs, and arms.
3. Follow the instructions in your Insulin Delivery Device User Manual to prepare for
injection.
4.
After injecting the dose, pull the needle out and apply gentle pressure over the injection
site for several seconds. Do not rub the area.
5. After the injection, remove the needle from the Humulin 70/30 Pen. Do not reuse
needles.
6.
Place the used needle in a puncture-resistant disposable container and properly dispose of
the puncture-resistant container as directed by your healthcare provider.
DOSAGE
Your doctor has told you which insulin to use, how much, and when and how often to inject it.
Because each patient’s diabetes is different, this schedule has been individualized for you.
Your usual dose of Humulin 70/30 may be affected by changes in your diet, activity, or work
schedule. Carefully follow your doctor’s instructions to allow for these changes. Other things
that may affect your Humulin 70/30 dose are:
Illness
Illness, especially with nausea and vomiting, may cause your insulin requirements to change.
Even if you are not eating, you will still require insulin. You and your doctor should establish a
sick day plan for you to use in case of illness. When you are sick, test your blood glucose
frequently. If instructed by your doctor, test your ketones and report the results to your doctor.
Pregnancy
Good control of diabetes is especially important for you and your unborn baby. Pregnancy may
make managing your diabetes more difficult. If you are planning to have a baby, are pregnant, or
are nursing a baby, talk to your doctor.
Medication
Insulin requirements may be increased if you are taking other drugs with blood-glucose-raising
activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy. Insulin
requirements may be reduced in the presence of drugs that lower blood glucose or affect how
your body responds to insulin, such as oral antidiabetic agents, salicylates (for example, aspirin),
sulfa antibiotics, alcohol, certain antidepressants and some kidney and blood pressure medicines.
Your healthcare provider may be aware of other medications that may affect your diabetes
control. Therefore, always discuss any medications you are taking with your doctor.
Before you use Humulin 70/30, tell your healthcare provider if you:
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with Humulin 70/30.
Exercise
Exercise may lower your body’s need for insulin during and for some time after the physical
activity. Exercise may also speed up the effect of an insulin dose, especially if the exercise
involves the area of injection site (for example, the leg should not be used for injection just prior
to running). Discuss with your doctor how you should adjust your insulin regimen to
accommodate exercise.
Travel
When traveling across more than 2 time zones, you should talk to your doctor concerning
adjustments in your insulin schedule.
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
COMMON PROBLEMS OF DIABETES
Hypoglycemia (Low Blood Sugar)
Hypoglycemia (too little glucose in the blood) is one of the most frequent adverse events
experienced by insulin users. It can be brought about by:
1. Missing or delaying meals.
2.
Taking too much insulin.
3. Exercising or working more than usual.
4. An infection or illness associated with diarrhea or vomiting.
5.
A change in the body’s need for insulin.
6.
Diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney or liver
disease.
7. Interactions with certain drugs, such as oral antidiabetic agents, salicylates (for example,
aspirin), sulfa antibiotics, certain antidepressants and some kidney and blood pressure
medicines.
8. Consumption of alcoholic beverages.
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
• sweating
• drowsiness
• dizziness
• sleep disturbances
• palpitation
• anxiety
• tremor
• blurred vision
• hunger
• slurred speech
• restlessness
• depressed mood
• tingling in the hands, feet, lips, or tongue
• irritability
• lightheadedness
• abnormal behavior
• inability to concentrate
• unsteady movement
• headache
• personality changes
Signs of severe hypoglycemia can include:
• disorientation
• seizures
• unconsciousness
• death
Therefore, it is important that assistance be obtained immediately.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, changing insulin preparations, or intensified control (3 or more insulin injections
per day) of diabetes.
A few patients who have experienced hypoglycemic reactions after transfer from animal-
source insulin to human insulin have reported that the early warning symptoms of
hypoglycemia were less pronounced or different from those experienced with their
previous insulin.
Without recognition of early warning symptoms, you may not be able to take steps to avoid
more serious hypoglycemia. Be alert for all of the various types of symptoms that may indicate
hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should
monitor their blood glucose frequently, especially prior to activities such as driving. If the blood
glucose is below your normal fasting glucose, you should consider eating or drinking sugar-
containing foods to treat your hypoglycemia.
Mild to moderate hypoglycemia may be treated by eating foods or drinks that contain sugar.
Patients should always carry a quick source of sugar, such as hard candy or glucose tablets. More
severe hypoglycemia may require the assistance of another person. Patients who are unable to
take sugar orally or who are unconscious require an injection of glucagon or should be treated
with intravenous administration of glucose at a medical facility.
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
You should learn to recognize your own symptoms of hypoglycemia. If you are uncertain
about these symptoms, you should monitor your blood glucose frequently to help you learn to
recognize the symptoms that you experience with hypoglycemia.
If you have frequent episodes of hypoglycemia or experience difficulty in recognizing the
symptoms, you should talk to your doctor to discuss possible changes in therapy, meal plans,
and/or exercise programs to help you avoid hypoglycemia.
Hyperglycemia (High Blood Sugar) and Diabetic Ketoacidosis (DKA)
Hyperglycemia (too much glucose in the blood) may develop if your body has too little insulin.
Hyperglycemia can be brought about by any of the following:
1. Omitting your insulin or taking less than your doctor has prescribed.
2.
Eating significantly more than your meal plan suggests.
3.
Developing a fever, infection, or other significant stressful situation.
In patients with type 1 or insulin-dependent diabetes, prolonged hyperglycemia can result in
DKA (a life-threatening emergency). The first symptoms of DKA usually come on gradually,
over a period of hours or days, and include a drowsy feeling, flushed face, thirst, loss of appetite,
and fruity odor on the breath. With DKA, blood and urine tests show large amounts of glucose
and ketones. Heavy breathing and a rapid pulse are more severe symptoms. If uncorrected,
prolonged hyperglycemia or DKA can lead to nausea, vomiting, stomach pain, dehydration, loss
of consciousness, or death. Therefore, it is important that you obtain medical assistance
immediately.
Lipodystrophy
Rarely, administration of insulin subcutaneously can result in lipoatrophy (seen as an apparent
depression of the skin) or lipohypertrophy (seen as a raised area of the skin). If you notice either
of these conditions, talk to your doctor. A change in your injection technique may help alleviate
the problem.
Allergy
Local Allergy — Patients occasionally experience redness, swelling, and itching at the site of
injection. This condition, called local allergy, usually clears up in a few days to a few weeks. In
some instances, this condition may be related to factors other than insulin, such as irritants in the
skin cleansing agent or poor injection technique. If you have local reactions, talk to your doctor.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in
blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life
threatening. If you think you are having a generalized allergic reaction to insulin, call your
doctor immediately.
ADDITIONAL INFORMATION
Information about diabetes may be obtained from your diabetes educator.
Additional information about diabetes and Humulin can be obtained by calling The Lilly
Answers Center at 1-800-LillyRx (1-800-545-5979) or by visiting www.LillyDiabetes.com.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1998, yyyy, Eli Lilly and Company. All rights reserved.
A3.0PA 9147 FSAMP
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Lilly
Prefilled Insulin Delivery Device
User Manual
Instructions for Use
Read and follow all of these instructions carefully. If you
do not follow these instructions completely, you may
get too much or too little insulin.
Every time you inject:
• Use a new needle
• Prime to make sure the Pen is ready to dose
• Make sure you got your full dose (see page
18)
Also, read the “Patient Information” enclosed
in your Pen box.
Pen Features
• A multiple dose, prefilled insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Table of Contents
_______________________________________________________________
Pen Parts ..........................................................................................................3
Important Notes................................................................................................ 4
Preparing the Pen ............................................................................................ 6
Attaching the Needle........................................................................................ 8
Priming the Pen.............................................................................................. 10
Setting a Dose................................................................................................ 14
Injecting a Dose ............................................................................................. 16
Following an Injection..................................................................................... 18
Questions and Answers ................................................................................. 20
_______________________________________________________________
2
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Pen Parts
3
3
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Important Notes
• Read and follow all of these instructions carefully. If you do not follow these
instructions completely, you may get too much or too little insulin.
• Use a new needle for each injection.
• Be sure a needle is completely attached to the Pen before priming, setting
the dose and injecting your insulin.
• Prime every time.
• The Pen must be primed before each injection to make sure the Pen is
ready to dose. Performing the priming step is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect
in the insulin cartridge during normal use. See Section III. “Priming the Pen”,
pages 10-13.
• If you do not prime, you may get too much or too little insulin.
• Make sure you get your full dose.
• To make sure you get your full dose, you must push the injection button all the
way down until you see a diamond (♦) or an arrow (
) in the center of the dose
window. See “Following an Injection”, page 18.
• The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
• Do not share your Pen or needles.
• Keep your Pen and needles out of the reach of children.
• Pens that have not been used should be stored in a refrigerator but not in a freezer.
Do not use a Pen if it has been frozen. Refer to the “Patient Information” for
complete storage instructions.
4
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Important Notes
(Continued)
• After a Pen is used for the first time, it should NOT be refrigerated but should be
kept at room temperature [below 86°F (30°C)] and away from direct heat and light.
• An unrefrigerated Pen should be discarded according to the time specified in the
“Patient Information”, even if it still contains insulin.
• Never use a Pen after the expiration date stamped on the label.
• Do not store your Pen with the needle attached. Doing so may allow insulin to leak
from the Pen and air bubbles to form in the cartridge. Additionally, with suspension
(cloudy) insulins, crystals may clog the needle.
• Always carry an extra Pen in case yours is lost or damaged.
• Follow your Health Care Professional’s instruction for safe handling of needles and
disposal of empty pens.
• This Pen is not recommended for use by blind or visually impaired persons without
the assistance of a person trained in the proper use of the product.
• The directions regarding needle handling are not intended to replace local, Health
Care Professional, or institutional policies.
• Any changes in insulin should be made cautiously and only under medical
supervision.
5
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
I. Preparing the Pen
1. Before proceeding, refer to the “Patient Information” for instructions on checking the
appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has
been prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7
I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges
contain a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal
on the end of the Pen.
7
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen
needles.
1. Always use a new needle for each injection. Do not push injection button
without a needle attached. Storing the Pen with the needle attached may allow
insulin to leak from the Pen and air bubbles to form in the cartridge.
2. Remove the paper tab from the outer needle
shield.
3. Attach the capped needle onto the end of the
Pen by turning it clockwise until tight.
8
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
9
II. Attaching the Needle
(Continued)
4. Hold the Pen with the needle pointing up and
remove the outer needle shield. Keep it to
use during needle removal.
5. Remove the inner needle shield and discard.
9
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
10
III. Priming the Pen
• Prime every time. The Pen must be primed to a stream of insulin (not just a few
drops) before each injection to make sure the Pen is ready to dose.
• You may need to prime a new Pen up to six times before a stream of insulin
appears.
• If you do not prime, you may get too much or too little insulin.
• Always use a new needle for each injection.
1. Make sure the arrow (
) is in the center of the
dose window as shown.
2. If you do not see the arrow in the center of the
dose window, push in the injection button fully
and turn the dose knob until the arrow is seen
in the center of the dose window.
Correct
10
Reference ID: 3273550
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11
III. Priming the Pen
(Continued)
3. With the arrow in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window.
4. Turn the dose knob clockwise until the number
“2” is seen in the dose window. If the number
you have dialed is too high, simply turn the
dose knob backward until the number “2” is
seen in the dose window.
11
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
III. Priming the Pen
(Continued)
5. Hold your Pen with the needle pointing straight
up. Tap the clear cartridge holder gently with
your finger so any air bubbles collect near the
top.
Using your thumb, if possible, push in the
injection button completely. Keep pressing and
continue to hold the injection button firmly
while counting slowly to 5. You should see a
stream of insulin come out of the tip of the
needle.
If a stream of insulin does not come out of the
tip of the needle, repeat steps 1 through 5. If
after six attempts a stream of insulin does not
come out of the tip of the needle, change the
needle. Repeat steps 1 through 5 up to two
more times. If you are still unable to get insulin
flowing out of the needle, do NOT use the
Pen. Contact your Health Care Professional or
Lilly.
12
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
III. Priming the Pen
(Continued)
6. At the completion of the priming step, a
diamond (♦) must be seen in the center of the
dose window. If a diamond (♦) is not seen in
the center of the dose window, continue
pushing on the injection button until you see a
diamond (♦) in the center of the dose window.
Correct
Note: A small air bubble may remain in the cartridge after the completion of
the priming step. If you have properly primed the Pen, this small air bubble
will not affect your insulin dose.
7. Now you are ready to set your dose. See next page.
13
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
IV. Setting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not push in the injection button while setting your dose. Failure to
follow these instructions carefully may result in getting too much or too little
insulin. If you accidentally push the injection button while setting your dose,
you must prime the Pen again before injecting your dose. See Section III.
“Priming the Pen”, pages 10-13.
1. A diamond must be seen in the center of the dose window before setting your dose.
If you do not see a diamond in the center of the dose
window, the Pen has not been primed correctly and
you are not ready to set your dose. Before continuing,
repeat the priming steps.
Correct
2. Turn the dose knob clockwise until the arrow
(
) is seen in the center of the dose window
and the notches on the Pen and dose knob are
in line.
14
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
IV. Setting a Dose
(Continued)
3. With the arrow (
) in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window. A dose cannot be dialed until the dose
knob is pulled out.
4. Turn the dose knob clockwise until your dose
is seen in the dose window. If the dose you
have dialed is too high, simply turn the dose
knob backward until the correct dose is seen in
the dose window.
5. If you cannot dial your full dose, see the “Questions and Answers” section,
Question 5, at the end of this manual.
15
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
V. Injecting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not attempt to change the dose after you begin to push in the
injection button. Failure to follow these instructions carefully may result in
getting too much or too little insulin.
• The effort needed to push in the injection button may increase while you are
injecting your insulin dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers” section, Question 7, at the end
of this manual.
• Do not inject a dose unless the Pen is primed, just before injection, or you may get
too much or too little insulin.
•
If you have set a dose and pushed in the injection button without a needle attached
or if no insulin comes out of the needle, see the “Questions and Answers” section,
Questions 1 and 2.
16
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
V. Injecting a Dose
(Continued)
1. Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2. Insert the needle into your skin. Inject the
insulin by using your thumb, if possible, to
push in the injection button completely.
3. Keep pressing and continue to hold the
injection button firmly while counting
slowly to 5.
4. When the injection is done, a diamond (♦) or an
arrow (
) must be seen in the center of the dose
window. This means your full dose has been
delivered. If you do not see a diamond or an
arrow in the center of the dose window, you
did not get your full dose. Contact your Health
Care Professional for additional instructions.
Correct
Correct
17
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
VI. Following an Injection
1. Make sure you got your full dose by checking
that the injection button has been completely
pushed in and you can see a diamond (♦) or
an arrow (
) in the center of the dose window.
If you do not see a diamond (♦) or an arrow
(
) in the center of the dose window, you
have not received your full dose. Contact your
Health Care Professional for additional
instructions.
2. Carefully replace the outer needle shield as
instructed by your Health Care Professional.
18
Outer
Needle
Shield
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
VI. Following an Injection
(Continued)
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly throw it away as directed by your
Health Care Professional.
4. Replace the cap on the Pen.
5. The Pen that you are using should NOT be refrigerated but should be kept at room
temperature [below 86°F (30°C)] and away from direct heat and light. It should be
discarded according to the time specified in the “Patient Information”, even if it still
contains insulin.
Do not store or dispose of the Pen with a needle attached. Storing the Pen with
the needle attached may allow insulin to leak from the Pen and air bubbles to
form in the cartridge.
19
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Questions and Answers
Problem
Action
1. Dose dialed and injection
button pushed in without a
needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen.
2. Insulin does not come out
of the needle.
Note: You may need to prime
a new pen up to six times
before a stream of insulin
appears.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen. See Section III. “Priming
the Pen”, pages 10-13.
20
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Questions and Answers
(Continued)
Problem
Action
3. Why do I need to prime a
new pen up to six times?
The first time you use a new pen, priming up
to six times may be needed to see a stream
of insulin come out of the tip of the needle. If
you do not prime until you see a stream of
insulin, you may get too much or too little
insulin.
4. Wrong dose (too high or
too low) dialed.
If you have not pushed in the injection
button, simply turn the dose knob backward
or forward to correct the dose.
5. Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing
down. The scale (20 units between marks)
on the clear cartridge holder shows an
estimate of the number of units remaining.
These numbers should not be used for
measuring an insulin dose.
21
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Questions and Answers
(Continued)
Problem
Action
6. Full dose cannot be dialed.
The Pen will not allow you to dial a dose
greater than the number of insulin units
remaining in the cartridge. For example, if
you need 31 units and only 25 units remain
in the Pen, you will not be able to dial past
25. Do not attempt to dial past this point.
(The insulin that remains is unusable and
not part of the 300 units.) If a partial dose
remains in the Pen you may either:
1) Give the partial dose and then give the
remaining dose using a new Pen, or
2) Give the full dose with a new Pen.
7. A small amount of insulin
remains in the cartridge but
a dose cannot be dialed.
The Pen design prevents the cartridge from
being completely emptied. The Pen has
delivered 300 units of usable insulin.
22
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Questions and Answers
(Continued)
Problem
Action
8. Cannot completely push in
the injection button when
priming the Pen or injecting
a dose.
1) Needle is not attached or is clogged.
a. Attach a new needle.
b. Push in the injection button
completely (even if a “0” is seen in
the window) until a diamond (♦) or an
arrow (
) is seen in the center of the
dose window.
c. Prime the Pen.
2)
If you are sure insulin is coming out of
the needle, push in the injection button
more slowly to reduce the effort needed
and maintain a constant pressure until
the injection button is completely
pushed in.
23
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
For additional information call,
1-800-LILLY-RX (1-800-545-5979),
or visit our website at www.Humalog.com
Revised XXX xx, 200x
Manufactured by Lilly France S.A.S.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
24
Reference ID: 3273550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:21.919182 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019717s099lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 99} |
1,537 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN 70/30 safely and effectively. See full prescribing information
for HUMULIN 70/30.
HUMULIN® 70/30 (70% human insulin isophane suspension and 30%
human insulin injection [rDNA origin]) injectable suspension, for
subcutaneous use
Initial U.S. Approval: 1989
--------------------------- RECENT MAJOR CHANGES -------------------------
Warnings and Precautions (5.5)
03/2013
----------------------------INDICATIONS AND USAGE --------------------------
HUMULIN 70/30 is an insulin indicated to improve glycemic control in adult
patients with diabetes mellitus. (1)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
•
Only administer subcutaneously (in abdominal wall, thigh, upper arm, or
buttocks). (2.2)
•
Individualize and adjust dosage based on metabolic needs, blood glucose
monitoring results and glycemic control goal. (2.3)
•
See Full Prescribing Information for dosage adjustments due to drug
interactions and patients with renal and hepatic impairment. (2.3)
•
Administer approximately 30-45 minutes before a meal. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS --------------------
Injectable suspension 100 units per mL (U-100) available as 10 mL vials or
3 mL vials or 3 mL prefilled pens. (3)
-------------------------------CONTRAINDICATIONS -----------------------------
•
During episodes of hypoglycemia. (4)
•
In patients with hypersensitivity to HUMULIN 70/30 or any of its
excipients. (4)
------------------------WARNINGS AND PRECAUTIONS ----------------------
•
Changes in Insulin Regimen: Carry out under close medical supervision
and increase frequency of blood glucose monitoring. (5.1)
•
Hypoglycemia: May be life-threatening. Monitor blood glucose and
increase monitoring frequency with changes to insulin dosage, use of
glucose lowering medications, meal pattern, physical activity; in patients
with renal or hepatic impairment; and in patients with hypoglycemia
unawareness. (5.2, 7, 8.6, 8.7)
•
Hypersensitivity Reactions: May be life-threatening. Discontinue
HUMULIN 70/30, monitor and treat if indicated. (5.3)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk of hypokalemia and treat if indicated. (5.4)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure
occurs. (5.5)
-------------------------------ADVERSE REACTIONS -----------------------------
Adverse reactions observed with insulin therapy include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight
gain, and edema. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545 5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS -----------------------------
•
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage
may be needed. (7.1, 7.2, 7.3)
•
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (5.2, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 11/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Route of Administration
2.3
Dosage Information
2.4
Timing of Subcutaneous Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Changes in Insulin Regimen
5.2
Hypoglycemia
5.3
Hypersensitivity Reactions
5.4
Hypokalemia
5.5
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect
of HUMULIN 70/30
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN 70/30
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
HUMULIN 70/30 is a fixed ratio premix recombinant human insulin formulation indicated to improve glycemic control in
adult patients with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inspect HUMULIN 70/30 visually before use. It should not contain particulate matter and should appear uniformly cloudy
after mixing. Do not use HUMULIN 70/30 if particulate matter is seen. Do not mix HUMULIN 70/30 with any other insulins or
diluents.
2.2
Route of Administration
HUMULIN 70/30 should only be administered subcutaneously. Administer in the subcutaneous tissue of the abdominal wall,
thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy, rotate the injection site within the same region from one injection to
the next [see Adverse Reactions (6)].
Do not administer HUMULIN 70/30 intravenously or intramuscularly and do not use HUMULIN 70/30 in an insulin infusion
pump.
2.3
Dosage Information
Individualize and adjust the dosage of HUMULIN 70/30 based on the individual’s metabolic needs, blood glucose monitoring
results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e.,
macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and
Precautions (5.1, 5.2), and Use in Specific Populations (8.6, 8.7)].
The proportion of rapid acting and long acting insulin is fixed in a premixed insulin such as HUMULIN 70/30. Independent
adjustment of the basal or prandial dose is not possible when using a premixed insulin.
Physiological factors, disease states and concomitant drugs may impact the onset and duration of action of all insulins.
HUMULIN 70/30 dose requirements may change with changes in level of physical activity, meal patterns (i.e., macronutrient content
or timing of food intake), during major illness, or with some coadministered drugs [see Warnings and Precautions (5.2), Drug
Interactions (7), and Use in Specific Populations (8.6, 8.7)].
2.4
Timing of Subcutaneous Administration
HUMULIN 70/30 should be given subcutaneously approximately 30-45 minutes before a meal.
3
DOSAGE FORMS AND STRENGTHS
HUMULIN 70/30 injectable suspension: 100 units per mL (U-100) is available as:
•
10 mL vials
•
3 mL vials
•
3 mL prefilled pens
4
CONTRAINDICATIONS
HUMULIN 70/30 is contraindicated:
•
During episodes of hypoglycemia [see Warnings and Precautions (5.2)], and
•
In patients who have had hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Warnings and
Precautions (5.3)].
5
WARNINGS AND PRECAUTIONS
5.1
Changes in Insulin Regimen
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to
hypoglycemia [see Warnings and Precautions (5.2)] or hyperglycemia. These changes should be made cautiously and under close
medical supervision and the frequency of blood glucose monitoring should be increased.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN 70/30. Severe
hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction
time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other
machinery).
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic
nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions
(7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when
the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of
HUMULIN 70/30 may vary in different individuals or at different times in the same individual and depends on many conditions,
including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other
factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals),
changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or
hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an
essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have
reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
5.3
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including
HUMULIN 70/30. If hypersensitivity reactions occur, discontinue HUMULIN 70/30; treat per standard of care and monitor until
symptoms and signs resolve [see Adverse Reactions (6)]. HUMULIN 70/30 is contraindicated in patients who have had
hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Contraindications (4)].
5.4
Hypokalemia
All insulin products, including HUMULIN 70/30, cause a shift in potassium from the extracellular to intracellular space,
possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor
potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations).
5.5
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-
related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.
Patients treated with insulin, including HUMULIN 70/30, and a PPAR-gamma agonist should be observed for signs and symptoms of
heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose
reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.2)].
•
Hypokalemia [see Warnings and Precautions (5.4)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN 70/30. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to
establish a causal relationship to drug exposure.
Allergic Reactions
Some patients taking HUMULIN 70/30 have experienced erythema, local edema, and pruritus at the site of injection. These
conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and
Precautions (5.3)].
Peripheral Edema
Some patients taking HUMULIN 70/30 have experienced sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Lipodystrophy
Administration of insulin subcutaneously, including HUMULIN 70/30, has resulted in lipoatrophy (depression in the skin) or
lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] in some patients.
Weight gain
Weight gain has occurred with some insulin therapies including HUMULIN 70/30 and has been attributed to the anabolic
effects of insulin and the decrease in glycosuria.
Immunogenicity
Development of antibodies that react with human insulin have been observed with all insulin, including HUMULIN 70/30.
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN 70/30 use may be increased when co-administered with antidiabetic
agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, disopyramide, fibrates, propoxyphene,
pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide). Dose adjustment
and increased frequency of glucose monitoring may be required when HUMULIN 70/30 is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30
The glucose lowering effect of HUMULIN 70/30 may be decreased when co-administered with corticosteroids, isoniazid,
niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol,
terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones. Dose adjustment and increased
frequency of glucose monitoring may be required when HUMULIN 70/30 is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30
The glucose lowering effect of HUMULIN 70/30 may be increased or decreased when co-administered with beta-blockers,
clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN 70/30 is co-administered with
these drugs.
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.2)] may be blunted when beta-blockers,
clonidine, guanethidine, and reserpine are co-administered with HUMULIN 70/30.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This
background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is
essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. In patients with diabetes or gestational diabetes, insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is
essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they
become pregnant while taking HUMULIN 70/30.
Human Data
While there are no adequate and well-controlled studies of HUMULIN 70/30 in pregnant women, evidence from published
literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal
benefits.
Animal Data
Reproduction and fertility toxicity studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk; it is unknown whether HUMULIN 70/30 is present in human milk. Insulin
orally ingested is degraded in the gastrointestinal tract. No adverse reactions associated with infant exposure to insulin through the
consumption of human milk have been reported. Good glucose control supports lactation in patients with diabetes. Women with
diabetes who are lactating may require adjustments in their insulin dose.
8.4
Pediatric Use
Safety and effectiveness of HUMULIN 70/30 in patients less than 18 years of age has not been established.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied [see Clinical
Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN 70/30, may be at increased risk of
hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.2)].
8.6
Renal Impairment
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied
[see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may require more
frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.
8.7
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied
[see Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more
frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.2, 5.4)] Mild
episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or physical activity level may
be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
HUMULIN 70/30 (70% human insulin isophane suspension and 30% human insulin injection [rDNA origin]) is a human
insulin suspension. Human insulin is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of
Escherichia coli. HUMULIN 70/30 is a suspension of crystals produced from combining human insulin and protamine sulfate under
appropriate conditions for crystal formation and mixing with human insulin injection. The amino acid sequence of HUMULIN 70/30
is identical to human insulin and has the empirical formula C257H383N65O77S6 with a molecular weight of 5808.
HUMULIN 70/30 is a sterile white suspension. Each milliliter of HUMULIN 70/30 contains 100 units of insulin human,
0.24 mg of protamine sulfate, 16 mg of glycerin, 3.78 mg of dibasic sodium phosphate, 1.6 mg of metacresol, 0.65 mg of phenol, zinc
oxide content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or
hydrochloric acid may be added during manufacture to adjust the pH.
Reference ID: 3403625
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
HUMULIN 70/30 lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting
hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.
12.2
Pharmacodynamics
HUMULIN 70/30 combines an intermediate-acting insulin with the more rapid onset of action of regular human insulin. In
healthy males (n=18) given HUMULIN 70/30 (0.3 unit/kg) subcutaneously, the pharmacologic effect began at approximately 50
minutes (range: 30 to 90 minutes) (see Figure 1). The effect was maximal at approximately 3.5 hours (range: 1.5 to 6.5 hours) and the
mean duration of action was relatively long (approximately 23 hours; range: 18-24 hours).
Figure 1 should be considered only as a representative example since the time course of action of insulin may vary in different
individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected
by the site of injection, physical activity level, and other variables [see Warnings and Precautions (5.2)]. graph
Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of HUMULIN 70/30 or HUMULIN® R
U-100 (0.3 unit/kg) in Healthy Subjects.
12.3
Pharmacokinetics
Absorption — In healthy male subjects given HUMULIN 70/30 (0.3 unit/kg) subcutaneously, the mean peak serum
concentration occurred at 2.2 hours (range: 1 to 5 hours) after dosing.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the
liver being the major organ involved in the clearance of insulin.
Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be accurately
estimated from the terminal slope of the concentration versus time curve.
Specific Populations
The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN 70/30 have not been
studied.
Careful glucose monitoring and dose adjustments of insulin, including HUMULIN 70/30, may be necessary in patients with
renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic in the in
vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN 70/30 100 units per mL (U-100) is available as:
10 mL vials
NDC 0002-8715-01 (HI-710)
3 mL vials
NDC 0002-8715-17 (HI-713)
5 x 3 mL prefilled pen
NDC 0002-8770-59 (HP-8770)
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use after the expiration date.
Not In-Use (Unopened) HUMULIN 70/30 Vials
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31days.
In-Use (Opened) HUMULIN 70/30 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must be used
within 31 days or be discarded, even if they still contain HUMULIN 70/30.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31 days, even if the vial still contains
HUMULIN 70/30.
Not In-Use (Unopened) HUMULIN 70/30 Pen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 10 days.
In-Use (Opened) HUMULIN 70/30 Pen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 10 days, even if the pen still contains
HUMULIN 70/30. See storage table below:
Not In-Use (Unopened)
Refrigerated
Not In-Use (Unopened)
Room Temperature
In-Use (Opened)
10 mL vial
3 mL vial
Until expiration date
31 days
31 days, refrigerated/room
temperature
3 mL pen
Until expiration date
10 days
10 days, room temperature.
Do not refrigerate.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management
of hypoglycemia and hyperglycemia especially at initiation of HUMULIN 70/30 therapy. Instruct patients on handling of special
situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent
administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of
hypoglycemia.
Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who
have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery
[see Warnings and Precautions (5.2)].
Inform patients that accidental mix-ups between HUMULIN 70/30 and other insulins have been reported. Instruct patients to
always carefully check that they are administering the correct insulin (e.g., by checking the insulin label before each injection) to
avoid medication errors between HUMULIN 70/30 and other insulins.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with HUMULIN 70/30. Inform patients on the symptoms of
hypersensitivity reactions [see Warnings and Precautions (5.3)].
Females with Reproductive Potential
Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are contemplating
pregnancy [see Use in Specific Populations (8.1)].
Visual Inspection Prior to Use
Instruct patients to visually inspect HUMULIN 70/30 before use and to use HUMULIN 70/30 only if it contains no particulate
matter and appears uniformly cloudy after mixing [see Dosage and Administration (2.1)].
Expiration Date
Instruct patients not to use HUMULIN 70/30 after the printed expiration date.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A6.0NL 8470 AMP
Copyright © 1992, 2013, Eli Lilly and Company. All rights reserved.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL 5724 AMP
PATIENT INFORMATION
HUMULIN® (HU-mu-lin) 70/30
(70% human insulin isophane suspension and
30% human insulin injection [rDNA origin])
What is HUMULIN 70/30?
•
HUMULIN 70/30 is a man-made insulin that is used to control high blood sugar in adults with
diabetes mellitus.
Who should not use HUMULIN 70/30?
Do not use HUMULIN 70/30 if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to HUMULIN 70/30 or any of the ingredients in HUMULIN 70/30.
Before using HUMULIN 70/30, tell your healthcare provider about all your medical
conditions including, if you:
•
have liver or kidney problems.
•
take any other medicines, especially ones commonly called TZDs (thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse while
you take TZDs with HUMULIN 70/30.
•
are pregnant, planning to become pregnant, or are breastfeeding.
•
are taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.
Before you start using HUMULIN 70/30, talk to your healthcare provider about low
blood sugar and how to manage it.
How should I use HUMULIN 70/30?
•
Read the Instructions for Use that come with your HUMULIN 70/30.
•
Use HUMULIN 70/30 exactly as your healthcare provider tells you to.
•
Know the type and strength of insulin you use. Do not change the type of insulin you use
unless your healthcare provider tells you to. The amount of insulin and the best time for you to
take your insulin may need to change if you use different types of insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should
be and when you should check your blood sugar levels.
Your HUMULIN 70/30 dose may need to change because of:
•
change in level of physical activity or exercise, weight gain or loss, increased stress, illness,
change in diet.
What should I avoid while using HUMULIN 70/30?
While using HUMULIN 70/30 do not:
•
Drive or operate heavy machinery, until you know how HUMULIN 70/30 affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of HUMULIN 70/30?
HUMULIN 70/30 may cause serious side effects that can lead to death, including:
•
low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar
include:
•
dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred
speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger.
•
serious allergic reaction (whole body reaction). Get medical help right away, if you
have any of these symptoms of an allergic reaction:
•
a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with HUMULIN
70/30 may cause heart failure in some people. This can happen even if you have never had
heart failure or heart problems before. If you already have heart failure it may get worse while
you use TZDs with HUMULIN 70/30. Your healthcare provider should monitor you closely while
you are taking TZDs with HUMULIN 70/30. Tell your healthcare provider if you have any new or
worse symptoms of heart failure including:
•
shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and HUMULIN 70/30 may need to be adjusted or stopped by your
healthcare provider if you have new or worse heart failure.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL 7480 AMP
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat,
sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of HUMULIN 70/30 include:
•
low blood sugar (hypoglycemia), allergic reactions including reactions at the injection site,
skin thickening or pits at the injection site (lipodystrophy), itching, rash, weight gain, and swelling
of your hands and feet. These are not all the possible side effects of HUMULIN 70/30. Call your
doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
General information about the safe and effective use of HUMULIN 70/30:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. You can ask your pharmacist or healthcare provider for information about HUMULIN 70/30
that is written for health professionals. Do not use HUMULIN 70/30 for a condition for which it was
not prescribed. Do not give HUMULIN 70/30 to other people, even if they have the same
symptoms that you have. It may harm them.
What are the ingredients in HUMULIN 70/30?
Active Ingredient: insulin human (rDNA origin)
Inactive Ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol,
phenol, zinc oxide, water for injection, hydrochloric acid or sodium hydroxide
For more information, call 1-800-545-5979 or go to www.humulin.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: Month DD, YYYY
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL 8520 AMP
Instructions for Use
HUMULIN® (HU-mu-lin) 70/30
(70% human insulin isophane suspension and
30% human insulin injection [rDNA origin])
vial (100 Units/mL, U-100)
Read the Instructions for Use before you start taking HUMULIN 70/30 and each
time you get a new HUMULIN 70/30 vial. There may be new information. This
information does not take the place of talking to your healthcare provider about
your medical condition or your treatment.
Do not share your syringes or needles with anyone else. You may give an
infection to them or get an infection from them.
Supplies needed to give your injection:
• a HUMULIN 70/30 vial
• a U-100 insulin syringe and needle
• 2 alcohol swabs
• 1 sharps container for throwing away used needles and syringes. See
“Disposing of used needles and syringes” at the end of these
instructions.
usage illus
trat
ion
Preparing your HUMULIN 70/30 dose:
• Wash your hands with soap and water.
• Check the HUMULIN 70/30 label to make sure you are taking the
right type of insulin. This is especially important if you use more
than 1 type of insulin.
• Do not use HUMULIN 70/30 past the expiration date printed on the label or
31 days after you first use it.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(Example Dose: 20 units shown)
•
Always use a new needle for each injection to help ensure sterility and
prevent blocked needles.
Step 1:
Gently roll the vial between the palms of your
hands at least 10 times.
Step 2:
Invert the vial at least 10 times.
Do not shake.
Mixing is important to make sure you get the
right dose. Humulin 70/30 should look white and
cloudy after mixing. Do not use it if it looks clear
or contains any lumps or particles.
Step 3:
If you are using a new vial, pull off the plastic
Protective Cap, but do not remove the Rubber
Stopper.
Step 4:
Wipe the Rubber Stopper with an alcohol swab.
Step 5:
Hold the syringe with the needle pointing up. Pull
down on the Plunger until the tip of the Plunger
reaches the line for the number of units for your
prescribed dose.
Step 6:
Push the needle through the Rubber Stopper of the
vial.
usage illustrationusage illustrationusage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 7:
Push the plunger all the way in. This puts air into
the vial.
Step 8:
Turn the vial and syringe upside down and slowly
pull the Plunger down until the tip is a few units
past the line for your prescribed dose.
(Example Dose: 20 units
Plunger is shown at 24 units)
If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top.
Step 9:
Slowly push the Plunger up until the tip reaches
the line for your prescribed dose.
Check the syringe to make sure that you have the
right dose.
(Example Dose: 20 units shown)
Step 10:
Pull the syringe out of the vial’s Rubber Stopper.
usage illustrationusage illustration
Giving your HUMULIN 70/30 injection:
•
Inject your insulin exactly as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 11:
Choose your injection site.
HUMULIN 70/30 is injected under the skin
(subcutaneously) of your stomach area (abdomen),
buttocks, upper legs or upper arms.
Wipe the skin with an alcohol swab. Let the
injection site dry before you inject your dose.
Step 12:
Insert the needle into your skin.
Step 13:
Push down on the Plunger to inject your dose.
The needle should stay in your skin for at least 5
seconds to make sure you have injected all of your
insulin dose.
Step 14:
Pull the needle out of your skin.
•
If you see blood after you take the needle
out of your skin, press the injection site with
a piece of gauze or an alcohol swab. Do not
rub the area.
•
Do not recap the needle. Recapping the
needle can lead to a needle stick injury.
usage illustrationusage illustrationusage illustrationusage illustration
Disposing of used needles and syringes:
• Put your used needles and syringes in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and
syringes in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
o made of a heavy-duty plastic,
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
o upright and stable during use,
o leak-resistant, and
Reference ID: 3403625
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For current labeling information, please visit https://www.fda.gov/drugsatfda
o properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
• Do not recycle the container.
How should I store HUMULIN 70/30?
All unopened HUMULIN 70/30 vials:
• Store all unopened vials in the refrigerator.
• Do not freeze. Do not use if it has been frozen.
• Keep away from heat and out of direct light.
• Unopened vials can be used until the expiration date on the carton and label, if
they have been stored in the refrigerator.
• Unopened vials should be thrown away after 31 days, if they are stored at room
temperature.
After HUMULIN 70/30 vials have been opened:
• Store opened vials in the refrigerator or at room temperature below 86°F (30°C)
for up to 31 days.
• Keep away from heat and out of direct light.
• Throw away all opened vials after 31 days of use, even if there is still insulin left
in the vial.
General information about the safe and effective use of HUMULIN 70/30.
Keep HUMULIN 70/30 vials, syringes, needles, and all medicines out of the reach of
children.
If you have any questions or problems with your HUMULIN, contact Lilly at 1-800
Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more
information on HUMULIN and insulin, go to www.humulin.com. logo
Scan this code to launch the humulin.com website
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A3.0NL8520AMP
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, yyyy, Eli Lilly and Company. All rights reserved.
Revised: Month/Year
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.0 NL 9550 AMP
Instructions for Use
HUMULIN® 70/30 KwikPen™
(70% human insulin isophane suspension
30% human insulin injection [rDNA origin]) usage illustration
Read the Instructions for Use before you start taking HUMULIN 70/30 and each time
you get another HUMULIN® 70/30 KwikPen™. There may be new information. This
information does not take the place of talking to your healthcare provider about your
medical condition or your treatment.
HUMULIN 70/30 KwikPen (“Pen”) is a disposable pen containing 3 mL (300 units) of
U-100 HUMULIN® 70/30 (70% human insulin isophane suspension and 30% human
insulin injection [rDNA origin]) insulin. You can inject from 1 to 60 units in a single
injection.
HUMULIN 70/30 KwikPen has a blue and brown Label with a matching brown Dose
Knob (See the KwikPen Parts diagram below).
Do not share your HUMULIN 70/30 KwikPen or needles with another
person. You may give an infection to them or get an infection from them.
This Pen is not recommended for use by the blind or visually impaired
without the assistance of a person trained in the proper use of the product. usage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Supplies you will need to give your HUMULIN 70/30 injection:
• HUMULIN 70/30 KwikPen
• KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles
recommended)
• alcohol swab
Preparing HUMULIN 70/30 KwikPen:
• Wash your hands with soap and water.
• Check the HUMULIN 70/30 KwikPen Label to make sure you are taking
the right type of insulin. This is especially important if you use more
than 1 type of insulin.
• Do not use HUMULIN 70/30 past the expiration date printed on the Label or
10 days after you start using the Pen.
• Always use a new needle for each injection to help ensure sterility and
prevent blocked needles.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 1:
•
Pull the Pen Cap straight off.
•
Wipe the Rubber Seal with an
alcohol swab.
- Do not twist the cap.
-
Do not remove the HUMULIN
70/30 KwikPen Label.
- Do not attach the Needle
before mixing.
Step 2:
•
Gently roll the Pen between your
hands 10 times.
Step 3:
•
Move the Pen up and down (invert)
the Pen 10 times.
Mixing by rolling and inverting the
Pen is important to make sure you
get the right dose.
Step 4:
•
Check the liquid in the Pen.
HUMULIN 70/30 should look white and
cloudy after mixing. Do not use if it
looks clear or has any lumps or
particles in it.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer
Needle Shield.
Step 6:
•
Push the capped Needle straight onto
the Pen and twist the Needle on until
it is tight.
Step 7:
•
Pull off the Outer Needle Shield. Do
not throw it away.
•
Pull off the Inner Needle Shield and
throw it away.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 8:
•
Turn the Dose Knob to select 2 units.
Step 9:
•
Hold the Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top.
Step 10:
•
Hold the Pen with Needle pointing up.
Push the Dose Knob in until it stops,
and “0” is seen in the Dose Window.
•
Hold the Dose Knob in and count
to 5 slowly.
A stream of insulin should be seen
from the needle.
- If you do not see a stream of
insulin, repeat steps 8 to 10, no
more than 4 times.
- If you still do not see a stream of
insulin, change the needle and
repeat steps 8 to 10.
Priming the HUMULIN 70/30 KwikPen:
Prime the HUMULIN 70/30 KwikPen before each injection. Priming ensures the
Pen is ready to dose and removes air that may collect in the cartridge during normal
use. If you do not prime before each injection, you may get too much or too little
insulin. usage illustrationusage illustrationusage illustration
Reference ID: 3403625
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Selecting your dose:
Step 11:
•
Turn the Dose Knob to select the
number of units you need to inject.
The Dose Indicator should line up with
your dose.
The dose can be corrected by turning
the Dose Knob in either direction until
the correct dose lines up with the
Dose Indicator.
-
The even numbers are printed on
the dial.
(Example: 10 units shown)
-
The odd numbers, after the
number 1, are shown as full lines.
(Example: 15 units shown)
• The HUMULIN 70/30 KwikPen will not let you dial more than the number of
units left in the Pen.
• If your dose is more than the number of units left in the Pen, you may either:
-
inject the amount left in your Pen and then use a new Pen to give the rest
of your dose, or
-
get a new Pen and inject the full dose.
• The Pen is designed to deliver a total of 300 units of insulin. The cartridge
contains an additional small amount of insulin that cannot be delivered.
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Giving your HUMULIN 70/30 injection:
• Inject your HUMULIN 70/30 exactly as your healthcare provider has shown
you.
• Change (rotate) your injection site for each injection.
• Do not try to change your dose while injecting HUMULIN 70/30.
Step 12:
•
Choose your injection site.
HUMULIN 70/30 is injected under the
skin (subcutaneously) of your
stomach area, buttocks, upper legs or
upper arms.
•
Wipe the skin with an alcohol swab,
and let the injection site dry before
you inject your dose.
Step 13:
•
Insert the Needle into your skin.
Step 14:
•
Put your thumb on the Dose Knob
and push the Dose Knob in until it
stops.
•
Hold the Dose Knob in and slowly
count to 5.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 15:
•
Pull the Needle out of your skin.
You should see “0” in the Dose
Window. If you do not see “0” in the
Dose Window, you did not receive
your full dose.
- If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
- A drop of insulin at the needle tip
is normal. It will not affect your
dose.
- If you do not think you
received your full dose, do not
take another dose. Call Lilly at
1-800-LillyRx (1-800-545-5979) or
your healthcare provider for help.
Step 16:
•
Carefully replace the Outer Needle
Shield.
Step 17:
•
Unscrew the capped Needle and throw
it away.
•
Do not store the Pen with the Needle
attached to prevent leaking, blocking
of the Needle, and air from entering
the Pen.
usage illustrationusage illustrationusage illustration
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 18:
•
Replace the Pen Cap by lining up the
Cap Clip with the Dose Indicator and
pushing straight on.
usage illustration
After your injection:
• Put your used needles and pens in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and pens in
your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store my HUMULIN 70/30 KwikPen?
• Store unused HUMULIN 70/30 KwikPens in the refrigerator at 36°F to 46°F
(2°C to 8°C). The Pen you are currently using should be stored at room
temperature, below 86°F (30°C).
• Do not freeze HUMULIN 70/30. Do not use HUMULIN 70/30 if it has been
frozen.
• Unused Pens may be used until the expiration date printed on the Label, if kept
in the refrigerator.
• The HUMULIN 70/30 Pen you are using should be thrown away after 10 days,
even if it still has insulin left in it.
• Keep HUMULIN 70/30 away from heat and out of the light.
General information about the safe and effective use of HUMULIN 70/30
KwikPen.
• Keep HUMULIN 70/30 KwikPen and needles out of the reach of
children.
• Do not use the Pen if any part looks broken or damaged.
• Always carry an extra Pen in case yours is lost or damaged.
• If you cannot remove the Pen Cap, gently twist the Pen Cap back and forth,
and then pull the Pen Cap straight off.
• If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and
get a new one.
-
It may help to push the Dose Knob more slowly during your injection.
• Use the space below to keep track of how long you should use each HUMULIN
70/30 KwikPen.
-
Write down the date you start using your HUMULIN 70/30 KwikPen. Count
forward 10 days.
- Write down the date you should throw it away.
Example:
First used on _______ + 10 days = Throw out on ______
Date
Date
Pen 1 - First used on _______ Throw out on _______
Date
Date
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.0 NL 9550 AMP
Pen 2 - First used on _______ Throw out on _______
Date
Date
Pen 3 - First used on _______ Throw out on _______
Date
Date
Pen 4 - First used on _______ Throw out on _______
Date
Date
Pen 5 - First used on _______ Throw out on _______
Date
Date
If you have any questions or problems with your HUMULIN 70/30 KwikPen, contact
Lilly at 1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help. For
more information on HUMULIN 70/30 KwikPen and insulin, go to www.lilly.com.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
HUMULIN® and HUMULIN® KwikPen™ are trademarks of Eli Lilly and Company.
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © YYYY, Eli Lilly and Company. All rights reserved.
HUMULIN 70/30 KwikPen meets the current dose accuracy and functional
requirements of ISO 11608-1:2000.
Issued: Month Day, Year
Reference ID: 3403625
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:22.068876 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019717s098s101lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 101} |
1,539 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMULIN 70/30 safely and effectively. See full prescribing
information for HUMULIN 70/30.
HUMULIN® 70/30 (70% human insulin isophane suspension and
30% human insulin injection [rDNA origin]) injectable suspension,
for subcutaneous use
Initial U.S. Approval: 1989
--------------------------- RECENT MAJOR CHANGES --------------------------
Warnings and Precautions
Never Share a HUMULIN 70/30 Pen, HUMULIN 70/30 KwikPen,
or Syringe Between Patients (5.1)
02/2015
---------------------------- INDICATIONS AND USAGE ---------------------------
HUMULIN 70/30 is an insulin indicated to improve glycemic control in
adult patients with diabetes mellitus. (1)
------------------------ DOSAGE AND ADMINISTRATION -----------------------
•
Only administer subcutaneously (in abdominal wall, thigh, upper
arm, or buttocks). (2.2)
•
Individualize and adjust dosage based on metabolic needs, blood
glucose monitoring results and glycemic control goal. (2.3)
•
See Full Prescribing Information for dosage adjustments due to
drug interactions and patients with renal and hepatic impairment.
(2.3)
•
Administer approximately 30-45 minutes before a meal. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS ---------------------
Injectable suspension 100 units per mL (U100) available as 10 mL
vials, 3 mL vials, 3 mL prefilled pens and 3 mL HUMULIN® 70/30
KwikPen® (prefilled). (3)
------------------------------- CONTRAINDICATIONS ------------------------------
•
During episodes of hypoglycemia. (4)
•
In patients with hypersensitivity to HUMULIN 70/30 or any of its
excipients. (4)
------------------------ WARNINGS AND PRECAUTIONS -----------------------
•
Never share a HUMULIN 70/30 pen, HUMULIN 70/30 KwikPen,
or syringe between patients, even if the needle is changed. (5.1)
•
Changes in Insulin Regimen: Carry out under close medical
supervision and increase frequency of blood glucose monitoring.
(5.2)
•
Hypoglycemia: May be life-threatening. Monitor blood glucose
and increase monitoring frequency with changes to insulin
dosage, use of glucose lowering medications, meal pattern,
physical activity; in patients with renal or hepatic impairment; and
in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7)
•
Hypersensitivity Reactions: May be life-threatening. Discontinue
HUMULIN 70/30, monitor and treat if indicated. (5.4)
•
Hypokalemia: May be life-threatening. Monitor potassium levels in
patients at risk of hypokalemia and treat if indicated. (5.5)
•
Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of
heart failure; consider dosage reduction or discontinuation if heart
failure occurs. (5.6)
------------------------------- ADVERSE REACTIONS ------------------------------
Adverse reactions observed with insulin therapy include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, rash,
weight gain, and edema. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-
FDA-1088 or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS ------------------------------
•
Drugs that Affect Glucose Metabolism: Adjustment of insulin
dosage may be needed. (7.1, 7.2, 7.3)
•
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine,
guanethidine, and reserpine): Signs and symptoms of
hypoglycemia may be reduced or absent. (5.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 02/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
2.2
Route of Administration
2.3
Dosage Information
2.4
Timing of Subcutaneous Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a HUMULIN 70/30 Pen, HUMULIN 70/30
KwikPen, or Syringe Between Patients
5.2
Changes in Insulin Regimen
5.3
Hypoglycemia
5.4
Hypersensitivity Reactions
5.5
Hypokalemia
5.6
Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
7.2
Drugs That May Decrease the Blood Glucose Lowering
Effect of HUMULIN 70/30
7.3
Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of HUMULIN 70/30
7.4
Drugs That May Blunt Signs and Symptoms of
Hypoglycemia
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
HUMULIN 70/30 is a fixed ratio premix recombinant human insulin formulation indicated to improve glycemic
control in adult patients with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Important Administration Instructions
Inspect HUMULIN 70/30 visually before use. It should not contain particulate matter and should appear uniformly
cloudy after mixing. Do not use HUMULIN 70/30 if particulate matter is seen. Do not mix HUMULIN 70/30 with any other
insulins or diluents.
2.2
Route of Administration
HUMULIN 70/30 should only be administered subcutaneously. Administer in the subcutaneous tissue of the
abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy, rotate the injection site within the same
region from one injection to the next [see Adverse Reactions (6)].
Do not administer HUMULIN 70/30 intravenously or intramuscularly and do not use HUMULIN 70/30 in an insulin
infusion pump.
2.3
Dosage Information
Individualize and adjust the dosage of HUMULIN 70/30 based on the individual’s metabolic needs, blood glucose
monitoring results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity,
changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or
during acute illness [see Warnings and Precautions (5.2, 5.3), and Use in Specific Populations (8.6, 8.7)].
The proportion of rapid acting and long acting insulin is fixed in a premixed insulin such as HUMULIN 70/30.
Independent adjustment of the basal or prandial dose is not possible when using a premixed insulin.
Physiological factors, disease states and concomitant drugs may impact the onset and duration of action of all
insulins. HUMULIN 70/30 dose requirements may change with changes in level of physical activity, meal patterns (i.e.,
macronutrient content or timing of food intake), during major illness, or with some coadministered drugs [see Warnings
and Precautions (5.3), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
2.4
Timing of Subcutaneous Administration
HUMULIN 70/30 should be given subcutaneously approximately 30-45 minutes before a meal.
3
DOSAGE FORMS AND STRENGTHS
HUMULIN 70/30 injectable suspension: 100 units per mL (U100) is available as:
•
10 mL vials
•
3 mL vials
•
3 mL prefilled pens
•
3 mL HUMULIN 70/30 KwikPen (prefilled)
4
CONTRAINDICATIONS
HUMULIN 70/30 is contraindicated:
•
During episodes of hypoglycemia [see Warnings and Precautions (5.3)], and
•
In patients who have had hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Warnings
and Precautions (5.4)].
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a HUMULIN 70/30 Pen, HUMULIN 70/30 KwikPen, or Syringe Between Patients
HUMULIN 70/30 pens and HUMULIN 70/30 KwikPens must never be shared between patients, even if the needle
is changed. Patients using HUMULIN 70/30 vials must never share needles or syringes with another person. Sharing
poses a risk for transmission of blood-borne pathogens.
5.2
Changes in Insulin Regimen
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and
predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. These changes should be made
cautiously and under close medical supervision and the frequency of blood glucose monitoring should be increased.
5.3
Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN 70/30. Severe
hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability
and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g.,
driving or operating other machinery).
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the
same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding
diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system
(e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is
highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering
effect time course of HUMULIN 70/30 may vary in different individuals or at different times in the same individual and
depends on many conditions, including the area of injection as well as the injection site blood supply and temperature
[see Clinical Pharmacology (12.2)]. Other factors which may increase the risk of hypoglycemia include changes in meal
pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-
administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of
hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood
glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for
hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood
glucose monitoring is recommended.
5.4
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including
HUMULIN 70/30. If hypersensitivity reactions occur, discontinue HUMULIN 70/30; treat per standard of care and monitor
until symptoms and signs resolve [see Adverse Reactions (6)]. HUMULIN 70/30 is contraindicated in patients who have
had hypersensitivity reactions to HUMULIN 70/30 or any of its excipients [see Contraindications (4)].
5.5
Hypokalemia
All insulin products, including HUMULIN 70/30, cause a shift in potassium from the extracellular to intracellular
space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia,
and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-
lowering medications, patients taking medications sensitive to serum potassium concentrations).
5.6
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can
cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or
exacerbate heart failure. Patients treated with insulin, including HUMULIN 70/30, and a PPAR-gamma agonist should be
observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.3)].
•
Hypokalemia [see Warnings and Precautions (5.5)].
The following additional adverse reactions have been identified during post-approval use of HUMULIN 70/30.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or to establish a causal relationship to drug exposure.
Allergic Reactions
Some patients taking HUMULIN 70/30 have experienced erythema, local edema, and pruritus at the site of
injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been
reported [see Warnings and Precautions (5.4)].
Peripheral Edema
Some patients taking HUMULIN 70/30 have experienced sodium retention and edema, particularly if previously
poor metabolic control is improved by intensified insulin therapy.
Lipodystrophy
Administration of insulin subcutaneously, including HUMULIN 70/30, has resulted in lipoatrophy (depression in the
skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] in some patients.
Weight gain
Weight gain has occurred with some insulin therapies including HUMULIN 70/30 and has been attributed to the
anabolic effects of insulin and the decrease in glycosuria.
Immunogenicity
Development of antibodies that react with human insulin have been observed with all insulin, including
HUMULIN 70/30.
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with HUMULIN 70/30 use may be increased when co-administered with
antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, disopyramide, fibrates,
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g.,
octreotide). Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN 70/30 is
co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30
The glucose lowering effect of HUMULIN 70/30 may be decreased when co-administered with corticosteroids,
isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid
hormones. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN 70/30 is co-
administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN 70/30
The glucose lowering effect of HUMULIN 70/30 may be increased or decreased when co-administered with beta-
blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when
HUMULIN 70/30 is co-administered with these drugs.
7.4
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)] may be blunted when beta-
blockers, clonidine, guanethidine, and reserpine are co-administered with HUMULIN 70/30.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug
exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with
good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. In patients with diabetes or gestational diabetes, insulin
requirements may decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female
patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking
HUMULIN 70/30.
Human Data
While there are no adequate and well-controlled studies of HUMULIN 70/30 in pregnant women, evidence from
published literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant
maternal and fetal benefits.
Animal Data
Reproduction and fertility toxicity studies were not performed in animals.
8.3
Nursing Mothers
Endogenous insulin is present in human milk; it is unknown whether HUMULIN 70/30 is present in human milk.
Insulin orally ingested is degraded in the gastrointestinal tract. No adverse reactions associated with infant exposure to
insulin through the consumption of human milk have been reported. Good glucose control supports lactation in patients
with diabetes. Women with diabetes who are lactating may require adjustments in their insulin dose.
8.4
Pediatric Use
Safety and effectiveness of HUMULIN 70/30 in patients less than 18 years of age has not been established.
8.5
Geriatric Use
The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been studied [see
Clinical Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN 70/30, may be at
increased risk of hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.3)].
8.6
Renal Impairment
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not been
studied [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may
require more frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.
8.7
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN 70/30 has not
been studied [see Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia
and may require more frequent HUMULIN 70/30 dose adjustment and more frequent blood glucose monitoring.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3,
5.5)]. Mild episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
physical activity level may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated
with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and
observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be
corrected appropriately.
11
DESCRIPTION
HUMULIN 70/30 (70% human insulin isophane suspension and 30% human insulin injection [rDNA origin]) is a
human insulin suspension. Human insulin is produced by recombinant DNA technology utilizing a non-pathogenic
laboratory strain of Escherichia coli. HUMULIN 70/30 is a suspension of crystals produced from combining human insulin
and protamine sulfate under appropriate conditions for crystal formation and mixing with human insulin injection. The
amino acid sequence of HUMULIN 70/30 is identical to human insulin and has the empirical formula C257H383N65O77S6
with a molecular weight of 5808.
HUMULIN 70/30 is a sterile white suspension. Each milliliter of HUMULIN 70/30 contains 100 units of insulin
human, 0.24 mg of protamine sulfate, 16 mg of glycerin, 3.78 mg of dibasic sodium phosphate, 1.6 mg of metacresol,
0.65 mg of phenol, zinc oxide content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.8.
Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
HUMULIN 70/30 lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by
inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.
12.2
Pharmacodynamics
HUMULIN 70/30 combines an intermediate-acting insulin with the more rapid onset of action of regular human
insulin. In healthy males (n=18) given HUMULIN 70/30 (0.3 unit/kg) subcutaneously, the pharmacologic effect began at
approximately 50 minutes (range: 30 to 90 minutes) (see Figure 1). The effect was maximal at approximately 3.5 hours
(range: 1.5 to 6.5 hours) and the mean duration of action was relatively long (approximately 23 hours; range: 18-24
hours).
Figure 1 should be considered only as a representative example since the time course of action of insulin may vary
in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is
known to be affected by the site of injection, physical activity level, and other variables [see Warnings and Precautions
(5.3)].
Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of HUMULIN 70/30 or
HUMULIN® R U100 (0.3 unit/kg) in Healthy Subjects.
12.3
Pharmacokinetics
Absorption — In healthy male subjects given HUMULIN 70/30 (0.3 unit/kg) subcutaneously, the mean peak serum
concentration occurred at 2.2 hours (range: 1 to 5 hours) after dosing.
Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and
adipocytes, with the liver being the major organ involved in the clearance of insulin.
Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be
accurately estimated from the terminal slope of the concentration versus time curve.
Specific Populations
The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN 70/30
have not been studied.
Reference ID: 3706715
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6
Careful glucose monitoring and dose adjustments of insulin, including HUMULIN 70/30, may be necessary in
patients with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic
in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
HUMULIN 70/30 100 units per mL (U100) is available as:
10 mL vials
NDC 0002-8715-01 (HI-710)
3 mL vials
NDC 0002-8715-17 (HI-713)
5 x 3 mL prefilled pen
NDC 0002-8770-59 (HP-8770)
5 x 3 mL HUMULIN 70/30 KwikPen (prefilled)
NDC 0002-8803-59 (HP-8803)
Each prefilled HUMULIN 70/30 pen and HUMULIN 70/30 KwikPen is for use by a single patient. HUMULIN 70/30
pens and HUMULIN 70/30 KwikPens must never be shared between patients, even if the needle is changed. Patients
using HUMULIN 70/30 vials must never share needles or syringes with another person.
16.2
Storage and Handling
Protect from heat and light. Do not freeze. Do not use after the expiration date.
Not In-Use (Unopened) HUMULIN 70/30 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31days.
In-Use (Opened) HUMULIN 70/30 Vials
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen. Vials must
be used within 31 days or be discarded, even if they still contain HUMULIN 70/30.
Room Temperature
If stored at room temperature, below 86°F (30°C) the vial must be discarded after 31 days, even if the vial still
contains HUMULIN 70/30.
Not In-Use (Unopened) HUMULIN 70/30 Pen and KwikPen
Refrigerated
Store in a refrigerator (36° to 46°F [2° to 8°C]), but not in the freezer. Do not use if it has been frozen.
Room Temperature
If stored at room temperature, below 86°F (30°C) the pen must be discarded after 10 days.
In-Use (Opened) HUMULIN 70/30 Pen and KwikPen
Refrigerated
Do NOT store in a refrigerator.
Room Temperature
Store at room temperature, below 86°F (30°C) and the pen must be discarded after 10 days, even if the pen still
contains HUMULIN 70/30. See storage table below:
Not In-Use (Unopened)
Refrigerated
Not In-Use (Unopened)
Room Temperature
In-Use (Opened)
10 mL vial
3 mL vial
Until expiration date
31 days
31 days, refrigerated/room
temperature
3 mL pen
3 mL HUMULIN 70/30
KwikPen (prefilled)
Until expiration date
10 days
10 days, room
temperature.
Do not refrigerate.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Never Share a HUMULIN 70/30 Pen, HUMULIN 70/30 KwikPen, or Syringe Between Patients
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Advise patients that they must never share a HUMULIN 70/30 pen or HUMULIN 70/30 KwikPen with another
person, even if the needle is changed. Advise patients using HUMULIN 70/30 vials not to share needles or syringes with
another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and
management of hypoglycemia and hyperglycemia especially at initiation of HUMULIN 70/30 therapy. Instruct patients on
handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or
skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals.
Instruct patients on the management of hypoglycemia.
Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise
patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when
driving or operating machinery [see Warnings and Precautions (5.3)].
Inform patients that accidental mix-ups between HUMULIN 70/30 and other insulins have been reported. Instruct
patients to always carefully check that they are administering the correct insulin (e.g., by checking the insulin label before
each injection) to avoid medication errors between HUMULIN 70/30 and other insulins.
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with HUMULIN 70/30. Inform patients on the
symptoms of hypersensitivity reactions [see Warnings and Precautions (5.4)].
Females with Reproductive Potential
Advise females of reproductive potential with diabetes to inform their doctor if they are pregnant or are
contemplating pregnancy [see Use in Specific Populations (8.1)].
Visual Inspection Prior to Use
Instruct patients to visually inspect HUMULIN 70/30 before use and to use HUMULIN 70/30 only if it contains no
particulate matter and appears uniformly cloudy after mixing [see Dosage and Administration (2.1)].
Expiration Date
Instruct patients not to use HUMULIN 70/30 after the printed expiration date.
____________
HUMULIN® and HUMULIN® 70/30 KwikPen® are trademarks of Eli Lilly and Company.
Literature revised February 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, YYYY, Eli Lilly and Company. All rights reserved.
A1.01-LIN7030-8470-USPI-YYYYMMDD
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
PATIENT INFORMATION
HUMULIN® (HU-mu-lin) 70/30
(70% human insulin isophane suspension and
30% human insulin injection [rDNA origin])
Do not share your HUMULIN 70/30 Pen, HUMULIN 70/30 KwikPen, or syringes with
other people, even if the needle has been changed. You may give other people a
serious infection or get a serious infection from them.
What is HUMULIN 70/30?
•
HUMULIN 70/30 is a man-made insulin that is used to control high blood sugar in
adults with diabetes mellitus.
Who should not use HUMULIN 70/30?
Do not use HUMULIN 70/30 if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to HUMULIN 70/30 or any of the ingredients in HUMULIN 70/30.
Before using HUMULIN 70/30, tell your healthcare provider about all your medical
conditions including, if you:
•
have liver or kidney problems.
•
take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
•
have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with HUMULIN 70/30.
•
are pregnant, planning to become pregnant, or are breastfeeding.
•
are taking new prescription or over-the-counter medicines, vitamins, or herbal
supplements.
Before you start using HUMULIN 70/30, talk to your healthcare provider about low
blood sugar and how to manage it.
How should I use HUMULIN 70/30?
•
Read the Instructions for Use that come with your HUMULIN 70/30.
•
Use HUMULIN 70/30 exactly as your healthcare provider tells you to.
•
Know the type and strength of insulin you use. Do not change the type of insulin you
use unless your healthcare provider tells you to. The amount of insulin and the best
time for you to take your insulin may need to change if you use different types of
insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood
sugars should be and when you should check your blood sugar levels.
•
Do not share your HUMULIN 70/30 Pen, HUMULIN 70/30 KwikPen, or syringes
with other people, even if the needle has been changed. You may give other
people a serious infection or get a serious infection from them.
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Your HUMULIN 70/30 dose may need to change because of:
•
change in level of physical activity or exercise, weight gain or loss, increased stress,
illness, change in diet.
What should I avoid while using HUMULIN 70/30?
While using HUMULIN 70/30 do not:
•
Drive or operate heavy machinery, until you know how HUMULIN 70/30 affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of HUMULIN 70/30?
HUMULIN 70/30 may cause serious side effects that can lead to death, including:
•
low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood
sugar include:
•
dizziness or light-headedness, sweating, confusion, headache, blurred vision,
slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes,
hunger.
•
serious allergic reaction (whole body reaction). Get medical help right away, if
you have any of these symptoms of an allergic reaction:
•
a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with
HUMULIN 70/30 may cause heart failure in some people. This can happen even if
you have never had heart failure or heart problems before. If you already have heart
failure it may get worse while you take TZDs with HUMULIN 70/30. Your healthcare
provider should monitor you closely while you are taking TZDs with HUMULIN 70/30.
Tell your healthcare provider if you have any new or worse symptoms of heart failure
including:
•
shortness of breath, swelling of your ankles or feet, sudden weight gain
Treatment with TZDs and HUMULIN 70/30 may need to be adjusted or stopped by
your healthcare provider if you have new or worse heart failure.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue,
or throat, sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of HUMULIN 70/30 include:
•
low blood sugar (hypoglycemia), allergic reactions including reactions at the injection
site, skin thickening or pits at the injection site (lipodystrophy), itching, rash, weight
gain, and swelling of your hands and feet. These are not all the possible side effects
of HUMULIN 70/30. Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of HUMULIN 70/30:
Medicines are sometimes prescribed for purposes other than those listed in a Patient
Information leaflet. You can ask your pharmacist or healthcare provider for information
about HUMULIN 70/30 that is written for health professionals. Do not use
HUMULIN 70/30 for a condition for which it was not prescribed. Do not give
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
HUMULIN 70/30 to other people, even if they have the same symptoms that you have.
It may harm them.
What are the ingredients in HUMULIN 70/30?
Active Ingredient: insulin human (rDNA origin)
Inactive Ingredients: protamine sulfate, glycerin, dibasic sodium phosphate,
metacresol, phenol, zinc oxide, water for injection, hydrochloric acid or sodium
hydroxide
For more information, call 1-800-545-5979 or go to www.humulin.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Patient Information revised February 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, YYYY, Eli Lilly and Company. All rights reserved.
A1.01-LIN7030-5725-PPI-YYYYMMDD
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Instructions for Use
HUMULIN® 70/30 KwikPen®
(70% human insulin isophane suspension
30% human insulin injection [rDNA origin])
Read the Instructions for Use before you start taking HUMULIN 70/30 and each time you get
another HUMULIN® 70/30 KwikPen®. There may be new information. This information does not
take the place of talking to your healthcare provider about your medical condition or your
treatment.
Do not share your HUMULIN 70/30 KwikPen with other people, even if the needle has been
changed. You may give other people a serious infection or get a serious infection from
them.
HUMULIN 70/30 KwikPen (“Pen”) is a disposable pen containing 3 mL (300 units) of U-100
HUMULIN® 70/30 (70% human insulin isophane suspension and 30% human insulin injection
[rDNA origin]) insulin. You can inject from 1 to 60 units in a single injection.
HUMULIN 70/30 KwikPen has a blue and brown Label with a matching brown Dose Knob (See
the KwikPen Parts diagram below).
This Pen is not recommended for use by the blind or visually impaired without the
assistance of a person trained in the proper use of the product.
Supplies you will need to give your HUMULIN 70/30 injection:
•
HUMULIN 70/30 KwikPen
•
KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles
recommended)
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
•
alcohol swab
Preparing HUMULIN 70/30 KwikPen:
•
Wash your hands with soap and water.
•
Check the HUMULIN 70/30 KwikPen Label to make sure you are taking the right type
of insulin. This is especially important if you use more than 1 type of insulin.
•
Do not use HUMULIN 70/30 past the expiration date printed on the Label or 10 days after
you start using the Pen.
•
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles. Do not reuse or share needles with other people. You may give
other people a serious infection or get a serious infection from them.
Step 1:
•
Pull the Pen Cap straight off.
•
Wipe the Rubber Seal with an alcohol
swab.
-
Do not twist the cap.
-
Do not remove the
HUMULIN 70/30 KwikPen Label.
-
Do not attach the Needle before
mixing.
Step 2:
•
Gently roll the Pen between your
hands 10 times.
Step 3:
•
Move the Pen up and down (invert) 10
times.
Mixing by rolling and inverting the
Pen is important to make sure you
get the right dose.
Step 4:
•
Check the liquid in the Pen.
HUMULIN 70/30 should look white and
cloudy after mixing. Do not use if it
looks clear or has any lumps or
particles in it.
Reference ID: 3706715
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3
Step 5:
•
Select a new Needle.
•
Pull off the Paper Tab from the Outer
Needle Shield.
Step 6:
•
Push the capped Needle straight onto
the Pen and twist the Needle on until it
is tight.
Step 7:
•
Pull off the Outer Needle Shield. Do
not throw it away.
•
Pull off the Inner Needle Shield and
throw it away.
Priming the HUMULIN 70/30 KwikPen:
Prime the HUMULIN 70/30 KwikPen before each injection. Priming ensures the Pen is ready
to dose and removes air that may collect in the cartridge during normal use. If you do not prime
before each injection, you may get too much or too little insulin.
Step 8:
•
Turn the Dose Knob to select 2 units.
Step 9:
•
Hold the Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top.
Step 10:
•
Hold the Pen with Needle pointing up.
Push the Dose Knob in until it stops,
and “0” is seen in the Dose Window.
•
Hold the Dose Knob in and count to
5 slowly.
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
A stream of insulin should be seen
from the needle.
-
If you do not see a stream of
insulin, repeat steps 8 to 10, no
more than 4 times.
-
If you still do not see a stream of
insulin, change the needle and
repeat steps 8 to 10.
Reference ID: 3706715
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Selecting your dose:
Step 11:
•
Turn the Dose Knob to select the
number of units you need to inject. The
Dose Indicator should line up with your
dose.
The dose can be corrected by turning
the Dose Knob in either direction until
the correct dose lines up with the Dose
Indicator.
-
The even numbers are printed on
the dial.
-
The odd numbers, after the
number 1, are shown as full lines.
(Example: 10 units shown)
(Example: 15 units shown)
•
The HUMULIN 70/30 KwikPen will not let you dial more than the number of units left in the
Pen.
•
If your dose is more than the number of units left in the Pen, you may either:
-
inject the amount left in your Pen and then use a new Pen to give the rest of your
dose, or
-
get a new Pen and inject the full dose.
•
The Pen is designed to deliver a total of 300 units of insulin. The cartridge contains an
additional small amount of insulin that cannot be delivered.
Giving your HUMULIN 70/30 injection:
•
Inject your HUMULIN 70/30 exactly as your healthcare provider has shown you.
•
Change (rotate) your injection site for each injection.
•
Do not try to change your dose while injecting HUMULIN 70/30.
Reference ID: 3706715
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6
Step 12:
•
Choose your injection site.
HUMULIN 70/30 is injected under the
skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper
arms.
•
Wipe the skin with an alcohol swab,
and let the injection site dry before you
inject your dose.
Step 13:
•
Insert the Needle into your skin.
Step 14:
•
Put your thumb on the Dose Knob and
push the Dose Knob in until it stops.
•
Hold the Dose Knob in and slowly
count to 5.
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Step 15:
•
Pull the Needle out of your skin.
You should see “0” in the Dose
Window. If you do not see “0” in the
Dose Window, you did not receive your
full dose.
-
If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
-
A drop of insulin at the needle tip is
normal. It will not affect your dose.
-
If you do not think you received
your full dose, do not take
another dose. Call Lilly at
1-800-LillyRx (1-800-545-5979) or
your healthcare provider for help.
Step 16:
•
Carefully replace the Outer Needle
Shield.
Step 17:
•
Unscrew the capped Needle and throw
it away.
•
Do not store the Pen with the Needle
attached to prevent leaking, blocking of
the Needle, and air from entering the
Pen.
Step 18:
•
Replace the Pen Cap by lining up the
Cap Clip with the Dose Indicator and
pushing straight on.
After your injection:
•
Put your used needles in a FDA-cleared sharps disposal container right away after use.
Do not throw away (dispose of) loose needles in your household trash.
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
• If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to
come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be
state or local laws about how you should throw away used needles and syringes. For
more information about safe sharps disposal, and for specific information about sharps
disposal in the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household trash unless
your community guidelines permit this. Do not recycle your used sharps disposal
container.
•
The used Pen may be discarded in your household trash after you have removed the
needle.
How should I store my HUMULIN 70/30 KwikPen?
•
Store unused HUMULIN 70/30 KwikPens in the refrigerator at 36°F to 46°F (2°C to 8°C).
The Pen you are currently using should be stored at room temperature, below 86°F
(30°C).
•
Do not freeze HUMULIN 70/30. Do not use HUMULIN 70/30 if it has been frozen.
•
Unused Pens may be used until the expiration date printed on the Label, if kept in the
refrigerator.
•
The HUMULIN 70/30 Pen you are using should be thrown away after 10 days, even if it
still has insulin left in it.
•
Keep HUMULIN 70/30 away from heat and out of the light.
General information about the safe and effective use of HUMULIN 70/30 KwikPen.
•
Keep HUMULIN 70/30 KwikPen and needles out of the reach of children.
•
Always use a new needle for each injection.
•
Do not share your Pen or needles with other people. You may give other people a
serious infection or get a serious infection from them.
•
Do not use the Pen if any part looks broken or damaged.
•
Always carry an extra Pen in case yours is lost or damaged.
•
If you cannot remove the Pen Cap, gently twist the Pen Cap back and forth, and then pull
the Pen Cap straight off.
•
If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new
one.
-
It may help to push the Dose Knob more slowly during your injection.
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9
•
Use the space below to keep track of how long you should use each HUMULIN 70/30
KwikPen.
-
Write down the date you start using your HUMULIN 70/30 KwikPen. Count forward 10
days.
-
Write down the date you should throw it away.
Example:
First used on _______ + 10 days = Throw out on ______
Date Date
Pen 1 - First used on _______
Throw out on _______
Date
Date
Pen 2 - First used on _______
Throw out on _______
Date
Date
Pen 3 - First used on _______
Throw out on _______
Date
Date
Pen 4 - First used on _______
Throw out on _______
Date
Date
Pen 5 - First used on _______
Throw out on _______
Date
Date
If you have any questions or problems with your HUMULIN 70/30 KwikPen, contact Lilly at
1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help. For more information on
HUMULIN 70/30 KwikPen and insulin, go to www.lilly.com.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
HUMULIN® and HUMULIN® KwikPen® are trademarks of Eli Lilly and Company.
Revised: February 2015
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2013, YYYY, Eli Lilly and Company. All rights reserved.
HUMULIN 70/30 KwikPen meets the current dose accuracy and functional requirements of ISO
11608-1:2000.
A2.01-LIN7030-9550-KP-IFU-YYYYMMDD
Reference ID: 3706715
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Instructions for Use
HUMULIN® (HU-mu-lin) 70/30
(70% human insulin isophane suspension and
30% human insulin injection [rDNA origin])
vial (100 Units/mL, U-100)
Read the Instructions for Use before you start taking HUMULIN 70/30 and each time you get a
new HUMULIN 70/30 vial. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your treatment.
Do not share your syringes with other people, even if the needle has been changed. You
may give other people a serious infection or get a serious infection from them.
Supplies needed to give your injection:
• a HUMULIN 70/30 vial
• a U-100 insulin syringe and needle
• 2 alcohol swabs
• 1 sharps container for throwing away used needles and syringes. See “Disposing of
used needles and syringes” at the end of these instructions.
Preparing your HUMULIN 70/30 dose:
• Wash your hands with soap and water.
• Check the HUMULIN 70/30 label to make sure you are taking the right type of
insulin. This is especially important if you use more than 1 type of insulin.
• Do not use HUMULIN 70/30 past the expiration date printed on the label or 31 days
after you first use it.
• Always use a new syringe or needle for each injection to help ensure sterility and
prevent blocked needles. Do not reuse or share your syringes or needles with
Protective
Cap
Rubber
Stopper
(under Cap)
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other people. You may give other people a serious infection or get a serious
infection from them.
Step 1:
Gently roll the vial between the palms of your hands at
least 10 times.
Step 2:
Invert the vial at least 10 times.
Do not shake.
Mixing is important to make sure you get the right dose.
Humulin 70/30 should look white and cloudy after mixing.
Do not use it if it looks clear or contains any lumps or
particles.
Step 3:
If you are using a new vial, pull off the plastic Protective
Cap, but do not remove the Rubber Stopper.
Step 4:
Wipe the Rubber Stopper with an alcohol swab.
Step 5:
Hold the syringe with the needle pointing up. Pull down on
the Plunger until the tip of the Plunger reaches the line for
the number of units for your prescribed dose.
(Example Dose: 20 units shown)
Step 6:
Push the needle through the Rubber Stopper of the vial.
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Step 7:
Push the plunger all the way in. This puts air into the vial.
Step 8:
Turn the vial and syringe upside down and slowly pull the
Plunger down until the tip is a few units past the line for
your prescribed dose.
If there are air bubbles, tap the syringe gently a few times
to let any air bubbles rise to the top.
(Example Dose: 20 units
Plunger is shown at 24 units)
Step 9:
Slowly push the Plunger up until the tip reaches the line
for your prescribed dose.
Check the syringe to make sure that you have the right
dose.
(Example Dose: 20 units shown)
Step 10:
Pull the syringe out of the vial’s Rubber Stopper.
Giving your HUMULIN 70/30 injection:
• Inject your insulin exactly as your healthcare provider has shown you.
• Change (rotate) your injection site for each injection.
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Step 11:
Choose your injection site.
HUMULIN 70/30 is injected under the skin
(subcutaneously) of your stomach area (abdomen),
buttocks, upper legs or upper arms.
Wipe the skin with an alcohol swab. Let the injection site
dry before you inject your dose.
Step 12:
Insert the needle into your skin.
Step 13:
Push down on the Plunger to inject your dose.
The needle should stay in your skin for at least 5 seconds
to make sure you have injected all of your insulin dose.
Step 14:
Pull the needle out of your skin.
• If you see blood after you take the needle out of
your skin, press the injection site with a piece of
gauze or an alcohol swab. Do not rub the area.
• Do not recap the needle. Recapping the needle can
lead to a needle stick injury.
Disposing of used needles and syringes:
• Put your used needles and syringes in a FDA-cleared sharps disposal container right away
after use. Do not throw away (dispose of) loose needles and syringes in your household
trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
- made of a heavy-duty plastic,
- can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to
come out,
- upright and stable during use,
- leak-resistant, and
- properly labeled to warn of hazardous waste inside the container.
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• When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be state
or local laws about how you should throw away used needles and syringes. For more
information about safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
• Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
How should I store HUMULIN 70/30?
All unopened HUMULIN 70/30 vials:
• Store all unopened vials in the refrigerator.
•
Do not freeze. Do not use if it has been frozen.
•
Keep away from heat and out of direct light.
•
Unopened vials can be used until the expiration date on the carton and label, if they have
been stored in the refrigerator.
•
Unopened vials should be thrown away after 31 days, if they are stored at room
temperature.
After HUMULIN 70/30 vials have been opened:
• Store opened vials in the refrigerator or at room temperature below 86°F (30°C) for up to 31
days.
•
Keep away from heat and out of direct light.
•
Throw away all opened vials after 31 days of use, even if there is still insulin left in the vial.
General information about the safe and effective use of HUMULIN 70/30.
•
Keep HUMULIN 70/30 vials, syringes, needles, and all medicines out of the reach of
children.
•
Always use a new syringe or needle for each injection.
•
Do not reuse or share your syringes or needles with other people. You may give other
people a serious infection or get a serious infection from them.
If you have any questions or problems with your HUMULIN, contact Lilly at 1-800-Lilly-Rx (1-
800-545-5979) or call your healthcare provider for help. For more information on HUMULIN and
insulin, go to www.humulin.com.
Scan this code to launch the humulin.com website
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Humulin® is a trademark of Eli Lilly and Company.
Instructions for Use revised: February 2015
Reference ID: 3706715
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Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1992, YYYY, Eli Lilly and Company. All rights reserved.
A2.01-LIN7030-8520-VIAL-IFU-YYYYMMDD
Reference ID: 3706715
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Lilly
Prefilled Insulin Delivery Device
User Manual
Instructions for Use
Read and follow all of these
instructions carefully. If you do not
follow these instructions completely,
you may get too much or too little
insulin.
Every time you inject:
• Use a new needle
• Prime to make sure the Pen is ready to
dose
• Make sure you got your full dose (see page
18)
Also, read the “Patient Information” enclosed
in your Pen box.
Pen Features
• A multiple dose, prefilled insulin
delivery device (“insulin Pen”)
containing 3 mL (300 units) of U-100
insulin
• Delivers up to 60 units per dose
• Doses can be dialed by single units
Do not share your Pen with other people, even if the needle has
been changed. You may give other people a serious infection or
get a serious infection from them.
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Table of Contents
______________________________________________________________
Pen Parts ..........................................................................................................3
Important Notes ................................................................................................ 4
Preparing the Pen ............................................................................................ 6
Attaching the Needle ........................................................................................ 8
Priming the Pen .............................................................................................. 10
Setting a Dose ................................................................................................ 14
Injecting a Dose ............................................................................................. 16
Following an Injection ..................................................................................... 18
Questions and Answers ................................................................................. 20
______________________________________________________________
2
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Pen Parts
3
3
Injection Button
Dose Knob
Raised Notch
Raised Notch
Dose Window
Label
Insulin Cartridge
Clear Cartridge Holder
Rubber Seal
Paper
Tab
Outer Needle Shield
Inner Needle Shield
Needle
Pen Cap
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Important Notes
• Read and follow all of these instructions carefully. If you do not follow these
instructions completely, you may get too much or too little insulin.
• Always use a new needle for each injection to help ensure sterility and prevent
blocked needles. Do not reuse or share your needles with other people. You
may give other people a serious infection or get a serious infection from them.
• Be sure a needle is completely attached to the Pen before priming, setting
the dose and injecting your insulin.
• Prime every time.
• The Pen must be primed before each injection to make sure the Pen is
ready to dose. Performing the priming step is important to confirm that insulin
comes out when you push the injection button, and to remove air that may collect
in the insulin cartridge during normal use. See Section III. “Priming the Pen”,
pages 10-13.
• If you do not prime, you may get too much or too little insulin.
• Make sure you get your full dose.
• To make sure you get your full dose, you must push the injection button all the
way down until you see a diamond (♦) or an arrow (
) in the center of the dose
window. See “Following an Injection”, page 18.
• The numbers on the clear cartridge holder give an estimate of the amount of insulin
remaining in the cartridge. Do not use these numbers for measuring an insulin dose.
• Do not share your Pen with other people, even if the needle has been changed.
You may give other people a serious infection or get a serious infection from
them.
• Keep your Pen and needles out of the reach of children.
• Pens that have not been used should be stored in a refrigerator but not in a freezer.
Do not use a Pen if it has been frozen. Refer to the “Patient Information” for
complete storage instructions.
4
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Important Notes
(Continued)
• After a Pen is used for the first time, it should NOT be refrigerated but should be
kept at room temperature [below 86°F (30°C)] and away from direct heat and light.
• An unrefrigerated Pen should be discarded according to the time specified in the
“Patient Information”, even if it still contains insulin.
• Never use a Pen after the expiration date stamped on the label.
• Do not store your Pen with the needle attached. Doing so may allow insulin to leak
from the Pen and air bubbles to form in the cartridge. Additionally, with suspension
(cloudy) insulins, crystals may clog the needle.
• Always carry an extra Pen in case yours is lost or damaged.
• Follow your Health Care Professional’s instruction for safe handling of needles and
disposal of empty pens.
• This Pen is not recommended for use by blind or visually impaired persons without
the assistance of a person trained in the proper use of the product.
• The directions regarding needle handling are not intended to replace local, Health
Care Professional, or institutional policies.
• Any changes in insulin should be made cautiously and only under medical
supervision.
5
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I. Preparing the Pen
1. Before proceeding, refer to the “Patient Information” for instructions on checking the
appearance of your insulin.
2. Check the label on the Pen to be sure the Pen contains the type of insulin that has
been prescribed for you.
3. Always wash your hands before preparing your Pen for use.
4. Pull the Pen cap to remove.
6
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I. Preparing the Pen
(Continued)
5. If your insulin is a suspension (cloudy):
a. Roll the Pen back and forth 10 times then
perform step b.
b. Gently turn the Pen up and down 10 times
until the insulin is evenly mixed.
Note: Suspension (cloudy) insulin cartridges
contain a small glass bead to assist in mixing.
6. Use an alcohol swab to wipe the rubber seal
on the end of the Pen.
7
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II. Attaching the Needle
This device is suitable for use with Becton Dickinson and Company’s insulin pen
needles.
Always use a new needle for each injection. Do not reuse or share your needles
with other people. You may give other people a serious infection or get a serious
infection from them.
Do not push injection button without a needle attached. Storing the Pen with the
needle attached may allow insulin to leak from the Pen and air bubbles to form in
the cartridge.
1. Remove the paper tab from the outer needle
shield.
2. Attach the capped needle onto the end of the
Pen by turning it clockwise until tight.
8
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II. Attaching the Needle
(Continued)
3. Hold the Pen with the needle pointing up and
remove the outer needle shield. Keep it to
use during needle removal.
4. Remove the inner needle shield and discard.
9
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III. Priming the Pen
• Prime every time. The Pen must be primed to a stream of insulin (not just a few
drops) before each injection to make sure the Pen is ready to dose.
• You may need to prime a new Pen up to six times before a stream of insulin
appears.
• If you do not prime, you may get too much or too little insulin.
• Always use a new needle for each injection.
1. Make sure the arrow (
) is in the center of the
dose window as shown.
1. If you do not see the arrow in the center of the
dose window, push in the injection button fully
and turn the dose knob until the arrow is seen
in the center of the dose window.
Correct
10
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III. Priming the Pen
(Continued)
3. With the arrow in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window.
4. Turn the dose knob clockwise until the number
“2” is seen in the dose window. If the number
you have dialed is too high, simply turn the
dose knob backward until the number “2” is
seen in the dose window.
11
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III. Priming the Pen
(Continued)
5. Hold your Pen with the needle pointing straight
up. Tap the clear cartridge holder gently with
your finger so any air bubbles collect near the
top.
Using your thumb, if possible, push in the
injection button completely. Keep pressing and
continue to hold the injection button firmly
while counting slowly to 5. You should see a
stream of insulin come out of the tip of the
needle.
If a stream of insulin does not come out of the
tip of the needle, repeat steps 1 through 5. If
after six attempts a stream of insulin does not
come out of the tip of the needle, change the
needle. Repeat steps 1 through 5 up to two
more times. If you are still unable to get insulin
flowing out of the needle, do NOT use the
Pen. Contact your Health Care Professional or
Lilly.
12
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III. Priming the Pen
(Continued)
6. At the completion of the priming step, a
diamond (♦) must be seen in the center of the
dose window. If a diamond (♦) is not seen in
the center of the dose window, continue
pushing on the injection button until you see a
diamond (♦) in the center of the dose window.
Correct
Note: A small air bubble may remain in the cartridge after the completion of
the priming step. If you have properly primed the Pen, this small air bubble
will not affect your insulin dose.
7. Now you are ready to set your dose. See next page.
13
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IV. Setting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not push in the injection button while setting your dose. Failure to
follow these instructions carefully may result in getting too much or too little
insulin. If you accidentally push the injection button while setting your dose,
you must prime the Pen again before injecting your dose. See Section III.
“Priming the Pen”, pages 10-13.
1. A diamond must be seen in the center of the dose window before setting your dose.
If you do not see a diamond in the center of the dose
window, the Pen has not been primed correctly and
you are not ready to set your dose. Before continuing,
repeat the priming steps.
Correct
2. Turn the dose knob clockwise until the arrow (
) is seen in the center of the dose window
and the notches on the Pen and dose knob are
in line.
14
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IV. Setting a Dose
(Continued)
3. With the arrow (
) in the center of the dose
window, pull the dose knob out in the direction
of the arrow until a “0” is seen in the dose
window. A dose cannot be dialed until the dose
knob is pulled out.
4. Turn the dose knob clockwise until your dose
is seen in the dose window. If the dose you
have dialed is too high, simply turn the dose
knob backward until the correct dose is seen in
the dose window.
5. If you cannot dial your full dose, see the “Questions and Answers” section,
Question 6, at the end of this manual.
15
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V. Injecting a Dose
• Always use a new needle for each injection. Storing the Pen with the needle
attached may allow insulin to leak from the Pen and air bubbles to form in the
cartridge.
• Caution: Do not attempt to change the dose after you begin to push in the
injection button. Failure to follow these instructions carefully may result in
getting too much or too little insulin.
• The effort needed to push in the injection button may increase while you are
injecting your insulin dose. If you cannot completely push in the injection
button, refer to the “Questions and Answers” section, Question 8, at the end
of this manual.
• Do not inject a dose unless the Pen is primed, just before injection, or you may get
too much or too little insulin.
•
If you have set a dose and pushed in the injection button without a needle attached
or if no insulin comes out of the needle, see the “Questions and Answers” section,
Questions 1 and 2.
16
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V. Injecting a Dose
(Continued)
1. Wash hands. Prepare the skin and use the injection technique recommended by
your Health Care Professional.
2. Insert the needle into your skin. Inject the
insulin by using your thumb, if possible, to
push in the injection button completely.
3. Keep pressing and continue to hold the
injection button firmly while counting
slowly to 5.
4. When the injection is done, a diamond (♦) or an
arrow (
) must be seen in the center of the dose
window. This means your full dose has been
delivered. If you do not see a diamond or an
arrow in the center of the dose window, you
did not get your full dose. Contact your Health
Care Professional for additional instructions.
Correct
Correct
17
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VI. Following an Injection
1. Make sure you got your full dose by checking
that the injection button has been completely
pushed in and you can see a diamond (♦) or
an arrow (
) in the center of the dose window.
If you do not see a diamond (♦) or an arrow (
) in the center of the dose window, you have
not received your full dose. Contact your
Health Care Professional for additional
instructions.
2. Carefully replace the outer needle shield as
instructed by your Health Care Professional.
18
Outer
Needle
Shield
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VI. Following an Injection
(Continued)
3. Remove the capped needle by turning it
counterclockwise. Place the used needle in a
puncture-resistant disposable container and
properly throw it away as directed by your
Health Care Professional.
4. Replace the cap on the Pen.
5. The Pen that you are using should NOT be refrigerated but should be kept at room
temperature [below 86°F (30°C)] and away from direct heat and light. It should be
discarded according to the time specified in the “Patient Information”, even if it still
contains insulin.
Do not store or dispose of the Pen with a needle attached. Storing the Pen with
the needle attached may allow insulin to leak from the Pen and air bubbles to
form in the cartridge.
19
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Questions and Answers
Problem
Action
1. Dose dialed and injection
button pushed in without a
needle attached.
To obtain an accurate dose you must:
1) Attach a new needle.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen.
2. Insulin does not come out
of the needle.
Note: You may need to prime
a new pen up to six times
before a stream of insulin
appears.
To obtain an accurate dose you must:
1) Always attach a new needle to help
ensure sterility and prevent blocked
needles.
2) Push in the injection button completely
(even if a “0” is seen in the window) until
a diamond (♦) or an arrow (
) is seen in
the center of the dose window.
3) Prime the Pen. See Section III. “Priming
the Pen”, pages 10-13.
20
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Questions and Answers
(Continued)
Problem
Action
3. Why do I need to prime a
new pen up to six times?
The first time you use a new pen, priming up
to six times may be needed to see a stream
of insulin come out of the tip of the needle. If
you do not prime until you see a stream of
insulin, you may get too much or too little
insulin.
4. Wrong dose (too high or
too low) dialed.
If you have not pushed in the injection
button, simply turn the dose knob backward
or forward to correct the dose.
5. Not sure how much insulin
remains in the cartridge.
Hold the Pen with the needle end pointing
down. The scale (20 units between marks)
on the clear cartridge holder shows an
estimate of the number of units remaining.
These numbers should not be used for
measuring an insulin dose.
21
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Questions and Answers
(Continued)
Problem
Action
6. Full dose cannot be dialed.
The Pen will not allow you to dial a dose
greater than the number of insulin units
remaining in the cartridge. For example, if
you need 31 units and only 25 units remain
in the Pen, you will not be able to dial past
25. Do not attempt to dial past this point.
(The insulin that remains is unusable and
not part of the 300 units.) If a partial dose
remains in the Pen you may either:
1) Give the partial dose and then give the
remaining dose using a new Pen, or
2) Give the full dose with a new Pen.
7. A small amount of insulin
remains in the cartridge but
a dose cannot be dialed.
The Pen design prevents the cartridge from
being completely emptied. The Pen has
delivered 300 units of usable insulin.
22
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Questions and Answers
(Continued)
Problem
Action
8. Cannot completely push in
the injection button when
priming the Pen or injecting
a dose.
1) Needle is not attached or is clogged.
a. Attach a new needle to help ensure
sterility and prevent blocked needles.
b. Push in the injection button
completely (even if a “0” is seen in
the window) until a diamond (♦) or an
arrow (
) is seen in the center of the
dose window.
c. Prime the Pen.
2)
If you are sure insulin is coming out of
the needle, push in the injection button
more slowly to reduce the effort needed
and maintain a constant pressure until
the injection button is completely
pushed in.
23
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For additional information call,
1-800-LILLY-RX (1-800-545-5979),
or visit our website at www.Humalog.com
Revised February 2015
Manufactured by Lilly France S.A.S.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
A1.01-PEN-9117-IFU-YYYYMMDD
24
Reference ID: 3706715
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:22.266329 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019717s133lbl.pdf', 'application_number': 19717, 'submission_type': 'SUPPL ', 'submission_number': 133} |
1,819 | NDA 19-938/S-037
Page 1
NNPI submission date: 5/17/05
NovoPen®3
PenMate®
Instruction Manual
For use with the
following NovoPen® insulin delivery
devices:
NovoPen®3,
NovoPen® 3 Demi,
or NovoPen® Junior
Read this carefully before you use
NovoPen®3 PenMate® with
NovoPen®3, NovoPen® 3 Demi, or
NovoPen® Junior
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Page 2
NNPI submission date: 5/17/05
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NDA 19-938/S-037
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NDA 19-938/S-037
Page 4
NNPI submission date: 5/17/05
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NNPI submission date: 5/17/05
INTRODUCTION
NovoPen® 3 PenMate® helps to give an injection without seeing a needle and is
designed for use with the following Novo Nordisk 3 mL PenFill® cartridge
compatible insulin delivery devices: NovoPen® 3, NovoPen® 3 Demi, or
NovoPen® Junior (hereafter referred to as “NovoPen devices”). When the
NovoPen 3 PenMate is used with one of the NovoPen devices mentioned above,
it is called “NovoPen 3 PenMate system”. With NovoPen 3 PenMate system, you
don’t see a needle when you give an injection.
If you use NovoPen 3 PenMate with NovoPen 3, you can dial doses from 2
to 70 units in one unit steps.
If you use NovoPen 3 PenMate with NovoPen 3 Demi or NovoPen Junior,
you can dial doses from 1 to 35 units in half (½) unit steps.
NovoPen 3 PenMate should only be used in combination with the following
products that are compatible and recommended by Novo Nordisk.
NovoPen 3 PenMate system is designed to be used with:
NovoPen 3
NovoPen 3 Demi
NovoPen Junior
Novo Nordisk 3 mL PenFill insulin cartridges (PenFill cartridges)
NovoFine® disposable needles
NovoFine disposable needles are for single-use only.
NovoPen 3 PenMate system design allows you to use the same recommended
injection technique as the NovoPen devices.
This booklet contains instructions for using, storing and cleaning NovoPen 3
PenMate system. Please read the instructions carefully. You should read these
instructions even if you have used NovoPen devices, or NovoPen devices with
the NovoPen 3 PenMate before. The two previous pages provide illustrations of
NovoPen 3 and the NovoPen 3 PenMate. The diagrams in this booklet are
shown using NovoPen 3 and NovoPen 3 PenMate. NovoPen 3 Demi and
NovoPen Junior are different versions of NovoPen 3, but the NovoPen devices
all work with NovoPen 3 PenMate in the same way.
Always check that the PenFill cartridge you use contains the correct type of
insulin.
If you use more than one type of insulin in PenFill cartridges, you should use a
separate NovoPen 3 PenMate system for each type of insulin to avoid giving an
injection with the wrong type of insulin.
If you have any questions about your NovoPen 3 PenMate, NovoPen 3 PenMate
system, or your NovoPen devices, please call Novo Nordisk Inc. at
1-800-727-6500.
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NDA 19-938/S-037
Page 6
NNPI submission date: 5/17/05
Please complete and return the NovoPen 3 PenMate Warranty Card for full
warranty protection.
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
HOW TO USE THIS BOOKLET
This booklet gives you step-by-
step instructions for using
NovoPen 3 PenMate system.
Begin by reviewing the illustration of
the parts of the NovoPen devices,
NovoPen 3 PenMate, Novo Nordisk
3 mL PenFill insulin cartridge, and
NovoFine disposable needle. The
inside front cover opens out while
you read the rest of the booklet.
Most pages contain a diagram (using
NovoPen 3 and NovoPen 3
PenMate) on the right with numbered
instructions to the left of the diagram.
Important additional information is
given below the diagram.
We suggest that you read the text
and look at the diagrams to make
sure that you understand each step
thoroughly.
Also included is an illustration
showing a side-by-side comparison
of the NovoPen devices and the
NovoPen 3 PenMate. This illustration
allows you to see which part of the
NovoPen devices the NovoPen 3
PenMate replaces.
The main differences between
the NovoPen devices and the
NovoPen 3 PenMate system are
as follows:
• The PenFill cartridge holder
and the Pen cap of the
NovoPen devices are
replaced by the NovoPen 3
PenMate.
• With the NovoPen 3
PenMate system, you do
not see a needle when you
give an injection.
Look at the illustration inside the front cover for the names of the
different parts of NovoPen devices and NovoPen 3 PenMate. You can
unfold the illustration to help you while you follow the instructions.
2
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
TABLE OF CONTENTS
SECTION 1:
Assembly of the NovoPen 3 PenMate system................................................4
SECTION 2:
Air shot before each injection..........................................................................9
SECTION 3:
Choosing your dose .........................................................................................10
SECTION 4:
Giving the injection...........................................................................................12
SECTION 5:
Mechanical function check of NovoPen 3 PenMate system .........................17
SECTION 6:
For subsequent injections ...............................................................................18
SECTION 7:
What to do if the 3 mL PenFill cartridge is nearly empty ..............................19
SECTION 8:
Changing 3mL PenFill cartridge......................................................................20
SECTION 9:
Function check..................................................................................................21
IMPORTANT ......................................................................................................22
WHAT TO DO IF.................................................................................................25
MAINTENANCE .................................................................................................27
WARRANTY.......................................................................................................28
3
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 1 Assembly of the NovoPen 3 PenMate system
Assembly of the NovoPen 3 PenMate
system
1 Take the NovoPen 3 out of its
case by pressing the top of the
Pen cap, or take NovoPen 3
Demi or NovoPen Junior out of
the soft carrying case.
2 Gently twist the Pen cap until it
separates from the barrel.
3 Pull the Pen cap straight up to
remove it.
4 Unscrew and remove the PenFill
holder from the barrel.
You will not use the Pen cap and
PenFill holder with the NovoPen
3 PenMate system but you
should store them in case you
want to use the NovoPen device
without the NovoPen 3 PenMate
in the future.
4
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NNPI submission date: 5/17/05
SECTION 1 (cont.)
5 Press the push button all the way
in until you see zero (0) in the
dose indicator window. The zero
should be lined up with the stripe
next to the dose indicator
window.
6 The end of the piston rod should
be flat against the end of the
reset mechanism before inserting
a new 3 mL PenFill cartridge.
The piston rod should not be
sticking out.
If the piston rod is sticking out:
Turn the end of the reset
mechanism in a clockwise
direction until the piston rod is no
longer sticking out. Never push
the piston rod back in.
You should never reset the piston
rod until it is time to remove the
empty PenFill cartridge and insert a
new 3 mL PenFill cartridge.
If the reset mechanism locks, it is
usually due to improper technique.
Gently turn the reset mechanism
side to side until it unlocks. Then
call the toll free number 1-800-727-
6500 so we may go over your
technique with you.
5
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 1 (cont.)
7 To remove the PenFill cartridge
from its wrapper, push the PenFill
cartridge through the foil side of
the packaging.
Before use, check that the new
PenFill cartridge does not have
puncture holes in the rubber
stopper. If the rubber stopper
has holes in it, do not use the
cartridge.
8 If you use a suspension insulin
(white and cloudy), such as
Novolin® N, Novolin® 70/30, or
NovoLog® Mix 70/30, make sure
to mix the insulin in the cartridge
before use. You will find
instructions in the 3 mL PenFill
cartridge “Information For The
Patient” leaflet on how to prepare
the insulin.
Once the PenFill cartridge is
punctured (in use), it should be
stored at room temperature
below 86° F (30° C). Stored at this
temperature, the in-use PenFill
cartridge can be used for the
amount of days listed in the 3 mL
PenFill cartridge “Information For
The Patient” leaflet for the type of
insulin you are using.
If you use more than one type of insulin in PenFill cartridges, use a separate
NovoPen 3 PenMate system for each type of insulin to avoid giving an injection
with the wrong type of insulin.
6
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 1 (cont.)
9 Take NovoPen 3 PenMate out of
its case.
Pull off the cap and put it to one
side.
10 Put the PenFill cartridge into the
NovoPen 3 PenMate. The
threaded plastic cap goes in first.
If you use a suspension insulin
(white and cloudy), make sure to
mix the insulin in the cartridge
before you put it into the
NovoPen 3 PenMate. You will
find the instructions in the 3 mL
PenFill cartridge “Information For
The Patient” leaflet on how to mix
the insulin.
11 Tightly screw the barrel of the
NovoPen device into the
NovoPen 3 PenMate and you
have NovoPen 3 PenMate
system.
Make sure that the dose indicator
window on the mechanical
section is aligned with the yellow
push button on NovoPen 3 PenMate.
Each 3 mL PenFill cartridge contains 300 units of insulin. Make sure you are
using the correct type of insulin. The name of the insulin is on the glass part
of the PenFill cartridge.
PenFill cartridge is for single-person use only. DO NOT SHARE the PenFill
cartridge with anyone else even if you attach a new disposable needle for
each injection. Sharing the PenFill cartridge can spread disease.
Use only a new 3 mL PenFill cartridge when loading the NovoPen 3
PenMate. Never load a partially filled PenFill cartridge.
Never try to refill a used PenFill cartridge.
7
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NDA 19-938/S-037
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SECTION 1 (cont.)
12 Clean the front rubber stopper on
the PenFill cartridge with an
alcohol swab.
You must wipe the front rubber
stopper with an alcohol swab
before each injection, even if you
are using the same PenFill
cartridge.
13 Remove the protective tab from
the NovoFine disposable needle.
Screw the NovoFine disposable
needle firmly onto the threaded
plastic cap of the PenFill
cartridge until it is tight.
Pull off the outer and inner
needle caps.
For users of a suspension
insulin (white and cloudy),
always remix the insulin in the
PenFill cartridge before each
injection.
You will find instructions on how
to remix the suspension insulin in
the PenFill cartridge in the 3 mL
PenFill cartridge “Information For
The Patient” leaflet.
Never place a NovoFine disposable needle on your NovoPen 3 PenMate
system until you are ready to do an air shot and give an injection. If the
NovoFine needle is left on, some insulin may leak out from the PenFill
cartridge. This may cause a change in the concentration (strength) of a
suspension insulin (white and cloudy).
8
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 2 Air shot before each injection
Air shot before each injection
14 Small amounts of air may be
present in the needle and/or
PenFill cartridge. To avoid
injecting air bubbles and to make
sure of correct dosing, you must
perform an air shot before
each injection.
•
Check that the dial-a-dose
selector is set to zero.
•
Dial 2 units.
•
Hold the NovoPen 3 PenMate
system with the NovoFine needle
pointing up and tap gently near
the window of NovoPen 3
PenMate with your finger a few
times.
•
Press the push button at the end
of the barrel all the way in.
A drop of insulin should appear at
the needle tip.
If no insulin appears, repeat the
above steps until a drop of insulin
appears. There may still be some
small air bubble(s) in the PenFill
cartridge after this, but they will not
affect your dose and they will not be
injected.
If you dialed more than 2 units,
DO NOT turn the dial-a-dose
selector back to zero (0). If you
do, the extra insulin will squirt out
of the needle. You may complete
the air shot with the number of
units you have dialed or refer to
the instructions on how to reset
the dose to zero in Section 3
“Choosing your dose”, step 17.
9
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 3 Choosing your dose
Choosing your dose
15 NovoPen 3 PenMate system has
an insulin scale with marks
showing the approximate number
of units left in the PenFill
cartridge. Always check that
there is enough insulin left in the
3 mL PenFill cartridge for the
injection.
Grip the barrel of the NovoPen
device and the NovoPen 3
PenMate and firmly pull in
opposite directions until you hear
a click.
Important: Do not pull the dial-
a-dose selector.
Make sure that the dial-a-dose
selector is set to zero. If zero
does not appear, follow the
instructions in step 17.
16 Dial the number of units you need
to inject.
With the NovoPen 3, the odd
numbers (1, 3, 5, 7 ...) are shown
as long lines between the even
numbers. With the NovoPen 3
Demi and NovoPen Junior, half
units (1.5, 2.5, 3.5 ...) are shown
as long lines between the whole
numbers.
Do NOT use the clicking sound
as a guide for selecting your
dose.
The NovoPen 3 PenMate system can deliver from 2 to 70 units of insulin in one
unit increments if you use NovoPen 3 and from 1 to 35 units of insulin in half (½)
unit increments if you use NovoPen 3 Demi and NovoPen Junior. If you dialed
more than your dose, do NOT turn the dial back to zero (0). If you do, the
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NNPI submission date: 5/17/05
extra insulin will squirt out of the needle. For instructions on how to reset the
dose to zero (0), see step 17.
10
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NNPI submission date: 5/17/05
SECTION 3 (cont.)
17 If you dialed a larger dose than
you need, you need to reset your
NovoPen 3 PenMate system to
zero by following the instructions
below:
a. Pull the barrel of the NovoPen
device and the NovoPen 3
PenMate in opposite directions
and keep hold of them (see
diagram).
b. Press the push button on the
barrel of the NovoPen device with
your finger or gently press the
push button against a hard
surface. The zero should now be
lined up with the stripe next to the
dose indicator window.
c. Release your grip and the barrel
section will slide back into place.
d. You can now dial the correct
units of insulin.
11
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NNPI submission date: 5/17/05
SECTION 4 Giving the injection
Giving the injection
18 After the air shot is done, check
the dose indicator window to
make sure you have chosen the
correct number of units for your
dose.
Hold the NovoPen 3 PenMate
system at the correct site on the
body for an injection. Use the
injection technique recommended
by your health care professional.
If you use a suspension insulin
(white and cloudy), remix the
insulin before injecting. See the
3 mL PenFill cartridge
“Information For The Patient”
leaflet for instructions on
remixing. Make sure the insulin
in the PenFill cartridge looks
uniformly white and cloudy before
you inject.
The PenMate is designed with a
cut-away on one side. This cut-
away allows injections at various
angles other than 90°.
When you press the yellow push-
button on the NovoPen 3
PenMate system with your finger
(see arrow in diagram), the
needle will enter the skin.
12
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NNPI submission date: 5/17/05
SECTION 4 (cont.)
19 To inject your dose, press the
push button on the barrel of the
NovoPen device as far as it will
go to inject the insulin. Do not
force it (see arrow in diagram).
To make sure that all of the
insulin is injected, keep the
NovoFine needle in the skin for
several seconds after the
injection with your thumb on the
push button. Keep the push
button fully depressed for 6
seconds before removing the
needle from the injection site. Do
not rub the injection area.
If there is not enough insulin in
the 3 mL PenFill cartridge for the
whole dose, you will be able to
see the number of units you still
need to inject in the dose
indicator window. You must
always check the dose indicator
window after you have given an
injection.
Important: Never turn the dial-
a-dose selector to inject the
insulin.
When you press the push button, the
piston rod presses against the rear
rubber stopper of the PenFill
cartridge. This moves the rear
rubber stopper and pushes the
correct amount of insulin out through
the needle.
13
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NNPI submission date: 5/17/05
SECTION 4 (cont.)
After the injection, check the dose
indicator window to make sure it
shows zero (0). If it does not show
zero, you did not receive your full
dose.
For example: If you dial 25 units and
there are only 20 units in the PenFill
cartridge, the number 5 will appear in
the dose indicator window following
the injection (25-20=5). This means
you only received 20 units and need
to inject 5 more units. If this
happens, proceed with the following
steps to get your remaining units of
insulin dose:
a. Note the number of units in the
dose indicator window.
b. Remove the NovoFine needle
(see step 20).
c. Unscrew the barrel of the
NovoPen device from the
NovoPen 3 PenMate system.
d. Remove the empty PenFill
cartridge (see steps 26 and 27).
e. Insert a new 3 mL PenFill
cartridge (see steps 5 to 10).
f. Screw the barrel of the NovoPen
3 device into the NovoPen 3
PenMate (see step 11).
g. Attach a new NovoFine needle
(see steps 12 and 13).
h. Do an air shot (see step 14).
i. Dial the number of units you still
need to inject from the above
step (a).
j. Give the injection.
14
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 4 (cont.)
To make sure that the insulin has
been injected, do the following:
•
Check that you can see the
control line (solid white line) at
the top of the insulin scale (above
the number 300).
•
Check to see if your skin is wet
where you gave the injection.
If you cannot see the control line
after the injection or your skin is wet,
you did not receive your full dose of
insulin and need to do a mechanical
function check. See steps 21 and 22
to perform a mechanical function
check of NovoPen 3 PenMate
system.
If you suspect that your NovoPen 3
PenMate is not working properly, call
Novo Nordisk at 1-800-727-6500 so
we can review your injection
technique with you.
Call 1-800-727-6500 or your health
care professional if you have any
questions.
15
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NNPI submission date: 5/17/05
SECTION 4 (cont.)
20 Immediately after the injection,
place an outer needle cap on the
needle and carefully remove the
needle. Hold the NovoPen 3
PenMate system firmly while you
unscrew the NovoFine
disposable needle. Used
NovoFine disposable needles
should be placed in sharps
containers (such as red
biohazard containers), hard
plastic containers (such as
detergent bottles), or metal
containers (such as an empty
coffee can). Such containers
should be sealed and disposed of
properly.
Health care professionals,
relatives and other care givers
should also follow the instructions
for removing the needle to
eliminate the risk of unintended
needle stick.
The NovoFine disposable needle must be removed right after each
injection by placing an outer needle cap on the needle and turn counter-
clockwise. After the NovoFine disposable needle is removed, put the NovoPen
3 PenMate cap back on. If the NovoFine disposable needle is not removed,
some insulin may leak out of the PenFill cartridge. This may cause a change in
the concentration (strength) of a suspension insulin (white and cloudy).
For information on how to throw away needle containers properly, contact your
local trash company.
16
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NDA 19-938/S-037
Page 23
NNPI submission date: 5/17/05
SECTION 5 Mechanical function check of NovoPen 3 PenMate system
Mechanical function check of
NovoPen 3 PenMate system
21 Hold the NovoPen 3 PenMate
system with the needle pointing
up.
•
Grip the barrel of the NovoPen
device and the NovoPen 3
PenMate and firmly pull in
opposite directions until you hear
a click. If you do not hear a click,
contact Customer Relations at
the toll free number 1-800-727-
6500. Never use a NovoPen 3
PenMate unless you are sure that
it is working properly.
Important: Do not pull the dial-a-
dose selector.
Make sure that the dial-a-dose
selector is set to zero (0). If not,
press the push button all the way in.
22 Push the yellow push button and
the needle should appear.
You should now be able to see
the needle and the control line.
If you cannot see the needle, do
not use the NovoPen 3 PenMate
system. Never use the NovoPen
3 PenMate system unless you
are sure that it is working
properly.
17
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NNPI submission date: 5/17/05
SECTION 6 For subsequent injections
For subsequent injections
23 Remove the NovoPen 3 PenMate
cap. Check that the needle has
been removed since your last
injection. Make sure that
NovoPen 3 PenMate system
contains the correct type of
insulin for an injection. If your
NovoPen 3 PenMate system
contains a solution insulin (clear)
follow steps 12 to 20.
24 If your NovoPen 3 PenMate
system contains a suspension
insulin (white and cloudy), see
the 3 mL PenFill cartridge
“Information For The Patient”
leaflet on how to remix the
insulin.
Then continue as shown in steps
12 to 20 and inject immediately.
18
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NDA 19-938/S-037
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NNPI submission date: 5/17/05
SECTION 7 What to do if the 3 mL PenFill cartridge is nearly empty
What to do if the 3 mL PenFill
cartridge is nearly empty
25 If you use a suspension insulin
(white and cloudy), do not inject
if you can see the rubber piston
in the small inspection window. At
least 12 units of insulin must be
in the PenFill cartridge for
adequate mixing with the glass
ball.
With the NovoPen 3 PenMate
system, it is possible to select a
dose that is larger than the
number of units left in the PenFill
cartridge. If there is not enough
insulin in the PenFill cartridge for
the whole dose, you will be able
to see the number of units you
still need to inject in the dose
indicator window after the
injection.
To get the remaining units of your
dose, refer to Section 4 “Giving
the injection”, Page14, a through
j.
When you get near to the end of a PenFill cartridge, you may need to give
yourself two injections to receive your full dose. Always check the dose indicator
window after giving an injection. If zero (0) does not show in the dose indicator
window, you did not receive your full dose. See Section 4 “Giving the injection”
on page 14 for instructions on how to get the remaining units of your dose.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 26
NNPI submission date: 5/17/05
SECTION 8 Changing 3 mL PenFill cartridge
Changing 3 mL PenFill cartridge:
26 a. Unscrew the barrel of the
NovoPen device from the
NovoPen 3 PenMate system.
b. Press the push button of the
NovoPen device to set the
dose indicator back to zero (0).
c. Make sure that the piston rod
is not sticking out. If the piston
rod is sticking out, reset the
piston rod by gently turning the
end of the reset mechanism in
a clockwise direction until the
piston rod is no longer sticking
out. Never push the piston
rod back in.
27 Take out the empty PenFill
cartridge. Take a new 3 mL
PenFill cartridge and continue
as described in steps 7 and 8.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 27
NNPI submission date: 5/17/05
SECTION 9 Function check
Function check
28 If you think your NovoPen 3
PenMate system is not working
properly, follow this procedure:
a. Make sure that the barrel of the
NovoPen device and NovoPen 3
PenMate are screwed together
tightly and that the dose indicator
window on the barrel is aligned
with the yellow push button on
the NovoPen 3 PenMate.
b. Screw on a new NovoFine needle
as described in steps 12 and 13.
c. Do an air shot to remove air
bubbles as described in step 14.
d. DO NOT replace the inner
needle cap. Put the outer
needle cap over the needle.
e. Dispense 20 units into the outer
needle cap.
The insulin should fill the lower part
of the outer needle cap. If the pen
has delivered too much or too little
insulin, repeat the test. If it happens
again, do not use the NovoPen
device. Contact Novo Nordisk Inc. at
the toll free number 1-800-727-6500.
DO NOT try to repair a NovoPen
device or a NovoPen 3 PenMate.
Never use a NovoPen device
or NovoPen 3 PenMate unless
you are sure that they are
working properly.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 28
NNPI submission date: 5/17/05
IMPORTANT
•
Keep the NovoPen 3 PenMate system away from areas where temperatures
may get too hot or too cold such as in a car or in a refrigerator.
•
Once the PenFill cartridge is punctured (in use) inside the NovoPen 3 PenMate
system, it should be kept at room temperature (below 86◦F [30◦C]) for the length
of time stated in the storage information section of the “Information For The
Patient” leaflet supplied with the 3 mL PenFill cartridges.
•
Make sure that the piston rod is not sticking out before you screw together the
barrel of the NovoPen device and the NovoPen 3 PenMate. (see steps 5 to 6).
•
Always screw the mechanical section of the NovoPen device and NovoPen 3
PenMate tightly together.
•
Before each injection, make sure that you are using the correct type of insulin
PenFill cartridge.
•
Always clear air bubbles with the needle pointing up before each injection (see
step 14).
•
With NovoPen 3 PenMate system, it is possible to select a dose which is larger
than the number of units left in the 3 mL PenFill cartridge. Before you inject,
always check on the insulin scale window that there is enough insulin left in the
PenFill cartridge for your dose.
After the injection, always make sure that the dose indicator window is back to
zero (0). If not, you did not receive your full dose of insulin. See step 25.
•
Do not use the insulin scale on the NovoPen 3 PenMate system to measure the
amount of insulin to be injected.
•
Before an injection, always check the dose indicator window to make sure you
have dialed the correct number of units.
•
After an injection, make sure that NovoPen 3 PenMate system delivered your
full dose by making sure that the control line is at the top of the insulin scale and
that the insulin has been injected (see page 15).”
•
Take the needle off NovoPen 3 PenMate system right after each injection
by carefully replacing the outer needle cap on the needle and turn counter-
clockwise . If you do not remove the needle, temperature changes may cause
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 29
NNPI submission date: 5/17/05
insulin to leak out of the needle. With a suspension insulin (white and cloudy),
this may change the concentration (strength) of the insulin.
22
IMPORTANT (cont.)
•
Do not inject a suspension insulin (white and cloudy) if the rear rubber
stopper can be seen in the small inspection window.
•
Always keep a spare insulin delivery device available in case the NovoPen 3
PenMate system you are using is lost or damaged.
•
Keep NovoPen 3 PenMate, NovoPen 3 PenMate system, NovoPen device,
PenFill cartridges, and NovoFine disposable needles out of the reach of
children.
•
Your NovoPen device, NovoPen 3 PenMate, or NovoPen 3 PenMate system
should not be shared with anyone else even if you attach a new NovoFine
needle for each injection.
•
NovoPen 3 PenMate system is not recommended for blind or visually
impaired patients, without the assistance of a sighted individual trained to use
it.
•
If you use more than one type of insulin in Novo Nordisk 3 mL PenFill
cartridge, use a separate NovoPen 3 PenMate system for each type of insulin
to avoid giving an injection with a wrong type of insulin.
•
The American Diabetes Association recommends that insulin should be self-
administered. The proper age for self administration of insulin should be
decided by the adult caregiver.
•
Use only a new 3 mL PenFill cartridge when loading the NovoPen 3 PenMate
system. Never load the NovoPen 3 PenMate system with a partially filled
PenFill cartridge.
•
The NovoPen 3 PenMate system is designed for use with Novo Nordisk 3 mL
PenFill cartridges, NovoFine single-use disposable needles, and NovoPen
devices.
Novo Nordisk is not responsible for any consequences arising from the use of
the NovoPen 3 PenMate with products that are not recommended by Novo
Nordisk.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 30
NNPI submission date: 5/17/05
23
IMPORTANT (cont.)
Guidelines for storing the NovoPen 3 PenMate:
•
Store the NovoPen 3 PenMate system (with the PenFill cartridge inside)
at room temperature (below 86◦F [30◦C]). DO NOT store the NovoPen 3
PenMate system in a refrigerator or areas where there may be extreme
temperatures or moisture, such as in a car. Once the PenFill cartridge is
punctured (in use) inside the NovoPen 3 PenMate system, NovoPen 3
PenMate system should be kept at room temperature below 86°F (30°C).
Stored at this temperature, the PenFill cartridge can be used for the amount
of days listed in the 3 mL PenFill cartridge “Information For The Patient”
leaflet for the type of insulin you are using.
•
Store the NovoPen 3 PenMate system without the NovoFine needle attached
and with the NovoPen 3 PenMate cap placed in its position. Leaving the
needle on the NovoPen 3 PenMate system can cause the insulin to leak. This
may change the concentration (strength) of a suspension insulin (white and
cloudy).
•
For information on storing PenFill cartridges, see the “Information For The
Patient” leaflet that comes in the PenFill cartridge box.
•
The expiration date on the PenFill cartridge is for unused cartridges when
stored in the refrigerator.
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 31
NNPI submission date: 5/17/05
WHAT TO DO IF ...
Here are the answers to some questions you might have when using your
NovoPen 3 PenMate system.
No insulin appears when
I try to clear the air
bubbles.
• Check that your NovoPen 3
PenMate system was put
together correctly when you
changed the PenFill cartridge.
• Make sure that the piston rod
is not sticking out.
• Make sure that the barrel of
the NovoPen device and the
NovoPen 3 PenMate are
screwed tightly together.
(see steps 5 and 25).
No insulin appears when
I try to clear the air
bubbles and the push
button will not go in.
• The needle may be blocked.
Change the needle and repeat
air shots until insulin appears
at the needle tip.
• Check if the PenFill cartridge
is empty.
The push button will not
depress during the
injection.
• Do not try to force the push
button down.
• Check if the PenFill cartridge
is empty. If there was not
enough insulin in the PenFill
cartridge for the full dose, you
will see the number of units
you still need to inject in the
dose indicator window. Make
a note of this. Change the
PenFill cartridge and continue
as described in step 26.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 32
NNPI submission date: 5/17/05
WHAT TO DO IF ... (cont.)
I cannot press the push
button back to zero before I
return the piston rod.
• The reset mechanism may be
locked. Gently twist the reset
mechanism from side to side until
it unlocks. See the diagram in step
6. Then you can press the push
button back to zero. Never turn
the dial-a-dose selector back.
I cannot get the piston rod
back inside the reset
mechanism when I change
the PenFill cartridge.
• The reset mechanism may be
locked. Gently twist the reset
mechanism from side to side until
it unlocks. Then turn the reset
mechanism to the right until the
piston rod is completely inside it.
See the diagram in step 6.
I think the needle has not
entered the skin.
• Check that you can see the control
line at the top of the insulin scale.
• Check if your skin is wet at the
injection site. Carry out the
mechanical function check of the
NovoPen 3 PenMate system as
described in steps 21 and 22.
I think my NovoPen 3,
NovoPen 3 Demi, NovoPen
Junior, or my NovoPen 3
PenMate is not working
properly.
• Do the function check as
described in step 28. Make sure
that the lower part of the outer
needle cap is filled with 20 units of
insulin.
• Do the mechanical function check
of the NovoPen 3 PenMate
system as described in steps 21
and 22. Make sure that the control
line is visible when the NovoPen 3
PenMate system is released.
Never use a NovoPen device or
NovoPen 3 PenMate unless you
are sure that they are working
properly.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 33
NNPI submission date: 5/17/05
MAINTENANCE
How to store and look after your
NovoPen 3 PenMate system
NovoPen 3 PenMate system should
be handled with care. Avoid
situations where your NovoPen 3
PenMate system can be damaged.
Do not drop the device. Do not
expose the device to excessive
pressure or blows. Keep it in the
case whenever possible.
You can put PenFill cartridges in
NovoPen 3 PenMate system or carry
them with you as spares. Please
read the “Information For The
Patient” leaflet supplied with the
PenFill cartridges for details on how
to store the cartridges and how long
to keep them.
You can clean your NovoPen 3
PenMate system by wiping it with a
cotton swab moistened with ethyl or
isopropyl alcohol.
Your NovoPen devices and your
NovoPen 3 PenMate are sturdy
products but could still get
damaged. So handle them with care
and protect them against dust and
dirt when they are not in a case.
Do not try to repair a faulty
NovoPen device or a faulty
NovoPen 3 PenMate.
NovoPen 3 PenMate system
must only be used in the way
described in this booklet. The
manufacturer will not be
responsible for any problems
you have with the device if you
have not followed this booklet.
If you find your NovoPen 3
PenMate system faulty, Novo
Nordisk will replace it if:
You call Novo Nordisk Inc. at
the toll free number
1-800-727-6500 within three
years of getting it.
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 34
NNPI submission date: 5/17/05
WARRANTY
Should your NovoPen 3 PenMate
device be defective in materials or
workmanship within three (3) years
of purchase, Novo Nordisk Inc. will
replace it at no charge if you contact
Novo Nordisk Inc. at 1-800-727-6500
with a description of the problem.
Arrangements will be made for you
to return the defective NovoPen 3
PenMate along with the sales receipt
or other proof of purchase to Novo
Nordisk Inc.
Protected by U.S. Patents No.
5,980,491 and other Patents
Pending. Designed and
recommended for use with Novo
Nordisk 3 mL PenFill insulin
cartridges and NovoPen devices.
No other warranty is made with
respect to NovoPen 3 PenMate. The
mechanical section of the NovoPen
devices is covered by its own
separate warranty, which is
described in its instruction manual.
Warranty will be invalid and Novo
Nordisk A/S, Novo Nordisk Inc.,
Bristol-Myers Squibb Co., Nipro
Medical Industries Ltd., and Bang &
Olufsen A/S cannot be held
responsible in the case of
defects or damages arising
from:
•
The use of the NovoPen 3
PenMate with products
other than NovoPen
devices, Novo Nordisk 3
mL PenFill cartridges, or
NovoFine single-use
disposable needles.
•
The use of the NovoPen 3
PenMate not in accordance
with the instructions in this
booklet.
•
Physical damage to the
NovoPen 3 PenMate
caused by neglect, misuse,
unauthorized repair,
accident, or other
breakage.
Use of the NovoPen 3
PenMate does not extend the
warranty of the NovoPen
devices.
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 35
NNPI submission date: 5/17/05
NovoPen®, Novo Nordisk®, PenMate®, PenFill®, NovoFine®, Novolin® and
NovoLog® are registered trademarks owned by Novo Nordisk A/S.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 36
NNPI submission date: 5/17/05
For assistance or further information, write to:
Novo Nordisk Inc.
Customer Relations
100 College Road West
Princeton, NJ 08540
Or call: 1-800-727-6500
© 2002, 2005 Novo Nordisk Inc.
Novo Nordisk Inc.
Princeton, NJ 08540-7810
www.novonordisk-us.com
8-4241-31-001-2 5/17/05 Draft
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 1
Submission date: 12/20/04
1
Novo Nordisk®
2
R HUMAN
3
4
Information for the patient
5
6
Novolin® R PenFill®
7
8
Regular, Human Insulin Injection
9
(recombinant DNA origin)
10
3 mL Disposable Cartridge
11
(300 units per cartridge)
12
13
100 units/mL (U-100)
14
15
Please read this leaflet carefully before using this product.
16
Please note the special directions under PREPARING THE INJECTION.
17
Novolin® R PenFill® 3 mL is designed for use with Novo Nordisk 3 mL PenFill® cartridge
18
compatible insulin delivery devices, with or without the addition of a NovoPen® 3
19
PenMate®, and NovoFine® disposable needles.
20
PenFill® cartridge is for single person use only. See IMPORTANT NOTES section.
21
22
WARNING
23
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER
24
MEDICAL SUPERVISION. CHANGES IN PURITY, STRENGTH, BRAND
25
(MANUFACTURER), TYPE (REGULAR, NPH, LENTE®, ETC.), SPECIES (BEEF,
26
PORK, BEEF-PORK, HUMAN), AND/OR METHOD OF MANUFACTURE
27
(RECOMBINANT DNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE
28
NEED FOR A CHANGE IN DOSAGE.
29
SPECIAL CARE SHOULD BE TAKEN WHEN THE TRANSFER IS FROM A
30
STANDARD BEEF OR MIXED SPECIES INSULIN TO A PURIFIED PORK OR
31
HUMAN INSULIN. IF A DOSAGE ADJUSTMENT IS NEEDED, IT WILL USUALLY
32
BECOME APPARENT EITHER IN THE FIRST FEW DAYS OR OVER A PERIOD OF
33
SEVERAL WEEKS. ANY CHANGE IN TREATMENT SHOULD BE CAREFULLY
34
MONITORED.
35
PLEASE READ THE SECTIONS "INSULIN REACTION AND SHOCK" AND
36
"DIABETIC KETOACIDOSIS AND COMA" FOR SYMPTOMS OF HYPOGLYCEMIA
37
(LOW BLOOD GLUCOSE) AND HYPERGLYCEMIA (HIGH BLOOD GLUCOSE).
38
39
INSULIN USE IN DIABETES
40
Your physician has explained that you have diabetes and that your treatment involves
41
injections of insulin or insulin therapy combined with an oral antidiabetic medicine.
42
Insulin is normally produced by the pancreas, a gland that lies behind the stomach.
43
Without insulin, glucose (a simple sugar made from digested food) is trapped in the
44
bloodstream and cannot enter the cells of the body. Some patients who don't make
45
enough of their own insulin, or who cannot use the insulin they do make properly, must
46
take insulin by injection in order to control their blood glucose levels.
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 2
Submission date: 12/20/04
Each case of diabetes is different and requires direct and continued medical
48
supervision. Your physician has told you the type, strength and amount of insulin you
49
should use and the time(s) at which you should inject it, and has also discussed with
50
you a diet and exercise schedule. You should contact your physician if you experience
51
any difficulties or if you have questions.
52
53
TYPES OF INSULINS
54
Standard and purified animal insulins as well as human insulins are available. Standard
55
and purified insulins differ in their degree of purification and content of noninsulin
56
material. Standard and purified insulins also vary in species source; they may be of
57
beef, pork, or mixed beef and pork origin. Human insulin is identical in structure to the
58
insulin produced by the human pancreas, and thus differs from animal insulins. Insulins
59
vary in time of action; see PRODUCT DESCRIPTION for additional information. Your
60
physician has prescribed the insulin that is right for you; be sure you have purchased
61
the correct insulin and check it carefully before you use it.
62
63
PRODUCT DESCRIPTION
64
This package contains five (5) Novolin® R PenFill® 3 mL cartridges. Novolin R is
65
commonly known as Regular, Human Insulin Injection (recombinant DNA origin). The
66
concentration of this product is 100 units of insulin per milliliter. It is a clear, colorless
67
solution which has a short duration of action. The effect of Novolin R begins
68
approximately ½ hour after injection. The effect is maximal between 2½ and 5 hours
69
and ends approximately 8 hours after injection.
70
The time course of action of any insulin may vary considerably in different individuals, or
71
at different times in the same individual. Because of this variation, the time periods
72
listed here should be considered as general guidance only.
73
This human insulin (recombinant DNA origin) is structurally identical to the insulin
74
produced by the human pancreas. This human insulin is produced by recombinant
75
DNA technology utilizing Saccharomyces cerevisiae (bakers' yeast) as the production
76
organism.
77
78
INSULIN DELIVERY SYSTEMS
79
These Novolin R PenFill 3 mL cartridges are designed for use with Novo Nordisk® 3 mL
80
PenFill cartridge compatible insulin delivery devices, with or without the addition of a
81
NovoPen® 3 PenMate®, and NovoFine® disposable needles.
82
83
STORAGE
84
Insulin should be stored in a cold (36° - 46°F [2° - 8°C]) place, preferably in a
85
refrigerator, but not in the freezer. Do not let it freeze. Keep Novolin R PenFill
86
cartridges in the carton so that they will stay clean and protected from light. The
87
Novolin R PenFill cartridge that you are currently using should not be refrigerated
88
but should be kept as cool as possible (below 86°F [30°C]) and away from direct
89
heat and light. Unrefrigerated Novolin R PenFill cartridges must be discarded 28
90
days after the first use, even if they still contain Novolin R insulin. Never use
91
PenFill cartridges after the expiration date which is printed on the label and
92
carton.
93
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 3
Submission date: 12/20/04
Never use any Novolin R PenFill cartridge if the insulin becomes viscous (thickened) or
94
cloudy; use it only if it is clear and colorless.
95
96
IMPORTANT
97
Failure to follow the antiseptic measures listed below may lead to infections at the
98
injection site.
99
- Disposable needles are for single use; they should be used only once and destroyed.
100
- Clean your hands and the injection site with soap and water or with alcohol.
101
- Wipe the rubber stopper on the insulin cartridge with an alcohol swab.
102
103
PREPARING THE INJECTION
104
Never place a single-use disposable needle on your device until you are ready to give
105
an injection, and remove the needle immediately after the injection. Follow the
106
directions for use in the instruction manual for your insulin delivery device.
107
PenFill cartridges may contain a small amount of air bubbles. To prevent an
108
injection of air and to make certain a full dose of insulin is injected, an air shot
109
must be done before each injection. Directions for performing an air shot are
110
provided in your insulin delivery device instruction manual.
111
112
GIVING THE INJECTION
113
1. The following areas are suitable for subcutaneous insulin injection: thighs, upper
114
arms, buttocks, abdomen. Do not change areas without consulting your physician.
115
The actual point of injection should be changed each time; injection sites should be
116
about an inch apart.
117
2. The injection site should be clean and dry. Pinch up skin area to be injected and hold
118
it firmly.
119
3. Hold the device like a pencil and push the needle quickly and firmly into the pinched-
120
up area.
121
4. Release the skin and push the push-button all the way in to inject insulin beneath the
122
skin. After the injection, the needle should remain under the skin for at least 6
123
seconds. Keep the push button fully depressed until the needle is withdrawn from the
124
skin. This will ensure that the full dose has been injected.
125
5. Do not inject into a muscle unless your physician has advised it. You should never
126
inject insulin into a vein. Follow the directions for use of your insulin delivery device.
127
6. Remove the needle. If slight bleeding occurs, press lightly with a dry cotton swab for
128
a few seconds - do not rub.
129
Note: Use the injection technique recommended by your physician.
130
131
USAGE IN PREGNANCY
132
It is particularly important to maintain good control of your diabetes during pregnancy
133
and special attention must be paid to your diet, exercise and insulin regimens. If you
134
are pregnant or nursing a baby, consult your physician or nurse educator.
135
136
INSULIN REACTION AND SHOCK
137
Insulin reaction (hypoglycemia) occurs when the blood glucose falls very low. This can
138
happen if you take too much insulin, miss or delay a meal, exercise more than usual, or
139
work too hard without eating, or become ill (especially with vomiting or fever).
140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 4
Submission date: 12/20/04
Hypoglycemia can also happen if you combine insulin therapy and other medications
141
that lower blood glucose, such as oral antidiabetic agents or other prescription and
142
over-the-counter drugs. The first symptoms of an insulin reaction usually come on
143
suddenly. They may include a cold sweat, fatigue, nervousness or shakiness, rapid
144
heartbeat, or nausea. Personality change or confusion may also occur. If you drink or
145
eat something right away (a glass of milk or orange juice, or several sugar candies), you
146
can often stop the progression of symptoms. If symptoms persist, call your physician -
147
an insulin reaction can lead to unconsciousness. If a reaction results in loss of
148
consciousness, emergency medical care should be obtained immediately. If you have
149
had repeated reactions or if an insulin reaction has led to a loss of consciousness,
150
contact your physician. Severe hypoglycemia can result in temporary or permanent
151
impairment of brain function and death.
152
In certain cases, the nature and intensity of the warning symptoms of
153
hypoglycemia may change. A few patients have reported that after being
154
transferred to human insulin, the early warning symptoms of hypoglycemia were
155
less pronounced than they had been with animal-source insulin.
156
157
DIABETIC KETOACIDOSIS AND COMA
158
Diabetic ketoacidosis may develop if your body has too little insulin. The most common
159
causes are acute illness or infection or failure to take enough insulin by injection. If you
160
are ill, you should check your urine for ketones. The symptoms of diabetic ketoacidosis
161
usually come on gradually, over a period of hours or days, and include a drowsy feeling,
162
flushed face, thirst and loss of appetite. Notify your physician right away if the urine test
163
is positive for ketones (acetone) or if you have any of these symptoms. Fast, heavy
164
breathing and rapid pulse are more severe symptoms and you should have medical
165
attention right away. Severe, sustained hyperglycemia may result in diabetic coma and
166
death.
167
168
ADVERSE REACTIONS
169
A few people with diabetes develop red, swollen and itchy skin where the insulin has
170
been injected. This is called a "local reaction" and it may occur if the injection is not
171
properly made, if the skin is sensitive to the cleansing solution, or if you are allergic to
172
the insulin being used. If you have a local reaction, tell your physician.
173
Generalized insulin allergy occurs rarely, but when it does it may cause a serious
174
reaction, including skin rash over the body, shortness of breath, fast pulse, sweating,
175
and a drop in blood pressure. If any of these symptoms develop, you should seek
176
emergency medical care.
177
If severe allergic reactions to insulin have occurred (i.e., generalized rash, swelling or
178
breathing difficulties) you should be skin-tested with each new insulin preparation
179
before it is used.
180
181
IMPORTANT NOTES
182
1. A change in the type, strength, species or purity of insulin could require a dosage
183
adjustment. Any change in insulin should be made under medical supervision.
184
2. To avoid possible transmission of disease, PenFill cartridge should not be shared.
185
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
Page 5
Submission date: 12/20/04
3. Before use, check that the PenFill cartridge is intact (e.g. no cracks). Do not use if
186
any damage is visible, or if the part of the rubber piston that you see is wider than the
187
white bar code band.
188
4. You may have learned how to test your urine or your blood for glucose. It is
189
important to do these tests regularly and to record the results for review with your
190
physician or nurse educator.
191
5. If you have an acute illness, especially with vomiting or fever, continue taking your
192
insulin. If possible, stay on your regular diet. If you have trouble eating, drink fruit
193
juices, regular soft drinks, or clear soups; if you can, eat small amounts of bland
194
foods. Test your urine for glucose and ketones and, if possible, test your blood
195
glucose. Note the results and contact your physician for possible insulin dose
196
adjustment. If you have severe and prolonged vomiting, seek emergency medical
197
care.
198
6. You should always carry identification which states that you have diabetes.
199
7. Always ask your physician or pharmacist before taking any drug.
200
8. Do not try to refill a PenFill cartridge.
201
202
Always consult your physician if you have any questions about your condition or
203
the use of insulin.
204
Helpful information for people with diabetes is published by American Diabetes
205
Association, 1660 Duke Street, Alexandria, VA 22314
206
207
Date of issue:
208
209
Protected by U.S. Patent No. 6,126,646 and Des. 347,894 and other U.S. Patents
210
Pending, recommended for use with Novo Nordisk 3 mL PenFill cartridge compatible
211
insulin delivery devices, with or without a NovoPen 3 PenMate, and Novo Nordisk pen
212
needles.
213
214
© 2003, 2005 Novo Nordisk Inc.
215
216
Novo Nordisk®, Novolin®, PenFill®, NovoPen®, PenMate®, NovoFine® and Lente® are
217
trademarks owned by Novo Nordisk A/S
218
219
Novo Nordisk Inc.
220
Princeton, NJ 08540
221
Call 1-800-727-6500 for additional information
222
223
www.novonordisk-us.com
224
225
Manufactured by
226
Novo Nordisk A/S
227
DK-2880 Bagsvaerd, Denmark
228
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
FDA revision 12/20/04
Page 1
Front Panel:
List 185242
NovoPen® 3 PenMate®
CONTAINS ONE NOVOPEN® 3 PENMATE®
Designed for use with Novo Nordisk 3 mL PenFill®
cartridge compatible insulin delivery devices, PenFill® 3
mL cartridges and NovoFine® disposable needles
Novo Nordisk
Side Panel:
NovoPen® 3 PenMate®
NovoPen® 3 PenMate® is specially designed for
use with Novo Nordisk 3 ml PenFill® cartridge
compatible insulin delivery devices, PenFill® 3
mL cartridges and NovoFine® needles with a
length of up to 8 mm to allow the device to
function safely and effectively.
Carrying Case
Enclosed
Novo Nordisk delivery devices,
NovoFine® disposable needles and 3
mL PenFill® insulin cartridges not
included.
Back Panel:
For information contact:
Novo Nordisk Inc.
Princeton, NJ 08540
Manufactured in Denmark for:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
www.novonordisk-us.com
BARCODE
Protected by
U.S. Patent No. 5,980,491 and other Patents Pending.
Designed and recommended for use with Novo Nordisk 3 mL
PenFill® insulin cartridges and NovoPen® devices.
Novo Nordisk®, NovoPen®, PenMate®, PenFill® and NovoFine®
are registered trademarks of Novo Nordisk A/S.
novo nordisk®
Side Panel:
NovoPen® 3 PenMate®
NovoPen® 3 PenMate® is specially designed for
use with Novo Nordisk 3 mL PenFill® cartridges
compatible insulin delivery devices, PenFill® 3
mL cartridges and NovoFine® needles with a
length of up to 8 mm to allow the device to
function safely and effectively.
LIST: 185242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
FDA revision 12/20/04
Page 2
End Flap:
List: 185242
NovoPen® 3 PenMate®
Batch:
End Flap:
List: 185242
NovoPen® 3 PenMate®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-037
8-0199-31-201-X/12-7-04/DRAFT
Novo Nordisk®
NDC 0169-3473-18
Novolin® R PenFill®
Regular,
Human Insulin Injection
(rDNA origin)
3mL
100 units/mL
For use with Novo Nordisk 3mL PenFill®
cartridge compatible insulin delivery devices
For information contact:
BARCODE
Novo Nordisk Inc.
Princeton, NJ 08540
1-800-727-6500
8-0199-31-
Exp.Date:
201-X/12-7-04/DRAFT Control
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6 mm
1 mm
1 mm
8 mm
Q
Novo Nordisk Inc.
Princeton, NJ 08540
Regular,
Human Insulin Injection
(recombinant DNA origin)
For use with Novo Nordisk 3 mL PenFill®
cartridge compatible insulin delivery devices
100 units/mL (U-100)
5x3 mL
cartridges
List 347318
22-
481-23
Novo Nordisk™
Novolin
®R PenFill
®
Novolin
® R PenFill
®
Novolin
®R PenFill
®
NDC 0169-3473-18
Exp. date:
Control:
3 mL
5x3mL
cartridges
100 units/mL
5x3mL
cartridges
100 units/mL
Keep in a cold place
Avoid freezing
Warning
Any change of insulin should be made cautiously
and only under medical supervision.
PenFill® cartridge is for single person use only.
See package insert.
Contains metacresol 0.315% added
during manufacture as a preservative.
Novolin® , PenFill®, PenMate®, and NovoPen®
are trademarks owned by Novo Nordisk A/S.
Protected by U.S. Patent No.6,126,646 and Des. 347,894
and other U.S. Patents Pending. Recommended for use with Novo
Nordisk 3 mL PenFill® cartridge compatible insulin delivery devices,
with or without a NovoPen® 3 PenMate®, and NovoFine® disposable needles.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk Inc.
Princeton, NJ 08540
Call 1-800-727-6500 for additional
information
www.novonordisk-us.com
Manufactured by
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
| custom-source | 2025-02-12T13:43:22.487492 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019938s037lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 37} |
1,818 | 1
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NovoPen 3 PenMate Instruction Manual
Page 2
FDA revision #4 (final)
2
NovoPen® 3
3
previous page for graphic
4
PenMate®
5
6
Instruction Manual
7
8
Read this carefully
9
before you use
10
NovoPen® 3 PenMate®
11
and NovoPen® 3
12
13
14
15
16
INTRODUCTION
17
NovoPen® 3 PenMate® is a replacement component specifically designed to be used
18
with the NovoPen 3 insulin pen. NovoPen 3 PenMate helps you to insert the needle and
19
to give injections quickly and easily. With NovoPen 3 and NovoPen 3 PenMate, you can
20
dial doses in units of one from 2 to 70 units.
21
NovoPen 3 PenMate should only be used in combination with products that are
22
compatible and allow the device to function safely and effectively.
23
NovoPen 3 PenMate is designed to be used with:
24
§ NovoPen® 3
25
§ PenFill® 3 mL cartridges
26
§ NovoFine® 30G/8 mm and NovoFine® 31G/6 mm needles.
27
NovoFine disposable needles are for single-use only.
28
29
The NovoPen 3 PenMate can be used the same way as the NovoPen 3 insulin pen. Its
30
design allows you to use the same recommended injection technique as for the NovoPen
31
3 insulin pen.
32
33
This booklet contains instructions for using, storing, and cleaning NovoPen 3 PenMate in
34
combination with NovoPen 3. Please follow them carefully. You should read these
35
instructions even if you have used NovoPen 3, or NovoPen 3 in combination with the
36
NovoPen 3 PenMate before. The two following pages provide illustrations of both the
37
NovoPen 3 and the NovoPen 3 PenMate.
38
39
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NovoPen 3 PenMate Instruction Manual
Page 3
FDA revision #4 (final)
Always check that the PenFill® cartridge you use contains the correct type of insulin.
40
If you are treated with more than one type of insulin in PenFill cartridges, you should use
41
a separate NovoPen 3 PenMate and NovoPen 3 for each type of insulin.
42
43
If you have any questions about your NovoPen 3 PenMate or your NovoPen 3 insulin
44
delivery device, please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
45
Please complete and return the NovoPen 3 PenMate Warranty Card.
46
Thank you for choosing the NovoPen 3 PenMate and NovoPen 3 insulin delivery device.
47
Look at the diagram
48
49
50
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NovoPen 3 PenMate Instruction Manual
Page 4
FDA revision #4 (final)
51
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NovoPen 3 PenMate Instruction Manual
Page 5
FDA revision #4 (final)
52
PenFill Holder
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NovoPen 3 PenMate Instruction Manual
Page 6
FDA revision #4 (final)
53
HOW TO USE THIS BOOKLET
54
This booklet gives you step-by-stepinstructions for using the NovoPen 3 PenMate in
55
combination with the NovoPen 3.
56
57
Begin by reviewing the illustration layout of the parts of the NovoPen 3, NovoPen 3
58
PenMate, PenFill 3 mL cartridge and NovoFine disposable needle. The inside front cover
59
opens out so you have a handy reference while you read the rest of the booklet.
60
Most pages contain an illustration on the right with numbered instructions to the left of
61
the illustration.
62
Important additional information is given below the illustration.
63
We suggest that you read the text and look at the illustrations to make sure that you
64
understand each step thoroughly.
65
Also included is a diagram showing a side-by-side comparison of the NovoPen 3 and the
66
NovoPen 3 PenMate. This illustration allows you to see which part of the NovoPen 3 the
67
NovoPen 3 PenMate replaces.
68
69
The main differences between the NovoPen 3 and the NovoPen 3 PenMate are as
70
follows:
71
The PenFill cartridge holder and the Pen cap of the NovoPen 3 are replaced by the
72
NovoPen 3 PenMate.
73
NovoPen 3 PenMate allows for automatic insertion of the NovoFine needle under the
74
skin; NovoPen 3 requires manual needle insertion.
75
NovoPen 3 PenMate allows for the NovoFine needle to be completely hidden prior to
76
needle insertion; the needle is visible on the NovoPen 3 prior to needle insertion.
77
78
Look at the diagram inside the front cover for the names of the different parts of
79
NovoPen 3 and NovoPen 3 PenMate. You can unfold the diagram to help you while
80
you follow the instructions.
81
82
83
84
85
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NovoPen 3 PenMate Instruction Manual
Page 7
FDA revision #4 (final)
86
TABLE OF CONTENTS
87
SECTION 1:
88
Assembly of the NovoPen 3 PenMate............................................ 4
89
SECTION 2:
90
Air shot before each injection........................................... 9
91
SECTION 3:
92
Choosing your dose......................................................... 10
93
SECTION 4:
94
Giving the injection......................................................... 12
95
SECTION 5:
96
Mechanical function check of NovoPen 3 PenMate.......... 17
97
SECTION 6:
98
For subsequent injections................................................ 18
99
SECTION 7:
100
What to do when PenFill is nearly empty......................... 19
101
SECTION 8:
102
Changing PenFill............................................................ 20
103
SECTION 9:
104
Function check............................................................... 21
105
IMPORTANT................................................................ 22
106
WHAT TO DO IF.......................................................... 25
107
HOW TO STORE AND LOOK AFTER YOUR
108
NOVOPEN 3 AND YOUR NOVOPEN 3 PENMATE... 27
109
WARRANTY................................................................. 28
110
111
112
113
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NovoPen 3 PenMate Instruction Manual
Page 8
FDA revision #4 (final)
SECTION 1
Assembly of the NovoPen3 PenMate
114
Assembly of the NovoPen 3 PenMate
115
116
1 Take NovoPen 3 out of its case by pressing the top of the pen cap.
117
118
119
2 Gently twist the pen cap until it separates from the barrel.
120
121
3 Pull the pen cap straight up to remove it.
122
123
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NovoPen 3 PenMate Instruction Manual
Page 9
FDA revision #4 (final)
4 Unscrew and remove the PenFill holder from the barrel*
124
125
* See diagram.
126
You will not use the pen cap and PenFill holder with the NovoPen 3 PenMate but you
127
should store them in the case if you want to use NovoPen 3 without NovoPen 3 PenMate
128
in the future.
129
SECTION 1 (cont.)
130
5 The end of the piston rod should be flat against the end of the reset mechanism prior to
131
inserting each new Novolin PenFill 3 mL cartridge. It should not be sticking out.
132
133
If the piston rod is sticking out:
134
Turn the end of the reset mechanism in a clockwise direction until the piston rod is no
135
longer sticking out. Never push the piston rod back in.
136
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NovoPen 3 PenMate Instruction Manual
Page 10
FDA revision #4 (final)
137
Need Help? Call 1-800-727-6500
138
139
You should not reset the piston rod again until it is time to remove the used PenFill 3 mL
140
cartridge and insert a new one.
141
142
If the reset mechanism locks, it is usually due to improper technique. Gently turn the
143
mechanism side to side until it unlocks. Then call our toll free number (1-800-727-6500)
144
so that we may review your operating technique with you.
145
146
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NovoPen 3 PenMate Instruction Manual
Page 11
FDA revision #4 (final)
147
SECTION 1 (cont.)
148
6 Press the push button all the way in until zero (0) appears in the window. The zero
149
should be lined up with the stripe below the dose indicator window.
150
To remove the PenFill cartridge from its wrapper, push the cartridge through the foil
151
side of the packaging.
152
Before use, check that the PenFill cartridge is full and intact. If not, do not use it.
153
154
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NovoPen 3 PenMate Instruction Manual
Page 12
FDA revision #4 (final)
7 If you use Novolin 70/30 [70% NPH, Human Insulin Isophane Suspension and 30%
155
Regular, Human Insulin Injection (recombinant DNA origin)] or Novolin N, NPH
156
[Human Insulin Isophane Suspension (recombinant DNA origin)], mix the insulin:
157
158
a. Turn PenFill cartridge up and down between positions A and B, as shown.
159
b. Repeat this mixing step at least 10 times or until the insulin looks uniformly white
160
and cloudy.
161
162
163
If you use more than one type (N, R, or 70/30) of insulin, use a separate NovoPen 3
164
PenMate for each type.
165
166
Once the cartridge is punctured, it can be used at room temperature for the length of time
167
identified in the storage information section of the Information For The Patient supplied
168
with the PenFill cartridges. The expiration date on the cartridge is for unused cartridges
169
under refrigeration.
170
171
SECTION 1 (cont.)
172
Take the NovoPen 3 PenMate out of its case.
173
Pull off the pen cap and put it to one side.
174
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NovoPen 3 PenMate Instruction Manual
Page 13
FDA revision #4 (final)
Put the PenFill cartridge into the NovoPen 3 PenMate.
175
The threaded plastic cap goes in first.
176
177
8
Tightly screw the barrel of the NovoPen 3 into the NovoPen 3 PenMate.
178
Make sure that the dose indicator window on the mechanical section is aligned with
179
the yellow push button on NovoPen 3 PenMate.
180
181
182
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. There are five
183
cartridges in a box. Make sure you are using the correct type of insulin. The name of
184
the insulin is on the glass part of the cartridge.
185
Each PenFill cartridge is for single-person use only.
186
DO NOT share the cartridge with anyone even if you attach a new disposable needle
187
for each injection. This will prevent the spread of disease.
188
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NovoPen 3 PenMate Instruction Manual
Page 14
FDA revision #4 (final)
Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 PenMate.
189
Never load a partially filled cartridge. Never try to refill a used PenFill 3 mL
190
cartridge.
191
192
SECTION 1 (cont.)
193
9 Clean the front rubber stopper on the PenFill cartridge with an alcohol swab.
194
You must wipe the front rubber stopper with an alcohol swab before each injection, even
195
if you are using the same PenFill cartridge.
196
197
198
10 Remove the protective tab from the NovoFine® disposable needle.
199
Screw the NovoFine needle firmly onto the threaded plastic cap until it is tight.
200
Pull off the outer and inner needle caps.
201
202
For users of Novolin 70/30 or Novolin N insulin: Always remix the insulin before
203
each injection.
204
To remix the insulin, turn the NovoPen 3 PenMate up and down between positions A
205
and B, as on page 4, 10 times or until the insulin looks uniformly white and cloudy.
206
207
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NovoPen 3 PenMate Instruction Manual
Page 15
FDA revision #4 (final)
208
Never place a NovoFine disposable needle on your NovoPen 3 PenMate until you are
209
ready to do an air shot and give an injection. If the NovoFine needle is “left on”,
210
some liquid may leak out of the PenFill cartridge. This may cause a change in the
211
strength of Novolin 70/30 or Novolin N insulin.
212
213
214
SECTION 2
Air shot before each injection
215
216
Air shot before each injection
217
218
11 The PenFill cartridge may contain an air bubble, and small amounts of air may
219
collect in the needle and PenFill cartridge when you use them. To avoid the injection
220
of air and ensure proper dosing, you must perform an air shot prior to each injection.
221
222
§ Check that the dial-a-dose selector is set at zero.
223
§ Dial 2 units. Hold the NovoPen 3 PenMate with the needle upwards and tap
224
gently near the window of NovoPen 3 PenMate with your finger a few times.
225
§ Press the push button at the end of the barrel all the way in.
226
227
A drop of insulin should appear at the needle tip.
228
If not, repeat the procedure until a drop of insulin appears. There may still be some small
229
air bubble(s) in the PenFill cartridge after this, but they will not affect your dose and they
230
will not be injected.
231
232
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you do, the
233
extra insulin will squirt out of the needle. You may complete the air shot with the
234
number of units you have dialed or refer to the instructions on how to reset the dose to
235
zero in step 14.
236
237
238
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NovoPen 3 PenMate Instruction Manual
Page 16
FDA revision #4 (final)
SECTION 3
Choosing your dose
239
240
Choosing your dose
241
242
12 NovoPen 3 PenMate has an insulin scale with marks showing the approximate
243
number of units left in the PenFill cartridge. Always check that there is enough
244
insulin left for the injection. To activate, grip the barrel and the NovoPen 3 PenMate
245
and firmly pull in opposite directions until you hear a click.
246
Important: Do not pull the dial-a-dose selector.
247
Check that the dial-a-dose selector is set at zero. If zero does not appear, follow the
248
instructions on page 11.
249
250
251
13 Dial the number of units you need to inject.
252
The odd numbers are shown as full lines between the even numbers.
253
Do not use the clicking sound as a guide for selecting your dose.
254
255
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NovoPen 3 PenMate Instruction Manual
Page 17
FDA revision #4 (final)
256
257
The NovoPen 3 PenMate can deliver from 2 to 70 units of insulin in one unit increments.
258
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you do,
259
the extra insulin will squirt out of the needle. For instructions on how to reset the dose to
260
zero (0) so you can start again, see the next page.
261
262
SECTION 3 (cont.)
263
14 If you dial a larger dose than you need, you need to reset your NovoPen 3 PenMate to
264
zero.
265
To reset to zero (0) if you set the wrong dose:
266
a. Pull the barrel and the NovoPen 3 PenMate in opposite directions and keep hold
267
of them (see picture).
268
b. Press the push button on the barrel back to zero (0).
269
c. Release your grip and the barrel section will slide back into place.
270
d. You can now dial the correct units of insulin.
271
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NovoPen 3 PenMate Instruction Manual
Page 18
FDA revision #4 (final)
272
273
274
275
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NovoPen 3 PenMate Instruction Manual
Page 19
FDA revision #4 (final)
276
SECTION 4
Giving the injection
277
278
Giving the injection
279
15 Before injecting always check the dose indicator window to make sure you have
280
dialed the correct number of units.
281
After the airshot (see page 9) and choosing your dose, hold the NovoPen 3 PenMate
282
at the correct site on the body for an injection. Use the injection technique
283
recommended by your healthcare professional. The PenMate is designed with a cut-
284
away on one side. This cut-away allows injections at various angles other than 90°.
285
Press the yellow push-button on the NovoPen 3 PenMate with your finger (see arrow
286
in diagram). The needle will automatically enter the skin.
287
288
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NovoPen 3 PenMate Instruction Manual
Page 20
FDA revision #4 (final)
289
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NovoPen 3 PenMate Instruction Manual
Page 21
FDA revision #4 (final)
SECTION 4 (cont.)
290
16 To inject your dose, press the push button of the barrel section as far as it will go.
291
Do not force it (see arrow in diagram).
292
293
After injection, the needle should remain under the skin for several seconds. Keep the
294
push button fully depressed until the needle has been withdrawn from the skin.
295
If there is not enough insulin in the PenFill cartridge for the whole dose, you will be
296
able to see the number of units you still need to inject in the dose indicator window.
297
You must always check this after you have given the injection.
298
299
Important: Never turn the dial-a-dose selector to inject the insulin.
300
301
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NovoPen 3 PenMate Instruction Manual
Page 22
FDA revision #4 (final)
302
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NovoPen 3 PenMate Instruction Manual
Page 23
FDA revision #4 (final)
303
When you press the push button, the piston rod presses against the rear rubber stopper of
304
the cartridge. This moves the rear rubber stopper and pushes the correct amount of
305
insulin out through the needle.
306
307
308
SECTION 4 (cont.)
309
Check that the dose indicator window shows zero. If it does not show zero, you did not
310
receive your full dose.
311
For example: If you dial 25 units and there are only 20 units left in the PenFill cartridge,
312
the number 5 will appear in the window following the injection (25-20=5). If this occurs,
313
proceed with the following steps:
314
To get the remaining part of your dose:
315
a. Note the number of units in the dose indicator window.
316
b. Remove the NovoFine needle (see Section 5).
317
c. Remove the empty Novolin PenFill 3 mL cartridge (see Section 8).
318
d. Insert a new Novolin PenFill 3 mL cartridge (see Section 1).
319
e. Attach a new NovoFine needle (see Section 1).
320
f. Do an air shot (see Section 2).
321
g. Dial the number of units noted in step a.
322
h. Give the injection.
323
324
SECTION 4 (cont.)
325
To make sure that the insulin has been injected, do the following to be certain that
326
the needle advanced and penetrated the skin:
327
§ Check that you can see the control line (solid white line) at the top of the insulin scale
328
(above the number 300).
329
§ Check to see if your skin is wet where you gave the injection.
330
331
If you cannot see the control line after the injection or your skin is wet, see SECTION 5
332
to perform a mechanical function check.
333
334
Call (800) 727-6500 or your healthcare professional if you have any questions.
335
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NovoPen 3 PenMate Instruction Manual
Page 24
FDA revision #4 (final)
336
337
SECTION 4 (cont.)
338
17 After the injection, remove the needle without recapping it. Hold the NovoPen 3
339
PenMate firmly while you unscrew the NovoFine disposable needle. Place the
340
NovoFine disposable needle in a puncture-resistant disposable container.
341
Health care professionals, relatives, and other caregivers should follow precautionary
342
measures for removal and disposal of needles to eliminate the risk of unintended
343
needle penetration.
344
345
346
347
Graphic to be
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NovoPen 3 PenMate Instruction Manual
Page 25
FDA revision #4 (final)
The NovoFine disposable needle must be removed immediately after each injection
348
without recapping. Put the NovoPen 3 PenMate cap back on. If the NovoFine
349
disposable needle is not removed, some liquid may leak out of the PenFill cartridge. This
350
may cause a change in the strength of Novolin 70/30 or Novolin N insulin.
351
For information on how to properly dispose of needle containers, call your local trash
352
disposal authorities.
353
354
SECTION 5
Mechanical function check
355
356
Mechanical function check of NovoPen 3 PenMate
357
18 Hold the NovoPen 3 PenMate with the needle pointing upwards.
358
To activate, grip the barrel and the PenFill holder of the NovoPen 3 PenMate and
359
firmly pull in opposite directions until you hear a click. If you do not hear a click,
360
contact Customer Relations at our toll free number 1-800-727-6500. Never use a
361
NovoPen 3 PenMate unless you are sure that it is working properly.
362
Important: Do not pull the dial-a-dose selector.
363
Check that the dial-a-dose selector is set to zero. If not, press the push button all the
364
way in.
365
366
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NovoPen 3 PenMate Instruction Manual
Page 26
FDA revision #4 (final)
367
19 Push the yellow push button and the needle should appear.
368
You should now be able to see the needle and the control line.
369
If you cannot see the needle, do not use the NovoPen 3 PenMate. Never use the
370
NovoPen 3 PenMate unless you are sure that it is working properly.
371
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NovoPen 3 PenMate Instruction Manual
Page 27
FDA revision #4 (final)
372
Need Help? Call 1-800-727-6500
373
374
SECTION 6
For subsequent injections
375
376
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NovoPen 3 PenMate Instruction Manual
Page 28
FDA revision #4 (final)
For subsequent injections
377
20 Pull off the NovoPen 3 PenMate cap. Check that the needle has been removed
378
since your last injection. Check that NovoPen 3 PenMate contains the type of insulin
379
you want to inject. If the PenFill holder of your NovoPen 3 PenMate contains a clear
380
insulin PenFill cartridge such as Novolin R, follow steps 9 to 17.
381
382
21 If your NovoPen 3 PenMate contains an insulin suspension cartridge, such as Novolin
383
70/30 or Novolin N mix the insulin by turning the device up and down between
384
positions A and B -as shown in the picture. The movement must be performed so that
385
the glass ball in the cartridge moves from one end to the other. Do this at least ten
386
times until the liquid is white and uniformly cloudy.
387
Then continue as shown in steps 9 to15 and inject immediately.
388
389
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NovoPen 3 PenMate Instruction Manual
Page 29
FDA revision #4 (final)
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391
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NovoPen 3 PenMate Instruction Manual
Page 30
FDA revision #4 (final)
393
SECTION 7
What to do when PenFill is nearly empty
394
395
What to do when PenFill is nearly empty
396
22 Do not start to inject an insulin suspension such as Novolin N or Novolin 70/30 if you
397
can see the rubber piston in the small inspection window. The glass ball must have
398
adequate space to resuspend the insulin. With the NovoPen 3 PenMate, it is possible
399
to select a dose that is larger than the number of units left in the PenFill cartridge. If
400
there is not enough insulin in the PenFill cartridge for the whole dose, you will be
401
able to see the number of units you still need to inject in the dose indicator window
402
after the injection.
403
To get the remaining part of your dose refer to Section 4, Page 14, a through h.
404
405
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NovoPen 3 PenMate Instruction Manual
Page 31
FDA revision #4 (final)
407
408
When you get near the end of a PenFill cartridge, you may need to give yourself two
409
injections to receive your full dose. If, after giving an injection, zero does not appear in
410
the dose indicator window, you did not receive your full dose.
411
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NovoPen 3 PenMate Instruction Manual
Page 32
FDA revision #4 (final)
412
SECTION 8
Changing PenFill
413
414
Changing PenFill
415
23 a) Unscrew the barrel from the NovoPen 3 PenMate.
416
b) Press the push button to set the dose indicator to zero.
417
c) Make sure that the piston rod is not out (see Section 1, Page 5). (Twist it gently
418
from side to side, if necessary).
419
420
421
422
423
24 Take out the empty PenFill cartridge. Take a new PenFill cartridge and continue
424
as described from steps 6 and 7.
425
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NovoPen 3 PenMate Instruction Manual
Page 33
FDA revision #4 (final)
426
Need Help? Call 1-800-727-6500
427
428
SECTION 9
Function check
429
430
Function check
431
25 If you think your NovoPen 3 PenMate is not working properly, follow this procedure:
432
a) Check that the barrel and the NovoPen 3 PenMate are screwed together tightly and
433
that the dose indicator window on the barrel is aligned with the yellow push button on
434
the NovoPen 3 PenMate.
435
b) Screw on a new NovoFine needle as described in step10.
436
c) Clear the air bubbles as described in step11.
437
d) Put the outer needle cap over the needle.
438
e) Dispense 20 units into the needle cap.
439
440
The insulin should fill the lower part of the outer needle cap. If the pen has delivered
441
too much or too little insulin, repeat the test. If it happens again, do not use the pen.
442
Contact your supplier.
443
Do not try to repair a faulty NovoPen 3 or a faulty NovoPen 3 PenMate.
444
Never use NovoPen 3 or NovoPen 3 PenMate unless you are sure that they are
445
working properly.
446
447
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NovoPen 3 PenMate Instruction Manual
Page 34
FDA revision #4 (final)
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NovoPen 3 PenMate Instruction Manual
Page 35
FDA revision #4 (final)
IMPORTANT
449
§ Keep the NovoPen 3 PenMate away from areas where temperatures may get too hot
450
or too cold such as a car or refrigerator.
451
§ Once the cartridge is punctured, it can be kept at room temperature for the length of
452
time identified in the storage information section of the Information For The Patient
453
supplied with the PenFill cartridges.
454
§ Make sure that the piston rod is completely inside the reset mechanism before you
455
screw together the barrel and the NovoPen 3 PenMate. (see step 5).
456
§ Always screw the mechanical section of NovoPen 3 and NovoPen 3 PenMate tightly
457
together.
458
§ Before each injection, make sure that you are using the right insulin preparation.
459
§ Always clear air bubbles with the needle pointing upwards before each injection (see
460
step 11).
461
§ With the NovoPen 3 PenMate, it is possible to select a dose which is larger than the
462
number of units left in the PenFill cartridge. Before you inject, always check on the
463
insulin scale that there is enough insulin left in the PenFill cartridge for your dose.
464
After the injection, always make sure that you have injected the whole dose by
465
checking that the dose indicator window reads 0. If not, see step 22.
466
§ Do not use the insulin scale on the NovoPen 3 PenMate to measure the amount of
467
insulin to be injected.
468
§ Before injecting, always check the dose indicator window to make sure you have
469
dialed the correct number of units.
470
§ After injecting, make sure that NovoPen 3 PenMate was released and that the insulin
471
has been injected (see step16).
472
§ Take the needle off the NovoPen 3 PenMate immediately after each injection. If
473
you do not remove it, temperature changes may cause liquid to leak out of the
474
needle. With Novolin N or Novolin 70/30, this may change the concentration of
475
the insulin.
476
§ Do not inject Novolin N or Novolin 70/30 if the rear rubber stopper can be seen in the
477
small inspection window.
478
§ Always have extra insulin of the same type(s) you use available for alternative
479
administration in case your NovoPen 3 PenMate, NovoPen 3, or PenFill gets lost or
480
damaged.
481
482
IMPORTANT (cont.)
483
§ Keep NovoPen 3 PenMate, NovoPen 3, PenFill, and NovoFine out of reach of
484
children.
485
§ Your NovoPen 3 and NovoPen 3 PenMate are for use by the same person only.
486
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NovoPen 3 PenMate Instruction Manual
Page 36
FDA revision #4 (final)
§ The NovoPen 3 PenMate is not recommended for the blind or visually impaired,
487
without the assistance of a sighted individual who knows how to use NovoPen 3
488
PenMate.
489
§ If you use more than one type (N, R, or 70/30) of insulin, use a separate NovoPen 3
490
PenMate for each type of insulin.
491
§ The American Diabetes Association recommends that insulin should be self-
492
administered. The proper age for initiating this should be assessed by the adult
493
caregiver.
494
§ Use only a new PenFill cartridge when loading the NovoPen 3 PenMate. Never load
495
the NovoPen 3 PenMate with a partially filled PenFill cartridge.
496
§ The NovoPen 3 PenMate is designed for use with PenFill 3 mL insulin cartridges and
497
NovoFine single-use disposable needles.
498
§ Novo Nordisk is not responsible for any consequences arising from the use of the
499
NovoPen 3 PenMate with products that are not recommended by Novo Nordisk.
500
IMPORTANT (cont.)
501
Guidelines for storing the NovoPen 3 PenMate and PenFill 3 mL cartridges:
502
§
Store the NovoPen 3 PenMate (with the PenFill cartridge inside) at room
503
temperature. Do not store the NovoPen 3 PenMate in a refrigerator or areas where
504
there may be extreme temperatures or moisture, such as your car. Once the cartridge
505
is punctured, it can be kept at room temperature for the length of time identified in
506
the storage information section of the Information For The Patient supplied with the
507
PenFill cartridges.
508
§
Store the NovoPen 3 PenMate without the NovoFine needle attached and with the
509
pen cap in position. Leaving the needle on can cause the insulin to leak. This will
510
affect the concentration of an insulin suspension.
511
§
For information on storing PenFill cartridges, see the package insert that comes in
512
the PenFill cartridge box. Once the cartridge is punctured, it can be kept at room
513
temperature for the length of time identified in the storage information section of the
514
Information For The Patient supplied with the PenFill cartridges. The expiration
515
date on the cartridge is for unused cartridges under refrigeration.
516
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NovoPen 3 PenMate Instruction Manual
Page 37
FDA revision #4 (final)
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518
WHAT TO DO IF ...
519
Here are the answers to some questions you might need to ask when using your NovoPen
520
3 PenMate.
521
No insulin appears when I try to clear the air bubbles.
522
Check that your NovoPen 3 PenMatewas put together correctly when you changed the
523
PenFill cartridge. Make sure that the piston rod is completely inside the reset mechanism.
524
Also make sure that the barrel and the NovoPen 3 PenMate are screwed tightly together
525
(see steps 5 and 25).
526
No insulin appears when I try to clear the air bubbles and the push button will not
527
go in.
528
The needle may be blocked. Change the needle and repeat air shots until insulin appears
529
at the needle tip. Check if the PenFill cartridge is empty.
530
531
The push button will not depress during the injection.
532
533
Do not try to force the push button down. Check if the PenFill cartridge is empty.
534
If there was not enough insulin in PenFill cartridge for the whole dose, you will see the
535
number of units you still need to inject in the dose indicator window. Make a note of this.
536
Change the PenFill cartridge and continue as described from step 23.
537
538
539
540
541
542
WHAT TO DO IF ... (cont.)
543
I cannot press the push button back to zero before I return the piston rod.
544
The reset mechanism may be locked. Gently twist the reset mechanism from side to side
545
until it unlocks. See the picture in step 5. Then you can press the push button down to
546
zero. Never turn the dosage selector back.
547
I cannot get the piston rod back inside the reset mechanism when I change the
548
PenFill cartridge.
549
The reset mechanism may be locked. Gently twist the reset mechanism from side to side
550
until it unlocks. Then turn the reset mechanism to the right until the piston rod is
551
completely inside it. See the picture in step 5.
552
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NovoPen 3 PenMate Instruction Manual
Page 38
FDA revision #4 (final)
553
I think the needle has not entered the skin.
554
Check that you can see the control line at the top of the insulin scale.
555
Also check if your skin is wet at the injection site. Carry out the mechanical function
556
check as described in steps 18 and 19.
557
I think my NovoPen 3 or my NovoPen 3 PenMate is not working properly.
558
Carry out the function check described in step 25. Make sure that the lower part of the
559
outer needle cap is filled with 20 units of insulin. Also carry out the mechanical function
560
check as described in steps18 and 19. Make sure that the control line is visible when
561
NovoPen 3 PenMate is released. Never use your NovoPen 3 or your NovoPen 3 PenMate
562
unless you are sure that they are working properly.
563
564
MAINTENANCE
565
566
How to store and look after your NovoPen 3 and your NovoPen 3 PenMate
567
NovoPen 3 and NovoPen 3 PenMate are designed to work accurately. They should be
568
handled with care. Avoid situations where your NovoPen 3 and NovoPen 3 PenMate can
569
be damaged. Do not drop. Do not expose to excessive pressure or blows. Keep them in
570
the soft case whenever possible.
571
572
You can put PenFill cartridges in NovoPen 3 PenMate or carry them with you as spares.
573
Please read the Information For The Patient supplied with the PenFill cartridges
574
for details of how to store the cartridges and how long to keep them.
575
576
You can clean your NovoPen 3 and your NovoPen 3 PenMate by wiping them with a
577
cotton swab moistened with ethyl or isopropyl alcohol.
578
579
Your NovoPen 3 and your NovoPen 3 PenMate are sturdy products but could still get
580
damaged. So handle them with care and protect them against dust and dirt when they are
581
not carried in the case.
582
583
Do not try to repair a faulty NovoPen 3 or a faulty NovoPen 3 PenMate.
584
585
NovoPen 3 and NovoPen 3 PenMate must only be used in the way described in this
586
booklet. The manufacturer will not be responsible for any problems you have with the
587
equipment if you have not followed this booklet. If you find your NovoPen 3 or your
588
NovoPen 3 PenMate faulty, Novo Nordisk will replace it if:
589
§ You call Novo Nordisk Pharmaceuticals, Inc. at our toll free number 1-800-727-6500
590
within three years of getting it.
591
592
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NovoPen 3 PenMate Instruction Manual
Page 39
FDA revision #4 (final)
WARRANTY
593
594
Should your NovoPen 3 PenMate device be defective in materials or workmanship within
595
three (3) years of purchase, Novo Nordisk Pharmaceuticals, Inc., will replace it at no
596
charge if you mail the defective unit along with a description of the problem and the sales
597
receipt or other proof of purchase to:
598
599
Novo Nordisk Pharmaceuticals, Inc.
600
Customer Relations
601
100 College Road West
602
Princeton, New Jersey 08540-7810.
603
604
No other warranty is made with respect to NovoPen 3 PenMate. The mechanical section
605
of the NovoPen 3 insulin pen is covered by its own separate warranty. which is described
606
in its instruction manual. This warranty will be invalid and Novo Nordisk A/S, Novo
607
Nordisk Pharmaceuticals, Inc., Bristol-Myers Squibb Co., Nipro Medial Industries Ltd.,
608
and Bang & Olufsen A/S cannot beheld responsible in the case of defects or damages
609
arising from:
610
611
§ The use of the NovoPen 3 PenMate with products other than NovoPen 3, PenFill 3 mL
612
cartridges, and NovoFine single-use disposable needles.
613
614
§ The use of the NovoPen 3 PenMate not in accordance with the instructions in this
615
booklet.
616
617
§ Physical damage to the NovoPen 3 PenMate caused by neglect, misuse, unauthorized
618
repair, accident, or other breakage.
619
620
Use of the NovoPen 3 PenMate does not extend the warranty of the NovoPen 3 insulin
621
pen.
622
623
For assistance or further information, write to:
624
Novo Nordisk Pharmaceuticals, Inc.
625
Customer Relations
626
100 College Road West
627
Princeton, NJ 08540-7810
628
629
Or call: 1-800-727-6500
630
631
License under U.S. Patents Nos. 5,462,535; 5,693,02; 5,626,566 and Des. 347,894
632
(cartridge) restricted to use with Novo Nordisk insulin cartridges and Novo Nordisk pen
633
needles.
634
635
Novolin®, NovoPen®, PenFill®, NovoPen® 3 PenMate®, and NovoFine® are
636
trademarks owned by Novo Nordisk A/S.
637
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NovoPen 3 PenMate Instruction Manual
Page 40
FDA revision #4 (final)
638
2002 Novo Nordisk Pharmaceuticals, Inc.
639
640
www.novonordisk-us.com
641
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---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
David Orloff
3/11/02 05:06:34 PM
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| custom-source | 2025-02-12T13:43:22.507522 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19-938S30lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 30} |
1,821 |
Novopen Illustration
Introduction
Read the Patient Instructions for Use that comes with NovoPen
4 before you start using it and each time you get a refill. There
may be new information. This leaflet does not take the place of
talking with your healthcare provider about your medical
condition or your treatment.
NovoPen 4 is an insulin pen that can deliver insulin doses from 1
to 60 units, in increments of 1 unit. NovoPen 4 is designed to be
used with PenFill 3 mL insulin cartridges and NovoFine
disposable needles.
NovoFine disposable needles are for one time use only.
You should read the instructions in this manual even if you have
used NovoPen 4 or other Novo Nordisk delivery systems before.
NovoPen 4 should not be used by people who are blind or have
visual problems without the help of a person who has good
eyesight and who is trained to use the NovoPen 4 the right way.
Getting Ready
Make sure you have the following items:
• NovoPen 4
• alcohol swabs
• PenFill 3 mL insulin cartridge
• NovoFine disposable needle Novopen Illustration
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Usage Illustration
Preparing your NovoPen 4
Before you start to prepare your injection, check the label to
make sure that you are taking the right type of insulin (such as
Novolin R, Novolin N, Novolin 70/30, or NovoLog).
A. Pull off the cap. See Figure A.
B. Unscrew and remove the cartridge holder from the
mechanical part. See Figure B.
C. Push in the piston rod, by gently pressing the piston rod head
(see Figure C1) in until it stops and looks like Figure C2.
Please note when NovoPen 4 is apart while removing the PenFill
cartridge, the piston rod can move back and forth without
pressing it.
If you use more than one kind of insulin, you should use a
separate delivery device for each product. Usage Illustration
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D. Use a new PenFill cartridge.
To remove the PenFill cartridge from its wrapper, push the
cartridge through the foil side of the packaging (see Figure D1).
Before use, check that the PenFill cartridge is full and intact and
with no cracks. If not, do not use it.
How to prepare (resuspend) the insulin if the PenFill cartridge
contains an insulin suspension (white and cloudy insulin) such
as Novolin 70/30 or Novolin N you must:
Before inserting a 3 mL cartridge into your NovoPen 4 for
the first time:,
o Roll the PenFill cartridge between your hands 10 times.
These steps should be done with the 3 mL PenFill
cartridge in a flat (horizontal) position (see Figure D2)
o Then turn the PenFill cartridge up and down between
positions A and B (see Figure D3) so the glass ball
moves from one end of the cartridge to the other. Do
this at least 10 times. Repeat the rolling and turning
steps until the insulin looks white and cloudy. Mixing is
easier when the insulin is at room temperature.
After the first use of the 3 mL PenFill cartridge
o With the cartridge in the NovoPen 4, turn it upside
down between positions A and B (see Figure D3
above), so that the glass ball moves from one end of
the 3 mL PenFill cartridge to the other. Do this until all
of the insulin looks white and cloudy.
o Before you inject your insulin:
make sure there is at least 12 units of insulin left in
the cartridge this helps to make sure that the
remaining insulin is evenly mixed. If there is less
than 12 units left in the cartridge, use a new 3 mL
PenFill cartridge. Usage Illustration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Each PenFill 3 mL cartridge contains a total of 300 units of
insulin. There are five cartridges in a box. Each PenFill cartridge
is for only one person to use.
DO NOT share your NovoPen 4 with other people even if they
have diabetes. Sharing the PenFill cartridge can spread
disease.
Use only a new PenFill 3 mL cartridge when loading the
NovoPen 4. Never load a partially filled PenFill cartridge. Never
try to refill a used PenFill 3 mL cartridge.
E. Insert the PenFill cartridge into the cartridge holder, colored
cap first. See Figure E.
You can see the PenFill cartridge scale in the cartridge window.
The cartridge holder has a scale with marks showing about how
much insulin is left in the PenFill cartridge.
F. Screw the mechanical part together with the cartridge holder
until you hear or feel a click. See Figure F1.
Before each injection, check the amount of insulin left in the
PenFill cartridge:
If the rear rubber stopper cannot be seen in the cartridge
window, you have enough insulin for mixing left in the PenFill
cartridge. See Figure F2.
If the rear rubber stopper can be seen in the cartridge holder
window, you do not have enough insulin left in the PenFill
cartridge and must use a new PenFill 3 mL cartridge. Usage Illustration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Wipe the rubber stopper with an alcohol swab. See Figure F3.
G. Remove the protective tab from a NovoFine disposable
needle. Screw the needle tightly onto the colored cap. See
Figure G.
Always use a new NovoFine disposable needle for each
injection.
Never place a NovoFine disposable needle on your NovoPen 4
until you are ready to do an air shot and take your injection.
H. Pull off the outer needle cap. Carefully pull off the inner
needle cap and throw it away. See Figure H1. A droplet of
insulin may appear at the needle tip. This is normal.
Do not bend or damage the needle. To lessen the risk of
unexpected needle sticks, never put the inner needle cap back
on the needle.
Always take off the needle after each injection and store the
NovoPen 4 without a needle attached. This prevents
contamination, infection, leakage of insulin, and will ensure
accurate dosing.
Do an “Air Shot” before each injection
Before each injection a small amount of air may collect in the
PenFill cartridge. To avoid injecting air and ensure proper
dosing, you must do an air shot before each injection.
Before starting the air shot, the dose indicator window must
show zero (0) see Figure H2.
Set the NovoPen 4 for the air shot: Usage IllustrationUsage IllustrationUsage Illustration
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I. Make sure that a NovoFine disposable needle is attached.
See Figure I.
J. Pull out the dose button, if it is not already pulled out. See
Figure J.
K. Turn the dose button to select:
4 units with a new PenFill cartridge. 4 units are selected
when the number 4 lines up with the dose indicator. See
Figure K.
OR
1 unit with a cartridge already in use. 1 unit is selected
when the number 1 lines up with the dose indicator. See
Figure K.
1 increment is equal to 1 unit.
The even numbers are shown. The odd numbers are indicated
by the lines between the even numbers.
L. Hold your NovoPen 4 with the needle pointing up.
Tap the PenFill cartridge holder gently with your finger a few
times to make any air bubbles collect at the top of the cartridge.
See Figure L. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
M. Keep the needle pointing up, press the dose button all the
way in, until you hear or feel a click. The display will return to 0.
A drop of insulin must appear at the needle tip. See Figure M. If
you do not see a drop of insulin at the needle tip, repeat steps I
to L until you see a drop of insulin at the needle tip. You may
need to do this up to 6 times. If you do not see a drop of insulin
after 6 times, do not use the NovoPen 4 and call Novo Nordisk
at 1-800-727-6500.
It is very important that a drop of insulin is seen at the needle tip
before you take your injection. This will ensure accurate dosing.
A small air bubble may remain in the PenFill cartridge. This is
normal it will not affect your dose and will not be injected.
Select your dose
Be sure to do an air shot before giving an injection.
N. Pull out the dose button, if it is not already pulled out. See
Figure N.
O. Turn the dose button to the number of units you need to
inject. The pointer should line up with your dose that is needed.
Remember that 60 units is the maximum dose you can take in
one injection. See Figure O.
If you select a different dose than you need, turn the dose button
until the correct dose lines up with the dose indicator.
If you need more than 60 units, you must divide your dose into
two injections. Inject the 60 units first and then make a new
injection with the remaining number of units needed to complete
your dose. For example, to inject 65 units you must inject 60
units first and then make a new injection with 5 units of insulin to
complete your dose. Always use a new disposable needle for
each injection. See Figure O.
Give your injection
Give the injection exactly as shown to you by your healthcare
provider.
P. Insert the needle into your skin. Inject the dose by pressing
the dose button all the way in, until you hear or feel a click.
Check the dose indicator window to make sure it shows zero (0).
See Figure P. Usage IllustrationUsage Illustration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Q. Keep the NovoFine needle in the skin for at least 6 seconds.
See Figure Q
This will make sure that the full insulin dose has is given.
Be careful only to press the dose button to inject the insulin.
Turning the dose button will not inject insulin.
R. Take the needle out of your skin. You have completed your
injection and the selected insulin dose has been given. The
display will show 0. If zero (0) does not appear, you did not get
the full dose. See Figure R.
After you take the needle out of your skin, you may see a few
drops of insulin at the needle tip. This is normal and has no
effect on the dose you just received.
If your injection is given by another person, this person must be
careful when removing and disposing of needles to prevent
accidental needle stick injury.
After the injection
The NovoFine disposable needle must be removed immediately
after each injection without replacing the cap.
Do not recap the needle. Recapping can lead to a needle stick
injury. Remove the needle from the NovoPen 4 after each
injection. This helps to prevent infection, leakage of insulin, and
will help to make sure you inject the right dose of insulin.
S. Carefully remove the needle (see Figure S), put the needle
and any empty PenFill cartridge in a sharps container, or some
type of hard plastic or metal container with a screw top such as a
detergent bottle or empty coffee can. These containers should
be sealed and thrown away the right way. Check with your
healthcare provider about the right way to throw away used
needles and syringes. There may be local or state laws about
how to throw away used needles. Do not throw away used
needles in household trash or recycling bins.
Always replace the pen cap after each use.
Put the pen cap on the NovoPen 4 and store the NovoPen 4
without the needle attached. This helps to ensure sterility,
prevent leakage of insulin, and will help to make sure you inject
the right dose of insulin with your next injection. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Change the PenFill cartridge
When the PenFill cartridge is almost empty:
T. The cartridge scale on the PenFill cartridge holder shows the
approximate number of insulin units left in the PenFill cartridge
as in Figure A. Do not use the cartridge scale to measure the
amount of insulin to be injected. See Figure T.
U. If the PenFill cartridge has less than 60 units in it, the exact
number of units left can be read in the display. To do this, pull
out the dose button, if it is not already pulled out, and turn it until
it stops. The number of units left will line up with the dose
indicator as seen in Figure B. If the dose indicator is positioned
between two lines, adjust to the lower of the two dose amounts.
You can not select a dose larger than the number of units left in
the PenFill cartridge. See Figure U.
Do not force the dose button to turn as this can damage your
NovoPen 4.
Insulin suspension (white and cloudy insulin):
V. Do not try to inject an insulin suspension (white and cloudy
insulin) if the rubber stopper (plunger) is below the white line on
the holder as in Figure V. The glass ball inside the PenFill
cartridge must have enough space to mix the insulin.
If you need more insulin than the amount left in the PenFill
cartridge, you can:
Inject the amount of insulin left in the PenFill cartridge,
making a note of the number of units you inject or replace the
used PenFill cartridge with a new one for your full dose.
To change the PenFill cartridge see Figure T to U.
Always attach a new NovoFine needle.
Do an airshot as described in Figure I to M.
Select and inject the number of insulin units needed to
complete your dose.
Storage
Storage and handling
Be careful when handling your NovoPen 4, do not drop it and
avoid knocking it against hard surfaces.
Always remove the needle and replace the pen cap after each
use. Usage IllustrationUsage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Protect your NovoPen 4 against direct sunlight, water, dust and
dirt.
When a PenFill cartridge is inserted in the NovoPen 4, store
your NovoPen 4 at 59oF to 86°F (15oC to 30°C) for the amount
of days listed in the PenFill “Information for the Patient” leaflet
for the type of insulin you are using.
The expiration date printed on the PenFill cartridge is for
unused PenFill cartridges stored in the refrigerator. Never use
the PenFill cartridge after the expiration date on the PenFill
cartridge or on the box.
For information on storing PenFill cartridges, see the
Information For The Patient leaflet that comes in the PenFill
cartridge box.
Keep your NovoPen 4 in the case supplied when possible.
Maintenance
Cleaning and maintenance
You can clean the outside of your NovoPen 4 by wiping it with
a damp cloth.
Do not soak in water, wash or lubricate your NovoPen 4, this
may damage it.
Clean off dirt and dust with a dry cloth.
Important Things to Know
Always keep a spare insulin delivery system in case your
NovoPen 4 is lost or damaged.
Keep your NovoPen 4, PenFill cartridges, and NovoFine
needles out of the reach of children.
Keep the NovoPen 4 away from areas where temperatures
may get too hot or too cold such as a car or refrigerator.
Use a separate insulin delivery device if you are using more
than one type of insulin in PenFill cartridges.
Novo Nordisk is not responsible for harm due to using the
NovoPen 4 with products other than PenFill 3 mL insulin
cartridges, and NovoFine single use disposable needles.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Warranty
Do not try to repair a faulty NovoPen 4.
If you think your NovoPen 4 is not working the right way, contact
Novo Nordisk at 1-800-727-6500.
The LOT number of your NovoPen 4 it is located on the
mechanical part as illustrated in the inside cover.
For assistance or further information, write to:
Novo Nordisk Inc.
Customer Care
100 College Road West
Princeton, NJ 08540
Or call: 1-800-727-6500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Quick Guide Usage Illustration
Preparing NovoPen 4
Pull off the cap. Unscrew and remove the cartridge holder from
the mechanical part. See Figure 1.
Push in the piston rod, by pressing the piston rod head in until it
stops and looks like Figure 2.
If you are using an insulin suspension (white and cloudy insulin),
always mix (resuspend) it before use. See the NovoPen 4
Instruction Manual for details on how to mix (resuspend) the
insulin.
Insert the PenFill cartridge into the cartridge holder, the color-
coded cap goes in first. See Figure 3. Usage Illustration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Screw NovoPen 4 together (see Figure 4).
Wipe the front rubber stopper with an alcohol swab and screw
on a new NovoFine disposable needle. Pull off the outer and
inner needle caps. Dispose of the needle caps. See Figure 5.
Do an “Air Shot” before each injection
Always do an airshot before each injection.
Pull out the dose button, if it is not already pulled out, and turn it
to select: See Figure 6.
4 units with a new PenFill cartridge
OR
1 unit with a cartridge already in use
Hold your NovoPen 4 with the needle facing upwards.
Tap the cartridge holder gently with your finger a few times to
make any air bubbles collect at the top of the cartridge. See
Figure 7.
Press the dose button all the way in, until you hear or feel a
click. The display will return to (0) See Figure 8. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A drop of insulin must appear at the needle tip. See Figure 9.
If you do not see a drop of insulin, repeat steps in Figures 5 to 7
until you see a drop of insulin. You may need to do this up to 6
times. If you do not see a drop of insulin after 6 times, do not
use the NovoPen 4 and call Novo Nordisk at 1-800-727-6500.
Select your dose
Pull out the dose button, if it is not already pulled out, and turn
the dose button until your needed dose lines up with the dose
indicator. See Figure 10.
If you select a different dose than you need, turn the dose button
until the correct dose lines up with the dose indicator.
Give your injection
Give the injection exactly as shown to you by your healthcare
provider.
To inject, press the dose button completely in, until you hear or
feel a click. Turning the dose button will not inject insulin.
Leave the needle under the skin for at least 6 seconds. See
Figure 11. Take the needle out of your skin, your selected dose
has been given. Remove and dispose of the needle (follow the
detailed instructions in the NovoPen 4 Instruction Manual).
Put the pen cap back on. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Front of carton:
List: XXXXXX
NovoPen® 4
Dial-A-Dose
Insulin Delivery Pen
CONTAINS ONE NOVOPEN 4
Designed for use with PenFill 3 mL cartridges and NovoFine disposable needles
Side Flap of Carton:
NovoPen® 4
Dial-A-Dose
Insulin Delivery Pen
List: XXXXXXX
Lot
Side Flap of Carton:
NovoPen 4
Dial-A-Dose
Insulin Delivery Pen
Convenient Carrying Case Enclosed
The NovoPen 4 is designed for use with PenFill 3 mL cartridges and NovoFine
disposable needles.
Needles and cartridges not included.
Back of Carton:
For information contact:
Novo Nordisk Inc.
Princeton, NJ 08540
www.novonordisk-us.com
Manufactured in Denmark by Novo Nordisk A/S
2880 Bagvaerd, Denmark
NovoPen 4 is covered under US Patent No. 5,693,027, US
Patent No. 6,663,602, US Patent No. 7,241,278, and other patents pending.
Novo Nordisk, NovoPen, NovoFine, NovoLog, PenFill, and Novolin are registered
trademarks of Novo Nordisk A/S.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:22.589838 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019938s064,019959s067,019991s068,020986s055lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 64} |
1,820 |
R HUMAN
Novo Nordisk®
Patient Information for Novolin® R
NOVOLIN® R (NO-voe-lin)
Regular,
Human Insulin Injection
(recombinant DNA origin) USP
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information leaflet that comes with Novolin R before you start taking it
and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin R?
Novolin R is a man-made insulin (recombinant DNA origin) that is structurally identical
to the insulin produced by the human pancreas that is used control high blood sugar in
patients with diabetes mellitus.
Who should not use Novolin R?
Do not take Novolin R if:
• Your blood sugar is too low (hypoglycemia)
• You are allergic to anything in Novolin R. See the end of this leaflet for a
complete list of ingredients in Novolin R. Check with your healthcare provider if
you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin R.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin R has not been studied in pregnant or nursing women.
• about all of the medicines you take, including prescription and non
prescription medicines, vitamins and herbal supplements. Many medicines can
affect your blood sugar levels and your insulin needs. Your Novolin R dose may
need to change if you take other medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin R?
Only use Novolin R if it appears clear and colorless. There may be air bubbles. This is
normal. If it looks cloudy, thickened, or colored, or if it contains solid particles do not
use it, and call Novo Nordisk at 1-800-727-6500.
Novolin R comes in:
• 10 mL vials (small bottles) for use with syringe
• 3 mL PenFill® cartridges for use with Novo Nordisk insulin delivery devices that
work with the 3 mL PenFill cartridge and NovoFine® disposable needles. The
cartridge delivery device can be used with a NovoPen® 3 PenMate®.
• 3 mL InnoLet® prefilled insulin syringe
Read the instructions for use that come with your Novolin R product. Talk to your
healthcare provider if you have any questions. Your healthcare provider should show
you how to inject Novolin R before you start taking it. Follow your healthcare provider’s
instructions to make changes to your insulin dose.
• Take Novolin R exactly as prescribed.
• Novolin R is a fast-acting insulin. The effects of Novolin R start working ½
hour after injection.
• The greatest blood sugar lowering effect is between 2½ and 5 hours after the
injection. This blood sugar lowering lasts for 8 hours.
• While using Novolin R you may have to change your total dose of insulin,
your dose of longer-acting insulin, or the number of injections of longer-acting
insulin you use.
• Do not mix Novolin R with any insulins other than NPH in the same syringe.
• Inject Novolin R into the skin of your stomach area, upper arms, buttocks
or upper legs. Novolin R may affect your blood sugar levels sooner if you inject
it into the skin of your stomach area. Never inject Novolin R into a vein or into
a muscle.
• Due to risk of precipitation in some pump catheters, Novolin R is not
recommended for use in insulin pumps.
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
each injection.
• If you take too much Novolin R, your blood sugar may fall low
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin R?”
for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin R, your blood sugar may go too
high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can
lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin R?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin R.
• Driving and operating machinery. You may have difficulty concentrating or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin R?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentration or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin R and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin R. Ask your healthcare
provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store Novolin R?
All Unopened Novolin R:
• Keep all unopened Novolin R in the refrigerator between 36° to 46°F
(2° to 8°C).
• Do not freeze. Do not use Novolin R if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet
prefilled syringe may be kept at room temperature for up to 28 days, as
long as it is kept at or below 86°F (30°C).
• Keep unopened Novolin R in the carton to protect from light.
Novolin R in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin
R label, if the medicine has been stored in a refrigerator.
PenFill Cartridges
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store a PenFill cartridge that you are using in the
refrigerator.
• Keep PenFill cartridges away from direct heat or light.
• Throw away a used PenFill cartridge after 28 days, even if there is
insulin left in the cartridge.
InnoLet prefilled syringe
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store an InnoLet prefilled syringe that you are using in the
refrigerator.
• Keep InnoLet prefilled syringes away from direct heat or light.
• Throw away a used InnoLet prefilled syringe after 28 days, even if
there is insulin left in the prefilled syringe.
General advice about Novolin R
Novolin R is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin R for a condition for which it was not prescribed. Do not give Novolin R to other
people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin R. If you would
like more information about Novolin R or diabetes, talk with your healthcare provider.
For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street Alexandria, VA 22311 and on
www.diabetes.org.
Novolin R ingredients include:
• Regular Human Insulin Injection
• Metacresol
(recombinant DNA origin) USP
• Zinc chloride
• Glycerol
• Sodium hydroxide
• Hydrochloric acid
• Water for injections
All Novolin R vials, PenFill cartridges, and InnoLet disposable prefilled syringes are
latex-free.
Date of issue: Month, Year
Version: x
Novolin®, PenFill®, NovoFine®, NovoPen®, PenMate®, and InnoLet® are trademarks of
Novo Nordisk A/S.
PenFill® Cartridges are protected by US Patent Nos.: 5,693,027, 6,126,646, and
D347,894
InnoLet® prefilled syringe is protected by US Patent Nos. 5,9479,234, 6,074,372,
6,582,404 and other patents pending.
© 200x-200x Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® R 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin R vial?
1. Check to make sure that you have the correct type of insulin. This is especially important
if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be clear and colorless. The tamper-
resistant cap should be in place before the first use. If the cap had been removed before
your first use of the vial, or if the insulin is cloudy, colored, or contains any particles, do
not use it and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your healthcare provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Do not roll or shake the vial. Shaking right before the dose is drawn into the syringe may
cause bubbles or froth. This can cause you to draw up the wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond the correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin R in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the pinched skin.
Press the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin R at the needle
tip. This is normal and has no effect on the dose you just received. If you see blood after
you take the needle out of your skin, press the injection site lightly with a piece of gauze
or an alcohol wipe. Do not rub the area.
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
How should I mix Novolin R with NPH insulin?
Different insulins should be mixed only under instruction from a healthcare provider. Do not
mix Novolin R with any other type of insulin besides NPH insulin. Novolin R should be
mixed only when injections with syringes are used. Insulin syringes may vary in the amount of
space between the bottom line and the needle (“dead space”), so if you are mixing two types of
insulin be sure to discuss any change in the model and brand of syringe you are using with your
healthcare provider. Novolin R can be mixed with NPH insulin right before use. When you are
mixing Novolin R insulin with NPH insulin, always draw the Novolin R (clear) insulin into the
syringe first.
1. Add together the doses (total number of units) of NPH and Novolin R that you need to
inject. The total dose will determine the final amount (volume) in the syringe after
drawing up both insulins into the syringe. For example, if you need 5 units of NPH and 2
units of Novolin R, the total dose of insulin in the syringe would be 7 units.
2. Roll the NPH vial between your hands until the liquid is equally cloudy throughout.
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air into the
NPH vial and then remove the needle from the vial but do not withdraw any of the NPH
insulin. (Transferring NPH to the Novolin R vial will contaminate the Novolin R vial
and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the Novolin R dose. Inject this air into
the Novolin R vial. With the needle in place, turn the vial upside down and withdraw the
correct dose of Novolin R. The tip of the needle must be in the Novolin R to get the full
dose and not an air dose.
5. After withdrawing the needle from the Novolin R vial, insert the needle into the NPH
vial. Turn the NPH vial upside down with the syringe and needle still in it. Withdraw the
correct dose of NPH.
6. Inject right away to avoid changes in how quickly the insulin works.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
N HUMAN
Novo Nordisk®
Patient Information for Novolin® N
NOVOLIN® N (NO-voe-lin)
NPH,
Human Insulin Isophane Suspension Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information that comes with Novolin N before you start taking it and
each time you get a refill. There may be new information. This leaflet does not take the
place of talking with your healthcare provider about your diabetes or your treatment.
Make sure you know how to manage your diabetes. Ask your healthcare provider if you
have any questions about managing your diabetes.
What is Novolin N?
Novolin N is a man-made insulin (recombinant DNA origin) NPH, Human Insulin
Isophane Suspension that is structurally identical to the insulin produced by the human
pancreas that is used control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin N?
Do not take Novolin N if:
• Your blood sugar is too low (hypoglycemia)
• You are allergic to anything in Novolin N. See the end of this leaflet for a
complete list of ingredients in Novolin N. Check with your healthcare provider if
you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin N.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin N has not been studied in pregnant or nursing women.
• about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
blood sugar levels and your insulin needs. Your Novolin N dose may need to
change if you take other medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin N?
Only use Novolin N if it appears cloudy or milky. There may be air bubbles. This is
normal. If the precipitate (the white deposit at the bottom of the vial) has become lumpy
or granular in appearance or has formed a deposit of solid particles on the wall of the
vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not be
used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin N comes in:
• 10 mL vials (small bottles) for use with syringe
• 3 mL PenFill® cartridges for use with Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery devices, and NovoFine® disposable needles. The
cartridge delivery device can be used with a NovoPen® 3 PenMate®
• 3 mL InnoLet® prefilled insulin syringe
Read the instructions for use that come with your Novolin N product. Talk to
your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject Novolin N before you start taking it. Follow your
healthcare provider’s instructions to make changes to your insulin dose.
• Take Novolin N exactly as prescribed.
• Novolin N is an intermediate-acting insulin. The effects of Novolin N start
working 1½ hours after injection.
• The greatest blood sugar lowering effect is between 4 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
• While using Novolin N, any change of insulin should be made cautiously and
only under medical supervision. Doses of oral anti-diabetic medicines may also
need to change, if your insulin is changed.
• Do not mix Novolin N with any insulins other than Regular human insulin in the
same syringe.
• Inject Novolin N into the skin of your stomach area, upper arms, buttocks
or upper legs. Novolin N may affect your blood sugar levels sooner if you inject
it into the skin of your stomach area. Never inject Novolin N into a vein or into
a muscle.
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
each injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you take too much Novolin N, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin N?”
for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin N, your blood sugar may go too
high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can
lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin N?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin N.
• Driving and operating machinery. You may have difficulty concentrating or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
you often have:
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin N?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentration or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin N and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin N. Ask your healthcare
provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
to FDA at 1-800-FDA-1088.
How should I store Novolin N?
All Unopened Novolin N:
• Keep all unopened Novolin N in the refrigerator between 36° to 46°F
(2° to 8°C).
• Do not freeze. Do not use Novolin N if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet
prefilled syringe may be kept at room temperature for up to 14 days, as
long as it is kept at or below 86°F (30°C).
• Keep unopened Novolin N in the carton to protect from light.
Novolin N in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin
N label, if the medicine has been stored in a refrigerator.
PenFill Cartridges
• Keep at room temperature below 86°F (30°C) for up to 14 days.
• Do not store a PenFill cartridge that you are using in the
refrigerator.
• Keep PenFill cartridges away from direct heat or light.
• Throw away a used PenFill cartridge after 14 days, even if there is
insulin left in the cartridge.
InnoLet prefilled syringe
• Keep at room temperature below 86°F (30°C) for up to 14 days.
• Do not store an InnoLet prefilled syringe that you are using in the
refrigerator.
• Keep InnoLet prefilled syringes away from direct heat or light.
• Throw away a used InnoLet prefilled syringe after 14 days, even if
there is insulin left in the prefilled syringe.
General advice about Novolin N
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin N is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Novolin N for a condition for which it was not prescribed. Do not give Novolin N to other
people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin N. If you would
like more information about Novolin N or diabetes, talk with your healthcare provider.
For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin N ingredients include:
• Human Insulin Isophane
Suspension (recombinant DNA
origin)
• Zinc chloride
• Sodium hydroxide
• Phenol
• Disodium phosphate dihydrate
• Metacresol
• Glycerol
• Hydrochloric acid
• Protamine sulfate
• Water for injections
All Novolin N vials, PenFill cartridges, and InnoLet disposable prefilled syringes are
latex-free.
Date of issue: Month, Year
Version: x
Novolin®, PenFill®, NovoFine®, NovoPen®, PenMate®, and InnoLet® are trademarks of
Novo Nordisk A/S.
PenFill® Cartridges are protected by US Patent Nos.: 5,693,027, 6,126,646, and
D347,894
InnoLet® prefilled syringe is protected by US Patent Nos. 5,9479,234, 6,074,372,
6,582,404 and other patents pending.
© 200x-200x Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin N contact:
Novo Nordisk Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
100 College Road West
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® N 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin N vial?
1. Check to make sure that you have the correct type of insulin. This is especially important
if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond the correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin N in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the pinched skin.
Press the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin N at the needle
tip. This is normal and has no effect on the dose you just received. If you see blood after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
you take the needle out of your skin, press the injection site lightly with a piece of gauze
or an alcohol wipe. Do not rub the area.
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
How should I mix Novolin N with Regular human insulin?
Different insulins should be mixed only under instruction from a health care provider. Do not
mix Novolin N with any other type of insulin besides Regular human insulin. Novolin N
should be mixed only when injections with syringes are used. Insulin syringes may vary in the
amount of space between the bottom line and the needle (“dead space”), so if you are mixing two
types of insulin be sure to discuss any change in the model and brand of syringe you are using
with your healthcare provider. Novolin N can be mixed with Regular human insulin right before
use. When you are mixing Novolin N insulin with Regular human insulin, always draw the
Regular human (clear) insulin into the syringe first.
1. Add together the doses (total number of units) of Regular human insulin and Novolin N
that you need to inject. The total dose will determine the final amount (volume) in the
syringe after drawing up both insulins into the syringe. For example, if you need 5 units
of Novolin N and 2 units of Regular human insulin, the total dose of insulin in the syringe
would be 7 units.
2. Roll the Novolin N vial between your hands until the liquid is equally cloudy throughout.
3. Draw into the syringe the same amount of air as the Novolin N dose. Inject this air into
the Novolin N vial and then remove the needle from the vial but do not withdraw any of
the Novolin N insulin. (Transferring Novolin N to the Regular human insulin vial will
contaminate the Regular human insulin vial and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the Regular human insulin dose. Inject
this air into the Regular human insulin vial. With the needle in place, turn the vial upside
down and withdraw the correct dose of Regular human insulin. The tip of the needle must
be in the Regular human insulin to get the full dose and not an air dose.
5. After withdrawing the needle from the Regular human insulin vial, insert the needle into
the Novolin N vial. Turn the Novolin N vial upside down with the syringe and needle
still in it. Withdraw the correct dose of Novolin N.
6. Inject right away to avoid changes in how quickly the insulin works.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
70/30 HUMAN
Novo Nordisk®
Patient Information for Novolin® 70/30
NOVOLIN® 70/30 (NO-voe-lin)
70% NPH, Human Insulin Isophane Suspension and
30% Regular, Human Insulin Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information that comes with Novolin 70/30 before you start taking it
and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin 70/30?
Novolin 70/30 is a man-made insulin (recombinant DNA origin) which is a mixture of
70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin
Injection that is structurally identical to the insulin produced by the human pancreas that
is used control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin 70/30?
Do not take Novolin 70/30 if:
• Your blood sugar is too low (hypoglycemia)
• You are allergic to anything in Novolin 70/30. See the end of this leaflet for a
complete list of ingredients in Novolin 70/30. Check with your healthcare
provider if you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin 70/30.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin 70/30 has not been studied in pregnant or nursing
women.
• about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
blood sugar levels and your insulin needs. Your Novolin 70/30 dose may need to
change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin 70/30?
Only use Novolin 70/30 if it appears cloudy or milky. There may be air bubbles. This is
normal. If the precipitate (the white deposit at the bottom of the vial) has become lumpy
or granular in appearance or has formed a deposit of solid particles on the wall of the
vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not be
used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin 70/30 comes in:
• 10 mL vials (small bottles) for use with syringe
• 3 mL PenFill® cartridges for use with Novo Nordisk insulin delivery devices that
work with the 3 mL PenFill cartridge and NovoFine® disposable needles. The
cartridge delivery device can be used with a NovoPen® 3 PenMate®.
• 3 mL InnoLet® prefilled insulin syringe
Read the instructions for use that come with your Novolin 70/30 product. Talk to
your healthcare provider if you have any questions. Your healthcare provider should
show you how to inject Novolin 70/30 before you start taking it. Follow your healthcare
provider’s instructions to make changes to your insulin dose.
• Take Novolin 70/30 exactly as prescribed.
• Novolin 70/30 is an intermediate-acting insulin. The effects of Novolin 70/30
start working ½ hour after injection.
• The greatest blood sugar lowering effect is between 2 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
• While using Novolin 70/30, any change of insulin should be made cautiously
and only under medical supervision. Doses of oral anti-diabetic medicines may
also need to change, if your insulin is changed.
• Do not mix Novolin 70/30 with any insulins.
• Inject Novolin 70/30 into the skin of your stomach area, upper arms,
buttocks or upper legs. Novolin 70/30 may affect your blood sugar levels
sooner if you inject it into the skin of your stomach area. Never inject Novolin
70/30 into a vein or into a muscle.
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
each injection.
• If you take too much Novolin 70/30, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin
70/30?” for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin 70/30, your blood sugar may go
too high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it
can lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin 70/30?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin 70/30.
• Driving and operating machinery. You may have difficulty concentrating or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin 70/30?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentration or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions or they
are serious talk to your healthcare provider. You may need to stop using Novolin
70/30 and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin 70/30. Ask your
healthcare provider or pharmacist for more information.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store Novolin 70/30?
All Unopened Novolin 70/30:
• Keep all unopened Novolin 70/30 in the refrigerator between 36° to
46°F (2° to 8°C).
• Do not freeze. Do not use Novolin 70/30 if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet
prefilled syringe may be kept at room temperature for up to 10 days, as
long as it is kept at or below 86°F (30°C).
• Keep unopened Novolin 70/30 in the carton to protect from light.
Novolin 70/30 in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin
70/30 label, if the medicine has been stored in a refrigerator.
PenFill Cartridges
• Keep at room temperature below 86°F (30°C) for up to 10 days.
• Do not store a PenFill cartridge that you are using in the
refrigerator.
• Keep PenFill cartridges away from direct heat or light.
• Throw away a used PenFill cartridge after 10 days, even if there is
insulin left in the cartridge.
InnoLet prefilled syringe
• Keep at room temperature below 86°F (30°C) for up to 10 days.
• Do not store an InnoLet prefilled syringe that you are using in the
refrigerator.
• Keep InnoLet prefilled syringes away from direct heat or light.
• Throw away a used InnoLet prefilled syringe after 10 days, even if
there is insulin left in the prefilled syringe.
General advice about Novolin 70/30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin 70/30 is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Novolin 70/30 for a condition for which it was not prescribed. Do not give Novolin 70/30
to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin 70/30. If you
would like more information about Novolin 70/30 or diabetes, talk with your healthcare
provider. For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin 70/30 ingredients include:
• 70% NPH, Human Insulin
• Metacresol
Isophane Suspension and 30%
Regular, Human Insulin Injection
(recombinant DNA origin)
• Zinc chloride
• Glycerol
• Sodium hydroxide
• Hydrochloric acid
• Phenol
• Protamine sulfate
• Disodium phosphate dihydrate
• Water for injections
All Novolin 70/30 vials, PenFill cartridges, and InnoLet disposable prefilled syringes are
latex-free.
Date of issue: Month, Year
Version: x
Novolin®, PenFill®, NovoFine®, NovoPen®, PenMate®, and InnoLet® are trademarks of
Novo Nordisk A/S.
PenFill® Cartridges are protected by US Patent Nos.: 5,693,027, 6,126,646, and
D347,894
InnoLet® prefilled syringe is protected by US Patent Nos. 5,9479,234, 6,074,372,
6,582,404 and other patents pending.
© 200x-200x Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin 70/30 contact:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® 70/30 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin 70/30 vial?
1. Check to make sure that you have the correct type of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin 70/30 in the syringe.
11. Pull the syringe needle out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the skin. Press
the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin 70/30 at the
needle tip. This is normal and has no effect on the dose you just received. If you see
blood after you take the needle out of your skin, press the injection site lightly with a
piece of gauze or an alcohol wipe. Do not rub the area.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:22.684106 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019938s063,019959s066,019991s067lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 63} |
1,857 |
R HUMAN
Novo Nordisk®
Patient Information for Novolin® R
NOVOLIN® R (NO-voe-lin)
Regular,
Human Insulin Injection
(recombinant DNA origin) USP
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information leaflet that comes with Novolin R before you start taking it
and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin R?
Novolin R is a man-made insulin (recombinant DNA origin) that is structurally identical
to the insulin produced by the human pancreas that is used control high blood sugar in
patients with diabetes mellitus.
Who should not use Novolin R?
Do not take Novolin R if:
• Your blood sugar is too low (hypoglycemia)
• You are allergic to anything in Novolin R. See the end of this leaflet for a
complete list of ingredients in Novolin R. Check with your healthcare provider if
you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin R.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin R has not been studied in pregnant or nursing women.
• about all of the medicines you take, including prescription and non
prescription medicines, vitamins and herbal supplements. Many medicines can
affect your blood sugar levels and your insulin needs. Your Novolin R dose may
need to change if you take other medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin R?
Only use Novolin R if it appears clear and colorless. There may be air bubbles. This is
normal. If it looks cloudy, thickened, or colored, or if it contains solid particles do not
use it, and call Novo Nordisk at 1-800-727-6500.
Novolin R comes in:
• 10 mL vials (small bottles) for use with syringe
• 3 mL PenFill® cartridges for use with Novo Nordisk insulin delivery devices that
work with the 3 mL PenFill cartridge and NovoFine® disposable needles. The
cartridge delivery device can be used with a NovoPen® 3 PenMate®.
• 3 mL InnoLet® prefilled insulin syringe
Read the instructions for use that come with your Novolin R product. Talk to your
healthcare provider if you have any questions. Your healthcare provider should show
you how to inject Novolin R before you start taking it. Follow your healthcare provider’s
instructions to make changes to your insulin dose.
• Take Novolin R exactly as prescribed.
• Novolin R is a fast-acting insulin. The effects of Novolin R start working ½
hour after injection.
• The greatest blood sugar lowering effect is between 2½ and 5 hours after the
injection. This blood sugar lowering lasts for 8 hours.
• While using Novolin R you may have to change your total dose of insulin,
your dose of longer-acting insulin, or the number of injections of longer-acting
insulin you use.
• Do not mix Novolin R with any insulins other than NPH in the same syringe.
• Inject Novolin R into the skin of your stomach area, upper arms, buttocks
or upper legs. Novolin R may affect your blood sugar levels sooner if you inject
it into the skin of your stomach area. Never inject Novolin R into a vein or into
a muscle.
• Due to risk of precipitation in some pump catheters, Novolin R is not
recommended for use in insulin pumps.
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
each injection.
• If you take too much Novolin R, your blood sugar may fall low
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin R?”
for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin R, your blood sugar may go too
high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can
lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin R?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin R.
• Driving and operating machinery. You may have difficulty concentrating or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin R?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentration or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin R and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin R. Ask your healthcare
provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store Novolin R?
All Unopened Novolin R:
• Keep all unopened Novolin R in the refrigerator between 36° to 46°F
(2° to 8°C).
• Do not freeze. Do not use Novolin R if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet
prefilled syringe may be kept at room temperature for up to 28 days, as
long as it is kept at or below 86°F (30°C).
• Keep unopened Novolin R in the carton to protect from light.
Novolin R in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin
R label, if the medicine has been stored in a refrigerator.
PenFill Cartridges
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store a PenFill cartridge that you are using in the
refrigerator.
• Keep PenFill cartridges away from direct heat or light.
• Throw away a used PenFill cartridge after 28 days, even if there is
insulin left in the cartridge.
InnoLet prefilled syringe
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store an InnoLet prefilled syringe that you are using in the
refrigerator.
• Keep InnoLet prefilled syringes away from direct heat or light.
• Throw away a used InnoLet prefilled syringe after 28 days, even if
there is insulin left in the prefilled syringe.
General advice about Novolin R
Novolin R is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin R for a condition for which it was not prescribed. Do not give Novolin R to other
people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin R. If you would
like more information about Novolin R or diabetes, talk with your healthcare provider.
For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street Alexandria, VA 22311 and on
www.diabetes.org.
Novolin R ingredients include:
• Regular Human Insulin Injection
• Metacresol
(recombinant DNA origin) USP
• Zinc chloride
• Glycerol
• Sodium hydroxide
• Hydrochloric acid
• Water for injections
All Novolin R vials, PenFill cartridges, and InnoLet disposable prefilled syringes are
latex-free.
Date of issue: Month, Year
Version: x
Novolin®, PenFill®, NovoFine®, NovoPen®, PenMate®, and InnoLet® are trademarks of
Novo Nordisk A/S.
PenFill® Cartridges are protected by US Patent Nos.: 5,693,027, 6,126,646, and
D347,894
InnoLet® prefilled syringe is protected by US Patent Nos. 5,9479,234, 6,074,372,
6,582,404 and other patents pending.
© 200x-200x Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® R 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin R vial?
1. Check to make sure that you have the correct type of insulin. This is especially important
if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be clear and colorless. The tamper-
resistant cap should be in place before the first use. If the cap had been removed before
your first use of the vial, or if the insulin is cloudy, colored, or contains any particles, do
not use it and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your healthcare provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Do not roll or shake the vial. Shaking right before the dose is drawn into the syringe may
cause bubbles or froth. This can cause you to draw up the wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond the correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin R in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the pinched skin.
Press the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin R at the needle
tip. This is normal and has no effect on the dose you just received. If you see blood after
you take the needle out of your skin, press the injection site lightly with a piece of gauze
or an alcohol wipe. Do not rub the area.
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
How should I mix Novolin R with NPH insulin?
Different insulins should be mixed only under instruction from a healthcare provider. Do not
mix Novolin R with any other type of insulin besides NPH insulin. Novolin R should be
mixed only when injections with syringes are used. Insulin syringes may vary in the amount of
space between the bottom line and the needle (“dead space”), so if you are mixing two types of
insulin be sure to discuss any change in the model and brand of syringe you are using with your
healthcare provider. Novolin R can be mixed with NPH insulin right before use. When you are
mixing Novolin R insulin with NPH insulin, always draw the Novolin R (clear) insulin into the
syringe first.
1. Add together the doses (total number of units) of NPH and Novolin R that you need to
inject. The total dose will determine the final amount (volume) in the syringe after
drawing up both insulins into the syringe. For example, if you need 5 units of NPH and 2
units of Novolin R, the total dose of insulin in the syringe would be 7 units.
2. Roll the NPH vial between your hands until the liquid is equally cloudy throughout.
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air into the
NPH vial and then remove the needle from the vial but do not withdraw any of the NPH
insulin. (Transferring NPH to the Novolin R vial will contaminate the Novolin R vial
and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the Novolin R dose. Inject this air into
the Novolin R vial. With the needle in place, turn the vial upside down and withdraw the
correct dose of Novolin R. The tip of the needle must be in the Novolin R to get the full
dose and not an air dose.
5. After withdrawing the needle from the Novolin R vial, insert the needle into the NPH
vial. Turn the NPH vial upside down with the syringe and needle still in it. Withdraw the
correct dose of NPH.
6. Inject right away to avoid changes in how quickly the insulin works.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
N HUMAN
Novo Nordisk®
Patient Information for Novolin® N
NOVOLIN® N (NO-voe-lin)
NPH,
Human Insulin Isophane Suspension Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information that comes with Novolin N before you start taking it and
each time you get a refill. There may be new information. This leaflet does not take the
place of talking with your healthcare provider about your diabetes or your treatment.
Make sure you know how to manage your diabetes. Ask your healthcare provider if you
have any questions about managing your diabetes.
What is Novolin N?
Novolin N is a man-made insulin (recombinant DNA origin) NPH, Human Insulin
Isophane Suspension that is structurally identical to the insulin produced by the human
pancreas that is used control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin N?
Do not take Novolin N if:
• Your blood sugar is too low (hypoglycemia)
• You are allergic to anything in Novolin N. See the end of this leaflet for a
complete list of ingredients in Novolin N. Check with your healthcare provider if
you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin N.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin N has not been studied in pregnant or nursing women.
• about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
blood sugar levels and your insulin needs. Your Novolin N dose may need to
change if you take other medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin N?
Only use Novolin N if it appears cloudy or milky. There may be air bubbles. This is
normal. If the precipitate (the white deposit at the bottom of the vial) has become lumpy
or granular in appearance or has formed a deposit of solid particles on the wall of the
vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not be
used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin N comes in:
• 10 mL vials (small bottles) for use with syringe
• 3 mL PenFill® cartridges for use with Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery devices, and NovoFine® disposable needles. The
cartridge delivery device can be used with a NovoPen® 3 PenMate®
• 3 mL InnoLet® prefilled insulin syringe
Read the instructions for use that come with your Novolin N product. Talk to
your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject Novolin N before you start taking it. Follow your
healthcare provider’s instructions to make changes to your insulin dose.
• Take Novolin N exactly as prescribed.
• Novolin N is an intermediate-acting insulin. The effects of Novolin N start
working 1½ hours after injection.
• The greatest blood sugar lowering effect is between 4 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
• While using Novolin N, any change of insulin should be made cautiously and
only under medical supervision. Doses of oral anti-diabetic medicines may also
need to change, if your insulin is changed.
• Do not mix Novolin N with any insulins other than Regular human insulin in the
same syringe.
• Inject Novolin N into the skin of your stomach area, upper arms, buttocks
or upper legs. Novolin N may affect your blood sugar levels sooner if you inject
it into the skin of your stomach area. Never inject Novolin N into a vein or into
a muscle.
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
each injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you take too much Novolin N, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin N?”
for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin N, your blood sugar may go too
high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can
lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin N?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin N.
• Driving and operating machinery. You may have difficulty concentrating or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
you often have:
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin N?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentration or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin N and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin N. Ask your healthcare
provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
to FDA at 1-800-FDA-1088.
How should I store Novolin N?
All Unopened Novolin N:
• Keep all unopened Novolin N in the refrigerator between 36° to 46°F
(2° to 8°C).
• Do not freeze. Do not use Novolin N if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet
prefilled syringe may be kept at room temperature for up to 14 days, as
long as it is kept at or below 86°F (30°C).
• Keep unopened Novolin N in the carton to protect from light.
Novolin N in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin
N label, if the medicine has been stored in a refrigerator.
PenFill Cartridges
• Keep at room temperature below 86°F (30°C) for up to 14 days.
• Do not store a PenFill cartridge that you are using in the
refrigerator.
• Keep PenFill cartridges away from direct heat or light.
• Throw away a used PenFill cartridge after 14 days, even if there is
insulin left in the cartridge.
InnoLet prefilled syringe
• Keep at room temperature below 86°F (30°C) for up to 14 days.
• Do not store an InnoLet prefilled syringe that you are using in the
refrigerator.
• Keep InnoLet prefilled syringes away from direct heat or light.
• Throw away a used InnoLet prefilled syringe after 14 days, even if
there is insulin left in the prefilled syringe.
General advice about Novolin N
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin N is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Novolin N for a condition for which it was not prescribed. Do not give Novolin N to other
people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin N. If you would
like more information about Novolin N or diabetes, talk with your healthcare provider.
For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin N ingredients include:
• Human Insulin Isophane
Suspension (recombinant DNA
origin)
• Zinc chloride
• Sodium hydroxide
• Phenol
• Disodium phosphate dihydrate
• Metacresol
• Glycerol
• Hydrochloric acid
• Protamine sulfate
• Water for injections
All Novolin N vials, PenFill cartridges, and InnoLet disposable prefilled syringes are
latex-free.
Date of issue: Month, Year
Version: x
Novolin®, PenFill®, NovoFine®, NovoPen®, PenMate®, and InnoLet® are trademarks of
Novo Nordisk A/S.
PenFill® Cartridges are protected by US Patent Nos.: 5,693,027, 6,126,646, and
D347,894
InnoLet® prefilled syringe is protected by US Patent Nos. 5,9479,234, 6,074,372,
6,582,404 and other patents pending.
© 200x-200x Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin N contact:
Novo Nordisk Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
100 College Road West
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® N 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin N vial?
1. Check to make sure that you have the correct type of insulin. This is especially important
if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond the correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin N in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the pinched skin.
Press the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin N at the needle
tip. This is normal and has no effect on the dose you just received. If you see blood after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
you take the needle out of your skin, press the injection site lightly with a piece of gauze
or an alcohol wipe. Do not rub the area.
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
How should I mix Novolin N with Regular human insulin?
Different insulins should be mixed only under instruction from a health care provider. Do not
mix Novolin N with any other type of insulin besides Regular human insulin. Novolin N
should be mixed only when injections with syringes are used. Insulin syringes may vary in the
amount of space between the bottom line and the needle (“dead space”), so if you are mixing two
types of insulin be sure to discuss any change in the model and brand of syringe you are using
with your healthcare provider. Novolin N can be mixed with Regular human insulin right before
use. When you are mixing Novolin N insulin with Regular human insulin, always draw the
Regular human (clear) insulin into the syringe first.
1. Add together the doses (total number of units) of Regular human insulin and Novolin N
that you need to inject. The total dose will determine the final amount (volume) in the
syringe after drawing up both insulins into the syringe. For example, if you need 5 units
of Novolin N and 2 units of Regular human insulin, the total dose of insulin in the syringe
would be 7 units.
2. Roll the Novolin N vial between your hands until the liquid is equally cloudy throughout.
3. Draw into the syringe the same amount of air as the Novolin N dose. Inject this air into
the Novolin N vial and then remove the needle from the vial but do not withdraw any of
the Novolin N insulin. (Transferring Novolin N to the Regular human insulin vial will
contaminate the Regular human insulin vial and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the Regular human insulin dose. Inject
this air into the Regular human insulin vial. With the needle in place, turn the vial upside
down and withdraw the correct dose of Regular human insulin. The tip of the needle must
be in the Regular human insulin to get the full dose and not an air dose.
5. After withdrawing the needle from the Regular human insulin vial, insert the needle into
the Novolin N vial. Turn the Novolin N vial upside down with the syringe and needle
still in it. Withdraw the correct dose of Novolin N.
6. Inject right away to avoid changes in how quickly the insulin works.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
70/30 HUMAN
Novo Nordisk®
Patient Information for Novolin® 70/30
NOVOLIN® 70/30 (NO-voe-lin)
70% NPH, Human Insulin Isophane Suspension and
30% Regular, Human Insulin Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information that comes with Novolin 70/30 before you start taking it
and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin 70/30?
Novolin 70/30 is a man-made insulin (recombinant DNA origin) which is a mixture of
70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin
Injection that is structurally identical to the insulin produced by the human pancreas that
is used control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin 70/30?
Do not take Novolin 70/30 if:
• Your blood sugar is too low (hypoglycemia)
• You are allergic to anything in Novolin 70/30. See the end of this leaflet for a
complete list of ingredients in Novolin 70/30. Check with your healthcare
provider if you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin 70/30.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin 70/30 has not been studied in pregnant or nursing
women.
• about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
blood sugar levels and your insulin needs. Your Novolin 70/30 dose may need to
change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin 70/30?
Only use Novolin 70/30 if it appears cloudy or milky. There may be air bubbles. This is
normal. If the precipitate (the white deposit at the bottom of the vial) has become lumpy
or granular in appearance or has formed a deposit of solid particles on the wall of the
vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not be
used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin 70/30 comes in:
• 10 mL vials (small bottles) for use with syringe
• 3 mL PenFill® cartridges for use with Novo Nordisk insulin delivery devices that
work with the 3 mL PenFill cartridge and NovoFine® disposable needles. The
cartridge delivery device can be used with a NovoPen® 3 PenMate®.
• 3 mL InnoLet® prefilled insulin syringe
Read the instructions for use that come with your Novolin 70/30 product. Talk to
your healthcare provider if you have any questions. Your healthcare provider should
show you how to inject Novolin 70/30 before you start taking it. Follow your healthcare
provider’s instructions to make changes to your insulin dose.
• Take Novolin 70/30 exactly as prescribed.
• Novolin 70/30 is an intermediate-acting insulin. The effects of Novolin 70/30
start working ½ hour after injection.
• The greatest blood sugar lowering effect is between 2 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
• While using Novolin 70/30, any change of insulin should be made cautiously
and only under medical supervision. Doses of oral anti-diabetic medicines may
also need to change, if your insulin is changed.
• Do not mix Novolin 70/30 with any insulins.
• Inject Novolin 70/30 into the skin of your stomach area, upper arms,
buttocks or upper legs. Novolin 70/30 may affect your blood sugar levels
sooner if you inject it into the skin of your stomach area. Never inject Novolin
70/30 into a vein or into a muscle.
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
each injection.
• If you take too much Novolin 70/30, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin
70/30?” for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin 70/30, your blood sugar may go
too high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it
can lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin 70/30?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin 70/30.
• Driving and operating machinery. You may have difficulty concentrating or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin 70/30?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentration or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions or they
are serious talk to your healthcare provider. You may need to stop using Novolin
70/30 and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin 70/30. Ask your
healthcare provider or pharmacist for more information.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store Novolin 70/30?
All Unopened Novolin 70/30:
• Keep all unopened Novolin 70/30 in the refrigerator between 36° to
46°F (2° to 8°C).
• Do not freeze. Do not use Novolin 70/30 if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet
prefilled syringe may be kept at room temperature for up to 10 days, as
long as it is kept at or below 86°F (30°C).
• Keep unopened Novolin 70/30 in the carton to protect from light.
Novolin 70/30 in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin
70/30 label, if the medicine has been stored in a refrigerator.
PenFill Cartridges
• Keep at room temperature below 86°F (30°C) for up to 10 days.
• Do not store a PenFill cartridge that you are using in the
refrigerator.
• Keep PenFill cartridges away from direct heat or light.
• Throw away a used PenFill cartridge after 10 days, even if there is
insulin left in the cartridge.
InnoLet prefilled syringe
• Keep at room temperature below 86°F (30°C) for up to 10 days.
• Do not store an InnoLet prefilled syringe that you are using in the
refrigerator.
• Keep InnoLet prefilled syringes away from direct heat or light.
• Throw away a used InnoLet prefilled syringe after 10 days, even if
there is insulin left in the prefilled syringe.
General advice about Novolin 70/30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin 70/30 is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Novolin 70/30 for a condition for which it was not prescribed. Do not give Novolin 70/30
to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin 70/30. If you
would like more information about Novolin 70/30 or diabetes, talk with your healthcare
provider. For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin 70/30 ingredients include:
• 70% NPH, Human Insulin
• Metacresol
Isophane Suspension and 30%
Regular, Human Insulin Injection
(recombinant DNA origin)
• Zinc chloride
• Glycerol
• Sodium hydroxide
• Hydrochloric acid
• Phenol
• Protamine sulfate
• Disodium phosphate dihydrate
• Water for injections
All Novolin 70/30 vials, PenFill cartridges, and InnoLet disposable prefilled syringes are
latex-free.
Date of issue: Month, Year
Version: x
Novolin®, PenFill®, NovoFine®, NovoPen®, PenMate®, and InnoLet® are trademarks of
Novo Nordisk A/S.
PenFill® Cartridges are protected by US Patent Nos.: 5,693,027, 6,126,646, and
D347,894
InnoLet® prefilled syringe is protected by US Patent Nos. 5,9479,234, 6,074,372,
6,582,404 and other patents pending.
© 200x-200x Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin 70/30 contact:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® 70/30 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin 70/30 vial?
1. Check to make sure that you have the correct type of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin 70/30 in the syringe.
11. Pull the syringe needle out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the skin. Press
the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin 70/30 at the
needle tip. This is normal and has no effect on the dose you just received. If you see
blood after you take the needle out of your skin, press the injection site lightly with a
piece of gauze or an alcohol wipe. Do not rub the area.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:22.817590 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019938s063,019959s066,019991s067lbl.pdf', 'application_number': 19959, 'submission_type': 'SUPPL ', 'submission_number': 66} |
1,862 | N HUMAN
Novo Nordisk®
Patient Information for Novolin® N
NOVOLIN® N (NO-voe-lin)
NPH,
Human Insulin Isophane Suspension Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information leaflet that comes with Novolin® N before you start taking it
and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin® N?
Novolin® N is a man-made insulin (recombinant DNA origin) NPH, Human Insulin
Isophane Suspension that is structurally identical to the insulin produced by the human
pancreas that is used to control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin® N?
Do not take Novolin® N if:
Your blood sugar is too low (hypoglycemia).
You are allergic to anything in Novolin® N. See the end of this leaflet for a
complete list of ingredients in Novolin® N. Check with your healthcare provider if
you are not sure.
Tell your healthcare provider:
about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin® N.
if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin® N has not been studied in pregnant or nursing women.
about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
blood sugar levels and your insulin needs. Your Novolin® N dose may need to
change if you take other medicines.
Reference ID: 3273187
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For current labeling information, please visit https://www.fda.gov/drugsatfda
if you take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
if you have heart failure or other heart problems. If you have heart failure, it
may get worse while you take TZDs with Novolin® N.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin® N?
Only use Novolin® N if it appears cloudy or milky. There may be air bubbles. This is
normal. If the precipitate (the white deposit at the bottom of the vial) has become lumpy
or granular in appearance or has formed a deposit of solid particles on the wall of the
vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not be
used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin® N comes in:
10 mL vials (small bottles) for use with syringe
Read the instructions for use that come with your Novolin® N product. Talk to
your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject Novolin® N before you start taking it. Follow your
healthcare provider’s instructions to make changes to your insulin dose.
Take Novolin® N exactly as prescribed.
Novolin® N is an intermediate-acting insulin. The effects of Novolin® N start
working 1½ hours after injection.
The greatest blood sugar lowering effect is between 4 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
While using Novolin® N, any change of insulin should be made cautiously and
only under medical supervision. Doses of oral anti-diabetic medicines may also
need to change, if your insulin is changed.
Do not mix Novolin® N with any insulins other than Regular human insulin in the
same syringe.
Inject Novolin® N into the skin of your stomach area, upper arms, buttocks
or upper legs. Novolin® N may affect your blood sugar levels sooner if you
inject it into the skin of your stomach area. Never inject Novolin® N into a vein
or into a muscle.
Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
each injection.
Reference ID: 3273187
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If you take too much Novolin® N, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin® N?”
for more information on low blood sugar (hypoglycemia).
If you forget to take your dose of Novolin® N, your blood sugar may go too
high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can
lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
increased thirst
fruity smell on breath
frequent urination and
dehydration
high amounts of sugar and
ketones in your urine
confusion or drowsiness
nausea, vomiting (throwing
up) or stomach pain
loss of appetite
a hard time breathing
Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
illness
change in diet
stress
change in physical activity or
exercise
other medicines you take
surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin® N?
Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin® N.
Driving and operating machinery. You may have difficulty concentrating or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
Reference ID: 3273187
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car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
low blood sugar
decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin® N?
Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
sweating
trouble concentrating or confusion
dizziness or lightheadedness
blurred vision
shakiness
slurred speech
hunger
anxiety, irritability or mood
changes
fast heart beat
headache
tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin® N and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
Swelling of your hands and feet
Heart Failure. Taking certain diabetes pills called thiazolidinediones or “TZDs”
with Novolin® N may cause heart failure in some people. This can happen even
if you have never had heart failure or heart problems before. If you already have
heart failure it may get worse while you take TZDs with Novolin® N. Your
healthcare provider should monitor you closely while you are taking TZDs with
Novolin® N. Tell your healthcare provider if you have any new or worse
symptoms of heart failure including:
Reference ID: 3273187
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shortness of breath
swelling of your ankles or feet
sudden weight gain
Treatment with TZDs and Novolin® N may need to be adjusted or stopped by
your healthcare provider if you have new or worse heart failure.
Vision changes
Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin® N. Ask your healthcare
provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store Novolin® N?
All Unopened Novolin® N:
Keep all unopened Novolin® N in the refrigerator between 36° to 46°F
(2° to 8°C).
Do not freeze. Do not use Novolin® N if it has been frozen.
If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
Keep unopened Novolin® N in the carton to protect from light.
Novolin® N in use:
Vials
Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
Keep vials away from direct heat or light.
Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
Unopened vials can be used until the expiration date on the
Novolin® N label, if the medicine has been stored in a refrigerator.
General advice about Novolin® N
Novolin® N is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Novolin® N for a condition for which it was not prescribed. Do not give Novolin® N to
other people, even if they have the same symptoms you have. It may harm them.
Reference ID: 3273187
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For current labeling information, please visit https://www.fda.gov/drugsatfda
This leaflet summarizes the most important information about Novolin® N. If you would
like more information about Novolin® N or diabetes, talk with your healthcare provider.
For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin® N ingredients include:
Human Insulin Isophane
Suspension (recombinant DNA
origin)
Metacresol
Zinc chloride
Glycerol
Sodium hydroxide
Hydrochloric acid
Phenol
Protamine sulfate
Disodium phosphate dihydrate
Water for injections
All Novolin® N vials are latex-free.
Date of issue: XXXX
Version: X
Novolin® and Novo Nordisk® are registered trademarks of Novo Nordisk A/S.
© 2005 - 201X Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin® N contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
Reference ID: 3273187
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® N 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin N vial?
1. Check to make sure that you have the correct type of insulin. This is especially important
if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800-
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond the correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin N in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the pinched skin.
Press the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin N at the needle
tip. This is normal and has no effect on the dose you just received. If you see blood after
Reference ID: 3273187
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you take the needle out of your skin, press the injection site lightly with a piece of gauze
or an alcohol wipe. Do not rub the area.
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
How should I mix Novolin N with Regular human insulin?
Different insulins should be mixed only under instruction from a health care provider. Do not
mix Novolin N with any other type of insulin besides Regular human insulin. Novolin N
should be mixed only when injections with syringes are used. Insulin syringes may vary in the
amount of space between the bottom line and the needle (“dead space”), so if you are mixing two
types of insulin be sure to discuss any change in the model and brand of syringe you are using
with your healthcare provider. Novolin N can be mixed with Regular human insulin right before
use. When you are mixing Novolin N insulin with Regular human insulin, always draw the
Regular human (clear) insulin into the syringe first.
1. Add together the doses (total number of units) of Regular human insulin and Novolin N
that you need to inject. The total dose will determine the final amount (volume) in the
syringe after drawing up both insulins into the syringe. For example, if you need 5 units
of Novolin N and 2 units of Regular human insulin, the total dose of insulin in the syringe
would be 7 units.
2. Roll the Novolin N vial between your hands until the liquid is equally cloudy throughout.
3. Draw into the syringe the same amount of air as the Novolin N dose. Inject this air into
the Novolin N vial and then remove the needle from the vial but do not withdraw any of
the Novolin N insulin. (Transferring Novolin N to the Regular human insulin vial will
contaminate the Regular human insulin vial and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the Regular human insulin dose. Inject
this air into the Regular human insulin vial. With the needle in place, turn the vial upside
down and withdraw the correct dose of Regular human insulin. The tip of the needle must
be in the Regular human insulin to get the full dose and not an air dose.
5. After withdrawing the needle from the Regular human insulin vial, insert the needle into
the Novolin N vial. Turn the Novolin N vial upside down with the syringe and needle
still in it. Withdraw the correct dose of Novolin N.
6. Inject right away to avoid changes in how quickly the insulin works.
Reference ID: 3273187
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.092367 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019959s073lbl.pdf', 'application_number': 19959, 'submission_type': 'SUPPL ', 'submission_number': 73} |
1,856 | 1
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NovoPen 3 PenMate Instruction Manual
Page 2
FDA revision #4 (final)
2
NovoPen® 3
3
previous page for graphic
4
PenMate®
5
6
Instruction Manual
7
8
Read this carefully
9
before you use
10
NovoPen® 3 PenMate®
11
and NovoPen® 3
12
13
14
15
16
INTRODUCTION
17
NovoPen® 3 PenMate® is a replacement component specifically designed to be used
18
with the NovoPen 3 insulin pen. NovoPen 3 PenMate helps you to insert the needle and
19
to give injections quickly and easily. With NovoPen 3 and NovoPen 3 PenMate, you can
20
dial doses in units of one from 2 to 70 units.
21
NovoPen 3 PenMate should only be used in combination with products that are
22
compatible and allow the device to function safely and effectively.
23
NovoPen 3 PenMate is designed to be used with:
24
§ NovoPen® 3
25
§ PenFill® 3 mL cartridges
26
§ NovoFine® 30G/8 mm and NovoFine® 31G/6 mm needles.
27
NovoFine disposable needles are for single-use only.
28
29
The NovoPen 3 PenMate can be used the same way as the NovoPen 3 insulin pen. Its
30
design allows you to use the same recommended injection technique as for the NovoPen
31
3 insulin pen.
32
33
This booklet contains instructions for using, storing, and cleaning NovoPen 3 PenMate in
34
combination with NovoPen 3. Please follow them carefully. You should read these
35
instructions even if you have used NovoPen 3, or NovoPen 3 in combination with the
36
NovoPen 3 PenMate before. The two following pages provide illustrations of both the
37
NovoPen 3 and the NovoPen 3 PenMate.
38
39
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NovoPen 3 PenMate Instruction Manual
Page 3
FDA revision #4 (final)
Always check that the PenFill® cartridge you use contains the correct type of insulin.
40
If you are treated with more than one type of insulin in PenFill cartridges, you should use
41
a separate NovoPen 3 PenMate and NovoPen 3 for each type of insulin.
42
43
If you have any questions about your NovoPen 3 PenMate or your NovoPen 3 insulin
44
delivery device, please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
45
Please complete and return the NovoPen 3 PenMate Warranty Card.
46
Thank you for choosing the NovoPen 3 PenMate and NovoPen 3 insulin delivery device.
47
Look at the diagram
48
49
50
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NovoPen 3 PenMate Instruction Manual
Page 4
FDA revision #4 (final)
51
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 5
FDA revision #4 (final)
52
PenFill Holder
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 6
FDA revision #4 (final)
53
HOW TO USE THIS BOOKLET
54
This booklet gives you step-by-stepinstructions for using the NovoPen 3 PenMate in
55
combination with the NovoPen 3.
56
57
Begin by reviewing the illustration layout of the parts of the NovoPen 3, NovoPen 3
58
PenMate, PenFill 3 mL cartridge and NovoFine disposable needle. The inside front cover
59
opens out so you have a handy reference while you read the rest of the booklet.
60
Most pages contain an illustration on the right with numbered instructions to the left of
61
the illustration.
62
Important additional information is given below the illustration.
63
We suggest that you read the text and look at the illustrations to make sure that you
64
understand each step thoroughly.
65
Also included is a diagram showing a side-by-side comparison of the NovoPen 3 and the
66
NovoPen 3 PenMate. This illustration allows you to see which part of the NovoPen 3 the
67
NovoPen 3 PenMate replaces.
68
69
The main differences between the NovoPen 3 and the NovoPen 3 PenMate are as
70
follows:
71
The PenFill cartridge holder and the Pen cap of the NovoPen 3 are replaced by the
72
NovoPen 3 PenMate.
73
NovoPen 3 PenMate allows for automatic insertion of the NovoFine needle under the
74
skin; NovoPen 3 requires manual needle insertion.
75
NovoPen 3 PenMate allows for the NovoFine needle to be completely hidden prior to
76
needle insertion; the needle is visible on the NovoPen 3 prior to needle insertion.
77
78
Look at the diagram inside the front cover for the names of the different parts of
79
NovoPen 3 and NovoPen 3 PenMate. You can unfold the diagram to help you while
80
you follow the instructions.
81
82
83
84
85
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NovoPen 3 PenMate Instruction Manual
Page 7
FDA revision #4 (final)
86
TABLE OF CONTENTS
87
SECTION 1:
88
Assembly of the NovoPen 3 PenMate............................................ 4
89
SECTION 2:
90
Air shot before each injection........................................... 9
91
SECTION 3:
92
Choosing your dose......................................................... 10
93
SECTION 4:
94
Giving the injection......................................................... 12
95
SECTION 5:
96
Mechanical function check of NovoPen 3 PenMate.......... 17
97
SECTION 6:
98
For subsequent injections................................................ 18
99
SECTION 7:
100
What to do when PenFill is nearly empty......................... 19
101
SECTION 8:
102
Changing PenFill............................................................ 20
103
SECTION 9:
104
Function check............................................................... 21
105
IMPORTANT................................................................ 22
106
WHAT TO DO IF.......................................................... 25
107
HOW TO STORE AND LOOK AFTER YOUR
108
NOVOPEN 3 AND YOUR NOVOPEN 3 PENMATE... 27
109
WARRANTY................................................................. 28
110
111
112
113
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NovoPen 3 PenMate Instruction Manual
Page 8
FDA revision #4 (final)
SECTION 1
Assembly of the NovoPen3 PenMate
114
Assembly of the NovoPen 3 PenMate
115
116
1 Take NovoPen 3 out of its case by pressing the top of the pen cap.
117
118
119
2 Gently twist the pen cap until it separates from the barrel.
120
121
3 Pull the pen cap straight up to remove it.
122
123
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NovoPen 3 PenMate Instruction Manual
Page 9
FDA revision #4 (final)
4 Unscrew and remove the PenFill holder from the barrel*
124
125
* See diagram.
126
You will not use the pen cap and PenFill holder with the NovoPen 3 PenMate but you
127
should store them in the case if you want to use NovoPen 3 without NovoPen 3 PenMate
128
in the future.
129
SECTION 1 (cont.)
130
5 The end of the piston rod should be flat against the end of the reset mechanism prior to
131
inserting each new Novolin PenFill 3 mL cartridge. It should not be sticking out.
132
133
If the piston rod is sticking out:
134
Turn the end of the reset mechanism in a clockwise direction until the piston rod is no
135
longer sticking out. Never push the piston rod back in.
136
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NovoPen 3 PenMate Instruction Manual
Page 10
FDA revision #4 (final)
137
Need Help? Call 1-800-727-6500
138
139
You should not reset the piston rod again until it is time to remove the used PenFill 3 mL
140
cartridge and insert a new one.
141
142
If the reset mechanism locks, it is usually due to improper technique. Gently turn the
143
mechanism side to side until it unlocks. Then call our toll free number (1-800-727-6500)
144
so that we may review your operating technique with you.
145
146
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NovoPen 3 PenMate Instruction Manual
Page 11
FDA revision #4 (final)
147
SECTION 1 (cont.)
148
6 Press the push button all the way in until zero (0) appears in the window. The zero
149
should be lined up with the stripe below the dose indicator window.
150
To remove the PenFill cartridge from its wrapper, push the cartridge through the foil
151
side of the packaging.
152
Before use, check that the PenFill cartridge is full and intact. If not, do not use it.
153
154
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NovoPen 3 PenMate Instruction Manual
Page 12
FDA revision #4 (final)
7 If you use Novolin 70/30 [70% NPH, Human Insulin Isophane Suspension and 30%
155
Regular, Human Insulin Injection (recombinant DNA origin)] or Novolin N, NPH
156
[Human Insulin Isophane Suspension (recombinant DNA origin)], mix the insulin:
157
158
a. Turn PenFill cartridge up and down between positions A and B, as shown.
159
b. Repeat this mixing step at least 10 times or until the insulin looks uniformly white
160
and cloudy.
161
162
163
If you use more than one type (N, R, or 70/30) of insulin, use a separate NovoPen 3
164
PenMate for each type.
165
166
Once the cartridge is punctured, it can be used at room temperature for the length of time
167
identified in the storage information section of the Information For The Patient supplied
168
with the PenFill cartridges. The expiration date on the cartridge is for unused cartridges
169
under refrigeration.
170
171
SECTION 1 (cont.)
172
Take the NovoPen 3 PenMate out of its case.
173
Pull off the pen cap and put it to one side.
174
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NovoPen 3 PenMate Instruction Manual
Page 13
FDA revision #4 (final)
Put the PenFill cartridge into the NovoPen 3 PenMate.
175
The threaded plastic cap goes in first.
176
177
8
Tightly screw the barrel of the NovoPen 3 into the NovoPen 3 PenMate.
178
Make sure that the dose indicator window on the mechanical section is aligned with
179
the yellow push button on NovoPen 3 PenMate.
180
181
182
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. There are five
183
cartridges in a box. Make sure you are using the correct type of insulin. The name of
184
the insulin is on the glass part of the cartridge.
185
Each PenFill cartridge is for single-person use only.
186
DO NOT share the cartridge with anyone even if you attach a new disposable needle
187
for each injection. This will prevent the spread of disease.
188
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NovoPen 3 PenMate Instruction Manual
Page 14
FDA revision #4 (final)
Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 PenMate.
189
Never load a partially filled cartridge. Never try to refill a used PenFill 3 mL
190
cartridge.
191
192
SECTION 1 (cont.)
193
9 Clean the front rubber stopper on the PenFill cartridge with an alcohol swab.
194
You must wipe the front rubber stopper with an alcohol swab before each injection, even
195
if you are using the same PenFill cartridge.
196
197
198
10 Remove the protective tab from the NovoFine® disposable needle.
199
Screw the NovoFine needle firmly onto the threaded plastic cap until it is tight.
200
Pull off the outer and inner needle caps.
201
202
For users of Novolin 70/30 or Novolin N insulin: Always remix the insulin before
203
each injection.
204
To remix the insulin, turn the NovoPen 3 PenMate up and down between positions A
205
and B, as on page 4, 10 times or until the insulin looks uniformly white and cloudy.
206
207
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NovoPen 3 PenMate Instruction Manual
Page 15
FDA revision #4 (final)
208
Never place a NovoFine disposable needle on your NovoPen 3 PenMate until you are
209
ready to do an air shot and give an injection. If the NovoFine needle is “left on”,
210
some liquid may leak out of the PenFill cartridge. This may cause a change in the
211
strength of Novolin 70/30 or Novolin N insulin.
212
213
214
SECTION 2
Air shot before each injection
215
216
Air shot before each injection
217
218
11 The PenFill cartridge may contain an air bubble, and small amounts of air may
219
collect in the needle and PenFill cartridge when you use them. To avoid the injection
220
of air and ensure proper dosing, you must perform an air shot prior to each injection.
221
222
§ Check that the dial-a-dose selector is set at zero.
223
§ Dial 2 units. Hold the NovoPen 3 PenMate with the needle upwards and tap
224
gently near the window of NovoPen 3 PenMate with your finger a few times.
225
§ Press the push button at the end of the barrel all the way in.
226
227
A drop of insulin should appear at the needle tip.
228
If not, repeat the procedure until a drop of insulin appears. There may still be some small
229
air bubble(s) in the PenFill cartridge after this, but they will not affect your dose and they
230
will not be injected.
231
232
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you do, the
233
extra insulin will squirt out of the needle. You may complete the air shot with the
234
number of units you have dialed or refer to the instructions on how to reset the dose to
235
zero in step 14.
236
237
238
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NovoPen 3 PenMate Instruction Manual
Page 16
FDA revision #4 (final)
SECTION 3
Choosing your dose
239
240
Choosing your dose
241
242
12 NovoPen 3 PenMate has an insulin scale with marks showing the approximate
243
number of units left in the PenFill cartridge. Always check that there is enough
244
insulin left for the injection. To activate, grip the barrel and the NovoPen 3 PenMate
245
and firmly pull in opposite directions until you hear a click.
246
Important: Do not pull the dial-a-dose selector.
247
Check that the dial-a-dose selector is set at zero. If zero does not appear, follow the
248
instructions on page 11.
249
250
251
13 Dial the number of units you need to inject.
252
The odd numbers are shown as full lines between the even numbers.
253
Do not use the clicking sound as a guide for selecting your dose.
254
255
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NovoPen 3 PenMate Instruction Manual
Page 17
FDA revision #4 (final)
256
257
The NovoPen 3 PenMate can deliver from 2 to 70 units of insulin in one unit increments.
258
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you do,
259
the extra insulin will squirt out of the needle. For instructions on how to reset the dose to
260
zero (0) so you can start again, see the next page.
261
262
SECTION 3 (cont.)
263
14 If you dial a larger dose than you need, you need to reset your NovoPen 3 PenMate to
264
zero.
265
To reset to zero (0) if you set the wrong dose:
266
a. Pull the barrel and the NovoPen 3 PenMate in opposite directions and keep hold
267
of them (see picture).
268
b. Press the push button on the barrel back to zero (0).
269
c. Release your grip and the barrel section will slide back into place.
270
d. You can now dial the correct units of insulin.
271
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Page 18
FDA revision #4 (final)
272
273
274
275
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NovoPen 3 PenMate Instruction Manual
Page 19
FDA revision #4 (final)
276
SECTION 4
Giving the injection
277
278
Giving the injection
279
15 Before injecting always check the dose indicator window to make sure you have
280
dialed the correct number of units.
281
After the airshot (see page 9) and choosing your dose, hold the NovoPen 3 PenMate
282
at the correct site on the body for an injection. Use the injection technique
283
recommended by your healthcare professional. The PenMate is designed with a cut-
284
away on one side. This cut-away allows injections at various angles other than 90°.
285
Press the yellow push-button on the NovoPen 3 PenMate with your finger (see arrow
286
in diagram). The needle will automatically enter the skin.
287
288
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NovoPen 3 PenMate Instruction Manual
Page 20
FDA revision #4 (final)
289
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NovoPen 3 PenMate Instruction Manual
Page 21
FDA revision #4 (final)
SECTION 4 (cont.)
290
16 To inject your dose, press the push button of the barrel section as far as it will go.
291
Do not force it (see arrow in diagram).
292
293
After injection, the needle should remain under the skin for several seconds. Keep the
294
push button fully depressed until the needle has been withdrawn from the skin.
295
If there is not enough insulin in the PenFill cartridge for the whole dose, you will be
296
able to see the number of units you still need to inject in the dose indicator window.
297
You must always check this after you have given the injection.
298
299
Important: Never turn the dial-a-dose selector to inject the insulin.
300
301
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Page 22
FDA revision #4 (final)
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303
When you press the push button, the piston rod presses against the rear rubber stopper of
304
the cartridge. This moves the rear rubber stopper and pushes the correct amount of
305
insulin out through the needle.
306
307
308
SECTION 4 (cont.)
309
Check that the dose indicator window shows zero. If it does not show zero, you did not
310
receive your full dose.
311
For example: If you dial 25 units and there are only 20 units left in the PenFill cartridge,
312
the number 5 will appear in the window following the injection (25-20=5). If this occurs,
313
proceed with the following steps:
314
To get the remaining part of your dose:
315
a. Note the number of units in the dose indicator window.
316
b. Remove the NovoFine needle (see Section 5).
317
c. Remove the empty Novolin PenFill 3 mL cartridge (see Section 8).
318
d. Insert a new Novolin PenFill 3 mL cartridge (see Section 1).
319
e. Attach a new NovoFine needle (see Section 1).
320
f. Do an air shot (see Section 2).
321
g. Dial the number of units noted in step a.
322
h. Give the injection.
323
324
SECTION 4 (cont.)
325
To make sure that the insulin has been injected, do the following to be certain that
326
the needle advanced and penetrated the skin:
327
§ Check that you can see the control line (solid white line) at the top of the insulin scale
328
(above the number 300).
329
§ Check to see if your skin is wet where you gave the injection.
330
331
If you cannot see the control line after the injection or your skin is wet, see SECTION 5
332
to perform a mechanical function check.
333
334
Call (800) 727-6500 or your healthcare professional if you have any questions.
335
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NovoPen 3 PenMate Instruction Manual
Page 24
FDA revision #4 (final)
336
337
SECTION 4 (cont.)
338
17 After the injection, remove the needle without recapping it. Hold the NovoPen 3
339
PenMate firmly while you unscrew the NovoFine disposable needle. Place the
340
NovoFine disposable needle in a puncture-resistant disposable container.
341
Health care professionals, relatives, and other caregivers should follow precautionary
342
measures for removal and disposal of needles to eliminate the risk of unintended
343
needle penetration.
344
345
346
347
Graphic to be
changed
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NovoPen 3 PenMate Instruction Manual
Page 25
FDA revision #4 (final)
The NovoFine disposable needle must be removed immediately after each injection
348
without recapping. Put the NovoPen 3 PenMate cap back on. If the NovoFine
349
disposable needle is not removed, some liquid may leak out of the PenFill cartridge. This
350
may cause a change in the strength of Novolin 70/30 or Novolin N insulin.
351
For information on how to properly dispose of needle containers, call your local trash
352
disposal authorities.
353
354
SECTION 5
Mechanical function check
355
356
Mechanical function check of NovoPen 3 PenMate
357
18 Hold the NovoPen 3 PenMate with the needle pointing upwards.
358
To activate, grip the barrel and the PenFill holder of the NovoPen 3 PenMate and
359
firmly pull in opposite directions until you hear a click. If you do not hear a click,
360
contact Customer Relations at our toll free number 1-800-727-6500. Never use a
361
NovoPen 3 PenMate unless you are sure that it is working properly.
362
Important: Do not pull the dial-a-dose selector.
363
Check that the dial-a-dose selector is set to zero. If not, press the push button all the
364
way in.
365
366
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Page 26
FDA revision #4 (final)
367
19 Push the yellow push button and the needle should appear.
368
You should now be able to see the needle and the control line.
369
If you cannot see the needle, do not use the NovoPen 3 PenMate. Never use the
370
NovoPen 3 PenMate unless you are sure that it is working properly.
371
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NovoPen 3 PenMate Instruction Manual
Page 27
FDA revision #4 (final)
372
Need Help? Call 1-800-727-6500
373
374
SECTION 6
For subsequent injections
375
376
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NovoPen 3 PenMate Instruction Manual
Page 28
FDA revision #4 (final)
For subsequent injections
377
20 Pull off the NovoPen 3 PenMate cap. Check that the needle has been removed
378
since your last injection. Check that NovoPen 3 PenMate contains the type of insulin
379
you want to inject. If the PenFill holder of your NovoPen 3 PenMate contains a clear
380
insulin PenFill cartridge such as Novolin R, follow steps 9 to 17.
381
382
21 If your NovoPen 3 PenMate contains an insulin suspension cartridge, such as Novolin
383
70/30 or Novolin N mix the insulin by turning the device up and down between
384
positions A and B -as shown in the picture. The movement must be performed so that
385
the glass ball in the cartridge moves from one end to the other. Do this at least ten
386
times until the liquid is white and uniformly cloudy.
387
Then continue as shown in steps 9 to15 and inject immediately.
388
389
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Page 29
FDA revision #4 (final)
390
391
392
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NovoPen 3 PenMate Instruction Manual
Page 30
FDA revision #4 (final)
393
SECTION 7
What to do when PenFill is nearly empty
394
395
What to do when PenFill is nearly empty
396
22 Do not start to inject an insulin suspension such as Novolin N or Novolin 70/30 if you
397
can see the rubber piston in the small inspection window. The glass ball must have
398
adequate space to resuspend the insulin. With the NovoPen 3 PenMate, it is possible
399
to select a dose that is larger than the number of units left in the PenFill cartridge. If
400
there is not enough insulin in the PenFill cartridge for the whole dose, you will be
401
able to see the number of units you still need to inject in the dose indicator window
402
after the injection.
403
To get the remaining part of your dose refer to Section 4, Page 14, a through h.
404
405
406
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NovoPen 3 PenMate Instruction Manual
Page 31
FDA revision #4 (final)
407
408
When you get near the end of a PenFill cartridge, you may need to give yourself two
409
injections to receive your full dose. If, after giving an injection, zero does not appear in
410
the dose indicator window, you did not receive your full dose.
411
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NovoPen 3 PenMate Instruction Manual
Page 32
FDA revision #4 (final)
412
SECTION 8
Changing PenFill
413
414
Changing PenFill
415
23 a) Unscrew the barrel from the NovoPen 3 PenMate.
416
b) Press the push button to set the dose indicator to zero.
417
c) Make sure that the piston rod is not out (see Section 1, Page 5). (Twist it gently
418
from side to side, if necessary).
419
420
421
422
423
24 Take out the empty PenFill cartridge. Take a new PenFill cartridge and continue
424
as described from steps 6 and 7.
425
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NovoPen 3 PenMate Instruction Manual
Page 33
FDA revision #4 (final)
426
Need Help? Call 1-800-727-6500
427
428
SECTION 9
Function check
429
430
Function check
431
25 If you think your NovoPen 3 PenMate is not working properly, follow this procedure:
432
a) Check that the barrel and the NovoPen 3 PenMate are screwed together tightly and
433
that the dose indicator window on the barrel is aligned with the yellow push button on
434
the NovoPen 3 PenMate.
435
b) Screw on a new NovoFine needle as described in step10.
436
c) Clear the air bubbles as described in step11.
437
d) Put the outer needle cap over the needle.
438
e) Dispense 20 units into the needle cap.
439
440
The insulin should fill the lower part of the outer needle cap. If the pen has delivered
441
too much or too little insulin, repeat the test. If it happens again, do not use the pen.
442
Contact your supplier.
443
Do not try to repair a faulty NovoPen 3 or a faulty NovoPen 3 PenMate.
444
Never use NovoPen 3 or NovoPen 3 PenMate unless you are sure that they are
445
working properly.
446
447
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NovoPen 3 PenMate Instruction Manual
Page 34
FDA revision #4 (final)
448
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NovoPen 3 PenMate Instruction Manual
Page 35
FDA revision #4 (final)
IMPORTANT
449
§ Keep the NovoPen 3 PenMate away from areas where temperatures may get too hot
450
or too cold such as a car or refrigerator.
451
§ Once the cartridge is punctured, it can be kept at room temperature for the length of
452
time identified in the storage information section of the Information For The Patient
453
supplied with the PenFill cartridges.
454
§ Make sure that the piston rod is completely inside the reset mechanism before you
455
screw together the barrel and the NovoPen 3 PenMate. (see step 5).
456
§ Always screw the mechanical section of NovoPen 3 and NovoPen 3 PenMate tightly
457
together.
458
§ Before each injection, make sure that you are using the right insulin preparation.
459
§ Always clear air bubbles with the needle pointing upwards before each injection (see
460
step 11).
461
§ With the NovoPen 3 PenMate, it is possible to select a dose which is larger than the
462
number of units left in the PenFill cartridge. Before you inject, always check on the
463
insulin scale that there is enough insulin left in the PenFill cartridge for your dose.
464
After the injection, always make sure that you have injected the whole dose by
465
checking that the dose indicator window reads 0. If not, see step 22.
466
§ Do not use the insulin scale on the NovoPen 3 PenMate to measure the amount of
467
insulin to be injected.
468
§ Before injecting, always check the dose indicator window to make sure you have
469
dialed the correct number of units.
470
§ After injecting, make sure that NovoPen 3 PenMate was released and that the insulin
471
has been injected (see step16).
472
§ Take the needle off the NovoPen 3 PenMate immediately after each injection. If
473
you do not remove it, temperature changes may cause liquid to leak out of the
474
needle. With Novolin N or Novolin 70/30, this may change the concentration of
475
the insulin.
476
§ Do not inject Novolin N or Novolin 70/30 if the rear rubber stopper can be seen in the
477
small inspection window.
478
§ Always have extra insulin of the same type(s) you use available for alternative
479
administration in case your NovoPen 3 PenMate, NovoPen 3, or PenFill gets lost or
480
damaged.
481
482
IMPORTANT (cont.)
483
§ Keep NovoPen 3 PenMate, NovoPen 3, PenFill, and NovoFine out of reach of
484
children.
485
§ Your NovoPen 3 and NovoPen 3 PenMate are for use by the same person only.
486
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NovoPen 3 PenMate Instruction Manual
Page 36
FDA revision #4 (final)
§ The NovoPen 3 PenMate is not recommended for the blind or visually impaired,
487
without the assistance of a sighted individual who knows how to use NovoPen 3
488
PenMate.
489
§ If you use more than one type (N, R, or 70/30) of insulin, use a separate NovoPen 3
490
PenMate for each type of insulin.
491
§ The American Diabetes Association recommends that insulin should be self-
492
administered. The proper age for initiating this should be assessed by the adult
493
caregiver.
494
§ Use only a new PenFill cartridge when loading the NovoPen 3 PenMate. Never load
495
the NovoPen 3 PenMate with a partially filled PenFill cartridge.
496
§ The NovoPen 3 PenMate is designed for use with PenFill 3 mL insulin cartridges and
497
NovoFine single-use disposable needles.
498
§ Novo Nordisk is not responsible for any consequences arising from the use of the
499
NovoPen 3 PenMate with products that are not recommended by Novo Nordisk.
500
IMPORTANT (cont.)
501
Guidelines for storing the NovoPen 3 PenMate and PenFill 3 mL cartridges:
502
§
Store the NovoPen 3 PenMate (with the PenFill cartridge inside) at room
503
temperature. Do not store the NovoPen 3 PenMate in a refrigerator or areas where
504
there may be extreme temperatures or moisture, such as your car. Once the cartridge
505
is punctured, it can be kept at room temperature for the length of time identified in
506
the storage information section of the Information For The Patient supplied with the
507
PenFill cartridges.
508
§
Store the NovoPen 3 PenMate without the NovoFine needle attached and with the
509
pen cap in position. Leaving the needle on can cause the insulin to leak. This will
510
affect the concentration of an insulin suspension.
511
§
For information on storing PenFill cartridges, see the package insert that comes in
512
the PenFill cartridge box. Once the cartridge is punctured, it can be kept at room
513
temperature for the length of time identified in the storage information section of the
514
Information For The Patient supplied with the PenFill cartridges. The expiration
515
date on the cartridge is for unused cartridges under refrigeration.
516
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NovoPen 3 PenMate Instruction Manual
Page 37
FDA revision #4 (final)
517
518
WHAT TO DO IF ...
519
Here are the answers to some questions you might need to ask when using your NovoPen
520
3 PenMate.
521
No insulin appears when I try to clear the air bubbles.
522
Check that your NovoPen 3 PenMatewas put together correctly when you changed the
523
PenFill cartridge. Make sure that the piston rod is completely inside the reset mechanism.
524
Also make sure that the barrel and the NovoPen 3 PenMate are screwed tightly together
525
(see steps 5 and 25).
526
No insulin appears when I try to clear the air bubbles and the push button will not
527
go in.
528
The needle may be blocked. Change the needle and repeat air shots until insulin appears
529
at the needle tip. Check if the PenFill cartridge is empty.
530
531
The push button will not depress during the injection.
532
533
Do not try to force the push button down. Check if the PenFill cartridge is empty.
534
If there was not enough insulin in PenFill cartridge for the whole dose, you will see the
535
number of units you still need to inject in the dose indicator window. Make a note of this.
536
Change the PenFill cartridge and continue as described from step 23.
537
538
539
540
541
542
WHAT TO DO IF ... (cont.)
543
I cannot press the push button back to zero before I return the piston rod.
544
The reset mechanism may be locked. Gently twist the reset mechanism from side to side
545
until it unlocks. See the picture in step 5. Then you can press the push button down to
546
zero. Never turn the dosage selector back.
547
I cannot get the piston rod back inside the reset mechanism when I change the
548
PenFill cartridge.
549
The reset mechanism may be locked. Gently twist the reset mechanism from side to side
550
until it unlocks. Then turn the reset mechanism to the right until the piston rod is
551
completely inside it. See the picture in step 5.
552
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NovoPen 3 PenMate Instruction Manual
Page 38
FDA revision #4 (final)
553
I think the needle has not entered the skin.
554
Check that you can see the control line at the top of the insulin scale.
555
Also check if your skin is wet at the injection site. Carry out the mechanical function
556
check as described in steps 18 and 19.
557
I think my NovoPen 3 or my NovoPen 3 PenMate is not working properly.
558
Carry out the function check described in step 25. Make sure that the lower part of the
559
outer needle cap is filled with 20 units of insulin. Also carry out the mechanical function
560
check as described in steps18 and 19. Make sure that the control line is visible when
561
NovoPen 3 PenMate is released. Never use your NovoPen 3 or your NovoPen 3 PenMate
562
unless you are sure that they are working properly.
563
564
MAINTENANCE
565
566
How to store and look after your NovoPen 3 and your NovoPen 3 PenMate
567
NovoPen 3 and NovoPen 3 PenMate are designed to work accurately. They should be
568
handled with care. Avoid situations where your NovoPen 3 and NovoPen 3 PenMate can
569
be damaged. Do not drop. Do not expose to excessive pressure or blows. Keep them in
570
the soft case whenever possible.
571
572
You can put PenFill cartridges in NovoPen 3 PenMate or carry them with you as spares.
573
Please read the Information For The Patient supplied with the PenFill cartridges
574
for details of how to store the cartridges and how long to keep them.
575
576
You can clean your NovoPen 3 and your NovoPen 3 PenMate by wiping them with a
577
cotton swab moistened with ethyl or isopropyl alcohol.
578
579
Your NovoPen 3 and your NovoPen 3 PenMate are sturdy products but could still get
580
damaged. So handle them with care and protect them against dust and dirt when they are
581
not carried in the case.
582
583
Do not try to repair a faulty NovoPen 3 or a faulty NovoPen 3 PenMate.
584
585
NovoPen 3 and NovoPen 3 PenMate must only be used in the way described in this
586
booklet. The manufacturer will not be responsible for any problems you have with the
587
equipment if you have not followed this booklet. If you find your NovoPen 3 or your
588
NovoPen 3 PenMate faulty, Novo Nordisk will replace it if:
589
§ You call Novo Nordisk Pharmaceuticals, Inc. at our toll free number 1-800-727-6500
590
within three years of getting it.
591
592
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NovoPen 3 PenMate Instruction Manual
Page 39
FDA revision #4 (final)
WARRANTY
593
594
Should your NovoPen 3 PenMate device be defective in materials or workmanship within
595
three (3) years of purchase, Novo Nordisk Pharmaceuticals, Inc., will replace it at no
596
charge if you mail the defective unit along with a description of the problem and the sales
597
receipt or other proof of purchase to:
598
599
Novo Nordisk Pharmaceuticals, Inc.
600
Customer Relations
601
100 College Road West
602
Princeton, New Jersey 08540-7810.
603
604
No other warranty is made with respect to NovoPen 3 PenMate. The mechanical section
605
of the NovoPen 3 insulin pen is covered by its own separate warranty. which is described
606
in its instruction manual. This warranty will be invalid and Novo Nordisk A/S, Novo
607
Nordisk Pharmaceuticals, Inc., Bristol-Myers Squibb Co., Nipro Medial Industries Ltd.,
608
and Bang & Olufsen A/S cannot beheld responsible in the case of defects or damages
609
arising from:
610
611
§ The use of the NovoPen 3 PenMate with products other than NovoPen 3, PenFill 3 mL
612
cartridges, and NovoFine single-use disposable needles.
613
614
§ The use of the NovoPen 3 PenMate not in accordance with the instructions in this
615
booklet.
616
617
§ Physical damage to the NovoPen 3 PenMate caused by neglect, misuse, unauthorized
618
repair, accident, or other breakage.
619
620
Use of the NovoPen 3 PenMate does not extend the warranty of the NovoPen 3 insulin
621
pen.
622
623
For assistance or further information, write to:
624
Novo Nordisk Pharmaceuticals, Inc.
625
Customer Relations
626
100 College Road West
627
Princeton, NJ 08540-7810
628
629
Or call: 1-800-727-6500
630
631
License under U.S. Patents Nos. 5,462,535; 5,693,02; 5,626,566 and Des. 347,894
632
(cartridge) restricted to use with Novo Nordisk insulin cartridges and Novo Nordisk pen
633
needles.
634
635
Novolin®, NovoPen®, PenFill®, NovoPen® 3 PenMate®, and NovoFine® are
636
trademarks owned by Novo Nordisk A/S.
637
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 40
FDA revision #4 (final)
638
2002 Novo Nordisk Pharmaceuticals, Inc.
639
640
www.novonordisk-us.com
641
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
David Orloff
3/11/02 05:06:34 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.105660 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19-938S30lbl.pdf', 'application_number': 19959, 'submission_type': 'SUPPL ', 'submission_number': 31} |
1,858 |
Novopen Illustration
Introduction
Read the Patient Instructions for Use that comes with NovoPen
4 before you start using it and each time you get a refill. There
may be new information. This leaflet does not take the place of
talking with your healthcare provider about your medical
condition or your treatment.
NovoPen 4 is an insulin pen that can deliver insulin doses from 1
to 60 units, in increments of 1 unit. NovoPen 4 is designed to be
used with PenFill 3 mL insulin cartridges and NovoFine
disposable needles.
NovoFine disposable needles are for one time use only.
You should read the instructions in this manual even if you have
used NovoPen 4 or other Novo Nordisk delivery systems before.
NovoPen 4 should not be used by people who are blind or have
visual problems without the help of a person who has good
eyesight and who is trained to use the NovoPen 4 the right way.
Getting Ready
Make sure you have the following items:
• NovoPen 4
• alcohol swabs
• PenFill 3 mL insulin cartridge
• NovoFine disposable needle Novopen Illustration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Usage Illustration
Preparing your NovoPen 4
Before you start to prepare your injection, check the label to
make sure that you are taking the right type of insulin (such as
Novolin R, Novolin N, Novolin 70/30, or NovoLog).
A. Pull off the cap. See Figure A.
B. Unscrew and remove the cartridge holder from the
mechanical part. See Figure B.
C. Push in the piston rod, by gently pressing the piston rod head
(see Figure C1) in until it stops and looks like Figure C2.
Please note when NovoPen 4 is apart while removing the PenFill
cartridge, the piston rod can move back and forth without
pressing it.
If you use more than one kind of insulin, you should use a
separate delivery device for each product. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
D. Use a new PenFill cartridge.
To remove the PenFill cartridge from its wrapper, push the
cartridge through the foil side of the packaging (see Figure D1).
Before use, check that the PenFill cartridge is full and intact and
with no cracks. If not, do not use it.
How to prepare (resuspend) the insulin if the PenFill cartridge
contains an insulin suspension (white and cloudy insulin) such
as Novolin 70/30 or Novolin N you must:
Before inserting a 3 mL cartridge into your NovoPen 4 for
the first time:,
o Roll the PenFill cartridge between your hands 10 times.
These steps should be done with the 3 mL PenFill
cartridge in a flat (horizontal) position (see Figure D2)
o Then turn the PenFill cartridge up and down between
positions A and B (see Figure D3) so the glass ball
moves from one end of the cartridge to the other. Do
this at least 10 times. Repeat the rolling and turning
steps until the insulin looks white and cloudy. Mixing is
easier when the insulin is at room temperature.
After the first use of the 3 mL PenFill cartridge
o With the cartridge in the NovoPen 4, turn it upside
down between positions A and B (see Figure D3
above), so that the glass ball moves from one end of
the 3 mL PenFill cartridge to the other. Do this until all
of the insulin looks white and cloudy.
o Before you inject your insulin:
make sure there is at least 12 units of insulin left in
the cartridge this helps to make sure that the
remaining insulin is evenly mixed. If there is less
than 12 units left in the cartridge, use a new 3 mL
PenFill cartridge. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each PenFill 3 mL cartridge contains a total of 300 units of
insulin. There are five cartridges in a box. Each PenFill cartridge
is for only one person to use.
DO NOT share your NovoPen 4 with other people even if they
have diabetes. Sharing the PenFill cartridge can spread
disease.
Use only a new PenFill 3 mL cartridge when loading the
NovoPen 4. Never load a partially filled PenFill cartridge. Never
try to refill a used PenFill 3 mL cartridge.
E. Insert the PenFill cartridge into the cartridge holder, colored
cap first. See Figure E.
You can see the PenFill cartridge scale in the cartridge window.
The cartridge holder has a scale with marks showing about how
much insulin is left in the PenFill cartridge.
F. Screw the mechanical part together with the cartridge holder
until you hear or feel a click. See Figure F1.
Before each injection, check the amount of insulin left in the
PenFill cartridge:
If the rear rubber stopper cannot be seen in the cartridge
window, you have enough insulin for mixing left in the PenFill
cartridge. See Figure F2.
If the rear rubber stopper can be seen in the cartridge holder
window, you do not have enough insulin left in the PenFill
cartridge and must use a new PenFill 3 mL cartridge. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Wipe the rubber stopper with an alcohol swab. See Figure F3.
G. Remove the protective tab from a NovoFine disposable
needle. Screw the needle tightly onto the colored cap. See
Figure G.
Always use a new NovoFine disposable needle for each
injection.
Never place a NovoFine disposable needle on your NovoPen 4
until you are ready to do an air shot and take your injection.
H. Pull off the outer needle cap. Carefully pull off the inner
needle cap and throw it away. See Figure H1. A droplet of
insulin may appear at the needle tip. This is normal.
Do not bend or damage the needle. To lessen the risk of
unexpected needle sticks, never put the inner needle cap back
on the needle.
Always take off the needle after each injection and store the
NovoPen 4 without a needle attached. This prevents
contamination, infection, leakage of insulin, and will ensure
accurate dosing.
Do an “Air Shot” before each injection
Before each injection a small amount of air may collect in the
PenFill cartridge. To avoid injecting air and ensure proper
dosing, you must do an air shot before each injection.
Before starting the air shot, the dose indicator window must
show zero (0) see Figure H2.
Set the NovoPen 4 for the air shot: Usage IllustrationUsage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
I. Make sure that a NovoFine disposable needle is attached.
See Figure I.
J. Pull out the dose button, if it is not already pulled out. See
Figure J.
K. Turn the dose button to select:
4 units with a new PenFill cartridge. 4 units are selected
when the number 4 lines up with the dose indicator. See
Figure K.
OR
1 unit with a cartridge already in use. 1 unit is selected
when the number 1 lines up with the dose indicator. See
Figure K.
1 increment is equal to 1 unit.
The even numbers are shown. The odd numbers are indicated
by the lines between the even numbers.
L. Hold your NovoPen 4 with the needle pointing up.
Tap the PenFill cartridge holder gently with your finger a few
times to make any air bubbles collect at the top of the cartridge.
See Figure L. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
M. Keep the needle pointing up, press the dose button all the
way in, until you hear or feel a click. The display will return to 0.
A drop of insulin must appear at the needle tip. See Figure M. If
you do not see a drop of insulin at the needle tip, repeat steps I
to L until you see a drop of insulin at the needle tip. You may
need to do this up to 6 times. If you do not see a drop of insulin
after 6 times, do not use the NovoPen 4 and call Novo Nordisk
at 1-800-727-6500.
It is very important that a drop of insulin is seen at the needle tip
before you take your injection. This will ensure accurate dosing.
A small air bubble may remain in the PenFill cartridge. This is
normal it will not affect your dose and will not be injected.
Select your dose
Be sure to do an air shot before giving an injection.
N. Pull out the dose button, if it is not already pulled out. See
Figure N.
O. Turn the dose button to the number of units you need to
inject. The pointer should line up with your dose that is needed.
Remember that 60 units is the maximum dose you can take in
one injection. See Figure O.
If you select a different dose than you need, turn the dose button
until the correct dose lines up with the dose indicator.
If you need more than 60 units, you must divide your dose into
two injections. Inject the 60 units first and then make a new
injection with the remaining number of units needed to complete
your dose. For example, to inject 65 units you must inject 60
units first and then make a new injection with 5 units of insulin to
complete your dose. Always use a new disposable needle for
each injection. See Figure O.
Give your injection
Give the injection exactly as shown to you by your healthcare
provider.
P. Insert the needle into your skin. Inject the dose by pressing
the dose button all the way in, until you hear or feel a click.
Check the dose indicator window to make sure it shows zero (0).
See Figure P. Usage IllustrationUsage Illustration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Q. Keep the NovoFine needle in the skin for at least 6 seconds.
See Figure Q
This will make sure that the full insulin dose has is given.
Be careful only to press the dose button to inject the insulin.
Turning the dose button will not inject insulin.
R. Take the needle out of your skin. You have completed your
injection and the selected insulin dose has been given. The
display will show 0. If zero (0) does not appear, you did not get
the full dose. See Figure R.
After you take the needle out of your skin, you may see a few
drops of insulin at the needle tip. This is normal and has no
effect on the dose you just received.
If your injection is given by another person, this person must be
careful when removing and disposing of needles to prevent
accidental needle stick injury.
After the injection
The NovoFine disposable needle must be removed immediately
after each injection without replacing the cap.
Do not recap the needle. Recapping can lead to a needle stick
injury. Remove the needle from the NovoPen 4 after each
injection. This helps to prevent infection, leakage of insulin, and
will help to make sure you inject the right dose of insulin.
S. Carefully remove the needle (see Figure S), put the needle
and any empty PenFill cartridge in a sharps container, or some
type of hard plastic or metal container with a screw top such as a
detergent bottle or empty coffee can. These containers should
be sealed and thrown away the right way. Check with your
healthcare provider about the right way to throw away used
needles and syringes. There may be local or state laws about
how to throw away used needles. Do not throw away used
needles in household trash or recycling bins.
Always replace the pen cap after each use.
Put the pen cap on the NovoPen 4 and store the NovoPen 4
without the needle attached. This helps to ensure sterility,
prevent leakage of insulin, and will help to make sure you inject
the right dose of insulin with your next injection. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Change the PenFill cartridge
When the PenFill cartridge is almost empty:
T. The cartridge scale on the PenFill cartridge holder shows the
approximate number of insulin units left in the PenFill cartridge
as in Figure A. Do not use the cartridge scale to measure the
amount of insulin to be injected. See Figure T.
U. If the PenFill cartridge has less than 60 units in it, the exact
number of units left can be read in the display. To do this, pull
out the dose button, if it is not already pulled out, and turn it until
it stops. The number of units left will line up with the dose
indicator as seen in Figure B. If the dose indicator is positioned
between two lines, adjust to the lower of the two dose amounts.
You can not select a dose larger than the number of units left in
the PenFill cartridge. See Figure U.
Do not force the dose button to turn as this can damage your
NovoPen 4.
Insulin suspension (white and cloudy insulin):
V. Do not try to inject an insulin suspension (white and cloudy
insulin) if the rubber stopper (plunger) is below the white line on
the holder as in Figure V. The glass ball inside the PenFill
cartridge must have enough space to mix the insulin.
If you need more insulin than the amount left in the PenFill
cartridge, you can:
Inject the amount of insulin left in the PenFill cartridge,
making a note of the number of units you inject or replace the
used PenFill cartridge with a new one for your full dose.
To change the PenFill cartridge see Figure T to U.
Always attach a new NovoFine needle.
Do an airshot as described in Figure I to M.
Select and inject the number of insulin units needed to
complete your dose.
Storage
Storage and handling
Be careful when handling your NovoPen 4, do not drop it and
avoid knocking it against hard surfaces.
Always remove the needle and replace the pen cap after each
use. Usage IllustrationUsage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Protect your NovoPen 4 against direct sunlight, water, dust and
dirt.
When a PenFill cartridge is inserted in the NovoPen 4, store
your NovoPen 4 at 59oF to 86°F (15oC to 30°C) for the amount
of days listed in the PenFill “Information for the Patient” leaflet
for the type of insulin you are using.
The expiration date printed on the PenFill cartridge is for
unused PenFill cartridges stored in the refrigerator. Never use
the PenFill cartridge after the expiration date on the PenFill
cartridge or on the box.
For information on storing PenFill cartridges, see the
Information For The Patient leaflet that comes in the PenFill
cartridge box.
Keep your NovoPen 4 in the case supplied when possible.
Maintenance
Cleaning and maintenance
You can clean the outside of your NovoPen 4 by wiping it with
a damp cloth.
Do not soak in water, wash or lubricate your NovoPen 4, this
may damage it.
Clean off dirt and dust with a dry cloth.
Important Things to Know
Always keep a spare insulin delivery system in case your
NovoPen 4 is lost or damaged.
Keep your NovoPen 4, PenFill cartridges, and NovoFine
needles out of the reach of children.
Keep the NovoPen 4 away from areas where temperatures
may get too hot or too cold such as a car or refrigerator.
Use a separate insulin delivery device if you are using more
than one type of insulin in PenFill cartridges.
Novo Nordisk is not responsible for harm due to using the
NovoPen 4 with products other than PenFill 3 mL insulin
cartridges, and NovoFine single use disposable needles.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Warranty
Do not try to repair a faulty NovoPen 4.
If you think your NovoPen 4 is not working the right way, contact
Novo Nordisk at 1-800-727-6500.
The LOT number of your NovoPen 4 it is located on the
mechanical part as illustrated in the inside cover.
For assistance or further information, write to:
Novo Nordisk Inc.
Customer Care
100 College Road West
Princeton, NJ 08540
Or call: 1-800-727-6500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Quick Guide Usage Illustration
Preparing NovoPen 4
Pull off the cap. Unscrew and remove the cartridge holder from
the mechanical part. See Figure 1.
Push in the piston rod, by pressing the piston rod head in until it
stops and looks like Figure 2.
If you are using an insulin suspension (white and cloudy insulin),
always mix (resuspend) it before use. See the NovoPen 4
Instruction Manual for details on how to mix (resuspend) the
insulin.
Insert the PenFill cartridge into the cartridge holder, the color-
coded cap goes in first. See Figure 3. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Screw NovoPen 4 together (see Figure 4).
Wipe the front rubber stopper with an alcohol swab and screw
on a new NovoFine disposable needle. Pull off the outer and
inner needle caps. Dispose of the needle caps. See Figure 5.
Do an “Air Shot” before each injection
Always do an airshot before each injection.
Pull out the dose button, if it is not already pulled out, and turn it
to select: See Figure 6.
4 units with a new PenFill cartridge
OR
1 unit with a cartridge already in use
Hold your NovoPen 4 with the needle facing upwards.
Tap the cartridge holder gently with your finger a few times to
make any air bubbles collect at the top of the cartridge. See
Figure 7.
Press the dose button all the way in, until you hear or feel a
click. The display will return to (0) See Figure 8. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A drop of insulin must appear at the needle tip. See Figure 9.
If you do not see a drop of insulin, repeat steps in Figures 5 to 7
until you see a drop of insulin. You may need to do this up to 6
times. If you do not see a drop of insulin after 6 times, do not
use the NovoPen 4 and call Novo Nordisk at 1-800-727-6500.
Select your dose
Pull out the dose button, if it is not already pulled out, and turn
the dose button until your needed dose lines up with the dose
indicator. See Figure 10.
If you select a different dose than you need, turn the dose button
until the correct dose lines up with the dose indicator.
Give your injection
Give the injection exactly as shown to you by your healthcare
provider.
To inject, press the dose button completely in, until you hear or
feel a click. Turning the dose button will not inject insulin.
Leave the needle under the skin for at least 6 seconds. See
Figure 11. Take the needle out of your skin, your selected dose
has been given. Remove and dispose of the needle (follow the
detailed instructions in the NovoPen 4 Instruction Manual).
Put the pen cap back on. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Front of carton:
List: XXXXXX
NovoPen® 4
Dial-A-Dose
Insulin Delivery Pen
CONTAINS ONE NOVOPEN 4
Designed for use with PenFill 3 mL cartridges and NovoFine disposable needles
Side Flap of Carton:
NovoPen® 4
Dial-A-Dose
Insulin Delivery Pen
List: XXXXXXX
Lot
Side Flap of Carton:
NovoPen 4
Dial-A-Dose
Insulin Delivery Pen
Convenient Carrying Case Enclosed
The NovoPen 4 is designed for use with PenFill 3 mL cartridges and NovoFine
disposable needles.
Needles and cartridges not included.
Back of Carton:
For information contact:
Novo Nordisk Inc.
Princeton, NJ 08540
www.novonordisk-us.com
Manufactured in Denmark by Novo Nordisk A/S
2880 Bagvaerd, Denmark
NovoPen 4 is covered under US Patent No. 5,693,027, US
Patent No. 6,663,602, US Patent No. 7,241,278, and other patents pending.
Novo Nordisk, NovoPen, NovoFine, NovoLog, PenFill, and Novolin are registered
trademarks of Novo Nordisk A/S.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.107895 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019938s064,019959s067,019991s068,020986s055lbl.pdf', 'application_number': 19959, 'submission_type': 'SUPPL ', 'submission_number': 67} |
1,863 |
N HUMAN
Novo Nordisk®
Patient Information for Novolin® N
NOVOLIN® N (NO-voe-lin)
NPH,
Human Insulin Isophane Suspension Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information leaflet that comes with Novolin® N before you start taking it
and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin® N?
Novolin® N is a man-made insulin (recombinant DNA origin) NPH, Human Insulin
Isophane Suspension that is structurally identical to the insulin produced by the human
pancreas that is used to control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin® N?
Do not take Novolin® N if:
• Your blood sugar is too low (hypoglycemia).
• You are allergic to anything in Novolin® N. See the end of this leaflet for a
complete list of ingredients in Novolin® N. Check with your healthcare provider if
you are not sure.
Tell your healthcare provider:
• about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin® N.
• if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin® N has not been studied in pregnant or nursing women.
• about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
blood sugar levels and your insulin needs. Your Novolin® N dose may need to
change if you take other medicines.
Reference ID: 3706638
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• if you take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
• if you have heart failure or other heart problems. If you have heart failure, it
may get worse while you take TZDs with Novolin® N.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin® N?
Only use Novolin® N if it appears cloudy or milky. There may be air bubbles. This is
normal. If the precipitate (the white deposit at the bottom of the vial) has become lumpy
or granular in appearance or has formed a deposit of solid particles on the wall of the
vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not be
used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin® N comes in:
• 10 mL vials (small bottles) for use with syringe
Read the instructions for use that come with your Novolin® N product. Talk to
your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject Novolin® N before you start taking it. Follow your
healthcare provider’s instructions to make changes to your insulin dose.
• Take Novolin® N exactly as prescribed.
• Novolin® N is an intermediate-acting insulin. The effects of Novolin® N start
working 1½ hours after injection.
• The greatest blood sugar lowering effect is between 4 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
• While using Novolin® N, any change of insulin should be made cautiously and
only under medical supervision. Doses of oral anti-diabetic medicines may also
need to change, if your insulin is changed.
• Do not mix Novolin® N with any insulins other than Regular human insulin in the
same syringe.
• Inject Novolin® N into the skin of your stomach area, upper arms, buttocks
or upper legs. Novolin® N may affect your blood sugar levels sooner if you
inject it into the skin of your stomach area. Never inject Novolin® N into a vein
or into a muscle.
Reference ID: 3706638
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
each injection.
• If you take too much Novolin® N, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin® N?”
for more information on low blood sugar (hypoglycemia).
• If you forget to take your dose of Novolin® N, your blood sugar may go too
high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can
lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
• increased thirst
• fruity smell on breath
• frequent urination and
• high amounts of sugar and
dehydration
ketones in your urine
• confusion or drowsiness
• nausea, vomiting (throwing
up) or stomach pain
• loss of appetite
• a hard time breathing
• Do not reuse or share your syringes or needles with other people. You
may give other people a serious infection, or get a serious infection from
them.
• Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
• illness
• change in diet
• stress
• change in physical activity or
exercise
• other medicines you take
• surgery
See the end of this patient information for instructions about preparing and giving the
injection.
Reference ID: 3706638
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while using Novolin® N?
• Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin® N.
• Driving and operating machinery. You may have difficulty concentrating or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
• low blood sugar
• decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin® N?
• Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
• sweating
• trouble concentrating or confusion
• dizziness or lightheadedness
• blurred vision
• shakiness
• slurred speech
• hunger
• anxiety, irritability or mood
changes
• fast heart beat
• headache
• tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
• Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin® N and use a different insulin. Do not inject insulin into skin that is red,
swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
• Swelling of your hands and feet
• Heart Failure. Taking certain diabetes pills called thiazolidinediones or “TZDs”
with Novolin® N may cause heart failure in some people. This can happen even
Reference ID: 3706638
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if you have never had heart failure or heart problems before. If you already have
heart failure it may get worse while you take TZDs with Novolin® N. Your
healthcare provider should monitor you closely while you are taking TZDs with
Novolin® N. Tell your healthcare provider if you have any new or worse
symptoms of heart failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and Novolin® N may need to be adjusted or stopped by
your healthcare provider if you have new or worse heart failure.
• Vision changes
• Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin® N. Ask your healthcare
provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store Novolin® N?
All Unopened Novolin® N:
• Keep all unopened Novolin® N in the refrigerator between 36° to 46°F
(2° to 8°C).
• Do not freeze. Do not use Novolin® N if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
• Keep unopened Novolin® N in the carton to protect from light.
Novolin® N in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the
Novolin® N label, if the medicine has been stored in a refrigerator.
General advice about Novolin® N
Novolin® N is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Reference ID: 3706638
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Novolin® N for a condition for which it was not prescribed. Do not give Novolin® N to
other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin® N. If you would
like more information about Novolin® N or diabetes, talk with your healthcare provider.
For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin® N ingredients include:
• Human Insulin Isophane
Suspension (recombinant DNA
origin)
• Zinc chloride
• Sodium hydroxide
• Phenol
• Disodium phosphate dihydrate
All Novolin® N vials are latex-free.
Date of issue: February 2015
Version: X
• Metacresol
• Glycerol
• Hydrochloric acid
• Protamine sulfate
• Water for injections
Novolin® and Novo Nordisk® are registered trademarks of Novo Nordisk A/S.
© 2005 -2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin® N contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
Reference ID: 3706638
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Patient Instructions for Use
Novolin® N 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin N vial?
1. Check to make sure that you have the correct type of insulin. This is especially important
if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond the correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin N in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the pinched skin.
Press the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin N at the needle
tip. This is normal and has no effect on the dose you just received. If you see blood after
Reference ID: 3706638
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| custom-source | 2025-02-12T13:43:23.195474 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019959s075lbl.pdf', 'application_number': 19959, 'submission_type': 'SUPPL ', 'submission_number': 75} |
1,886 | 1
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NovoPen 3 PenMate Instruction Manual
Page 2
FDA revision #4 (final)
2
NovoPen® 3
3
previous page for graphic
4
PenMate®
5
6
Instruction Manual
7
8
Read this carefully
9
before you use
10
NovoPen® 3 PenMate®
11
and NovoPen® 3
12
13
14
15
16
INTRODUCTION
17
NovoPen® 3 PenMate® is a replacement component specifically designed to be used
18
with the NovoPen 3 insulin pen. NovoPen 3 PenMate helps you to insert the needle and
19
to give injections quickly and easily. With NovoPen 3 and NovoPen 3 PenMate, you can
20
dial doses in units of one from 2 to 70 units.
21
NovoPen 3 PenMate should only be used in combination with products that are
22
compatible and allow the device to function safely and effectively.
23
NovoPen 3 PenMate is designed to be used with:
24
§ NovoPen® 3
25
§ PenFill® 3 mL cartridges
26
§ NovoFine® 30G/8 mm and NovoFine® 31G/6 mm needles.
27
NovoFine disposable needles are for single-use only.
28
29
The NovoPen 3 PenMate can be used the same way as the NovoPen 3 insulin pen. Its
30
design allows you to use the same recommended injection technique as for the NovoPen
31
3 insulin pen.
32
33
This booklet contains instructions for using, storing, and cleaning NovoPen 3 PenMate in
34
combination with NovoPen 3. Please follow them carefully. You should read these
35
instructions even if you have used NovoPen 3, or NovoPen 3 in combination with the
36
NovoPen 3 PenMate before. The two following pages provide illustrations of both the
37
NovoPen 3 and the NovoPen 3 PenMate.
38
39
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NovoPen 3 PenMate Instruction Manual
Page 3
FDA revision #4 (final)
Always check that the PenFill® cartridge you use contains the correct type of insulin.
40
If you are treated with more than one type of insulin in PenFill cartridges, you should use
41
a separate NovoPen 3 PenMate and NovoPen 3 for each type of insulin.
42
43
If you have any questions about your NovoPen 3 PenMate or your NovoPen 3 insulin
44
delivery device, please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
45
Please complete and return the NovoPen 3 PenMate Warranty Card.
46
Thank you for choosing the NovoPen 3 PenMate and NovoPen 3 insulin delivery device.
47
Look at the diagram
48
49
50
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NovoPen 3 PenMate Instruction Manual
Page 4
FDA revision #4 (final)
51
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NovoPen 3 PenMate Instruction Manual
Page 5
FDA revision #4 (final)
52
PenFill Holder
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NovoPen 3 PenMate Instruction Manual
Page 6
FDA revision #4 (final)
53
HOW TO USE THIS BOOKLET
54
This booklet gives you step-by-stepinstructions for using the NovoPen 3 PenMate in
55
combination with the NovoPen 3.
56
57
Begin by reviewing the illustration layout of the parts of the NovoPen 3, NovoPen 3
58
PenMate, PenFill 3 mL cartridge and NovoFine disposable needle. The inside front cover
59
opens out so you have a handy reference while you read the rest of the booklet.
60
Most pages contain an illustration on the right with numbered instructions to the left of
61
the illustration.
62
Important additional information is given below the illustration.
63
We suggest that you read the text and look at the illustrations to make sure that you
64
understand each step thoroughly.
65
Also included is a diagram showing a side-by-side comparison of the NovoPen 3 and the
66
NovoPen 3 PenMate. This illustration allows you to see which part of the NovoPen 3 the
67
NovoPen 3 PenMate replaces.
68
69
The main differences between the NovoPen 3 and the NovoPen 3 PenMate are as
70
follows:
71
The PenFill cartridge holder and the Pen cap of the NovoPen 3 are replaced by the
72
NovoPen 3 PenMate.
73
NovoPen 3 PenMate allows for automatic insertion of the NovoFine needle under the
74
skin; NovoPen 3 requires manual needle insertion.
75
NovoPen 3 PenMate allows for the NovoFine needle to be completely hidden prior to
76
needle insertion; the needle is visible on the NovoPen 3 prior to needle insertion.
77
78
Look at the diagram inside the front cover for the names of the different parts of
79
NovoPen 3 and NovoPen 3 PenMate. You can unfold the diagram to help you while
80
you follow the instructions.
81
82
83
84
85
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NovoPen 3 PenMate Instruction Manual
Page 7
FDA revision #4 (final)
86
TABLE OF CONTENTS
87
SECTION 1:
88
Assembly of the NovoPen 3 PenMate............................................ 4
89
SECTION 2:
90
Air shot before each injection........................................... 9
91
SECTION 3:
92
Choosing your dose......................................................... 10
93
SECTION 4:
94
Giving the injection......................................................... 12
95
SECTION 5:
96
Mechanical function check of NovoPen 3 PenMate.......... 17
97
SECTION 6:
98
For subsequent injections................................................ 18
99
SECTION 7:
100
What to do when PenFill is nearly empty......................... 19
101
SECTION 8:
102
Changing PenFill............................................................ 20
103
SECTION 9:
104
Function check............................................................... 21
105
IMPORTANT................................................................ 22
106
WHAT TO DO IF.......................................................... 25
107
HOW TO STORE AND LOOK AFTER YOUR
108
NOVOPEN 3 AND YOUR NOVOPEN 3 PENMATE... 27
109
WARRANTY................................................................. 28
110
111
112
113
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NovoPen 3 PenMate Instruction Manual
Page 8
FDA revision #4 (final)
SECTION 1
Assembly of the NovoPen3 PenMate
114
Assembly of the NovoPen 3 PenMate
115
116
1 Take NovoPen 3 out of its case by pressing the top of the pen cap.
117
118
119
2 Gently twist the pen cap until it separates from the barrel.
120
121
3 Pull the pen cap straight up to remove it.
122
123
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NovoPen 3 PenMate Instruction Manual
Page 9
FDA revision #4 (final)
4 Unscrew and remove the PenFill holder from the barrel*
124
125
* See diagram.
126
You will not use the pen cap and PenFill holder with the NovoPen 3 PenMate but you
127
should store them in the case if you want to use NovoPen 3 without NovoPen 3 PenMate
128
in the future.
129
SECTION 1 (cont.)
130
5 The end of the piston rod should be flat against the end of the reset mechanism prior to
131
inserting each new Novolin PenFill 3 mL cartridge. It should not be sticking out.
132
133
If the piston rod is sticking out:
134
Turn the end of the reset mechanism in a clockwise direction until the piston rod is no
135
longer sticking out. Never push the piston rod back in.
136
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NovoPen 3 PenMate Instruction Manual
Page 10
FDA revision #4 (final)
137
Need Help? Call 1-800-727-6500
138
139
You should not reset the piston rod again until it is time to remove the used PenFill 3 mL
140
cartridge and insert a new one.
141
142
If the reset mechanism locks, it is usually due to improper technique. Gently turn the
143
mechanism side to side until it unlocks. Then call our toll free number (1-800-727-6500)
144
so that we may review your operating technique with you.
145
146
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NovoPen 3 PenMate Instruction Manual
Page 11
FDA revision #4 (final)
147
SECTION 1 (cont.)
148
6 Press the push button all the way in until zero (0) appears in the window. The zero
149
should be lined up with the stripe below the dose indicator window.
150
To remove the PenFill cartridge from its wrapper, push the cartridge through the foil
151
side of the packaging.
152
Before use, check that the PenFill cartridge is full and intact. If not, do not use it.
153
154
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NovoPen 3 PenMate Instruction Manual
Page 12
FDA revision #4 (final)
7 If you use Novolin 70/30 [70% NPH, Human Insulin Isophane Suspension and 30%
155
Regular, Human Insulin Injection (recombinant DNA origin)] or Novolin N, NPH
156
[Human Insulin Isophane Suspension (recombinant DNA origin)], mix the insulin:
157
158
a. Turn PenFill cartridge up and down between positions A and B, as shown.
159
b. Repeat this mixing step at least 10 times or until the insulin looks uniformly white
160
and cloudy.
161
162
163
If you use more than one type (N, R, or 70/30) of insulin, use a separate NovoPen 3
164
PenMate for each type.
165
166
Once the cartridge is punctured, it can be used at room temperature for the length of time
167
identified in the storage information section of the Information For The Patient supplied
168
with the PenFill cartridges. The expiration date on the cartridge is for unused cartridges
169
under refrigeration.
170
171
SECTION 1 (cont.)
172
Take the NovoPen 3 PenMate out of its case.
173
Pull off the pen cap and put it to one side.
174
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NovoPen 3 PenMate Instruction Manual
Page 13
FDA revision #4 (final)
Put the PenFill cartridge into the NovoPen 3 PenMate.
175
The threaded plastic cap goes in first.
176
177
8
Tightly screw the barrel of the NovoPen 3 into the NovoPen 3 PenMate.
178
Make sure that the dose indicator window on the mechanical section is aligned with
179
the yellow push button on NovoPen 3 PenMate.
180
181
182
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. There are five
183
cartridges in a box. Make sure you are using the correct type of insulin. The name of
184
the insulin is on the glass part of the cartridge.
185
Each PenFill cartridge is for single-person use only.
186
DO NOT share the cartridge with anyone even if you attach a new disposable needle
187
for each injection. This will prevent the spread of disease.
188
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NovoPen 3 PenMate Instruction Manual
Page 14
FDA revision #4 (final)
Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 PenMate.
189
Never load a partially filled cartridge. Never try to refill a used PenFill 3 mL
190
cartridge.
191
192
SECTION 1 (cont.)
193
9 Clean the front rubber stopper on the PenFill cartridge with an alcohol swab.
194
You must wipe the front rubber stopper with an alcohol swab before each injection, even
195
if you are using the same PenFill cartridge.
196
197
198
10 Remove the protective tab from the NovoFine® disposable needle.
199
Screw the NovoFine needle firmly onto the threaded plastic cap until it is tight.
200
Pull off the outer and inner needle caps.
201
202
For users of Novolin 70/30 or Novolin N insulin: Always remix the insulin before
203
each injection.
204
To remix the insulin, turn the NovoPen 3 PenMate up and down between positions A
205
and B, as on page 4, 10 times or until the insulin looks uniformly white and cloudy.
206
207
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NovoPen 3 PenMate Instruction Manual
Page 15
FDA revision #4 (final)
208
Never place a NovoFine disposable needle on your NovoPen 3 PenMate until you are
209
ready to do an air shot and give an injection. If the NovoFine needle is “left on”,
210
some liquid may leak out of the PenFill cartridge. This may cause a change in the
211
strength of Novolin 70/30 or Novolin N insulin.
212
213
214
SECTION 2
Air shot before each injection
215
216
Air shot before each injection
217
218
11 The PenFill cartridge may contain an air bubble, and small amounts of air may
219
collect in the needle and PenFill cartridge when you use them. To avoid the injection
220
of air and ensure proper dosing, you must perform an air shot prior to each injection.
221
222
§ Check that the dial-a-dose selector is set at zero.
223
§ Dial 2 units. Hold the NovoPen 3 PenMate with the needle upwards and tap
224
gently near the window of NovoPen 3 PenMate with your finger a few times.
225
§ Press the push button at the end of the barrel all the way in.
226
227
A drop of insulin should appear at the needle tip.
228
If not, repeat the procedure until a drop of insulin appears. There may still be some small
229
air bubble(s) in the PenFill cartridge after this, but they will not affect your dose and they
230
will not be injected.
231
232
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you do, the
233
extra insulin will squirt out of the needle. You may complete the air shot with the
234
number of units you have dialed or refer to the instructions on how to reset the dose to
235
zero in step 14.
236
237
238
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NovoPen 3 PenMate Instruction Manual
Page 16
FDA revision #4 (final)
SECTION 3
Choosing your dose
239
240
Choosing your dose
241
242
12 NovoPen 3 PenMate has an insulin scale with marks showing the approximate
243
number of units left in the PenFill cartridge. Always check that there is enough
244
insulin left for the injection. To activate, grip the barrel and the NovoPen 3 PenMate
245
and firmly pull in opposite directions until you hear a click.
246
Important: Do not pull the dial-a-dose selector.
247
Check that the dial-a-dose selector is set at zero. If zero does not appear, follow the
248
instructions on page 11.
249
250
251
13 Dial the number of units you need to inject.
252
The odd numbers are shown as full lines between the even numbers.
253
Do not use the clicking sound as a guide for selecting your dose.
254
255
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NovoPen 3 PenMate Instruction Manual
Page 17
FDA revision #4 (final)
256
257
The NovoPen 3 PenMate can deliver from 2 to 70 units of insulin in one unit increments.
258
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you do,
259
the extra insulin will squirt out of the needle. For instructions on how to reset the dose to
260
zero (0) so you can start again, see the next page.
261
262
SECTION 3 (cont.)
263
14 If you dial a larger dose than you need, you need to reset your NovoPen 3 PenMate to
264
zero.
265
To reset to zero (0) if you set the wrong dose:
266
a. Pull the barrel and the NovoPen 3 PenMate in opposite directions and keep hold
267
of them (see picture).
268
b. Press the push button on the barrel back to zero (0).
269
c. Release your grip and the barrel section will slide back into place.
270
d. You can now dial the correct units of insulin.
271
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NovoPen 3 PenMate Instruction Manual
Page 18
FDA revision #4 (final)
272
273
274
275
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NovoPen 3 PenMate Instruction Manual
Page 19
FDA revision #4 (final)
276
SECTION 4
Giving the injection
277
278
Giving the injection
279
15 Before injecting always check the dose indicator window to make sure you have
280
dialed the correct number of units.
281
After the airshot (see page 9) and choosing your dose, hold the NovoPen 3 PenMate
282
at the correct site on the body for an injection. Use the injection technique
283
recommended by your healthcare professional. The PenMate is designed with a cut-
284
away on one side. This cut-away allows injections at various angles other than 90°.
285
Press the yellow push-button on the NovoPen 3 PenMate with your finger (see arrow
286
in diagram). The needle will automatically enter the skin.
287
288
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NovoPen 3 PenMate Instruction Manual
Page 20
FDA revision #4 (final)
289
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NovoPen 3 PenMate Instruction Manual
Page 21
FDA revision #4 (final)
SECTION 4 (cont.)
290
16 To inject your dose, press the push button of the barrel section as far as it will go.
291
Do not force it (see arrow in diagram).
292
293
After injection, the needle should remain under the skin for several seconds. Keep the
294
push button fully depressed until the needle has been withdrawn from the skin.
295
If there is not enough insulin in the PenFill cartridge for the whole dose, you will be
296
able to see the number of units you still need to inject in the dose indicator window.
297
You must always check this after you have given the injection.
298
299
Important: Never turn the dial-a-dose selector to inject the insulin.
300
301
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NovoPen 3 PenMate Instruction Manual
Page 22
FDA revision #4 (final)
302
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NovoPen 3 PenMate Instruction Manual
Page 23
FDA revision #4 (final)
303
When you press the push button, the piston rod presses against the rear rubber stopper of
304
the cartridge. This moves the rear rubber stopper and pushes the correct amount of
305
insulin out through the needle.
306
307
308
SECTION 4 (cont.)
309
Check that the dose indicator window shows zero. If it does not show zero, you did not
310
receive your full dose.
311
For example: If you dial 25 units and there are only 20 units left in the PenFill cartridge,
312
the number 5 will appear in the window following the injection (25-20=5). If this occurs,
313
proceed with the following steps:
314
To get the remaining part of your dose:
315
a. Note the number of units in the dose indicator window.
316
b. Remove the NovoFine needle (see Section 5).
317
c. Remove the empty Novolin PenFill 3 mL cartridge (see Section 8).
318
d. Insert a new Novolin PenFill 3 mL cartridge (see Section 1).
319
e. Attach a new NovoFine needle (see Section 1).
320
f. Do an air shot (see Section 2).
321
g. Dial the number of units noted in step a.
322
h. Give the injection.
323
324
SECTION 4 (cont.)
325
To make sure that the insulin has been injected, do the following to be certain that
326
the needle advanced and penetrated the skin:
327
§ Check that you can see the control line (solid white line) at the top of the insulin scale
328
(above the number 300).
329
§ Check to see if your skin is wet where you gave the injection.
330
331
If you cannot see the control line after the injection or your skin is wet, see SECTION 5
332
to perform a mechanical function check.
333
334
Call (800) 727-6500 or your healthcare professional if you have any questions.
335
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 24
FDA revision #4 (final)
336
337
SECTION 4 (cont.)
338
17 After the injection, remove the needle without recapping it. Hold the NovoPen 3
339
PenMate firmly while you unscrew the NovoFine disposable needle. Place the
340
NovoFine disposable needle in a puncture-resistant disposable container.
341
Health care professionals, relatives, and other caregivers should follow precautionary
342
measures for removal and disposal of needles to eliminate the risk of unintended
343
needle penetration.
344
345
346
347
Graphic to be
changed
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 25
FDA revision #4 (final)
The NovoFine disposable needle must be removed immediately after each injection
348
without recapping. Put the NovoPen 3 PenMate cap back on. If the NovoFine
349
disposable needle is not removed, some liquid may leak out of the PenFill cartridge. This
350
may cause a change in the strength of Novolin 70/30 or Novolin N insulin.
351
For information on how to properly dispose of needle containers, call your local trash
352
disposal authorities.
353
354
SECTION 5
Mechanical function check
355
356
Mechanical function check of NovoPen 3 PenMate
357
18 Hold the NovoPen 3 PenMate with the needle pointing upwards.
358
To activate, grip the barrel and the PenFill holder of the NovoPen 3 PenMate and
359
firmly pull in opposite directions until you hear a click. If you do not hear a click,
360
contact Customer Relations at our toll free number 1-800-727-6500. Never use a
361
NovoPen 3 PenMate unless you are sure that it is working properly.
362
Important: Do not pull the dial-a-dose selector.
363
Check that the dial-a-dose selector is set to zero. If not, press the push button all the
364
way in.
365
366
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NovoPen 3 PenMate Instruction Manual
Page 26
FDA revision #4 (final)
367
19 Push the yellow push button and the needle should appear.
368
You should now be able to see the needle and the control line.
369
If you cannot see the needle, do not use the NovoPen 3 PenMate. Never use the
370
NovoPen 3 PenMate unless you are sure that it is working properly.
371
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 27
FDA revision #4 (final)
372
Need Help? Call 1-800-727-6500
373
374
SECTION 6
For subsequent injections
375
376
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 28
FDA revision #4 (final)
For subsequent injections
377
20 Pull off the NovoPen 3 PenMate cap. Check that the needle has been removed
378
since your last injection. Check that NovoPen 3 PenMate contains the type of insulin
379
you want to inject. If the PenFill holder of your NovoPen 3 PenMate contains a clear
380
insulin PenFill cartridge such as Novolin R, follow steps 9 to 17.
381
382
21 If your NovoPen 3 PenMate contains an insulin suspension cartridge, such as Novolin
383
70/30 or Novolin N mix the insulin by turning the device up and down between
384
positions A and B -as shown in the picture. The movement must be performed so that
385
the glass ball in the cartridge moves from one end to the other. Do this at least ten
386
times until the liquid is white and uniformly cloudy.
387
Then continue as shown in steps 9 to15 and inject immediately.
388
389
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 29
FDA revision #4 (final)
390
391
392
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 30
FDA revision #4 (final)
393
SECTION 7
What to do when PenFill is nearly empty
394
395
What to do when PenFill is nearly empty
396
22 Do not start to inject an insulin suspension such as Novolin N or Novolin 70/30 if you
397
can see the rubber piston in the small inspection window. The glass ball must have
398
adequate space to resuspend the insulin. With the NovoPen 3 PenMate, it is possible
399
to select a dose that is larger than the number of units left in the PenFill cartridge. If
400
there is not enough insulin in the PenFill cartridge for the whole dose, you will be
401
able to see the number of units you still need to inject in the dose indicator window
402
after the injection.
403
To get the remaining part of your dose refer to Section 4, Page 14, a through h.
404
405
406
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 31
FDA revision #4 (final)
407
408
When you get near the end of a PenFill cartridge, you may need to give yourself two
409
injections to receive your full dose. If, after giving an injection, zero does not appear in
410
the dose indicator window, you did not receive your full dose.
411
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 32
FDA revision #4 (final)
412
SECTION 8
Changing PenFill
413
414
Changing PenFill
415
23 a) Unscrew the barrel from the NovoPen 3 PenMate.
416
b) Press the push button to set the dose indicator to zero.
417
c) Make sure that the piston rod is not out (see Section 1, Page 5). (Twist it gently
418
from side to side, if necessary).
419
420
421
422
423
24 Take out the empty PenFill cartridge. Take a new PenFill cartridge and continue
424
as described from steps 6 and 7.
425
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 33
FDA revision #4 (final)
426
Need Help? Call 1-800-727-6500
427
428
SECTION 9
Function check
429
430
Function check
431
25 If you think your NovoPen 3 PenMate is not working properly, follow this procedure:
432
a) Check that the barrel and the NovoPen 3 PenMate are screwed together tightly and
433
that the dose indicator window on the barrel is aligned with the yellow push button on
434
the NovoPen 3 PenMate.
435
b) Screw on a new NovoFine needle as described in step10.
436
c) Clear the air bubbles as described in step11.
437
d) Put the outer needle cap over the needle.
438
e) Dispense 20 units into the needle cap.
439
440
The insulin should fill the lower part of the outer needle cap. If the pen has delivered
441
too much or too little insulin, repeat the test. If it happens again, do not use the pen.
442
Contact your supplier.
443
Do not try to repair a faulty NovoPen 3 or a faulty NovoPen 3 PenMate.
444
Never use NovoPen 3 or NovoPen 3 PenMate unless you are sure that they are
445
working properly.
446
447
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NovoPen 3 PenMate Instruction Manual
Page 34
FDA revision #4 (final)
448
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 35
FDA revision #4 (final)
IMPORTANT
449
§ Keep the NovoPen 3 PenMate away from areas where temperatures may get too hot
450
or too cold such as a car or refrigerator.
451
§ Once the cartridge is punctured, it can be kept at room temperature for the length of
452
time identified in the storage information section of the Information For The Patient
453
supplied with the PenFill cartridges.
454
§ Make sure that the piston rod is completely inside the reset mechanism before you
455
screw together the barrel and the NovoPen 3 PenMate. (see step 5).
456
§ Always screw the mechanical section of NovoPen 3 and NovoPen 3 PenMate tightly
457
together.
458
§ Before each injection, make sure that you are using the right insulin preparation.
459
§ Always clear air bubbles with the needle pointing upwards before each injection (see
460
step 11).
461
§ With the NovoPen 3 PenMate, it is possible to select a dose which is larger than the
462
number of units left in the PenFill cartridge. Before you inject, always check on the
463
insulin scale that there is enough insulin left in the PenFill cartridge for your dose.
464
After the injection, always make sure that you have injected the whole dose by
465
checking that the dose indicator window reads 0. If not, see step 22.
466
§ Do not use the insulin scale on the NovoPen 3 PenMate to measure the amount of
467
insulin to be injected.
468
§ Before injecting, always check the dose indicator window to make sure you have
469
dialed the correct number of units.
470
§ After injecting, make sure that NovoPen 3 PenMate was released and that the insulin
471
has been injected (see step16).
472
§ Take the needle off the NovoPen 3 PenMate immediately after each injection. If
473
you do not remove it, temperature changes may cause liquid to leak out of the
474
needle. With Novolin N or Novolin 70/30, this may change the concentration of
475
the insulin.
476
§ Do not inject Novolin N or Novolin 70/30 if the rear rubber stopper can be seen in the
477
small inspection window.
478
§ Always have extra insulin of the same type(s) you use available for alternative
479
administration in case your NovoPen 3 PenMate, NovoPen 3, or PenFill gets lost or
480
damaged.
481
482
IMPORTANT (cont.)
483
§ Keep NovoPen 3 PenMate, NovoPen 3, PenFill, and NovoFine out of reach of
484
children.
485
§ Your NovoPen 3 and NovoPen 3 PenMate are for use by the same person only.
486
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 36
FDA revision #4 (final)
§ The NovoPen 3 PenMate is not recommended for the blind or visually impaired,
487
without the assistance of a sighted individual who knows how to use NovoPen 3
488
PenMate.
489
§ If you use more than one type (N, R, or 70/30) of insulin, use a separate NovoPen 3
490
PenMate for each type of insulin.
491
§ The American Diabetes Association recommends that insulin should be self-
492
administered. The proper age for initiating this should be assessed by the adult
493
caregiver.
494
§ Use only a new PenFill cartridge when loading the NovoPen 3 PenMate. Never load
495
the NovoPen 3 PenMate with a partially filled PenFill cartridge.
496
§ The NovoPen 3 PenMate is designed for use with PenFill 3 mL insulin cartridges and
497
NovoFine single-use disposable needles.
498
§ Novo Nordisk is not responsible for any consequences arising from the use of the
499
NovoPen 3 PenMate with products that are not recommended by Novo Nordisk.
500
IMPORTANT (cont.)
501
Guidelines for storing the NovoPen 3 PenMate and PenFill 3 mL cartridges:
502
§
Store the NovoPen 3 PenMate (with the PenFill cartridge inside) at room
503
temperature. Do not store the NovoPen 3 PenMate in a refrigerator or areas where
504
there may be extreme temperatures or moisture, such as your car. Once the cartridge
505
is punctured, it can be kept at room temperature for the length of time identified in
506
the storage information section of the Information For The Patient supplied with the
507
PenFill cartridges.
508
§
Store the NovoPen 3 PenMate without the NovoFine needle attached and with the
509
pen cap in position. Leaving the needle on can cause the insulin to leak. This will
510
affect the concentration of an insulin suspension.
511
§
For information on storing PenFill cartridges, see the package insert that comes in
512
the PenFill cartridge box. Once the cartridge is punctured, it can be kept at room
513
temperature for the length of time identified in the storage information section of the
514
Information For The Patient supplied with the PenFill cartridges. The expiration
515
date on the cartridge is for unused cartridges under refrigeration.
516
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 37
FDA revision #4 (final)
517
518
WHAT TO DO IF ...
519
Here are the answers to some questions you might need to ask when using your NovoPen
520
3 PenMate.
521
No insulin appears when I try to clear the air bubbles.
522
Check that your NovoPen 3 PenMatewas put together correctly when you changed the
523
PenFill cartridge. Make sure that the piston rod is completely inside the reset mechanism.
524
Also make sure that the barrel and the NovoPen 3 PenMate are screwed tightly together
525
(see steps 5 and 25).
526
No insulin appears when I try to clear the air bubbles and the push button will not
527
go in.
528
The needle may be blocked. Change the needle and repeat air shots until insulin appears
529
at the needle tip. Check if the PenFill cartridge is empty.
530
531
The push button will not depress during the injection.
532
533
Do not try to force the push button down. Check if the PenFill cartridge is empty.
534
If there was not enough insulin in PenFill cartridge for the whole dose, you will see the
535
number of units you still need to inject in the dose indicator window. Make a note of this.
536
Change the PenFill cartridge and continue as described from step 23.
537
538
539
540
541
542
WHAT TO DO IF ... (cont.)
543
I cannot press the push button back to zero before I return the piston rod.
544
The reset mechanism may be locked. Gently twist the reset mechanism from side to side
545
until it unlocks. See the picture in step 5. Then you can press the push button down to
546
zero. Never turn the dosage selector back.
547
I cannot get the piston rod back inside the reset mechanism when I change the
548
PenFill cartridge.
549
The reset mechanism may be locked. Gently twist the reset mechanism from side to side
550
until it unlocks. Then turn the reset mechanism to the right until the piston rod is
551
completely inside it. See the picture in step 5.
552
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NovoPen 3 PenMate Instruction Manual
Page 38
FDA revision #4 (final)
553
I think the needle has not entered the skin.
554
Check that you can see the control line at the top of the insulin scale.
555
Also check if your skin is wet at the injection site. Carry out the mechanical function
556
check as described in steps 18 and 19.
557
I think my NovoPen 3 or my NovoPen 3 PenMate is not working properly.
558
Carry out the function check described in step 25. Make sure that the lower part of the
559
outer needle cap is filled with 20 units of insulin. Also carry out the mechanical function
560
check as described in steps18 and 19. Make sure that the control line is visible when
561
NovoPen 3 PenMate is released. Never use your NovoPen 3 or your NovoPen 3 PenMate
562
unless you are sure that they are working properly.
563
564
MAINTENANCE
565
566
How to store and look after your NovoPen 3 and your NovoPen 3 PenMate
567
NovoPen 3 and NovoPen 3 PenMate are designed to work accurately. They should be
568
handled with care. Avoid situations where your NovoPen 3 and NovoPen 3 PenMate can
569
be damaged. Do not drop. Do not expose to excessive pressure or blows. Keep them in
570
the soft case whenever possible.
571
572
You can put PenFill cartridges in NovoPen 3 PenMate or carry them with you as spares.
573
Please read the Information For The Patient supplied with the PenFill cartridges
574
for details of how to store the cartridges and how long to keep them.
575
576
You can clean your NovoPen 3 and your NovoPen 3 PenMate by wiping them with a
577
cotton swab moistened with ethyl or isopropyl alcohol.
578
579
Your NovoPen 3 and your NovoPen 3 PenMate are sturdy products but could still get
580
damaged. So handle them with care and protect them against dust and dirt when they are
581
not carried in the case.
582
583
Do not try to repair a faulty NovoPen 3 or a faulty NovoPen 3 PenMate.
584
585
NovoPen 3 and NovoPen 3 PenMate must only be used in the way described in this
586
booklet. The manufacturer will not be responsible for any problems you have with the
587
equipment if you have not followed this booklet. If you find your NovoPen 3 or your
588
NovoPen 3 PenMate faulty, Novo Nordisk will replace it if:
589
§ You call Novo Nordisk Pharmaceuticals, Inc. at our toll free number 1-800-727-6500
590
within three years of getting it.
591
592
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 39
FDA revision #4 (final)
WARRANTY
593
594
Should your NovoPen 3 PenMate device be defective in materials or workmanship within
595
three (3) years of purchase, Novo Nordisk Pharmaceuticals, Inc., will replace it at no
596
charge if you mail the defective unit along with a description of the problem and the sales
597
receipt or other proof of purchase to:
598
599
Novo Nordisk Pharmaceuticals, Inc.
600
Customer Relations
601
100 College Road West
602
Princeton, New Jersey 08540-7810.
603
604
No other warranty is made with respect to NovoPen 3 PenMate. The mechanical section
605
of the NovoPen 3 insulin pen is covered by its own separate warranty. which is described
606
in its instruction manual. This warranty will be invalid and Novo Nordisk A/S, Novo
607
Nordisk Pharmaceuticals, Inc., Bristol-Myers Squibb Co., Nipro Medial Industries Ltd.,
608
and Bang & Olufsen A/S cannot beheld responsible in the case of defects or damages
609
arising from:
610
611
§ The use of the NovoPen 3 PenMate with products other than NovoPen 3, PenFill 3 mL
612
cartridges, and NovoFine single-use disposable needles.
613
614
§ The use of the NovoPen 3 PenMate not in accordance with the instructions in this
615
booklet.
616
617
§ Physical damage to the NovoPen 3 PenMate caused by neglect, misuse, unauthorized
618
repair, accident, or other breakage.
619
620
Use of the NovoPen 3 PenMate does not extend the warranty of the NovoPen 3 insulin
621
pen.
622
623
For assistance or further information, write to:
624
Novo Nordisk Pharmaceuticals, Inc.
625
Customer Relations
626
100 College Road West
627
Princeton, NJ 08540-7810
628
629
Or call: 1-800-727-6500
630
631
License under U.S. Patents Nos. 5,462,535; 5,693,02; 5,626,566 and Des. 347,894
632
(cartridge) restricted to use with Novo Nordisk insulin cartridges and Novo Nordisk pen
633
needles.
634
635
Novolin®, NovoPen®, PenFill®, NovoPen® 3 PenMate®, and NovoFine® are
636
trademarks owned by Novo Nordisk A/S.
637
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoPen 3 PenMate Instruction Manual
Page 40
FDA revision #4 (final)
638
2002 Novo Nordisk Pharmaceuticals, Inc.
639
640
www.novonordisk-us.com
641
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
3/11/02 05:06:34 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.431239 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19-938S30lbl.pdf', 'application_number': 19991, 'submission_type': 'SUPPL ', 'submission_number': 32} |
1,888 | 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 2
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 3
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 4
NovoPen
3 Demi Instruction Manual
4
5
Dial-A-Dose Insulin Delivery System
6
7
INTRODUCTION
8
9
10
11
12
NovoPen®3 Demi delivers a minimum dose of 1 unit to a maximum dose of 35
13
units of insulin in half unit steps. A raised circle on the push button makes it easy
14
for you to know your NovoPen 3 Demi from the ordinary NovoPen 3. This booklet
15
includes everything you need to know about using the NovoPen 3 Demi. Please
16
read it carefully before using your NovoPen 3 Demi for the first time.
17
18
The NovoPen 3 Demi is designed for use with:
19
! PenFill® 3 mL cartridges.
20
! NovoFine® disposable needles.
21
NovoFine disposable needles are for single-use only.
22
You will also need alcohol swabs.
23
24
If you have any questions about your NovoPen 3 Demi insulin delivery system,
25
please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
26
27
Please complete and return the NovoPen 3 Demi warranty card.
28
29
30
31
See Important Things to Know and Important Notes on pages 33-35.
32
33
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 5
HOW TO USE THIS BOOKLET
35
36
This booklet gives you step-by-step instructions for using the NovoPen 3
37
Demi.
38
39
Begin by reviewing the drawing layout of the parts of the NovoPen 3 Demi,
40
PenFill 3 mL cartridge, and NovoFine disposable needle. The inside front cover
41
opens out so you have a handy reference while you read the rest of the booklet.
42
43
Most pages contain a drawing on the right with numbered instructions to the left
44
of the drawing.
45
Important additional information is given below the drawing.
46
47
We suggest that you read the text and look at the drawing to make sure that
48
you understand each step thoroughly.
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
3
78
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 6
TABLE OF CONTENTS
79
80
SECTION 1:
81
Preparing the NovoPen 3 Demi…………......................................................5
82
83
SECTION 2:
84
Inserting the PenFill 3 mL Cartridge............................................................. 8
85
86
SECTION 3:
87
Attaching the NovoFine Disposable Needle................................................ 12
88
89
SECTION 4:
90
Doing an Air Shot ........................................................................................ 16
91
92
SECTION 5:
93
Giving the Injection ..................................................................................... 20
94
95
SECTION 6:
96
Removing the NovoFine Disposable Needle................................................ 24
97
98
SECTION 7:
99
Removing the PenFill 3 mL Cartridge......................................................... 26
100
101
FUNCTION CHECK ................................................................................... 28
102
103
STORAGE..................................................................................................
31
104
105
MAINTENANCE........................................................................................
32
106
107
IMPORTANT THINGS TO KNOW...........................................................
33
108
109
IMPORTANT NOTES.................................................................................
34
110
111
WHAT TO DO IF......................................................................................
36
112
113
WARRANTY .............................................................................................
37
114
Corrections on this page =
115
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 7
SECTION 1
Preparing the NovoPen 3 Demi
116
117
Remove the device cap:
118
1. Remove the NovoPen 3 Demi from the case.
119
2. Gently twist the pen cap until the cap separates from the barrel.
120
3. Pull the pen cap straight up to remove it.
121
122
123
124
If you use more than one insulin product (such as Novolin® R, Novolin® N,
125
Novolin® 70/30, or NovoLog®), use a separate insulin delivery device for each
126
product.
127
5
128
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NovoPen 3 Demi Final revision
Page 8
SECTION 1 (cont.)
129
130
Separate the cartridge holder from the barrel:
131
132
4. Unscrew and remove the cartridge holder from the barrel.
133
134
135
136
Make sure the dose indicator window shows zero:
137
138
5. Press the push button all the way in until zero (0) appears in the window.
139
The zero should be lined up with the stripe below the dose indicator
140
window.
141
142
143
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NovoPen 3 Demi Final revision
Page 9
6
144
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NovoPen 3 Demi Final revision
Page 10
145
SECTION 1 (cont.)
146
147
The end of the piston rod should be flat against the end of the reset mechanism
148
prior to inserting each new PenFill 3 mL cartridge. It should not be sticking out.
149
150
If the piston rod is sticking out:
151
152
Turn the end of the reset mechanism in a clockwise direction until it is no longer
153
sticking out. Never push the piston rod back in.
154
155
156
157
158
You should never reset the piston rod until it is time to remove the used PenFill 3
159
mL cartridge and insert a new one.
160
161
If the reset mechanism locks, it is usually due to improper technique. Gently turn
162
the mechanism side to side until it unlocks. Then call our toll free number (1-800-
163
727-6500) so that we may go over your technique with you.
164
165
7
166
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NovoPen 3 Demi Final revision
Page 11
SECTION 2
Inserting the PenFill 3 mL Cartridge
167
168
1. To remove the PenFill cartridge from its wrapper, push the cartridge
169
through the foil side of the packaging. Always make sure that the PenFill
170
cartridge you use contains the correct type of insulin (such as Novolin R,
171
Novolin N, Novolin 70/30, or NovoLog). If you are treated with more than
172
one type of insulin in PenFill cartridges, you should use a separate insulin
173
delivery device for each type of insulin. Before use, check that the PenFill
174
cartridge is full and intact. If not, do not use it.
175
176
2-1
177
1
178
2. In the PenFill Information For The Patient leaflet, you will find instructions
179
on how to prepare the insulin if the PenFill contains a suspension insulin
180
(white and cloudy) such as Novolin N or Novolin 70/30.
181
182
-4
183
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. Make sure
184
you are using the correct type of insulin. On the glass part of the cartridge is the
185
name of the insulin.
186
187
Each PenFill cartridge is for single-person use only. DO NOT share the same
188
cartridge with anyone even if you attach a new disposable needle for each
189
injection. Sharing the cartridge can spread disease.
190
Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 Demi.
191
Never load a partially filled cartridge.
192
Never try to refill a used PenFill 3 mL cartridge.
193
194
8
195
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NovoPen 3 Demi Final revision
Page 12
B
196
9
197
SECTION 2 (cont.)
198
199
Insert the PenFill cartridge:
200
201
2. Hold the cartridge holder so the wider opening is up.
202
3. Drop the PenFill cartridge into the cartridge holder, plastic cap first.
203
204
205
A threaded plastic cap surrounds the end of the PenFill® cartridge, like the cap
206
on a bottle. In the center is the front rubber stopper.
207
208
The rear rubber stopper is at the other end of the PenFill cartridge.
209
210
10
211
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NovoPen 3 Demi Final revision
Page 13
SECTION 2 (cont.)
212
213
Re-attach the cartridge holder:
214
215
4. Screw the barrel into the cartridge holder completely until it is tight.
216
217
218
219
220
221
You can see the cartridge in the insulin scale window. The cartridge holder has a
222
scale with marks showing about how much insulin is left in the PenFill cartridge.
223
224
11
225
2
226
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NovoPen 3 Demi Final revision
Page 14
SECTION 3
Attaching the NovoFine® Disposable Needle
227
228
At the end of the cartridge holder are two inspection windows. You can see the
229
cartridge through these windows.
230
231
If you use a suspension insulin (white and cloudy) such as Novolin® N or
232
Novolin® 70/30, use the windows to check if there is enough insulin left for
233
proper mixing. (see below)
234
235
Check the amount of insulin remaining:
236
! If the rear rubber stopper cannot be seen in the inspection window, you have
237
enough insulin for mixing left in the cartridge.
238
! If the rear rubber stopper can be seen in the inspection window, you do not
239
have enough insulin left in the cartridge and must insert a new PenFill 3 mL
240
cartridge.
241
242
See Section 7 for instructions on removing a PenFill cartridge and Section 2 for
243
inserting a new one.
244
245
At least
246
12
247
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NovoPen 3 Demi Final revision
Page 15
12
248
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NovoPen 3 Demi Final revision
Page 16
SECTION 3 (cont.)
249
250
For users of suspension insulin (white and cloudy) such as Novolin N or
251
Novolin 70/30:
252
253
Always remix the insulin before each injection.
254
To remix the insulin, turn the NovoPen 3 Demi up and down between positions A
255
and B 10 times or until the insulin looks uniformly white and cloud
256
257
258
259
260
13
261
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NovoPen 3 Demi Final revision
Page 17
SECTION 3 (cont.)
262
263
1. Wipe the front rubber stopper with an alcohol swab.
264
1
265
266
267
You must wipe the front rubber stopper with an alcohol swab before each
268
injection, even if you are using the same PenFill cartridge.
269
3-3
270
14
271
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NovoPen 3 Demi Final revision
Page 18
SECTION 3 (cont.)
272
273
2. Remove the protective tab from the NovoFine disposable needle.
274
3. Screw the NovoFine disposable needle firmly onto the PenFill 3 mL
275
cartridge until it is tight.
276
2 33
277
278
279
Never place a NovoFine disposable needle on your NovoPen 3 Demi until you
280
are ready to do an air shot and give an injection.
281
If the NovoFine needle is left on, some liquid may leak out of the PenFill
282
cartridge. This may cause a change in the strength of the suspension insulin
283
such as Novolin N or Novolin 70/30.
284
15
285
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NovoPen 3 Demi Final revision
Page 19
286
SECTION 4
Doing an Air Shot
287
288
The PenFill cartridge may contain an air bubble, and small amounts of air may
289
collect in the needle and PenFill cartridge when you use them. To avoid injecting
290
air and to ensure proper dosing, you must perform an air shot before each
291
injection.
292
293
Before doing the air shot, the dose indicator window must show zero (0).
294
295
If you use a suspension insulin, such as Novolin N or Novolin 70/30 and have
296
used the PenFill cartridge for previous injections, make sure there is enough
297
insulin left in the PenFill cartridge to properly mix the insulin (see page 12). If
298
there is enough insulin left in the PenFill cartridge, see the next page for
299
instructions.
300
301
16
302
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NovoPen 3 Demi Final revision
Page 20
SECTION 4 (cont.)
303
304
Set the NovoPen 3 Demi for the air shot:
305
306
1. Turn the dial-a-dose selector to 2 units. Full units are shown as numbers.
307
Half units are shown as long lines between the numbers.
308
1
309
310
4-1
311
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you
312
do, the extra insulin will squirt out of the needle. You may complete the air shot
313
with the number of units you have dialed or refer to Section 5 on page 21 for
314
instructions on how to reset the dose to zero.
315
17
316
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NovoPen 3 Demi Final revision
Page 21
SECTION 4 (cont.)
317
318
Uncap the NovoFine needle:
319
320
2. Pull off the outer needle cap and set aside.
321
3. Pull off the inner needle cap and discard.
322
2
323
Do not use the needle if it is bent or damaged.
324
325
326
327
4. Hold the NovoPen 3 Demi with the NovoFine needle pointing up.
328
5. Tap the cartridge holder with your finger a few times to raise any air
329
bubbles that may be present to the top of the cartridge.
330
331
332
18-3
333
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NovoPen 3 Demi Final revision
Page 22
SECTION 4 (cont.)
334
335
Do the air shot:
336
337
6. Press the push button all the way in. A drop of insulin should appear at the
338
needle tip.
339
340
If no insulin appears, repeat the following steps, until a drop of insulin
341
appears:
342
343
a. Make sure the NovoFine needle is securely attached.
344
b. Dial 2 units.
345
c. Tap the cartridge holder with your finger.
346
d. Press the push button all the way in.
347
348
There may still be some small air bubble(s) in the PenFill cartridge after this, but
349
they will not affect your dose and they will not be injected.
350
351
352
353
When you press the push button, the piston rod presses against the rear rubber
354
stopper. This moves the rear rubber stopper and pushes the correct amount of
355
insulin up through the needle.
356
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NovoPen 3 Demi Final revision
Page 23
19
357
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NovoPen 3 Demi Final revision
Page 24
SECTION 5
Giving the Injection
358
359
Be sure to do an air shot before giving each injection (see pages 16-19).
360
Select the dose:
361
362
1. Check that the dial-a-dose selector is set to zero. If not, follow the
363
instructions on the next page. Turn the dial-a-dose selector until you see
364
the correct number of units in the dose indicator window. Full units are
365
shown as numbers. Half units are shown as long lines between the
366
numbers.
367
368
1 DO NOT use the clicking sound as a guide for selecting your dose.
369
370
371
4-4
372
The NovoPen 3 Demi can deliver insulin in half unit steps from a minimum dose
373
of 1 unit to a maximum dose of 35 units.
374
375
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you
376
do, the extra insulin will squirt out of the needle. For instructions on how to reset
377
the dose to zero (0) so you can start again, see the next page.
378
379
380
20
381
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NovoPen 3 Demi Final revision
Page 25
SECTION 5 (cont.)
382
383
If you dial a larger dose than you need, pull the barrel and the cartridge holder
384
apart, as shown in the drawing A. While holding them apart, gently press the
385
push button against a hard surface and release your grip B. Your dose indicator
386
window should be back to zero (0).
387
388
You can now dial the correct number of units.
389
390
391
392
21
393
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NovoPen 3 Demi Final revision
Page 26
SECTION 5 (cont.)
394
395
Giving the injection:
396
397
2. After the air shot is done and you have chosen the correct number of
398
units, insert the NovoFine needle in the correct injection site on your body.
399
(Use the injection technique recommended by your health care
400
professional). If you use a suspension insulin such as Novolin N or
401
Novolin 70/30, mix the insulin (see page 13, Section 3) and make sure the
402
insulin looks uniformly white and cloudy before you inject.
403
404
3. Press the push button as far as it will go to deliver the insulin. Do not
405
force it.
406
407
To ensure that all the insulin is injected, keep the NovoFine needle in the skin for
408
several seconds after the injection with your thumb on the push button. Keep the
409
push button fully depressed until after the NovoFine needle has been withdrawn.
410
411
Important: Never turn the dial-a-dose selector to inject the insulin.
412
413
414
415
When you get near the end of a PenFill cartridge, you may need to give yourself
416
two injections to receive your full dose. Check the dose indicator window after
417
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NovoPen 3 Demi Final revision
Page 27
giving an injection. If zero does not appear in the dose indicator window, you did
418
not receive your full dose. See the next page for instructions on how to get the
419
remaining part of your dose.
420
22
421
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NovoPen 3 Demi Final revision
Page 28
422
SECTION 5 (cont.)
423
424
4. Check the dose indicator window to make sure it shows zero (0). If
425
zero does not appear, you did not receive the full dose.
426
427
If the dose indicator window does not show zero, there were not enough units of
428
insulin in the PenFill cartridge for you to receive the full dose. The dose indicator
429
window shows the number of units that you did not receive.
430
431
For example, if you dial 25 units and there are only 20 units left in the PenFill
432
cartridge, after the injection the number in the dose indicator window will be
433
5 (25-20 = 5). If this happens, proceed with the following steps to get the
434
remaining part of your dose:
435
436
437
a. Note the number of units in the dose indicator window.
438
b. Remove the NovoFine needle (see Section 6).
439
c. Remove the empty PenFill 3 mL cartridge (see Section 7).
440
d. Insert a new PenFill 3 mL cartridge (see Section 2).
441
e. Attach a NovoFine needle (see Section 3).
442
f. Do an air shot (see Section 4).
443
g. Dial the number of units noted in step a.
444
h. Give the injection.
445
446
447
4
448
449
23
450
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NovoPen 3 Demi Final revision
Page 29
SECTION 6 Removing the NovoFine Disposable Needle
451
452
Remove the NovoFine disposable needle:
453
454
1. After the injection, remove the needle without replacing the cap.
455
456
2. Hold the cartridge holder firmly while you unscrew the NovoFine
457
disposable needle.
458
459
3. Place the NovoFine disposable needle in a puncture-resistant disposable
460
container.
461
462
Health care professionals, relatives, and other caregivers should also follow the
463
above instructions to eliminate the risk of unintended needle penetration.
464
465
466
467
The NovoFine disposable needle must be removed immediately after each
468
injection without replacing the cap. If the NovoFine disposable needle is not
469
removed, some liquid may leak out of the PenFill cartridge. This may cause a
470
change in the strength of suspension insulins (white and cloudy) such as Novolin
471
N or Novolin 70/30.
472
473
For information on how to throw away needle containers properly, contact your
474
local trash company.
475
24
476
SECTION 6 (cont.)
477
478
Replace the pen cap:
479
480
4. After you remove the disposable needle, hold the pen cap so that the clip
481
is lined up with the dose indicator window.
482
483
5. Gently slide the pen cap onto the barrel.
484
485
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NovoPen 3 Demi Final revision
Page 30
486
4
487
25
488
489
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NovoPen 3 Demi Final revision
Page 31
490
SECTION 7 Removing the PenFill 3 mL Cartridge
491
492
You will need to remove the PenFill cartridge for the following reasons:
493
494
! When tThe PenFill cartridge is empty.
495
496
! If you use a suspension insulin such as Novolin N or Novolin 70/30:
497
498
When you see the rear rubber stopper in the inspection window, then you
499
do not have enough insulin left in the PenFill cartridge for proper mixing.
500
501
Remove the barrel:
502
503
1. Remove the pen cap.
504
505
2. Hold the NovoPen 3 Demi with the dose indicator window at the top.
506
507
3. Unscrew the barrel from the cartridge holder.
508
509
7-1
510
511
26
512
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NovoPen 3 Demi Final revision
Page 32
SECTION 7 (cont.)
513
514
Remove the PenFill 3 mL cartridge:
515
516
4. Tip the cartridge holder. The PenFill cartridge will drop out.
517
518
5. Press the push button all the way in until zero (0) appears in the window.
519
520
6. Turn the end of the reset mechanism in a clockwise direction until the
521
piston rod is no longer sticking out (refer to figure 1-4 on page 7).
522
523
7. To insert a new PenFill cartridge, please refer to Section 2.
524
525
526
527
If the reset mechanism locks, it is usually due to improper technique. Gently turn
528
the mechanism side to side until it unlocks and then call our toll free number (1-
529
800-727-6500) so that we may go over your technique with you.
530
5
531
27
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NovoPen 3 Demi Final revision
Page 33
FUNCTION CHECK
533
534
You should regularly check the functioning of your NovoPen 3 Demi, (for
535
example, once a month or before starting a new box of PenFill cartridges). The
536
function check is done by delivering 20 units of insulin into the outer needle cap.
537
You will not be injecting insulin into your body.
538
539
Always check the functioning of the NovoPen 3 Demi if you suspect it has been
540
damaged or if you are uncertain that it is delivering the correct dose.
541
542
Do not use NovoPen 3 Demi unless you are sure that it is working properly.
543
Help? Call 1-800-727-6500
544
To perform the function check:
545
546
1. Attach a NovoFine disposable needle(see pages 12-15).
547
548
2. Do an air shot (see pages 16-19).
549
550
28
551
1
552
This label may not be the latest approved by FDA.
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NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 34
553
FUNCTION CHECK (cont.)
554
555
556
3. Do not replace the inner needle cap. Place the outer needle cap
557
securely over the exposed NovoFine needle.
558
559
560
561
562
Expel 20 units of insulin into the outer needle cap:
563
564
4. Turn the dial-a-dose selector so the dose indicator window shows 20.
565
566
567
This label may not be the latest approved by FDA.
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NovoPen 3 Demi Final revision
Page 35
568
29
569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NovoPen 3 Demi Final revision
Page 36
FUNCTION CHECK (cont.)
570
571
5. Hold the NovoPen 3 Demi so the NovoFine disposable needle is pointing
572
down.
573
574
6. Slowly press the push button as far as it will go.
575
576
7. Check the dose indicator window to see if it shows zero (0). If it does not
577
show zero (0), there is not enough insulin in the cartridge to do a function
578
check. Insert a new PenFill cartridge (see pages 8-11) and repeat the
579
function check. If there is enough insulin in the cartridge but the dose
580
indicator window does not show zero, repeat the FUNCTION CHECK. If
581
you do not see zero after repeating the above steps, do not use your
582
NovoPen 3 Demi. Contact Novo Nordisk Pharmaceuticals, Inc. at our tool
583
free number (1-800-727-6500).
584
585
586
The insulin should fill the bottom part of the outer needle cap. This indicates the
587
device is functioning properly.
588
589
If the insulin does not fill or overfills this part of the cap, review the function
590
check procedure. Then repeat the function check with a new NovoFine
591
disposable needle and outer needle cap.
592
593
If the second function check also shows under- or over-filling, do not use your
594
NovoPen 3 Demi.
595
596
DO NOT try to repair a NovoPen 3 Demi that you think is not working
597
properly.
598
599
See Warranty section for further information.
600
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 37
230
601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NovoPen 3 Demi Final revision
Page 38
-3
602
STORAGE
603
604
Guidelines for storing the NovoPen 3 Demi and PenFill 3 mL cartridges:
605
606
! PenFill cartridges should be stored in a cool place, such as in a
607
refrigerator, but not in thea freezer.
608
609
! After the first use of PenFill cartridge in the NovoPen 3 Demi, the
610
NovoPen 3 Demi (with the PenFill cartridge inside) can be kept at room
611
temperature below 86°F (30°C) for the amount of time days specified
612
listed in the PenFill Information for the Patient leaflet for the type of insulin
613
you are using.
614
615
! Do not store the NovoPen 3 Demi (with the PenFill cartridge inside) in a
616
refrigerator or areas where there may be extreme temperatures or
617
moisture, such as in your car.
618
619
! The expiration date printed on the cartridge is for unused cartridges
620
under refrigeration. Never use the cartridge after the expiration date
621
on the cartridge or its box.
622
623
624
625
! Store the NovoPen 3 Demi without the NovoFine needle attached and
626
with the pen cap in position.
627
628
! For information on storing PenFill cartridges, see the package leaflet that
629
comes in the PenFill cartridge box.
630
631
632
31
633
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 39
MAINTENANCE
634
635
Guidelines for maintaining the NovoPen 3 Demi.
636
637
Be sure to:
638
639
1. Clean it by wiping with a soft cloth moistened with alcohol.
640
641
2. Protect it from dust, dirt, and moisture when not in its case.
642
643
644
Make certain you:
645
646
1. Do not soak it in alcohol, do not wash it in soap and water, or do not
647
lubricate it, since this may cause damage.
648
649
2. Do not expose it to excessive pressure or blows.
650
651
3. Do not drop it.
652
653
32
654
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 40
IMPORTANT THINGS TO KNOW
655
2
656
! The NovoPen 3 Demi is not recommended for the blind or visually
657
impaired, without the assistance of a sighted individual trained to use it.
658
659
! If you use more than one type of insulin (such as Novolin R, Novolin N, or
660
Novolin 70/30, or NovoLog), use a separate insulin delivery device for
661
each type of insulin.
662
663
! Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 Demi
664
Never load the NovoPen 3 Demi with a partially filled PenFill cartridge.
665
666
! Always keep a spare insulin delivery system available, in case your
667
NovoPen 3 Demi is lost or damaged.
668
669
! Keep the NovoPen 3 Demi, PenFill cartridges, and NovoFine needles out
670
of the reach of children. The American Diabetes Association recommends
671
that insulin should be self-administered. The proper age for initiating this
672
should be assessed by the adult caregiver.
673
674
! Keep the NovoPen 3 Demi away from areas where temperatures may get
675
too hot or too cold such as a car or refrigerator.
676
677
! The NovoPen 3 Demi is designed for use with PenFill 3 mL insulin
678
cartridges and NovoFine single-use disposable needles.
679
680
Novo Nordisk is not responsible for any consequences arising from the use of
681
the NovoPen 3 Demi with products other than PenFill 3 mL insulin cartridges
682
and NovoFine single-use disposable needles.
683
684
33
685
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 41
IMPORTANT NOTES
686
687
The following is a review of some important information about the use and
688
care of your NovoPen 3 Demi.
689
690
691
Before each injection, be certain:
692
693
1. The NovoPen 3 Demi contains the correct insulin cartridge (such as
694
Novolin R, Novolin N, Novolin 70/30, or NovoLog), if you use more than
695
one type of insulin.
696
697
2. The PenFill cartridge contains enough insulin for mixing, if you use a
698
suspension insulin (white and cloudy) such as Novolin N or Novolin
699
70/30.
700
701
3. To do an air shot with the NovoFine needle pointing up before each
702
injection.
703
1
704
2 3
705
Be sure to:
706
707
1. Check the dose indicator window after each injection to make sure you
708
have received your full dose (see page 23, Section 5).
709
710
2. Remove the NovoFine needle immediately after each injection without
711
replacing the cap.
712
713
3. Select your dose only by using the number in the dose indicator window.
714
715
4. Perform the function check regularly or if you think your NovoPen 3 Demi
716
is not working properly.
717
1
718
34
719
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 42
IMPORTANT NOTES (cont.)
720
721
Make certain you:
722
723
1. DO NOT place a NovoFine needle on the NovoPen 3 Demi until you are
724
ready to do an air shot and give an injection or do a function check.
725
Remove the needle immediately after each injection without recapping the
726
needle. If the NovoFine needle is not removed, some liquid may leak out
727
of the PenFill cartridge. This may cause a change in the strength of
728
suspension insulin (white and cloudy) such as Novolin N or Novolin
729
70/30.
730
731
2. DO NOT use the clicking sound to set your insulin dose.
732
733
3. DO NOT try to refill a PenFill cartridge.
734
735
4. DO NOT share the same PenFill cartridge with anyone else even if you
736
attach a new NovoFine needle for each injection. Sharing cartridge can
737
spread disease. Each PenFill cartridge is for single-person use only.
738
739
Blood glucose levels should be tested frequently to monitor your insulin regimen.
740
741
Any change in insulin should be made cautiously and only under medical
742
supervision.
743
Corrections on this
744
35
745
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 43
746
WHAT TO DO IF…
747
748
The dose indicator window does not show zero after the injection:
749
750
1. You did not receive your full dose.
751
1
Follow the steps on page 23 to get the remaining part of your dose.
752
753
2 Your NovoPen 3 Demi is malfunctioning.
754
Do not use your NovoPen 3 Demi. Contact Novo Nordisk
755
Pharmaceuticals, Inc. at our tool free number (1-800-727-6500).
756
757
No insulin appears when you do the air shot:
758
759
1. The piston rod is not far enough down the cartridge holder to reach
760
the rear rubber stopper.
761
Repeat the air shot (see pages 16-19).
762
763
2. The NovoFine needle may not be securely attached.
764
a. Put the plastic outer cap back on the NovoFine needle.
765
b. Turn the plastic outer cap in a clockwise direction to tighten the
766
NovoFine needle.
767
768
3. The NovoFine needle may be blocked.
769
Change the NovoFine needle (see pages 14-15) and do an air shot (see
770
pages 16-19).
771
772
The piston rod is sticking out too far to attach the cartridge holder to the
773
barrel:
774
775
You must screw the piston rod back into the barrel (see page 7). Never
776
try to push it in or you can damage the mechanism.
777
1
778
The push button will not return to zero or the piston rod will not turn back
779
into the reset mechanism:
780
781
The return mechanism may be locked. This is usually due to improper
782
technique. Gently turn the mechanism side to side until it unlocks and then
783
call our toll free number (1-800-727-6500) so that we may review go over
784
your technique with you.
785
786
36
787
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 44
WARRANTY
788
789
Should your NovoPen® 3 Demi device be defective in materials or
790
workmanship within two (2) years of purchase, Novo Nordisk
791
Pharmaceuticals, Inc. will replace it at no charge if you mail the defective
792
unit along with a description of the problem and the sales receipt or other
793
proof of purchase to:
794
795
Novo Nordisk Pharmaceuticals, Inc.
796
Product Safety
797
100 College Road West
798
Princeton, NJ 08540
799
800
Protected by U.S. Patent Nos. 5,693,027; 5,626,566; 6,126,646 and Des.
801
347,894 (cartridge) restricted to use with Novo Nordisk insulin cartridges and
802
Novo Nordisk pen needles.
803
804
No other warranty is made with respect to NovoPen® 3 Demi. This warranty will
805
be invalid and Novo Nordisk A/S, Novo Nordisk Pharmaceuticals, Inc., Bristol-
806
Myers Squibb Co., Nipro Medical Industries Ltd., and Bang & Olufsen A/S cannot
807
be held responsible in the case of defects or damages arising from:
808
809
! The use of the NovoPen® 3 Demi with products other than PenFill 3 mL
810
cartridges and NovoFine single-use disposable needles.
811
812
! The use of the NovoPen® 3 Demi not in accordance with the instructions
813
in this booklet.
814
815
! Physical damage to the NovoPen® 3 Demi caused by neglect, misuse,
816
unauthorized repair, accident, or other breakage.
817
37
818
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 45
For assistance or further information, write to:
819
820
Novo Nordisk Pharmaceuticals, Inc.
821
Customer Relations
822
100 College Road West
823
Princeton, NJ 08540
824
825
Or call: 1-800-727-6500
826
827
828
Novo Nordisk®, NovoPen®, Novolin®, NovoLog®, PenFill® and NovoFine® are
829
registered trademarks of Novo Nordisk A/S
830
831
© 2002 Novo Nordisk A/S
832
833
Novo Nordisk Pharmaceuticals, Inc.
834
Princeton, NJ 08540
835
836
http://www.novonordisk-us.com
837
838
8-4241-31-002-1
839
840
Corrections on this page =
841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
4/15/02 10:14:06 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.565374 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19938s33lbl.pdf', 'application_number': 19991, 'submission_type': 'SUPPL ', 'submission_number': 36} |
1,891 | 70/30 HUMAN
Novo Nordisk®
Patient Information for Novolin® 70/30
NOVOLIN® 70/30 (NO-voe-lin)
70% NPH, Human Insulin Isophane Suspension and
30% Regular, Human Insulin Injection
(recombinant DNA origin)
100 units/mL
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. The amount of insulin you take as well as the best time for
you to take your insulin may need to change if you take a different type of insulin.
Make sure that you know the type and strength of insulin that is prescribed for you.
Read the Patient Information leaflet that comes with Novolin® 70/30 before you start
taking it and each time you get a refill. There may be new information. This leaflet does
not take the place of talking with your healthcare provider about your diabetes or your
treatment. Make sure you know how to manage your diabetes. Ask your healthcare
provider if you have any questions about managing your diabetes.
What is Novolin® 70/30?
Novolin® 70/30 is a man-made insulin (recombinant DNA origin) which is a mixture of
70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin
Injection that is structurally identical to the insulin produced by the human pancreas that
is used to control high blood sugar in patients with diabetes mellitus.
Who should not use Novolin® 70/30?
Do not take Novolin® 70/30 if:
Your blood sugar is too low (hypoglycemia).
You are allergic to anything in Novolin® 70/30. See the end of this leaflet for a
complete list of ingredients in Novolin® 70/30. Check with your healthcare
provider if you are not sure.
Tell your healthcare provider:
about all of your medical conditions. Medical conditions can affect your
insulin needs and your dose of Novolin® 70/30.
if you are pregnant or breastfeeding. You and your healthcare provider should
talk about the best way to manage your diabetes while you are pregnant or
breastfeeding. Novolin® 70/30 has not been studied in pregnant or nursing
women.
about all of the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
Reference ID: 3273466
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For current labeling information, please visit https://www.fda.gov/drugsatfda
blood sugar levels and your insulin needs. Your Novolin® 70/30 dose may need
to change if you take other medicines.
if you take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
if you have heart failure or other heart problems. If you have heart failure, it
may get worse while you take TZDs with Novolin® 70/30.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers when you get a new medicine.
How should I take Novolin® 70/30?
Only use Novolin® 70/30 if it appears cloudy or milky. There may be air bubbles. This
is normal. If the precipitate (the white deposit at the bottom of the vial) has become
lumpy or granular in appearance or has formed a deposit of solid particles on the wall of
the vial, do not use it, and call Novo Nordisk at 1-800-727-6500. This insulin should not
be used if the liquid in the vial remains clear after the vial has been gently rotated.
Novolin® 70/30 comes in:
10 mL vials (small bottles) for use with syringe
Read the instructions for use that come with your Novolin® 70/30 product. Talk to
your healthcare provider if you have any questions. Your healthcare provider should
show you how to inject Novolin® 70/30 before you start taking it. Follow your healthcare
provider’s instructions to make changes to your insulin dose.
Take Novolin® 70/30 exactly as prescribed.
Novolin® 70/30 is an intermediate-acting insulin. The effects of Novolin®
70/30 start working ½ hour after injection.
The greatest blood sugar lowering effect is between 2 and 12 hours after the
injection. This blood sugar lowering may last up to 24 hours.
While using Novolin® 70/30, any change of insulin should be made cautiously
and only under medical supervision. Doses of oral anti-diabetic medicines may
also need to change, if your insulin is changed.
Do not mix Novolin® 70/30 with any insulins.
Inject Novolin® 70/30 into the skin of your stomach area, upper arms,
buttocks or upper legs. Novolin® 70/30 may affect your blood sugar levels
sooner if you inject it into the skin of your stomach area. Never inject Novolin®
70/30 into a vein or into a muscle.
Change (rotate) your injection site within the chosen area (for example,
stomach or upper arm) with each dose. Do not inject into the same spot for
Reference ID: 3273466
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each injection.
If you take too much Novolin® 70/30, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking
or eating something sugary right away (fruit juice, sugar candies, or glucose
tablets). It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (become unconscious). If
you pass out, you will need help from another person or emergency medical
services right away, and will need treatment with a glucagon injection or
treatment at a hospital. See “What are the possible side effects of Novolin®
70/30?” for more information on low blood sugar (hypoglycemia).
If you forget to take your dose of Novolin® 70/30, your blood sugar may go
too high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it
can lead to diabetic ketoacidosis, which can lead to serious problems, like loss of
consciousness (passing out), coma or even death. Follow your healthcare
provider’s instructions for treating high blood sugar (hyperglycemia), and talk to
your healthcare provider if high blood sugar is a problem for you. Severe or
continuing high blood sugar (hyperglycemia) requires prompt evaluation and
treatment by your healthcare provider. Know your symptoms of high blood sugar
(hyperglycemia) and diabetic ketoacidosis which may include:
increased thirst
fruity smell on breath
frequent urination and
dehydration
high amounts of sugar and
ketones in your urine
confusion or drowsiness
nausea, vomiting (throwing
up) or stomach pain
loss of appetite
a hard time breathing
Check your blood sugar levels. Ask your healthcare provider how often you
should check your blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
illness
change in diet
stress
change in physical activity or
exercise
other medicines you take
surgery
See the end of this patient information for instructions about preparing and giving the
injection.
What should I avoid while using Novolin® 70/30?
Alcohol. Alcohol, including beer and wine, may affect your blood sugar when
you take Novolin® 70/30.
Driving and operating machinery. You may have difficulty concentrating or
Reference ID: 3273466
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For current labeling information, please visit https://www.fda.gov/drugsatfda
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright to drive if
you often have:
low blood sugar
decreased or no warning signs of low blood
sugar
What are the possible side effects of Novolin® 70/30?
Low blood sugar (hypoglycemia). Symptoms of hypoglycemia (low blood
sugar) may include:
sweating
trouble concentrating or confusion
dizziness or lightheadedness
blurred vision
shakiness
slurred speech
hunger
anxiety, irritability or mood
changes
fast heart beat
headache
tingling of lips and tongue
Severe low blood sugar (hypoglycemia) can cause unconsciousness (passing
out), seizures, and death. Know your symptoms of low blood sugar. Follow your
healthcare provider’s instructions for treating low blood sugar. Talk to your
healthcare provider if low blood sugar is a problem for you.
Serious allergic reaction (whole body reaction). Get medical help right
away if you develop a rash over your whole body, have trouble breathing, a fast
heartbeat, or sweating.
Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having skin reactions, or
they are serious, talk to your healthcare provider. You may need to stop using
Novolin® 70/30 and use a different insulin. Do not inject insulin into skin that is
red, swollen, or itchy.
Skin thickens or pits at the injection site (lipodystrophy). Change (rotate)
where you inject your insulin to help prevent these skin changes from happening.
Do not inject insulin into this type of skin.
Swelling of your hands and feet
Heart Failure. Taking certain diabetes pills called thiazolidinediones or “TZDs”
with Novolin® 70/30 may cause heart failure in some people. This can happen
even if you have never had heart failure or heart problems before. If you already
have heart failure it may get worse while you take TZDs with Novolin® 70/30.
Your healthcare provider should monitor you closely while you are taking TZDs
with Novolin® 70/30. Tell your healthcare provider if you have any new or worse
symptoms of heart failure including:
Reference ID: 3273466
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For current labeling information, please visit https://www.fda.gov/drugsatfda
shortness of breath
swelling of your ankles or feet
sudden weight gain
Treatment with TZDs and Novolin® 70/30 may need to be adjusted or stopped by
your healthcare provider if you have new or worse heart failure.
Vision changes
Low potassium in your blood (hypokalemia)
These are not all of the possible side effects from Novolin® 70/30. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store Novolin® 70/30?
All Unopened Novolin® 70/30:
Keep all unopened Novolin® 70/30 in the refrigerator between 36° to
46°F (2° to 8°C).
Do not freeze. Do not use Novolin® 70/30 if it has been frozen.
If refrigeration is not possible, the unopened vial may be kept at room
temperature for up to 6 weeks (42 days), as long as it is kept at or below
77°F (25°C).
Keep unopened Novolin® 70/30 in the carton to protect from light.
Novolin® 70/30 in use:
Vials
Keep at room temperature below 77°F (25°C) for up to 6 weeks (42
days).
Keep vials away from direct heat or light.
Throw away an opened vial after 6 weeks (42 days) of use, even if
there is insulin left in the vial.
Unopened vials can be used until the expiration date on the
Novolin® 70/30 label, if the medicine has been stored in a
refrigerator.
General advice about Novolin® 70/30
Novolin® 70/30 is used for the treatment of diabetes only. Medicines are sometimes
prescribed for conditions that are not mentioned in the patient leaflet. Do not use
Novolin® 70/30 for a condition for which it was not prescribed. Do not give Novolin®
70/30 to other people, even if they have the same symptoms you have. It may harm
them.
Reference ID: 3273466
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For current labeling information, please visit https://www.fda.gov/drugsatfda
This leaflet summarizes the most important information about Novolin® 70/30. If you
would like more information about Novolin® 70/30 or diabetes, talk with your healthcare
provider. For more information, call 1-800-727-6500 or visit www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American Diabetes
Association, 1701 N Beauregard Street, Alexandria, VA 22311 and on
www.diabetes.org.
Novolin® 70/30 ingredients include:
70% NPH, Human Insulin
Isophane Suspension and 30%
Regular, Human Insulin Injection
(recombinant DNA origin)
Metacresol
Zinc chloride
Glycerol
Sodium hydroxide
Hydrochloric acid
Phenol
Protamine sulfate
Disodium phosphate dihydrate
Water for injections
All Novolin® 70/30 vials are latex-free.
Date of issue: XXXX
Version: X
Novolin® and Novo Nordisk® are registered trademarks of Novo Nordisk A/S.
©2005 - 201X Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin® 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
Reference ID: 3273466
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® 70/30 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing and giving your
insulin injection.
Never re-use syringes and needles.
How should I use the Novolin 70/30 vial?
1. Check to make sure that you have the correct type of insulin.
2. Look at the vial and the insulin. The insulin should be a cloudy or milky suspension.
The tamper-resistant cap should be in place before the first use. If the cap had been
removed before your first use of the vial, or if the precipitate (the white deposit at the
bottom of the vial) has become lumpy or granular in appearance or has formed a deposit
of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800-
727-6500.
3. Wash your hands with soap and water. If you clean your injection site with an alcohol
swab, let the injection site dry before you inject. Talk with your health care provider
about how to rotate injection sites and how to give an injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber stopper
with an alcohol swab.
5. Roll the vial gently 10 times in your hands to mix it. This procedure should be carried
out with the vial in a horizontal position. The rolling procedure must be repeated until
the suspension appears uniformly white and cloudy. Shaking right before the dose is
drawn into the syringe may cause bubbles or froth, which could cause you to draw up the
wrong dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for the
number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger all the way in
to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a few units
beyond correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles
to the top. Then slowly push the plunger to the marking for your correct dose. This
process should move any air bubbles present in the syringe back into the vial.
10. Check to make sure you have the right dose of Novolin 70/30 in the syringe.
11. Pull the syringe needle out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important to ask your doctor if you
did not receive instructions on pinching the skin. Insert the needle into the skin. Press
the plunger of the syringe to inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a drop of Novolin 70/30 at the
needle tip. This is normal and has no effect on the dose you just received. If you see
blood after you take the needle out of your skin, press the injection site lightly with a
piece of gauze or an alcohol wipe. Do not rub the area.
Reference ID: 3273466
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13. After your injection, do not recap the needle. Place used syringes, needles and used
insulin vials in a disposable puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes and
needles. There may be state or local laws about the right way to throw away used
syringes and needles. Do not throw away used needles and syringes in household trash or
recycle.
Reference ID: 3273466
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.624053 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019991s074lbl.pdf', 'application_number': 19991, 'submission_type': 'SUPPL ', 'submission_number': 74} |
1,887 | NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 1
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 2
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 3
3
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NovoPen Junior Final revision
Page 4
4
NovoPen
Junior Instruction
5
Manual
6
7
Dial-A-Dose Insulin Delivery System
8
9
INTRODUCTION
10
11
12
13
14
NovoPen® Junior delivers a minimum dose of 1 unit to a maximum dose of 35
15
units of insulin in half unit steps. A raised circle on the push button makes it easy
16
for you to know your NovoPen Junior from the ordinary NovoPen 3. This booklet
17
includes everything you need to know about using the NovoPen Junior. Please
18
read it carefully before using your NovoPen Junior for the first time.
19
20
The NovoPen Junior is designed for use with:
21
! PenFill® 3 mL cartridges.
22
! NovoFine® disposable needles.
23
NovoFine disposable needles are for single-use only.
24
You will also need alcohol swabs.
25
26
If you have any questions about your NovoPen Junior insulin delivery system,
27
please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
28
29
Please complete and return the NovoPen Junior warranty card.
30
31
32
33
34
See Important Things to Know and Important Notes on pages 33-35.
35
36
2
37
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NovoPen Junior Final revision
Page 5
HOW TO USE THIS BOOKLET
38
39
This booklet gives you step-by-step instructions for using the NovoPen
40
Junior.
41
42
Begin by reviewing the drawing layout of the parts of the NovoPen Junior, PenFill
43
3 mL cartridge, and NovoFine disposable needle. The inside front cover opens
44
out so you have a handy reference while you read the rest of the booklet.
45
46
Most pages contain a drawing on the right with numbered instructions to the left
47
of the drawing.
48
Important additional information is given below the drawing.
49
50
We suggest that you read the text and look at the drawing to make sure that
51
you understand each step thoroughly.
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
3
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NovoPen Junior Final revision
Page 6
TABLE OF CONTENTS
82
83
SECTION 1:
84
Preparing the NovoPen Junior..........................………......................……… 5
85
86
SECTION 2:
87
Inserting the PenFill 3 mL Cartridge............................................................. 8
88
89
SECTION 3:
90
Attaching the NovoFine Disposable Needle................................................ 12
91
92
SECTION 4:
93
Doing an Air Shot ........................................................................................ 16
94
95
SECTION 5:
96
Giving the Injection ..................................................................................... 20
97
98
SECTION 6:
99
Removing the NovoFine Disposable Needle................................................ 24
100
101
SECTION 7:
102
Removing the PenFill 3 mL Cartridge......................................................... 26
103
104
FUNCTION CHECK ................................................................................... 28
105
106
STORAGE..................................................................................................
31
107
108
MAINTENANCE........................................................................................
32
109
110
IMPORTANT THINGS TO KNOW...........................................................
33
111
112
IMPORTANT NOTES.................................................................................
34
113
114
WHAT TO DO IF......................................................................................
36
115
116
WARRANTY .............................................................................................
37
117
Corrections on this page =
118
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NovoPen Junior Final revision
Page 7
SECTION 1
Preparing the NovoPen Junior
119
120
Remove the device cap:
121
1. Remove the NovoPen Junior from the case.
122
2. Gently twist the pen cap until the cap separates from the barrel.
123
3. Pull the pen cap straight up to remove it.
124
125
126
127
If you use more than one insulin product (such as Novolin® R, Novolin® N,
128
Novolin® 70/30, or NovoLog®), use a separate insulin delivery device for each
129
product.
130
131
5
132
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NovoPen Junior Final revision
Page 8
SECTION 1 (cont.)
133
134
Separate the cartridge holder from the barrel:
135
136
4. Unscrew and remove the cartridge holder from the barrel.
137
138
139
140
Make sure the dose indicator window shows zero:
141
142
5. Press the push button all the way in until zero (0) appears in the window.
143
The zero should be lined up with the stripe below the dose indicator
144
window.
145
146
147
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6
148
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Page 10
149
SECTION 1 (cont.)
150
151
The end of the piston rod should be flat against the end of the reset mechanism
152
prior to inserting each new PenFill 3 mL cartridge. It should not be sticking out.
153
154
If the piston rod is sticking out:
155
156
Turn the end of the reset mechanism in a clockwise direction until it is no longer
157
sticking out. Never push the piston rod back in.
158
159
160
161
162
You should never reset the piston rod until it is time to remove the used PenFill 3
163
mL cartridge and insert a new one.
164
165
If the reset mechanism locks, it is usually due to improper technique. Gently turn
166
the mechanism side to side until it unlocks. Then call our toll free number (1-800-
167
727-6500) so that we may go over your technique with you.
168
169
7
170
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Page 11
SECTION 2
Inserting the PenFill 3 mL Cartridge
171
172
1. To remove the PenFill cartridge from its wrapper, push the cartridge
173
through the foil side of the packaging. Always make sure that the PenFill
174
cartridge you use contains the correct type of insulin (such as Novolin R,
175
Novolin N, Novolin 70/30, or NovoLog). If you are treated with more than
176
one type of insulin in PenFill cartridges, you should use a separate insulin
177
delivery device for each type of insulin. Before use, check that the PenFill
178
cartridge is full and intact. If not, do not use it.
179
180
2-1
181
182
2. In the PenFill Information For The Patient leaflet, you will find instructions
183
on how to prepare the insulin if the PenFill contains a suspension insulin
184
(white and cloudy insulin) such as Novolin N or Novolin 70/30.
185
186
1-4
187
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. Make sure
188
you are using the correct type of insulin. On the glass part of the cartridge is the
189
name of the insulin.
190
191
Each PenFill cartridge is for single-person use only. DO NOT share the same
192
cartridge with anyone even if you attach a new disposable needle for each
193
injection. Sharing the cartridge can spread disease.
194
Use only a new PenFill 3 mL cartridge when loading the NovoPen Junior. Never
195
load a partially filled cartridge.
196
Never try to refill a used PenFill 3 mL cartridge.
197
198
8
199
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Page 12
9
200
SECTION 2 (cont.)
201
202
Insert the PenFill cartridge:
203
204
2. Hold the cartridge holder so the wider opening is up.
205
3. Drop the PenFill cartridge into the cartridge holder, plastic cap first.
206
207
208
A threaded plastic cap surrounds the end of the PenFill® cartridge, like the cap
209
on a bottle. In the center is the front rubber stopper.
210
211
The rear rubber stopper is at the other end of the PenFill cartridge.
212
213
10
214
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Page 13
SECTION 2 (cont.)
215
216
Re-attach the cartridge holder:
217
218
4. Screw the barrel into the cartridge holder completely until it is tight.
219
220
221
222
223
224
You can see the cartridge in the insulin scale window. The cartridge holder has a
225
scale with marks showing about how much insulin is left in the PenFill cartridge.
226
227
11
228
2
229
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Page 14
SECTION 3
Attaching the NovoFine® Disposable Needle
230
231
At the end of the cartridge holder are two inspection windows. You can see the
232
cartridge through these windows.
233
234
If you use a suspension insulin (white and cloudy) such as Novolin® N or
235
Novolin® 70/30, use the windows to check if there is enough insulin left for
236
proper mixing. (see below)
237
238
Check the amount of insulin remaining:
239
240
! If the rear rubber stopper cannot be seen in the inspection window, you
241
have enough insulin for mixing left in the cartridge.
242
! If the rear rubber stopper can be seen in the inspection window, you do
243
not have enough insulin left in the cartridge and must insert a new PenFill
244
3 mL cartridge.
245
246
See Section 7 for instructions on removing a PenFill cartridge and Section 2 for
247
inserting a new one.
248
249
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Page 15
At least
250
12
251
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NovoPen Junior Final revision
Page 16
SECTION 3 (cont.)
252
253
For users of suspension insulin (white and cloudy) such as Novolin N or
254
Novolin 70/30:
255
256
Always remix the insulin before each injection.
257
To remix the insulin, turn the NovoPen Junior up and down between positions A
258
and B 10 times or until the insulin looks uniformly white and cloudy
259
260
261
262
263
13
264
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Page 17
SECTION 3 (cont.)
265
266
1. Wipe the front rubber stopper with an alcohol swab.
267
1
268
269
270
You must wipe the front rubber stopper with an alcohol swab before each
271
injection, even if you are using the same PenFill cartridge.
272
3-3
273
14
274
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Page 18
SECTION 3 (cont.)
275
276
2. Remove the protective tab from the NovoFine disposable needle.
277
3. Screw the NovoFine disposable needle firmly onto the PenFill 3 mL
278
cartridge until it is tight.
279
2 33
280
281
282
Never place a NovoFine disposable needle on your NovoPen Junior until you are
283
ready to do an air shot and give an injection.
284
If the NovoFine needle is left on, some liquid may leak out of the PenFill
285
cartridge. This may cause a change in the strength of the suspension insulin
286
such as Novolin N or Novolin 70/30.
287
15
288
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NovoPen Junior Final revision
Page 19
289
SECTION 4
Doing an Air Shot
290
291
The PenFill cartridge may contain an air bubble, and small amounts of air may
292
collect in the needle and PenFill cartridge when you use them. To avoid injecting
293
air and to ensure proper dosing, you must perform an air shot before each
294
injection.
295
296
Before doing the air shot, the dose indicator window must show zero (0).
297
298
If you use a suspension insulin, such as Novolin N or Novolin 70/30 and have
299
used the PenFill cartridge for previous injections, make sure there is enough
300
insulin left in the PenFill cartridge to properly mix the insulin (see page 12). If
301
there is enough insulin left in the PenFill cartridge, see the next page for
302
instructions.
303
304
16
305
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NovoPen Junior Final revision
Page 20
SECTION 4 (cont.)
306
307
Set the NovoPen Junior for the air shot:
308
309
1. Turn the dial-a-dose selector to 2 units. Full units are shown as numbers.
310
Half units are shown as long lines between the numbers.
311
1
312
313
4-1
314
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you
315
do, the extra insulin will squirt out of the needle. You may complete the air shot
316
with the number of units you have dialed or refer to Section 5 on page 21 for
317
instructions on how to reset the dose to zero.
318
319
17
320
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Page 21
SECTION 4 (cont.)
321
322
Uncap the NovoFine needle:
323
324
2. Pull off the outer needle cap and set aside.
325
3. Pull off the inner needle cap and discard.
326
2
327
Do not use the needle if it is bent or damaged.
328
329
330
331
4. Hold the NovoPen Junior with the NovoFine needle pointing up.
332
5. Tap the cartridge holder with your finger a few times to raise any air
333
bubbles that may be present to the top of the cartridge.
334
335
336
18-3
337
338
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NovoPen Junior Final revision
Page 22
SECTION 4 (cont.)
339
340
Do the air shot:
341
342
6. Press the push button all the way in. A drop of insulin should appear at the
343
needle tip.
344
345
If no insulin appears, repeat the following steps, until a drop of insulin
346
appears:
347
348
a. Make sure the NovoFine needle is securely attached.
349
b. Dial 2 units.
350
c. Tap the cartridge holder with your finger.
351
d. Press the push button all the way in.
352
353
There may still be some small air bubble(s) in the PenFill cartridge after this, but
354
they will not affect your dose and they will not be injected.
355
356
357
358
When you press the push button, the piston rod presses against the rear rubber
359
stopper. This moves the rear rubber stopper and pushes the correct amount of
360
insulin up through the needle.
361
362
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Page 23
19
363
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NovoPen Junior Final revision
Page 24
SECTION 5
Giving the Injection
364
365
Be sure to do an air shot before giving each injection (see pages 16-19).
366
Select the dose:
367
368
1 Check that the dial-a-dose selector is set to zero. If not, follow the
369
instructions on the next page. Turn the dial-a-dose selector until you see
370
the correct number of units in the dose indicator window. Full units are
371
shown as numbers. Half units are shown as long lines between the
372
numbers.
373
374
1 DO NOT use the clicking sound as a guide for selecting your dose.
375
376
377
4-4
378
The NovoPen Junior can deliver insulin in half unit steps from a minimum dose
379
of 1 unit to a maximum dose of 35 units.
380
381
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you
382
do, the extra insulin will squirt out of the needle. For instructions on how to reset
383
the dose to zero (0) so you can start again, see the next page.
384
385
386
20
387
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NovoPen Junior Final revision
Page 25
SECTION 5 (cont.)
388
389
If you dial a larger dose than you need, pull the barrel and the cartridge holder
390
apart, as shown in the drawing A. While holding them apart, gently press the
391
push button against a hard surface and release your grip B. Your dose indicator
392
window should be back to zero (0).
393
394
You can now dial the correct number of units.
395
396
397
398
21
399
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NovoPen Junior Final revision
Page 26
Corrections on this page =
400
SECTION 5 (cont.)
401
402
Giving the injection:
403
404
2. After the air shot is done and you have chosen the correct number of
405
units, insert the NovoFine needle in the correct injection site on your body.
406
(Use the injection technique recommended by your health care
407
professional). If you use a suspension insulin such as Novolin N or
408
Novolin 70/30, mix the insulin (see page 13, Section 3) and make sure the
409
insulin looks uniformly white and cloudy before you inject.
410
411
3. Press the push button as far as it will go to deliver the insulin. Do not
412
force it.
413
414
To ensure that all the insulin is injected, keep the NovoFine needle in the skin for
415
several seconds after injection with your thumb on the push button. Keep the
416
push button fully depressed until after the NovoFine needle has been withdrawn.
417
418
Important: Never turn the dial-a-dose selector to inject the insulin.
419
420
421
422
When you get near the end of a PenFill cartridge, you may need to give yourself
423
two injections to receive your full dose. Check the dose indicator window after
424
giving an injection. If zero does not appear in the dose indicator window, you did
425
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NovoPen Junior Final revision
Page 27
not receive your full dose. See the next page for instructions on how to get the
426
remaining part of your dose.
427
428
22
429
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NovoPen Junior Final revision
Page 28
430
SECTION 5 (cont.)
431
432
4. Check the dose indicator window to make sure it shows zero (0). If
433
zero does not appear, you did not receive the full dose.
434
435
If the dose indicator window does not show zero, there were not enough units of
436
insulin in the PenFill cartridge for you to receive the full dose. The dose indicator
437
window shows the number of units that you did not receive.
438
439
For example, if you dial 25 units and there are only 20 units left in the PenFill
440
cartridge, after the injection the number in the dose indicator window will be
441
5 (25-20 = 5). If this happens, proceed with the following steps to get the
442
remaining part of your dose:
443
444
a. Note the number of units in the dose indicator window.
445
b. Remove the NovoFine needle (see Section 6).
446
c. Remove the empty PenFill 3 mL cartridge (see Section 7).
447
d. Insert a new PenFill 3 mL cartridge (see Section 2).
448
e. Attach a NovoFine needle (see Section 3).
449
f. Do an air shot (see Section 4).
450
g. Dial the number of units noted in step a.
451
h. Give the injection.
452
453
454
4
455
456
23
457
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NovoPen Junior Final revision
Page 29
SECTION 6
Removing the NovoFine Disposable Needle
458
459
Remove the NovoFine disposable needle:
460
461
1. After the injection, remove the needle without replacing the cap.
462
463
2. Hold the cartridge holder firmly while you unscrew the NovoFine
464
disposable needle.
465
466
3. Place the NovoFine disposable needle in a puncture-resistant disposable
467
container.
468
469
Health care professionals, relatives and other caregivers should also follow the
470
above instructions to eliminate the risk of unintended needle penetration.
471
472
473
474
475
The NovoFine disposable needle must be removed immediately after each
476
injection without replacing the cap. If the NovoFine disposable needle is not
477
removed, some liquid may leak out of the PenFill cartridge. This may cause a
478
change in the strength of suspension insulins (white and cloudy) such as Novolin
479
N or Novolin 70/30.
480
481
For information on how to throw away needle containers properly, contact your
482
local trash company.
483
6-1
484
24
485
Corrections
486
487
SECTION 6 (cont.)
488
489
Replace the pen cap:
490
491
4. After you remove the disposable needle, hold the pen cap so that the clip
492
is lined up with the dose indicator window.
493
494
5. Gently slide the pen cap onto the barrel.
495
496
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Page 30
497
4
498
25
499
500
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NovoPen Junior Final revision
Page 31
501
SECTION 7
Removing the PenFill 3 mL Cartridge
502
503
You will need to remove the PenFill cartridge for the following reasons:
504
505
! When tThe PenFill cartridge is empty.
506
507
! If you use a suspension insulin such as Novolin N or Novolin 70/30:
508
509
When you see the rear rubber stopper in the inspection window, then you
510
do not have enough insulin left in the PenFill cartridge for proper mixing.
511
512
Remove the barrel:
513
514
1. Remove the pen cap.
515
516
2. Hold the NovoPen Junior with the dose indicator window at the top.
517
518
3. Unscrew the barrel from the cartridge holder.
519
520
7-1
521
522
26
523
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NovoPen Junior Final revision
Page 32
SECTION 7 (cont.)
524
525
Remove the PenFill 3 mL cartridge:
526
527
4. Tip the cartridge holder. The PenFill cartridge will drop out.
528
529
5. Press the push button all the way in until zero (0) appears in the window.
530
531
6. Turn the end of the reset mechanism in a clockwise direction until the
532
piston rod is no longer sticking out (refer to figure 1-4 on page 7).
533
534
7. To insert a new PenFill cartridge, please refer to Section 2.
535
536
537
538
If the reset mechanism locks, it is usually due to improper technique. Gently turn
539
the mechanism side to side until it unlocks and then call our toll free number (1-
540
800-727-6500) so that we may go over your technique with you.
541
5
542
27
543
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NovoPen Junior Final revision
Page 33
FUNCTION CHECK
544
545
You should regularly check the functioning of your NovoPen Junior, (for example,
546
once a month or before starting a new box of PenFill cartridges). The function
547
check is done by delivering 20 units of insulin into the outer needle cap. You will
548
not be injecting insulin into your body.
549
550
Always check the functioning of the NovoPen Junior if you suspect it has been
551
damaged or if you are uncertain that it is delivering the correct dose.
552
553
Do not use NovoPen Junior unless you are sure that it is working properly.
554
Help? Call 1-800-727-6500
555
To perform the function check:
556
557
1. Attach a NovoFine disposable needle (see pages 12-15).
558
559
2. Do an air shot (see pages 16-19).
560
561
28
562
1
563
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 34
564
FUNCTION CHECK (cont.)
565
566
3. Do not replace the inner needle cap. Place the outer needle cap
567
securely over the exposed NovoFine needle.
568
569
570
571
572
Expel 20 units of insulin into the outer needle cap:
573
574
4. Turn the dial-a-dose selector so the dose indicator window shows 20.
575
576
577
578
29
579
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 35
FUNCTION CHECK (cont.)
580
581
5. Hold the NovoPen Junior so the NovoFine disposable needle is pointing
582
down.
583
584
6. Slowly press the push button as far as it will go.
585
586
7. Check the dose indicator window to see if it shows zero (0). If it does not
587
show zero (0), there is not enough insulin in the cartridge to do a function
588
check. Insert a new PenFill cartridge (see pages 8-11) and repeat the
589
function check. If there is enough insulin in the cartridge but the dose
590
indicator window does not show zero, repeat the FUNCTION CHECK. If
591
you do not see zero after repeating the above steps, do not use your
592
NovoPen Junior. Contact Novo Nordisk Pharmaceuticals, Inc. at our toll
593
free number (1-800-727-6500).
594
595
596
597
598
The insulin should fill the bottom part of the outer needle cap. This indicates the
599
device is functioning properly.
600
601
If the insulin does not fill or overfills this part of the cap, review the function
602
check procedure. Then repeat the function check with a new NovoFine
603
disposable needle and outer needle cap.
604
605
If the second function check also shows under- or over-filling, do not use your
606
NovoPen Junior.
607
608
DO NOT try to repair a NovoPen Junior that you think is not working
609
properly.
610
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 36
See Warranty section for further information.
612
613
30
614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 37
-3
615
STORAGE
616
617
Guidelines for storing the NovoPen Junior and PenFill 3 mL cartridges:
618
619
! PenFill cartridges should be stored in a cool place, such as in a
620
refrigerator, but not in thea freezer.
621
622
! After the first use of PenFill cartridge in the NovoPen Junior, the NovoPen
623
Junior (with the PenFill cartridge inside) can be kept at room temperature
624
below 86°F (30°C) for the amount of time days specified listed in the
625
PenFill Information for the Patient leaflet for the type of insulin you are
626
using.
627
628
! Do not store the NovoPen 3 Junior (with the PenFill cartridge inside) in a
629
refrigerator or areas where there may be extreme temperatures or
630
moisture, such as in your car.
631
632
! The expiration date printed on the cartridge is for unused cartridges
633
under refrigeration. Never use the cartridge after the expiration date
634
on the cartridge or its box.
635
636
637
638
639
! Store the NovoPen Junior without the NovoFine needle attached and
640
with the pen cap in position.
641
642
! For information on storing PenFill cartridges, see the package leaflet that
643
comes in the PenFill cartridge box.
644
645
646
31
647
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 38
MAINTENANCE
648
649
Guidelines for maintaining the NovoPen Junior.
650
651
Be sure to:
652
653
1. Clean it by wiping with a soft cloth moistened with alcohol.
654
655
2. Protect it from dust, dirt, and moisture when not in its case.
656
657
658
Make certain you:
659
660
1. Do not soak it in alcohol, do not wash it in soap and water, or do not
661
lubricate it, since this may cause damage.
662
663
2. Do not expose it to excessive pressure or blows.
664
665
3. Do not drop it.
666
667
32
668
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 39
IMPORTANT THINGS TO KNOW
669
2
670
! The NovoPen Junior is not recommended for the blind or visually
671
impaired, without the assistance of a sighted individual trained to use it.
672
673
! If you use more than one type of insulin (such as Novolin R, Novolin N,
674
Novolin 70/30, or NovoLog), use a separate insulin delivery device for
675
each type of insulin.
676
677
! Use only a new PenFill 3 mL cartridge when loading the NovoPen Junior.
678
Never load the NovoPen Junior with a partially filled PenFill cartridge.
679
680
! Always keep a spare insulin delivery system available, in case your
681
NovoPen Junior is lost or damaged.
682
683
! Keep the NovoPen Junior, PenFill cartridges, and NovoFine needles out
684
of the reach of children. The American Diabetes Association recommends
685
that insulin should be self-administered. The proper age for initiating this
686
should be assessed by the adult caregiver.
687
688
! Keep the NovoPen Junior away from areas where temperatures may get
689
too hot or too cold such as a car or refrigerator.
690
691
! The NovoPen Junior is designed for use with PenFill 3 mL insulin
692
cartridges and NovoFine single-use disposable needles.
693
694
Novo Nordisk is not responsible for any consequences arising from the use of
695
the NovoPen Junior with products other than PenFill 3 mL insulin cartridges
696
and NovoFine single-use disposable needles.
697
698
33
699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 40
IMPORTANT NOTES
700
701
The following is a review of some important information about the use and
702
care of your NovoPen Junior.
703
704
705
Before each injection, be certain:
706
707
1. The NovoPen Junior contains the correct insulin cartridge (such as
708
Novolin R, Novolin N, Novolin 70/30, or NovoLog), if you use more than
709
one type of insulin.
710
711
2. The PenFill cartridge contains enough insulin for mixing, if you use a
712
suspension insulin (white and cloudy) such as Novolin N or Novolin 70/30.
713
714
3. To do an air shot with the NovoFine needle pointing up before each
715
injection.
716
1
717
2 3
718
Be sure to:
719
720
1. Check the dose indicator window after each injection to make sure you
721
have received your full dose (see page 23, Section 5).
722
723
2. Remove the NovoFine needle immediately after each injection without
724
replacing the cap.
725
726
3. Select your dose only by using the number in the dose indicator window.
727
728
4. Perform the function check regularly or if you think your NovoPen Junior is
729
not working properly.
730
1
731
34
732
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 41
IMPORTANT NOTES (cont.)
733
734
Make certain you:
735
736
1. DO NOT place a NovoFine needle on the NovoPen Junior until you are
737
ready to do an air shot and give an injection or do a function check.
738
Remove the needle immediately after each injection without replacing the
739
cap. If the NovoFine needle is not removed, some liquid may leak out of
740
the PenFill cartridge. This may cause a change in the strength of
741
suspension insulin (white and cloudy) such as Novolin N or Novolin 70/30.
742
743
2. DO NOT use the clicking sound to set your insulin dose.
744
745
3. DO NOT try to refill a PenFill cartridge.
746
747
4. DO NOT share the same PenFill cartridge with anyone else even if you
748
attach a new NovoFine needle for each injection. Sharing the cartridge
749
can spread disease. Each PenFill cartridge is for single-person use only.
750
751
Blood glucose levels should be tested frequently to monitor your insulin regimen.
752
753
Any change in insulin should be made cautiously and only under medical
754
supervision.
755
Corrections on this
756
35
757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 42
758
WHAT TO DO IF…
759
760
The dose indicator window does not show zero after the injection:
761
762
1. You did not receive your full dose.
763
1 Follow the steps on page 23 to get the remaining part of your dose.
764
765
2. Your NovoPen Junior is malfunctioning.
766
Do not use your NovoPen Junior. Contact Novo Nordisk Pharmaceuticals,
767
Inc. at our toll free number (1-800-727-6500).
768
769
No insulin appears when you do the air shot:
770
771
1. The piston rod is not far enough down the cartridge holder to reach
772
the rear rubber stopper.
773
Repeat the air shot (see pages 16-19).
774
775
2. The NovoFine needle may not be securely attached.
776
a. Put the plastic outer cap back on the NovoFine needle.
777
b. Turn the plastic outer cap in a clockwise direction to tighten the
778
NovoFine needle.
779
780
3. The NovoFine needle may be blocked.
781
Change the NovoFine needle (see pages 14-15) and do an air shot (see
782
pages 16-19).
783
784
The piston rod is sticking out too far to attach the cartridge holder to the
785
barrel:
786
787
You must screw the piston rod back into the barrel (see page 7). Never try to
788
push it in or you can damage the mechanism.
789
1
790
The push button will not return to zero or the piston rod will not turn back
791
into the reset mechanism:
792
793
The return mechanism may be locked. This is usually due to improper
794
technique. Gently turn the mechanism side to side until it unlocks and then
795
call our toll free number (1-800-727-6500) so that we may go over your
796
technique with you.
797
798
36
799
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 43
WARRANTY
800
801
Should your NovoPen® Junior device be defective in materials or
802
workmanship within two (2) years of purchase, Novo Nordisk
803
Pharmaceuticals, Inc. will replace it at no charge if you mail the defective unit
804
along with a description of the problem and the sales receipt or other proof of
805
purchase to:
806
807
Novo Nordisk Pharmaceuticals, Inc.
808
Product Safety
809
100 College Road West
810
Princeton, NJ 08540
811
812
Protected by U.S. Patent Nos. 5,693,027; 5,626,566; 6,126,646 and Des.
813
347,894 (cartridge) restricted to use with Novo Nordisk insulin cartridges and
814
Novo Nordisk pen needles.
815
816
No other warranty is made with respect to NovoPen® Junior. This warranty
817
will be invalid and Novo Nordisk A/S, Novo Nordisk Pharmaceuticals, Inc.,
818
Bristol-Myers Squibb Co., Nipro Medical Industries Ltd., and Bang & Olufsen
819
A/S cannot be held responsible in the case of defects or damages arising
820
from:
821
822
! The use of the NovoPen® Junior with products other than PenFill 3 mL
823
cartridges and NovoFine single-use disposable needles.
824
825
! The use of the NovoPen® Junior not in accordance with the instructions in
826
this booklet.
827
828
! Physical damage to the NovoPen® Junior caused by neglect, misuse,
829
unauthorized repair, accident, or other breakage.
830
831
37
832
833
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 44
834
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
4/11/02 07:24:52 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:23.692609 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19938s32lbl.pdf', 'application_number': 19991, 'submission_type': 'SUPPL ', 'submission_number': 35} |
2,288 | NDA 20-280/S-040
GENOTROPIN ZipTip
Needle-free Delivery Device for use with Genotropin® Lyophilized Powder (somatropin [rDNA
origin] for injection)
Instructions for Use
Important Note
Please read these instructions completely before using the
GENOTROPIN ZipTip. If there is anything you
do not understand or cannot do, call the toll-free
number listed at the end of these instructions.
If you have any questions about your dose or your treatment
with GENOTROPIN, call your healthcare professional.
GENOTROPIN ZipTip is a device used to mix and inject doses of GENOTROPIN Lyophilized
Powder (somatropin [rDNA origin] for injection). Use this device only for administration of
GENOTROPIN.
What You Will Need
• GENOTROPIN ZipTip Needle-free Delivery Device (reusable reset box, injector, and mixer)
• One disposable sterile ampoule (discarded after each injection)
• One disposable sterile connector (discarded every time the cartridge is changed)
• A two-chamber cartridge of GENOTROPIN (either 5.8 or 13.8 mg, as prescribed for you by your
doctor)
• Alcohol swab or disinfectant recommended by your health care professional
• Proper disposal container for used ampoules and connectors
Components of the GENOTROPIN ZipTip
The ZipTip system consists of 3 reusable components: a reset box, an injector, and a mixer. In
addition, 2 disposable components are needed for this system: an ampoule and a connector. The
diagrams below show the different components.
Reusable Reset box
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NDA 20-280/S-040
Reusable Injector
Reusable Mixer
Disposable Ampoule
Disposable Connector
Storage
To store GENOTROPIN after reconstitution (mixing the powder and liquid), keep the cartridge inside
the mixer, , and store it in the refrigerator for up to 21 days. Do not freeze. Protect from light. If you
do not use the reconstituted GENOTROPIN within 21 days, throw it away even if the cartridge is not
empty. Do not store reconstituted GENOTROPIN in the ampoule.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
When traveling, keep the cartridge with reconstituted GENOTROPIN inside the mixer and carry it in
an insulated bag to protect it from heat or freezing. Put the insulated bag in the refrigerator as soon as
possible.
To avoid malfunctions, store the GENOTROPIN ZipTip injector and reset box at room temperature
(between 59° and 86°F).
Before You Begin
To help prevent infection, always wash your hands well with soap and water before preparing or using
the GENOTROPIN ZipTip.
1. Reset the Injector
• Place the reset box on a flat surface with the hinge pointing
away from you. Hold the bottom half of the reset box with
one hand and using the other hand, lift the lid as far as it will
go.
• Make sure that the blue safety ring in the injector is in the
“safe” position (pushed as far as it will go toward the injector
body). Otherwise the injector will not fit inside the reset
box.
• Hold the injector body with the trigger release lever facing
up and the black end of the injector pointing away from you
and angled downward. Fit the black end of the injector over
the tip of the push rod located toward the hinge of the reset
box. Set the body of the injector into the box, with the
trigger release lever facing up.
• Hold the bottom of the box firmly with one hand, while
firmly pushing down on the lid with the other hand to close
the box. This resets the injector and prepares it to receive a
filled ampoule.
• Open the reset box all the way. Lift the injector and remove
it from the reset box. Set the injector on a clean surface.
• If you already have a cartridge with reconstituted
GENOTROPIN (the powder and liquid have been mixed)
inside the ZipTip mixer, go to Step 6, skipping Steps 2 to 5.
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NDA 20-280/S-040
2.
Prepare the Mixer
• Turn the barrel of the mixer counterclockwise (to the left) as
far as it will go.
3.
Insert a Cartridge of GENOTROPIN
• Take a cartridge of GENOTROPIN out of its packaging.
• Wipe the metal/rubber tip of the cartridge with an alcohol
swab.
• Insert the cartridge into the transparent compartment of the
mixer, with the powder side of the cartridge pointing up.
4.
Add Connector
• Take a new connector out of its packaging, being careful not
to touch the needle.
• Screw the needle end of the connector onto the tip of the
mixer by turning clockwise (to the right) as far as it will go,
while holding the transparent part of the mixer. You now
have a mixer assembly.
5.
Mix GENOTROPIN
• Hold the mixer assembly with the connector on top. Slowly
turn the barrel of the mixer clockwise (to the right) until the
two gray stoppers inside the cartridge come together. Do not
turn the barrel any further. The liquid in the rear chamber of
the cartridge is now mixed with the growth hormone powder
in the front chamber. It is normal to have an air bubble at the
top of the front chamber.
• Gently tip the mixer assembly from side to side to help
dissolve the powder completely. Do not shake the
assembly. Shaking may inactivate the growth hormone so it
will not work.
Check to make sure the solution is clear, indicating that the
growth hormone powder is completely dissolved. If you see
particles, or if the solution is discolored, do not inject it.
Instead, call the toll-free number listed at the end of this
leaflet.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
6. Fill an Ampoule
• Do this step just before you are going to inject
GENOTROPIN, because you should not store the
reconstituted product in the ampoule.
• Lift the protective cap of the connector by pushing up on the
lip.
• Take a new ampoule out of its packaging. Do not touch the
sterile tip (the end with the black rubber stopper) at any time.
• Push the plunger into the ampoule as far as it will go to
remove air from the ampoule.
• Screw the sterile tip of the ampoule into the open end of the
connector by turning clockwise (to the right) as far as it will
go.
• Turn the mixer assembly so that the ampoule is at the
bottom. Slowly, pull down on the ampoule plunger to
transfer your dose of GENOTROPIN to the ampoule.
Remove any air bubbles that may have been drawn into the
ampoule by pushing the plunger up. If necessary, pull down
on the plunger again to transfer more GENOTROPIN to the
ampoule. The uppermost line of the black rubber on the
plunger should be lined up with the number in the scale on
the barrel that represents the dose prescribed by your doctor.
Important: If you transfer more liquid than what you need
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
for your dose, turn the barrel of the mixer counterclockwise
(to the left) a few times and then slowly push up the ampoule
plunger to return the extra liquid back into the cartridge.
Do not use the product if you can see particles inside the
filled ampoule. Instead, remove the ampoule from the mixer
assembly and throw away as directed by your health care
professional. Check that the remaining solution in the
cartridge is clear and does not have particles. If there are no
particles in the cartridge, repeat step 6 with a new ampoule.
If you can see particles in the cartridge, do not use the
medicine and call the toll- free number listed at the end of
this leaflet.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
• Hold the barrel of the filled ampoule and unscrew it from the
connector by turning the ampoule counterclockwise (to the
left). Be careful not to touch the sterile tip of the ampoule at
any time.
• Close the protective cap on the connector and set aside the
mixer assembly.
Important: Keep the connector attached to the mixer until
the cartridge of GENOTROPIN is empty. After the cartridge
is empty, remove the cartridge and connector and throw them
away as instructed by your health care professional. Never
use the same connector for more than one cartridge.
Keep the mixer, which is reusable.
7.
Attach the Filled Ampoule
Carefully fit the plunger of the filled ampoule inside the
black end of the injector. Turn the ampoule clockwise (to the
right) as far as it will go. The rim of the ampoule should fit
snuggly against the end of the injector.
Important: If the plunger of the ampoule does not fit inside
the injector, you will need to reset the injector by following
the instructions given in Step 1.
Do not place anything other than a filled ampoule into the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
injector.
8. Prepare the Injector
• Slide the blue safety ring toward the ampoule to allow the
trigger release lever to work. The injector is now ready for
injection.
Important: After the injector is prepared, make sure never
to point it at yourself or anyone else, especially at the eyes or
other sensitive parts of the body. Accidental discharge of the
injector can cause injuries.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
9. Inject GENOTROPIN
• Check the filled ampoule again to make sure that it contains
the dose of GENOTROPIN that was prescribed by your
doctor.
• Select and disinfect an appropriate injection site as instructed
by your health care professional, allowing the disinfected
skin area to dry for a few seconds.
• Press the sterile tip of the ampoule firmly against the
injection site, applying enough pressure to slightly indent the
skin. Make sure that you hold the device straight up and
down (perpendicular to the skin), without pinching up or
creasing the skin.
• When you are ready, press the trigger release lever to inject
the GENOTROPIN. To avoid injuries to the skin, always
hold the injector straight up and down and firmly in position
while injecting your dose.
• After the injection, continue to hold the injector on the
injection site for another 5 seconds. Do not pull or stretch
the skin around the injection site.
• Lift the injector from the injection site. Never wipe the
injection site with alcohol after the injection. Although it is
not necessary, you can blot the skin gently with a clean
cotton ball if you wish.
• If some of the dose accidentally squirts into the air or on the
skin while you are injecting, do not give yourself another
injection that day. Instead, wait until your next scheduled
injection. If you have the same problem again, contact your
health care professional.
10. Store the ZipTip device
• Slide the blue safety ring away from the ampoule to
inactivate the trigger release lever.
Turn the ampoule counterclockwise (to the left) to remove it
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
from the injector. Throw away the ampoule as directed by your
health care professional.
Important: Never reuse an ampoule to avoid infection or injury
to yourself, or possible malfunction of the ampoule.
• It is important that you keep the injector clean and free from
dust, dirt, and medication residues. Wipe the outside of the
injector with a clean damp cloth. Never immerse the injector
in any liquid.
• Return the injector to the reset box and close the lid to reset
the injector for your next injection. Place the reset box inside
the gray carrying pouch and store it at room temperature.
• Never press the trigger release lever with an empty ampoule
attached, as this may damage the injector.
• Place the mixer assembly in the refrigerator until your next
injection.
Your Next Injection
If the mixer already has a cartridge containing reconstituted GENOTROPIN, prepare your next
injection by starting with Step 6 of the instructions.
If the cartridge does not have enough reconstituted GENOTROPIN for a full dose, follow Step 6 of the
instructions to transfer the rest of the medicine to the ampoule. Unscrew the ampoule and carefully
place it on a clean surface, making sure not to touch the sterile tip. Remove the cartridge and
connector from the mixer and throw them away as instructed by your health care professional. Then
follow Steps 3 to 5, using a new connector and cartridge. Using the partially filled ampoule you had
set aside, continue to fill the ampoule with a full dose of GENOTROPIN. Follow steps 7 to 9 to
complete the injection.
Questions about how to use the GENOTROPIN ZipTip?
Call Pharmacia & Upjohn Company toll-free at (800) 645-1280
Manufactured for:
by:
Pharmacia & Upjohn Company
Rösch AG Medizintechnik
A subsidiary of Pharmacia Corporation
Berlin, Germany
Kalamazoo, MI 49001, USA
Caution: Federal law restricts this device to sale by or on the order of a physician.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-280/S-040
Verification Code
Date
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Division Director Memo
NDA #
20-280/Supplement 060
Applicant
Pfizer
Drug Product
Genotropin® (recombinant human growth
hormone)
Indication
Idiopathic Short Stature
Background
Pfizer has submitted this efficacy supplement to expand the indication for Genotropin®,
recombinant human growth hormone (rhGH), for use in pediatric patients with idiopathic short
stature (ISS). Currently, of the 10 FDA-approved rhGH products, only two have an indication for
ISS. Humatrope® was approved in 2003 and Nutropin® was approved in 2004 for this indication.
For both of these products, the applicants provided evidence that their rhGH increased final
height compared to placebo (Humatrope) or no treatment (Nutropin).
Pfizer has provided data from two clinical trials in support of the ISS indication. Study TRN 88
080 (or 080) was considered the pivotal study and was a randomized, open-label, multicenter
study which enrolled 177 patients with short stature but who were NOT growth hormone
deficient. There were three different study arms in this trial: Genotropin 0.033 mg/kg/day,
Genotropin 0.067 mg/kg/day, and an observational or untreated control arm. In addition, patients
who were pre-pubertal after a one-year observation were randomized into each of these three
different arms whereas patients who reached puberty were randomized to the 0.067 mg/kg/day or
untreated control arm. Patients were followed until they reached final height. Study CTN 89-050
(or 050) was a 3-year, randomized, open-label multicenter study which enrolled 37 patients with
familial short stature. These patients were randomized to receive either Genotropin 0.047 mg/kg
or observation (an untreated control arm). Unlike Study 080, this trial did not follow patients
until they reached final height. Instead an atypical primary endpoint for short stature trials was
employed which compared the effect of Genotropin versus non-treatment on height for bone age.
However, more standard efficacy measures of linear growth (height SDS and growth velocity)
were secondary endpoint measures. In addition, all the patients evaluated in Study 050 were
prepubertal.
Dr. Roman and Ms. Mele have each thoroughly discussed the study design and efficacy findings
in their respective clinical and statistical reviews. In addition, Dr. Roman has conducted a safety
review and has not identified any unusual side effect or adverse event profile related to GH use in
the pediatric population that has not already been discussed in the labels of these products or in
published literature. Consequently, my memo serves to highlight the Division’s decisional memo
to approve this supplement and summarize any critical scientific or regulatory issues. Please
review Dr. Roman’s review dated May 1, 2008, and Ms. Mele’s review dated April 18, 2008, for
the complete FDA review of this application. Since Genotropin is an approved product for other
short stature indications and ISS did not require any further evaluation from clinical
pharmacology or pharmacology/toxicology, this supplement does not contain any such discipline
reviews. CMC did have to provide a review for a claim of categorical exclusion to the
environmental assessment requirements. Dr. Julia Pinto’s review dated April 28, 2008 has
addressed this supplement can be approved from a CMC perspective.
1
Key Clinical/Statistical Findings
In both clinical studies, Genotropin in a dose range of 0.033 to 0.067 mg/kg/day, demonstrated
significant effects on linear growth compared to no treatment in patients with ISS. The statistical
analysis plan (written by Pfizer after they acquired the trial data and were unblinded to the data)
proposed the combination of both Genotropin dose groups to compare to the untreated group.
However, Ms. Mele further evaluated the efficacy findings by subgroups (dose, gender, pubertal
status). A more notable effect on linear growth is observed with the higher dose, 0.067
mg/kg/day, particularly in pre-pubertal patients. The effect of Genotropin on linear growth is not
significant in the pubertal population, more likely reflecting the contribution of puberty to
epiphyseal closure and missed opportunity for improving final height.
The applicant had initially proposed a single dose regimen of 0.067 mg/kg/day for ISS; however,
it was agreed that since all doses evaluated demonstrated efficacy over no-treatment, a range of
recommended doses should be stated in the label to not encourage one single high dose regimen
of GH in the treatment of ISS.
Also during labeling discussions, there were two areas requiring lengthy negotiations. One of
these pertained to the inclusion of small for gestational age (SGA) patients in the description of
clinical trial and study results. The second was the definition of ISS under the INDICATIONS
section. With respect to the first issue, since the subgroup analysis with and without SGA
patients did not impact the overall efficacy (or safety) findings, it was agreed that a descriptive
presentation of how the trial was designed and implemented would be most appropriate since
identification of SGA/ISS was not a predefined aspect of Study 080.
Regarding the second issue, the applicant proposed to define ISS under the INDICATIONS
section based on a height SDS ≤ 2.0, a cut-point that would have distinguished this label from
Humatrope and Nutropin which uses a height SDS ≤ 2.25. The applicant argued that the
proposed definition reflected the inclusion criteria for identifying short stature patients in these
two trials. The division argued and the firm accepted that the same language be maintained
across all ISS labels for the following reason. The original language put forward by Humatrope
was based on concerns that approval of GH for a non-GH deficient short stature condition would
result in misuse of the product in a large patient population. By limiting the indication to those
who have more severe short stature, the risk-benefit and economic considerations would likely be
more favorable. FDA maintains that this rationale should be upheld and noted that such a
definition would not preclude a physician from prescribing it for SDS ≤ 2.0, if he/she felt the
published literature supported initiation of therapy in this population. Specific to Pfizer’s
argument about labeling based on the studied population, FDA pointed out that the study was not
initially designed to identify ISS patients and that ISS patients were identified after Pfizer
acquired the data. Furthermore, it is not atypical for use of broad inclusion criteria for a clinical
study to bolster patient numbers but that the final decision on target population must take into
consideration the risk-benefit calculus.
Regulatory Issues
Dr. Roman has thoroughly covered all regulatory/administrative issues in his excellent review
(pediatric, financial disclosure, DSI audits, data integrity). The only regulatory issue that requires
discussion in my memo is the applicant’s proposal for marketing, distribution, and promotion
with this new expanded indication.
2
The approval letters for Humatrope and Nutropin discusses plans proposed by both these
companies to limit promotion (no DTC advertisement), to have a limited sales force, education
programs, and controlled distribution. As stated above, these applications were approved in 2003
and 2004, before the 2007 re-authorization of PDUFA (or FDAAA – FDA Amendments Act).
Under FDAAA, certain approvals might be subject to a Risk Evaluation Mitigation Strategy
(REMS). This might include some of the proposals put forward by Pfizer that are in line with
previous commitments made by Humatrope and Nutropin. As such, this application was not
approved on its PDUFA goal date and consultation with Office of Regulatory Policy and Office
of Chief Counsel were necessary to determine if Genotropin’s approval for the ISS indication
would require a REMS.
On June 11, 2008, the review division was notified by the Safety Requirements Team that the
Office of Chief Counsel has cleared the approval of Genotropin for this ISS indication without a
requirement for a REMS.
Recommendation
I concur with the clinical and statistical reviewers that this application can be approved for the
new indication, idiopathic short stature.
3
---------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------------------
---------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
/s/
Mary Parks
6/12/2008 10:31:41 AM
MEDICAL OFFICER
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___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Genotropin
safely and effectively. See full prescribing information for Genotropin.
GENOTROPIN® (somatropin [rDNA origin] for injection)
Initial U.S. Approval: 1995
----------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1.1)
Idiopathic Short Stature
5/2008
Dosage and Administration (2.1)
Idiopathic Short Stature
5/2008
----------------------------INDICATIONS AND USAGE---------------------------
GENOTROPIN is a recombinant human growth hormone indicated for:
• Pediatric: Treatment of children with growth failure due to growth hormone
deficiency (GHD), Prader-Willi syndrome, Small for Gestational Age, Turner
syndrome, and Idiopathic Short Stature (1.1)
• Adult: Treatment of adults with either adult onset or childhood onset GHD (1.2)
----------------------DOSAGE AND ADMINISTRATION-----------------------
GENOTROPIN should be administered subcutaneously (2)
• Pediatric GHD: 0.16 to 0.24 mg/kg/week (2.1)
• Prader-Willi Syndrome: 0.24 mg/kg/week (2.1)
• Small for Gestational Age: 0.48 mg/kg/week (2.1)
• Turner Syndrome: 0.33 mg/kg/week (2.1)
• Idiopathic Short Stature: up to 0.47 mg/kg/week (2.1)
• Adult GHD: 0.04 mg/kg/week to be increased as tolerated to not more than 0.08
mg/kg/week at 4–8 week intervals, or a starting dose of approximately 0.2 mg/day
(range, 0.15–0.30 mg/day) increased gradually by increments of 0.1–0.2 mg/day
(2.2)
• GENOTROPIN cartridges are color-coded to correspond to a specific
GENOTROPIN PEN delivery device (2.3)
• Injection sites should always be rotated to avoid lipoatrophy (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
GENOTROPIN lyophilized powder in a two-chamber color-coded cartridge (3):
• 5 mg (green tip) and 12 mg (purple tip) (with preservative)
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-
chamber cartridge (without preservative):
• 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0
mg
-------------------------------CONTRAINDICATIONS------------------------------
• Acute Critical Illness (4.1, 5.1)
• Children with Prader-Willi syndrome who are severely obese or have severe
respiratory impairment – reports of sudden death (4.2, 5.2)
• Active Malignancy (4.3)
• Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy (4.4)
• Children with closed epiphyses (4.5)
• Known hypersensitivity to somatropin or m-cresol (4.6)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Acute Critical Illness: Potential benefit of treatment continuation should be
weighed against the potential risk (5.1).
• Prader-Willi syndrome in Children: Evaluate for signs of upper airway
obstruction and sleep apnea before initiation of treatment.
Discontinue treatment if these signs occur (5.2).
• Neoplasm: Monitor patients with preexisting tumors for progression or
recurrence. Increased risk of a second neoplasm in childhood cancer survivors
treated with somatropin—in particular meningiomas in patients treated with
radiation to the head for their first neoplasm (5.3).
• Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked.
Periodically monitor glucose levels in all patients. Doses of concurrent
antihyperglycemic drugs in diabetics may require adjustment (5.4).
• Intracranial Hypertension: Exclude preexisting papilledema. May develop
and is usually reversible after discontinuation or dose reduction (5.5).
• Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome – especially
in adults): May occur frequently. Reduce dose as necessary (5.6).
• Hypothyroidism: May first become evident or worsen (5.7).
• Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the
onset of a limp or hip/knee pain (5.8).
• Progression of Preexisting Scoliosis: May develop (5.9).
------------------------------ADVERSE REACTIONS-------------------------------
Other common somatropin-related adverse reactions include injection site
reactions/rashes and lipoatrophy (6.1) and headaches (6.3).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1: May require the
initiation of glucocorticoid replacement therapy. Patients treated with
glucocorticoid replacement for previously diagnosed hypoadrenalism may
require an increase in their maintenance doses (7.1).
• Glucocorticoid Replacement: Should be carefully adjusted (7.2)
• Cytochrome P450-Metabolized Drugs: Monitor carefully if used with
somatropin (7.3)
• Oral Estrogen: Larger doses of somatropin may be required in women (7.4)
• Insulin and/or Oral Hypoglycemic Agents: May require adjustment (7.5)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 9/2008
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Pediatric Patients
1.2 Adult Patients
2
DOSAGE AND ADMINISTRATION
2.1 Dosing of Pediatric Patients
2.2 Dosing of Adult Patients
2.3 Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1 Acute Critical Illness
4.2 Prader-Willi Syndrome in Children
4.3 Active Malignancy
4.4 Diabetic Retinopathy
4.5 Closed Epiphyses
4.6 Hypersensitivity
5
WARNINGS AND PRECAUTIONS
5.1 Acute Critical Illness
5.2 Prader-Willi Syndrome in Children
5.3 Neoplasms
5.4 Glucose Intolerance
5.5 Intracranial Hypertension
5.6 Fluid Retention
5.7 Hypothyroidism
5.8 Slipped Capital Femoral Epiphysis in Pediatric Patients
5.9 Progression of Preexisting Scoliosis in Pediatric Patients
5.10 Otitis Media and Cardiovascular Disorders in Turner Syndrome
5.11 Confirmation of Childhood Onset Adult GHD
5.12 Local and Systemic Reactions
5.13 Laboratory Tests
6
ADVERSE REACTIONS
6.1 Most Serious and/or Most Frequently Observed Adverse Reactions
6.2 Clinical Trials Experience
6.3 Post-Marketing Surveillance
7
DRUG INTERACTIONS
7.1 Inhibition of 11 β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
7.2 Glucocorticoid Replacement
7.3 Cytochrome P450- Metabolized Drugs
7.4 Oral Estrogen
7.5 Insulin and/or Oral Hypoglycemic Agents
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Adult Growth Hormone Deficiency
14.2 Prader-Willi Syndrome
14.3 SGA
14.4 Turner Syndrome
14.5 Idiopathic Short Stature
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Pediatric Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of
endogenous growth hormone.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome
(PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing (see CONTRAINDICATIONS).
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to
manifest catch-up growth by age 2.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure associated with Turner syndrome.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short
stature, defined by height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in
pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or
treated by other means.
1.2
Adult Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who
meet either of the following two criteria:
Adult Onset: Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary
disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
According to current standards, confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative
test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone
deficiency.
2
DOSAGE AND ADMINISTRATION
The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN must not be injected intravenously.
Therapy with GENOTROPIN should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure
associated with growth hormone deficiency (GHD), Prader-Willi syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA) or
Idiopathic Short Stature (ISS), and adult patients with either childhood onset or adult onset GHD.
2.1
Dosing of Pediatric Patients
General Pediatric Dosing Information
The GENOTROPIN dosage and administration schedule should be individualized based on the growth response of each patient.
Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during
the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism,
undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).
Treatment with GENOTROPIN for short stature should be discontinued when the epiphyses are fused.
Pediatric Growth Hormone Deficiency (GHD)
Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.
Prader-Willi Syndrome
Generally, a dose of 0.24 mg/kg body weight/week is recommended.
Small for Gestational Age
Generally, a dose of 0.48 mg/kg body weight/week is recommended.
Turner Syndrome
Generally, a dose of 0.33 mg/kg body weight/week is recommended.
Idiopathic Short Stature
Generally, a dose up to 0.47 mg/kg of body weight/week is recommended.
2.2
Dosing of Adult Patients
Adult Growth Hormone Deficiency (GHD)
Based on the weight-based dosing utilized in the original pivotal studies described herein, the recommended dosage at the start of therapy is not more than 0.04
mg/kg/week given as a daily subcutaneous injection. The dose may be increased at 4- to 8-week intervals according to individual patient requirements to a maximum of
0.08 mg/kg/week. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance in dose titration.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15–0.30 mg/day) may be used without consideration of body
weight. This dose can be increased gradually every 1–2 months by increments of approximately 0.1–0.2 mg/day, according to individual patient requirements based on
the clinical response and serum IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-I
levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger
individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment
goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
2.3
Preparation and Administration
The GENOTROPIN 5 and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green tip
to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
GENOTROPIN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.
GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.
3
DOSAGE FORMS AND STRENGTHS
GENOTROPIN lyophilized powder:
•
5 mg two-chamber cartridge (green tip, with preservative)
concentration of 5 mg/mL (approximately 15 IU/mL)
•
12 mg two-chamber cartridge (purple tip, with preservative)
concentration of 12 mg/mL (approximately 36 IU/mL)
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)
•
0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg
4
CONTRAINDICATIONS
4.1
Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery,
abdominal surgery or multiple accidental trauma, or those with acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult
patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses
5.3–8 mg/day) compared to those receiving placebo [see Warnings and Precautions (5.1)].
4.2
Prader-Willi Syndrome in Children
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe
respiratory impairment. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions (5.2)].
4.3
Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to
instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency may be an early sign
of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should
not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
4.4
Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
4.5
Closed Epiphyses
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
4.6
Hypersensitivity
GENOTROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of
GENOTROPIN lyophilized powder contain m-cresol as a preservative. These products should not be used by patients with a known sensitivity to this preservative. The
GENOTROPIN MINIQUICK presentations are preservative-free (see HOW SUPPLIED). Localized reactions are the most common hypersensitivity reactions.
5
WARNINGS AND PRECAUTIONS
5.1
Acute Critical Illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those
with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4.1)]. The safety of continuing
somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the
potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk.
5.2
Prader-Willi Syndrome in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk
factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be
at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of
treatment with somatropin. If during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new
onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be
monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4.2)].
5.3
Neoplasms
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the
underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system
(CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients
treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm,
were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor
recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions.
5.4
Glucose Intolerance
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose
tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated
with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with
preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic
drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.
5.5
Intracranial Hypertension
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with
somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and
symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating
treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy
during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-
associated signs and symptoms have resolved. Patients with Turner syndrome and Prader-Willi syndrome may be at increased risk for the development of IH.
5.6
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent.
5.7
Hypothyroidism
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome
have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central
(secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid
function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
In patients with hypopituitarism (multiple hormonal deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is
administered.
5.8
Slipped Capital Femoral Epiphyses in Pediatric Patients
Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing
rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.
5.9
Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are
treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal
abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi
syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
5.10
Otitis Media and Cardiovascular Disorders in Turner Syndrome
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing
disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be
monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
5.11
Confirmation of Childhood Onset Adult GHD
Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in Indications and
Usage (1.2) before continuing on somatropin therapy at the reduced dose level recommended for GHD adults.
5.12
Local and Systemic Reactions
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site
[see Dosage and Administration. (2.3) ].
As with any protein, local or systemic allergic reactions may occur. Parents/Patients should be informed that such reactions are possible and that prompt medical
attention should be sought if allergic reactions occur.
5.13
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most seriousb and/or most frequently observeda adverse reactions during treatment with somatropin:
• b Sudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and
unidentified respiratory infection [see Contraindications (4.2) and Warnings andPrecautions (5.2)]
• b Intracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a
first neoplasm and somatropin [see Contraindications (4.3) and Warnings and Precautions (5.3)]
• a, b Glucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Warnings and Precautions (5.4)]
• b Intracranial hypertension [see Warnings and Precautions (5.5)]
• b Significant diabetic retinopathy [see Contraindications (4.4)]
• b Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.8)]
• b Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.9)]
• aFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see Warnings and
Precautions (5.6)]
• aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.7)]
• aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings andPrecautions (5.11)]
6.2
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation
cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse
reaction rates observed in practice.
Clinical Trials in children with GHD
In clinical studies with GENOTROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning
associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild
hyperglycemia.
Clinical Trials in PWS
In two clinical studies with GENOTROPIN in pediatric patients with Prader-Willi syndrome, the following drug-related events were reported: edema, aggressiveness,
arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.
Clinical Trials in children with SGA
In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, the following clinically significant events were reported: mild
transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several
patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Anti-hGH antibodies were not detected in any
of the patients treated with GENOTROPIN.
Clinical Trials in children with Turner Syndrome
In two clinical studies with GENOTROPIN in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses
(influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint
pain.
Clinical Trials in children with Idiopathic Short Stature
In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract
infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies,
during Genotropin treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as
follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one
measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.
Clinical Trials in adults with GHD
In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including
peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during
therapy, and tended to be transient and/or responsive to dosage reduction.
Table 1 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also
presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of
GENOTROPIN and Placebo, Grouped by Duration of Treatment
Double Blind Phase
Open Label Phase
GENOTROPIN
Adverse Event
Placebo
GENOTROPIN
0–6 mo.
0–6 mo.
6–12 mo.
12–18 mo.
18–24 mo.
n = 572
n = 573
n = 504
n = 63
n = 60
% Patients
% Patients
% Patients
% Patients
% Patients
Swelling, peripheral
5.1
17.5*
5.6
0
1.7
Arthralgia
4.2
17.3*
6.9
6.3
3.3
Upper respiratory infection
14.5
15.5
13.1
15.9
13.3
Pain, extremities
5.9
14.7*
6.7
1.6
3.3
Edema, peripheral
2.6
10.8*
3.0
0
0
Paresthesia
1.9
9.6*
2.2
3.2
0
Headache
7.7
9.9
6.2
0
0
Stiffness of extremities
1.6
7.9*
2.4
1.6
0
Fatigue
3.8
5.8
4.6
6.3
1.7
Myalgia
1.6
4.9*
2.0
4.8
6.7
Back pain
4.4
2.8
3.4
4.8
5.0
*
Increased significantly when compared to placebo, P≤.025: Fisher´s Exact Test (one-sided)
n
= number of patients receiving treatment during the indicated period.
% = percentage of patients who reported the event during the indicated period.
Post-Trial Extension Studies in Adults
In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had
predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving
GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other
adverse events that have been reported include generalized edema and hypoesthesia.
Anti-hGH Antibodies
As with all protein drugs, a small percentage of patients may develop antibodies to the protein. GH antibodies with binding capacities lower than 2 mg/L have not been
associated with growth attenuation. In a very small number of patients, when binding capacity was greater than 2 mg/L, interference with the growth response was
observed.
In 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN or other growth
hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously
treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining
413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There
was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.
Periplasmic Escherichia coli Peptides
Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients
treated with GENOTROPIN, but these appear to be of no clinical significance.
6.3
Post-Marketing Surveillance
Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and
6.2 in children and adults.
Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is
uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis
of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any,
remains to be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].
The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults),rare gynecomastia (children),
and rare pancreatitis (children).
7
DRUG INTERACTIONS
7.1
Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
Somatropin inhibits 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) in adipose/hepatic tissue and may significantly impact the metabolism of cortisol and
cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring
glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an
increase in their maintenance or stress doses; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to
their biologically active metabolites is dependent on the activity of the 11βHSD-1 enzyme.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.2
Glucocorticoid Replacement
Excessive glucocorticoid therapy may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be
carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth.
7.3
Cytochrome P450-Metabolized Drugs
Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that
somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids,
anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450
liver enzymes. However, formal drug interaction studies have not been conducted.
7.4
Oral Estrogen
In patients on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see Dosage and Administration (2.2)].
7.5
Insulin and/or Oral Hypoglycemic Agents
In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated [see
Warnings and Precautions (5.4)]).
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. Reproduction studies carried out with GENOTROPIN at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3
mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively,
based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving SC doses during gametogenesis and up to 7
days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in
males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day
(approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted.
In perinatal and postnatal studies in rats, GENOTROPIN doses of 0.3, 1, and 3.3 mg/kg/day produced growth-promoting effects in the dams but not in the fetuses.
Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on
gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offsprings due to GENOTROPIN. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
8.3
Nursing Mothers
There have been no studies conducted with GENOTROPIN in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when GENOTROPIN is administered to a nursing woman.
8.5
Geriatric Use
The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the
action of GENOTROPIN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for
older patients [see Dosage and Administration (2.2)].
10
OVERDOSAGE
Short-Term
Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid
retention.
Long-Term
Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [see Dosage
and Administration (2)].
11
DESCRIPTION
GENOTROPIN lyophilized powder contains somatropin [rDNA origin], which is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues
and a molecular weight of 22,124 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin).
GENOTROPIN is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone. GENOTROPIN is a sterile
white lyophilized powder intended for subcutaneous injection.
GENOTROPIN 5 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 5.8 mg (approximately 17.4 IU), glycine 2.2 mg,
mannitol 1.8 mg, sodium dihydrogen phosphate anhydrous 0.32 mg, and disodium phosphate anhydrous 0.31 mg; the rear chamber contains 0.3% m-Cresol (as a
preservative) and mannitol 45 mg in 1.14 mL water for injection. The GENOTROPIN 5 mg two-chambered cartridge contains 5.8 mg of somatropin. The reconstituted
concentration is 5mg/ml . The cartridge contains overfill to allow for delivery of 1ml containing the stated amount of GENOTROPIN – 5 mg.
GENOTROPIN 12mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 13.8 mg (approximately 41.4 IU), glycine 2.3 mg,
mannitol 14.0 mg, sodium dihydrogen phosphate anhydrous 0.47 mg, and disodium phosphate anhydrous 0.47 mg; the rear chamber contains 0.3% m-Cresol (as a
preservative) and mannitol 32 mg in 1.13 mL water for injection. The GENOTROPIN 12 mg two-chambered cartridge contains 13.8 mg of somatropin. The
reconstituted concentration is 12 mg/ml . The cartridge contains overfill to allow for delivery of 1ml containing the stated amount of GENOTROPIN – 12 mg.
GENOTROPIN MINIQUICK® is dispensed as a single-use syringe device containing a two-chamber cartridge. GENOTROPIN MINIQUICK is available as individual
doses of 0.2 mg to 2.0 mg in 0.2 mg increments. The front chamber contains recombinant somatropin 0.22 to 2.2 mg (approximately 0.66 to 6.6 IU), glycine 0.23 mg,
mannitol 1.14 mg, sodium dihydrogen phosphate 0.05 mg, and disodium phosphate anhydrous 0.027 mg; the rear chamber contains mannitol 12.6 mg in water for
injection 0.275 mL. The reconstituted GENOTROPIN MINIQUICK two-chamber cartridge contains overfill to allow for delivery of 0.25 ml containing the stated
amount of GENOTROPIN.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
GENOTROPIN is a highly purified preparation. The reconstituted recombinant somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of
approximately 6.7. The concentration of the reconstituted solution varies by strength and presentation (see HOW SUPPLIED).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
In vitro, preclinical, and clinical tests have demonstrated that GENOTROPIN lyophilized powder is therapeutically equivalent to human growth hormone of pituitary
origin and achieves similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), have Prader-Willi syndrome
(PWS), were born small for gestational age (SGA), have Turner syndrome (TS), or have Idiopathic short stature (ISS), treatment with GENOTROPIN stimulates linear
growth. In patients with GHD or PWS, treatment with GENOTROPIN also normalizes concentrations of IGF-I (Insulin-like Growth Factor-I/Somatomedin C). In
adults with GHD, treatment with GENOTROPIN results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid
metabolism, and normalization of IGF-I concentrations.
In addition, the following actions have been demonstrated for GENOTROPIN and/or somatropin.
12.2
Pharmacodynamics
Tissue Growth
A. Skeletal Growth: GENOTROPIN stimulates skeletal growth in pediatric patients with GHD, PWS, SGA, TS, or ISS. The measurable increase in body
length after administration of GENOTROPIN results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role
in skeletal growth, are generally low in the serum of pediatric patients with GHD, PWS, or SGA, but tend to increase during treatment with GENOTROPIN.
Elevations in mean serum alkaline phosphatase concentration are also seen.
B.
Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as
compared with the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.
Protein Metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum
urea nitrogen, follows the initiation of therapy with GENOTROPIN.
Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN. Large doses of growth
hormone may impair glucose tolerance.
Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after
therapy with GENOTROPIN. Serum calcium is not significantly altered by GENOTROPIN. Growth hormone could increase calciuria.
Body Composition
Adult GHD patients treated with GENOTROPIN at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass
and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of GENOTROPIN is to modify body
composition, an effect that is maintained with continued treatment.
12.3
Pharmacokinetics
Absorption
Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically
available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been
observed in healthy adult male subjects.
In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35%
greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL,
respectively.
In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN.
The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.
Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between
injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.
There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.
Distribution
The mean volume of distribution of GENOTROPIN following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.
Metabolism
The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are
returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered
GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.
Excretion
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The mean clearance of subcutaneously administered GENOTROPIN in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.
Special Populations
Pediatric: The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.
Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and
females.
Race: No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.
Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN in these patient populations.
Table 2
Mean SC Pharmacokinetic Parameters in Adult GHD Patients
Bioavaila
bility
(%)
(N=15)
Tmax
(hours)
(N=16)
CL/F
(L/hr x
kg)
(N=16)
Vss/F
(L/kg)
(N=16)
T1/2
(hours)
(N=16)
Mean
(± SD)
80.5
*
5.9
(± 1.65)
0.3
(± 0.11)
1.3
(± 0.80)
3.0
(± 1.44)
95% CI
70.5 –
92.1
5.0 – 6.7
0.2 – 0.4
0.9 – 1.8
2.2 – 3.7
Tmax = time of maximum plasma concentration T 1/2 = terminal half-life
CL/F = plasma clearance
SD = standard deviation
Vss/F = volume of distribution
CI = confidence interval
* The absolute bioavailability was estimated under the assumption that the
log-transformed data follow a normal distribution. The mean and standard
deviation of the log-transformed data were mean = 0.22 (± 0.241).
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with GENOTROPIN. No potential mutagenicity of GENOTROPIN was revealed in a battery of tests including
induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact
animals (bone marrow cells in rats). See PREGNANCY section for effect on fertility.
14
CLINICAL STUDIES
14.1
Adult Growth Hormone Deficiency (GHD)
GENOTROPIN lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6
month double-blind treatment period, during which 85 patients received GENOTROPIN and 87 patients received placebo, followed by an open-label treatment period
in which participating patients received GENOTROPIN for up to a total of 24 months. GENOTROPIN was administered as a daily SC injection at a dose of 0.04
mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.
Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving GENOTROPIN as compared with the
placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body
composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline
values after 12 months of treatment.
14.2
Prader-Willi Syndrome (PWS)
The safety and efficacy of GENOTROPIN in the treatment of pediatric patients with Prader-Willi syndrome (PWS) were evaluated in two randomized, open-label,
controlled clinical trials. Patients received either GENOTROPIN or no treatment for the first year of the studies, while all patients received GENOTROPIN during the
second year. GENOTROPIN was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group
received GENOTROPIN at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.48
mg/kg/week. In Study 2, the treatment group received GENOTROPIN at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group
received GENOTROPIN at a dose of 0.36 mg/kg/week.
Patients who received GENOTROPIN showed significant increases in linear growth during the first year of study, compared with patients who received no treatment
(see Table 3). Linear growth continued to increase in the second year, when both groups received treatment with GENOTROPIN.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3
Efficacy of GENOTROPIN in Pediatric Patients with Prader-Willi
Syndrome (Mean ± SD)
Study 1
Study 2
GENOTR
OPIN
(0.24
mg/kg/we
ek)
n=15
Untreated
Control
n=12
GENOTR
OPIN
(0.36
mg/kg/we
ek)
n=7
Untreated
Control
n=9
Linear growth
(cm)
Baseline height
112.7 ±
14.9
109.5 ±
12.0
120.3 ±
17.5
120.5 ±
11.2
Growth from
months 0 to 12
11.6* ± 2.3
5.0 ± 1.2
10.7* ± 2.3
4.3 ± 1.5
Height
Standard
Deviation Score
(SDS) for age
Baseline SDS
-1.6 ± 1.3
-1.8 ± 1.5
-2.6 ± 1.7
-2.1 ± 1.4
SDS at 12
months
-0.5† ± 1.3
-1.9 ± 1.4
-1.4† ± 1.5
-2.2 ± 1.4
*
p ≤ 0.001
†
p ≤ 0.002 (when comparing SDS change at 12 months)
Changes in body composition were also observed in the patients receiving GENOTROPIN (see Table 4). These changes included a decrease in the amount of fat mass,
and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no
treatment. Treatment with GENOTROPIN did not accelerate bone age, compared with patients who received no treatment.
Table 4
Effect of GENOTROPIN on Body Composition
in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
GENOTROPIN
n=14
Untreated Control
n=10
Fat mass (kg)
Baseline
12.3 ± 6.8
9.4 ± 4.9
Change from
months 0 to 12
-0.9* ± 2.2
2.3 ± 2.4
Lean body mass
(kg)
Baseline
15.6 ± 5.7
14.3 ± 4.0
Change from
months 0 to 12
4.7* ± 1.9
0.7 ± 2.4
Lean body
mass/Fat mass
Baseline
1.4 ± 0.4
1.8 ± 0.8
Change from
months 0 to 12
1.0* ± 1.4
-0.1 ± 0.6
Body weight (kg) †
Baseline
27.2 ± 12.0
23.2 ± 7.0
Change from
months 0 to 12
3.7‡ ± 2.0
3.5 ± 1.9
*
p < 0.005
†
n=15 for the group receiving GENOTROPIN; n=12 for the
Control group
‡
n.s.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.3
SGA
Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2
The safety and efficacy of GENOTROPIN in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled
clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either GENOTROPIN (two doses per study, most
often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received
GENOTROPIN.
Patients who received any dose of GENOTROPIN showed significant increases in growth during the first 24 months of study, compared with patients who received no
treatment (see Table 5). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children
treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown).
Table 5
Efficacy of GENOTROPIN in Children Born Small for Gestational Age
(Mean ± SD)
GENOTRO
PIN
(0.24
mg/kg/week)
n=76
GENOTRO
PIN
(0.48
mg/kg/week)
n=93
Untreated
Control
n=40
Height Standard
Deviation Score (SDS)
Baseline SDS
-3.2 ± 0.8
-3.4 ± 1.0
-3.1 ± 0.9
SDS at 24 months
-2.0 ± 0.8
-1.7 ± 1.0
-2.9 ± 0.9
Change in SDS from
baseline to month 24
1.2* ± 0.5
1.7*† ± 0.6
0.1 ± 0.3
*
p = 0.0001 vs Untreated Control group
†
p = 0.0001 vs group treated with GENOTROPIN 0.24 mg/kg/week
14.4
Turner Syndrome
Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of GENOTROPIN in Turner syndrome patients with short stature.
Turner syndrome patients were treated with GENOTROPIN alone or GENOTROPIN plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38
patients were treated with GENOTROPIN alone in the two studies. In Study 055, 22 patients were treated for 12 months, and in Study 092, 16 patients were treated for
12 months. Patients received GENOTROPIN at a dose between 0.13 to 0.33 mg/kg/week.
SDS for height velocity and height are expressed using either the Tanner (Study 055) or Sempé (Study 092) standards for age-matched normal children as well as the
Ranke standard (both studies) for age-matched, untreated Turner syndrome patients. As seen in Table 5, height velocity SDS and height SDS values were smaller at
baseline and after treatment with GENOTROPIN when the normative standards were utilized as opposed to the Turner syndrome standard.
Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and
height SDS) after treatment with GENOTROPIN (see Table 6). The linear growth response was greater in Study 055 wherein patients were treated with a larger dose of
GENOTROPIN.
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6
Growth Parameters (mean ± SD) after 12 Months of Treatment with
GENOTROPIN
in Pediatric Patients with Turner Syndrome in Two Open Label Studies
GENOTROPIN
0.33 mg/kg/week
Study 055^ n=22
GENOTROPIN
0.13–0.23 mg/kg/week
Study 092# n=16
Height Velocity (cm/yr)
Baseline
4.1 ± 1.5
3.9 ± 1.0
Month 12
7.8 ± 1.6
6.1 ± 0.9
Change from baseline
(95% CI)
3.7 (3.0, 4.3)
2.2 (1.5, 2.9)
Height Velocity SDS
(Tanner^/Sempé#
Standards)
(n=20)
Baseline
-2.3 ± 1.4
-1.6 ± 0.6
Month 12
2.2 ± 2.3
0.7 ± 1.3
Change from baseline
(95% CI)
4.6 (3.5, 5.6)
2.2 (1.4, 3.0)
Height Velocity SDS
(Ranke Standard)
Baseline
-0.1 ± 1.2
-0.4 ± 0.6
Month 12
4.2 ± 1.2
2.3 ± 1.2
Change from baseline
(95% CI)
4.3 (3.5, 5.0)
2.7 (1.8, 3.5)
Height SDS
(Tanner^/Sempé#
Standards)
Baseline
-3.1 ± 1.0
-3.2 ± 1.0
Month 12
-2.7 ± 1.1
-2.9 ± 1.0
Change from baseline
(95% CI)
0.4 (0.3, 0.6)
0.3 (0.1, 0.4)
Height SDS
(Ranke Standard)
Baseline
-0.2 ± 0.8
-0.3 ± 0.8
Month 12
0.6 ± 0.9
0.1 ± 0.8
Change from baseline
(95% CI)
0.8 (0.7, 0.9)
0.5 (0.4, 0.5)
SDS = Standard Deviation Score
Ranke standard based on age-matched, untreated Turner syndrome patients
Tanner^/Sempé# standards based on age-matched normal children
p<0.05, for all changes from baseline
14.5
Idiopathic Short Stature
The long-term efficacy and safety of GENOTROPIN in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that
enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short
stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to
Genotropin or observation only and followed to final height. Two Genotropin doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47
mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD):
chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were
treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 7. GENOTROPIN therapy improved final height in
ISS children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to
untreated control subjects. A height gain of 1 SDS was observed in 10 % of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects
receiving 0.47 mg/kg/week
Table 7. Final height SDS results for pre-pubertal patients with ISS*
Untreated
(n=30)
GEN 0.033
(n=30)
GEN 0.067
(n=42)
GEN 0.033 vs.
Untreated
(95% CI)
GEN 0.067 vs.
Untreated
(95% CI)
Baseline height SDS
Final height SDS minus
baseline
Baseline predicted ht
Final height SDS minus
baseline predicted final
height SDS
0.41 (0.58)
0.23 (0.66)
0.95 (0.75)
0.73 (0.63)
1.36 (0.64)
1.05 (0.83)
+0.53 (0.20, 0.87)
p=0.0022
+0.60 (0.09, 1.11)
p=0.0217
+0.94 (0.63, 1.26)
p<0.0001
+0.90 (0.42, 1.39)
p=0.0004
*Mean (SD) are observed values.
**Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS)
.
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16
HOW SUPPLIED/STORAGE AND HANDLING
GENOTROPIN lyophilized powder is available in the following packages:
5 mg two-chamber cartridge (with preservative)
concentration of 5 mg/mL (approximately 15 IU/mL)
For use with the GENOTROPIN PEN® 5 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER™ Growth Hormone Reconstitution Device.
Package of 5 NDC 0013-2626-94
Package of 1 NDC 0013-2626-81
12 mg two-chamber cartridge (with preservative)
concentration of 12 mg/mL (approximately 36 IU/mL)
For use with the GENOTROPIN PEN 12 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER Growth Hormone Reconstitution Device.
Package of 5 NDC 0013-2646-94
Package of 1 NDC 0013-2646-81
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)
After reconstitution, each GENOTROPIN MINIQUICK delivers 0.25 mL, regardless of strength. Available in the following strengths, each in a package of 7:
0.2 mg
NDC 0013-2649-02
0.4 mg
NDC 0013-2650-02
0.6 mg
NDC 0013-2651-02
0.8 mg
NDC 0013-2652-02
1.0 mg
NDC 0013-2653-02
1.2 mg
NDC 0013-2654-02
1.4 mg
NDC 0013-2655-02
1.6 mg
NDC 0013-2656-02
1.8 mg
NDC 0013-2657-02
2.0 mg
NDC 0013-2658-02
Storage and Handling
Except as noted below, store GENOTROPIN lyophilized powder under refrigeration at 2° to 8°C (36° to 46°F). Do not freeze. Protect from light.
The 5 mg and 12 mg cartridges of GENOTROPIN contain a diluent with a preservative. Thus, after reconstitution, they may be stored under refrigeration for up to 28
days.
The GENOTROPIN MINIQUICK Growth Hormone Delivery Device should be refrigerated prior to dispensing, but may be stored at or below 25°C (77°F) for up to
three months after dispensing. The diluent has no preservative. After reconstitution, the GENOTROPIN MINIQUICK may be stored under refrigeration for up to 24
hours before use. The GENOTROPIN MINIQUICK should be used only once and then discarded.
17
PATIENT COUNSELING INFORMATION
Patients being treated with GENOTROPIN (and/or their parents) should be informed about the potential benefits and risks associated with GENOTROPIN treatment [in
particular, see Adverse Reactions (6.1) for a listing of the most serious and/or most frequently observed adverse reactions associated with somatropin treatment in
children and adults]. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects.
Patients and caregivers who will administer GENOTROPIN should receive appropriate training and instruction on the proper use of GENOTROPIN from the physician
or other suitably qualified health care professional. A puncture-resistant container for the disposal of used syringes and needles should be strongly recommended.
Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles and syringes. This information
is intended to aid in the safe and effective administration of the medication.
GENOTROPIN is supplied in a two-chamber cartridge, with the lyophilized powder in the front chamber and a diluent in the rear chamber. A reconstitution device is
used to mix the diluent and powder. The two-chamber cartridge contains overfill in order to deliver the stated amount of GENOTROPIN
The GENOTROPIN 5 mg and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green
tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Follow the directions for reconstitution provided with each device. Do not shake; shaking may cause denaturation of the active ingredient.
Please see accompanying directions for use of the reconstitution and/or delivery device.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
Vetter Pharma-Fertigung GmbH & Co. KG
Ravensburg, Germany
Or
Vetter Pharma-Fertigung GmbH & Co. KG
Langenargen, Germany
Rx only Company logo
LAB-0222-15.0
Revised January 2009
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Logo
Instructions for Use
Important Note
Please read these instructions completely before using the
GENOTROPIN MINIQUICK. If there is anything you
do not understand or cannot do, call the toll-free
number listed at the end of this leaflet.
If you have any questions about your dose or your treatment
with GENOTROPIN, call your healthcare provider right away.
Use this device only for the person for whom it was prescribed.
GENOTROPIN MINIQUICK is a device used to mix and administer a single dose of GENOTROPIN
Lyophilized Powder (somatropin [rDNA origin] for injection).
Each GENOTROPIN MINIQUICK comes preloaded with a two-chamber cartridge of GENOTROPIN.
GENOTROPIN MINIQUICK is available in ten different dose sizes. Be sure you have the dose your
doctor prescribed.
The GENOTROPIN MINIQUICK is disposable; after you administer the dose, you throw the empty unit
away. IMPORTANT – always throw away the GENOTROPIN MINIQUICK properly, as directed by your
healthcare provider.
Components
This system consists of the delivery device, the two-chamber cartridge of GENOTROPIN packaged inside
it, and a separate injection needle. The diagram below identifies the different components. Usage Illustration
A needle for injection is provided with each device. If you need additional needles, ask for Becton
Dickinson Ultra-Fine pen needles, either 29, 30 or 31 gauge.
The two-chamber cartridge of GENOTROPIN contains the growth hormone powder in one chamber and a
liquid in the other. When you turn the plunger rod clockwise (to the right), the GENOTROPIN MINIQUICK
automatically mixes the growth hormone powder and the liquid.
Storage
Before the drug is reconstituted (the powder mixed with the liquid), you can store the GENOTROPIN
MINIQUICK at room temperature (77° F or less) for up to three months. Keep it in the carton to protect it
from light.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
You should inject the GENOTROPIN right after you reconstitute it. If that is not possible, you can keep the
GENOTROPIN MINIQUICK in the refrigerator (in the carton) for up to 24 hours after reconstitution. Do not
freeze. If you do not use the GENOTROPIN MINIQUICK within 24 hours after reconstitution, throw it away.
Single Use
There are no preservatives in the GENOTROPIN MINIQUICK.
Use each GENOTROPIN MINIQUICK only once and then throw it away.
To help prevent infection, always wash your hands well with soap and water
before using the GENOTROPIN MINIQUICK.
1. Wipe the rubber stopper on the GENOTROPIN MINIQUICK with a pad or swab
moistened with rubbing alcohol. Usage Illustration
2. Peel the paper covering from the back of the injection needle. Leave both
protective caps (inner and outer) on the needle.
Screw the needle onto the GENOTROPIN MINIQUICK, turning it until it stops.
3. Hold the GENOTROPIN MINIQUICK with the needle pointing up. To mix the
growth hormone powder with the liquid, turn the plunger rod clockwise (to the
right) until it will go no further.
4. Do not shake the GENOTROPIN MINIQUICK. Shaking may inactivate the
growth hormone so it will not work.
Check to make sure the solution is clear, indicating that the growth hormone
powder is completely dissolved. If you see particles, or if the solution is
discolored, do not inject it. Instead, call the toll-free number listed at the end of
this leaflet.
If using the optional, reusable Needle Guard to hide the needle, go to step 5.
If the Needle Guard is not used, go to step 6.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. To attach the optional reusable Needle Guard, remove the outer protective
cap from the needle, place the Needle Guard on to the GENOTROPIN
MINIQUICK, and press gently until the Needle Guard snaps into place. Usage Illustration
6. Select and disinfect an appropriate injection site, as instructed by your
healthcare provider.
If the optional Needle Guard is not used, remove the outer and inner
protective caps from the needle. If the Needle Guard is used, remove the
inner protective cap from the needle.
7. Pinch a fold of skin at the injection site firmly, and push the needle straight
into the skinfold at a 90-degree angle. When using the Needle Guard, the
retractable plastic needle shield will push in as the GENOTROPIN
MINIQUICK is pushed against the skin.
8. Push the plunger rod as far as it will go, to inject all the medicine in the
GENOTROPIN MINIQUICK.
Wait a few seconds to be sure that all the growth hormone has been injected.
Then, pull out the needle.
9. After injection, carefully replace the outer protective cap on the needle if you
are not using the optional Needle Guard. If you are using the Needle Guard,
carefully replace the inner protective cap on the needle while the Needle
Guard is on the unit. Then remove the Needle Guard and save it for future
use. Throw away the GENOTROPIN MINIQUICK in a suitable container.
Always throw away the GENOTROPIN MINIQUICK properly, as
instructed by your healthcare provider.
The reusable Needle Guard may be cleaned by wiping with a damp cloth or
alcohol swab. If it cannot be cleaned satisfactorily, or does not function
properly, throw it away and contact Pharmacia & Upjohn for a replacement.
Questions about how to use the GENOTROPIN MINIQUICK?
Call Pharmacia & Upjohn Company toll-free at (800) 645-1280
Rx only
Manufactured by:
Vetter Pharma-Fertigung GmbH & Co. KG
Ravensburg, Germany Company logo
LAB-0227-3.0
Revised January 2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:24.230305 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020280s064lbl.pdf', 'application_number': 20280, 'submission_type': 'SUPPL ', 'submission_number': 64} |
3,207 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CREON
safely and effectively. See full prescribing information for CREON.
CREON (pancrelipase) delayed-release capsules
Initial U.S. Approval: 2009
-----------------------------RECENT MAJOR CHANGES------------------------------
Indications and Usage, Chronic Pancreatitis, Pancreatectomy (1)
4/2010
Dosage and Administration, Chronic Pancreatitis or Pancreatectomy (2.1) 4/2010
-----------------------------INDICATIONS AND USAGE-------------------------------
CREON is a combination of porcine-derived lipases, proteases, and amylases
indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. (1)
-------------------------DOSAGE AND ADMINISTRATION--------------------------
Dosage
CREON is not interchangeable with any other pancrelipase product.
Infants (up to 12 months)
● Infants may be given 2,000 to 4,000 lipase units per 120 mL of formula or per
breast-feeding. (2.1)
● Do not mix CREON capsule contents directly into formula or breast milk prior
to administration. (2.2)
Children Older than 12 Months and Younger than 4 Years
● Enzyme dosing should begin with 1,000 lipase units/kg of body weight per
meal for children less than age 4 years to a maximum of 2,500 lipase units/kg
of body weight per meal (or less than or equal to 10,000 lipase units/kg of body
weight per day), or less than 4,000 lipase units/g fat ingested per day.(2.1)
Children 4 Years and Older and Adults
● Enzyme dosing should begin with 500 lipase units/kg of body weight per meal
for those older than age 4 years to a maximum of 2,500 lipase units/kg of body
weight per meal (or less than or equal to 10,000 lipase units/kg of body weight
per day), or less than 4,000 lipase units/g fat ingested per day. (2.1)
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or
Pancreatectomy
● In one clinical trial, patients received CREON at a dose of 72,000 lipase units
per meal while consuming at least 100 g of fat per day. Lower starting doses
recommended in the literature are consistent with the 500 lipase units/kg of
body weight per meal lowest starting dose recommended for adults in the
Cystic Fibrosis Foundation Consensus Conferences Guidelines. Dosage should
be individualized based on clinical symptoms, the degree of steatorrhea present
and the fat content of the diet. (2.1)
Limitations on Dosing
● Dosing should not exceed the recommended maximum dosage set forth by the
Cystic Fibrosis Foundation Consensus Conferences Guidelines. (2.1)
Administration
● CREON should be swallowed whole. For infants or patients unable to swallow
intact capsules, the contents may be sprinkled on soft acidic food, e.g.,
applesauce. (2.2)
---------------------------DOSAGE FORMS AND STRENGTHS----------------------
● Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP
units of amylase capsules have an orange opaque cap with imprint “CREON
1206” and a blue opaque body. (3)
● Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000
USP units of amylase capsules have a brown opaque cap with imprint “CREON
1212” and a colorless transparent body. (3)
● Capsules: 24,000 USP units of lipase; 76,000 USP units of protease; 120,000
USP units of amylase capsules have an orange opaque cap with imprint
“CREON 1224” and a colorless transparent body. (3)
----------------------------------CONTRAINDICATIONS---------------------------------
None (4)
----------------------------WARNINGS AND PRECAUTIONS--------------------------
● Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme
replacement in the treatment of cystic fibrosis patients. Exercise caution when
doses of CREON exceed 2,500 lipase units/kg of body weight per meal (or
greater than 10,000 lipase units/kg of body weight per day). (5.1)
● To avoid irritation of oral mucosa, do not chew CREON or retain in the mouth..
(5.2)
● Exercise caution when prescribing CREON to patients with gout, renal
impairment, or hyperuricemia. (5.3)
● There is theoretical risk of viral transmission with all pancreatic enzyme
products including CREON. (5.4)
● Exercise caution when administering pancrelipase to a patient with a known
allergy to proteins of porcine origin. (5.5)
----------------------------------ADVERSE REACTIONS---------------------------------
● Treatment-emergent adverse events occurring in at least 2 cystic fibrosis
patients (greater than or equal to 6%) receiving CREON or placebo are
abdominal pain, abdominal pain upper, abnormal feces, cough, dizziness,
flatulence, headache, and weight decreased. (6.1)
● Treatment-emergent adverse events that occurred in at least 1 chronic
pancreatitis or pancreatectomy patient (greater than or equal to 4%) receiving
CREON were abdominal pain, abnormal feces, diabetes mellitus inadequate
control, flatulence, frequent bowel movements, hyperglycemia, hypoglycemia,
and nasopharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Abbott
Laboratories at 1-800-241-1643 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
---------------------------USE IN SPECIFIC POPULATIONS--------------------------
Pediatric Patients
● The safety and effectiveness of CREON were assessed in pediatric cystic
fibrosis patients, aged 12 to 17 years old. (8.4)
● The safety and efficacy of pancreatic enzyme products with different
formulations of pancrelipase in pediatric patients have been described in the
medical literature and through clinical experience. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: April 2010
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Dosage
2.2
Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
5.2
Potential for Irritation to Oral Mucosa
5.3
Potential for Risk of Hyperuricemia
5.4
Potential Viral Exposure from the Product Source
5.5 Allergic Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Cystic Fibrosis
14.2 Chronic Pancreatitis or Pancreatectomy
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1 Dosing and Administration
17.2 Fibrosing Colonopathy
17.3 Allergic Reactions
*Sections or subsections omitted from the full prescribing information are not
listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic
pancreatitis, pancreatectomy, or other conditions.
2
DOSAGE AND ADMINISTRATION
2.1
Dosage
CREON is not interchangeable with other pancrelipase products.
CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The
dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the
diet [see Limitations on Dosing below and see Warnings and Precautions (5.1)].
Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation
Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the recommendations of the Conferences
provided in the following paragraphs. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.
Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic
pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
Infants (up to 12 months)
Infants may be given 2,000 to 4,000 lipase units per 120 mL of formula or per breast-feeding. Do not mix CREON capsule
contents directly into formula or breast milk prior to administration [see Dosage and Administration (2.2)].
Children Older than 12 Months and Younger than 4 Years
Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a
maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or
less than 4,000 lipase units/g fat ingested per day.
Children 4 Years and Older and Adults
Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum
of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than
4,000 lipase units/g fat ingested per day.
Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack. The total daily
dose should reflect approximately three meals plus two or three snacks per day.
Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh
more but tend to ingest less fat per kilogram of body weight.
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy
In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat
per day [see Clinical Studies (14.2)]. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of
body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences
Guidelines.1, 2, 3, 4 The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the
degree of steatorrhea present, and the fat content of the diet.
Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
Limitations on Dosing
Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus
Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional.
Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes;
thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed
2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body
weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are
documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses
greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing
colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently receiving higher doses than
6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward
to a lower range.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2
Administration
CREON should always be taken as prescribed by a healthcare professional.
Infants (up to 12 months)
CREON should be administered to infants immediately prior to each feeding, using a dosage of 2,000 to 4,000 lipase units per
120 mL of formula or per breast-feeding. Contents of the capsule may be administered directly to the mouth or with a small amount of
applesauce. Administration should be followed by breast milk or formula. Contents of the capsule should not be mixed directly into
formula or breast milk as this may diminish efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained
in the mouth, to avoid irritation of the oral mucosa.
Children and Adults
CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents should not be
crushed or chewed. Capsules should be swallowed whole.
For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small
amount of acidic soft food with a pH of 4 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be
swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be
taken to ensure that no drug is retained in the mouth.
3
DOSAGE FORMS AND STRENGTHS
The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase. Each CREON capsule strength contains the specified amounts of lipase,
protease, and amylase as follows:
● 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have an orange opaque cap
with imprint “CREON 1206” and a blue opaque body.
● 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a brown opaque cap
with imprint “CREON 1212” and a colorless transparent body.
● 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have an orange opaque
cap with imprint “CREON 1224” and a colorless transparent body.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 5, 6 Fibrosing
colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a
prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of
fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per
meal have been associated with colonic stricture in children less than 12 years of age.1 Patients with fibrosing colonopathy should be
closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of
fibrosing colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500
lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g
fat ingested per day [see Dosage and Administration (2.1)].
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per
day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a
significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal
should be examined and the dosage either immediately decreased or titrated downward to a lower range.
5.2
Potential for Irritation to Oral Mucosa
Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or chewed or mixed in
foods having a pH greater than 4. These actions can disrupt the protective enteric coating resulting in early release of enzymes,
irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and Administration (2.2) and Patient Counseling Information
(17.1)]. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a
small amount of acidic soft food with a pH of 4 or less, such as applesauce, at room temperature. The CREON-soft food mixture
should be swallowed immediately and followed with water or juice to ensure complete ingestion.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.3
Potential for Risk of Hyperuricemia
Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia.
Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
5.4
Potential Viral Exposure from the Product Source
CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that CREON will transmit
an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses
during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified
viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of
transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.
5.5
Allergic Reactions
Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin.
Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme
products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued CREON
treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.
6
ADVERSE REACTIONS
The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient
(pancrelipase) include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions (5)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The short-term safety of CREON was assessed in two clinical trials conducted in 86 patients with exocrine pancreatic
insufficiency (EPI). Study 1 was conducted in 32 patients with EPI due to cystic fibrosis (CF); Study 2 was conducted in 54 patients
with EPI due to chronic pancreatitis or pancreatectomy.
Cystic Fibrosis
Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 32 patients, ages 12 to 43 years, with EPI due
to CF. In this study, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching
placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. The mean exposure
to CREON during this study was 5 days.
One patient experienced duodenitis and gastritis of moderate severity reported as a serious adverse event 16 days after
completing treatment with CREON.
Transient neutropenia without clinical sequelae was observed as an abnormal laboratory finding in one patient receiving
CREON and a macrolide antibiotic.
The incidence of adverse events (regardless of causality) was higher during placebo treatment (71%) than during CREON
treatment (50%). Adverse events reported during the study were predominantly gastrointestinal complaints, and the type and incidence
of adverse events were similar in adolescents (12 to 18 years) and adults (greater than 18 years).
Because clinical trials are conducted under controlled conditions, the observed adverse event rates may not reflect the rates
observed in clinical practice.
Table 1 enumerates treatment-emergent adverse events that occurred in at least 2 patients (greater than or equal to 6%) treated
with either CREON or placebo in Study 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1: Treatment-Emergent Adverse Events Occurring in at least 2 Patients (greater than or equal to 6%) in Either
Treatment Group of the Placebo-Controlled, Crossover Clinical Study of CREON in Cystic Fibrosis (Study 1)
MedDRA Primary System Organ Class
Preferred Term
CREON Capsules
n = 32 (%)
Placebo
n = 31 (%)
Gastrointestinal Disorders
Abnormal Feces
1 (3)
6 (19)
Flatulence
3 (9)
8 (26)
Abdominal Pain
3 (9)
8 (26)
Abdominal Pain Upper
0
3 (10)
Investigations
Weight Decreased
1 (3)
2 (6)
Nervous System Disorders
Headache
2 (6)
8 (26)
Dizziness
2 (6)
0
Respiratory, Thoracic and Mediastinal Disorders
Cough
2 (6)
0
Chronic Pancreatitis or Pancreatectomy
Study 2 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages 32 to 75 years, with
EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo treatment during a 5-day run-in period
followed by an intervening period of up to 16 days of investigator-directed treatment with no restrictions on pancreatic enzyme
replacement therapy. Patients were then randomized to receive CREON or matching placebo for 7 days. The CREON dose was 72,000
lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this
study was 6.8 days.
The incidence of treatment-emergent adverse events (regardless of causality) was 20% with CREON treatment and 21% with
placebo treatment. The most common adverse events reported during the study were related to glycemic control and were reported
more commonly during CREON treatment (12%) than during placebo treatment (7%).
Because clinical trials are conducted under controlled conditions, the observed adverse event rates may not reflect the rates
observed in clinical practice.
Table 2 enumerates treatment-emergent adverse events that occurred in at least 1 patient (greater than or equal to 4%) in the
CREON group.
Table 2: Treatment-Emergent Adverse Events Reported During the Randomized Period in at least 1 Patient
(greater than or equal to 4%) in the CREON Group in Chronic Pancreatitis or Pancreatectomy (Study 2)
MedDRA Primary System Organ Class
Preferred Term
CREON Capsules
n = 25 (%)
Placebo
n = 29 (%)
Gastrointestinal Disorders
Abdominal Pain
1 (4)
1 (3)
Abnormal Feces
1 (4)
0
Flatulence
1 (4)
0
Frequent Bowel Movements
1 (4)
0
Infections and Infestations
Nasopharyngitis
1 (4)
0
Metabolism and Nutritional Disorders
Diabetes Mellitus Inadequate Control
1 (4)
0
Hyperglycemia
1 (4)
2 (7)
Hypoglycemia
1 (4)
1 (3)
6.2
Postmarketing Experience
Postmarketing data from this formulation of CREON has been available since 2009. The following adverse events have been
reported with this formulation of CREON in spontaneous postmarketing reports: gastrointestinal disorders (including abdominal pain,
diarrhea, flatulence, constipation and nausea), skin disorders (including pruritus, urticaria and rash), blurred vision, myalgia, muscle
spasm, and asymptomatic elevations of liver enzymes.
Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active ingredient
(pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other
conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature.
The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. In general, these products have a
well defined and favorable risk-benefit profile in exocrine pancreatic insufficiency.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
7
DRUG INTERACTIONS
No drug interactions have been identified. No formal interaction studies have been conducted.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic effects
Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether
pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The risk and benefit of
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with
exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal
growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes. Patients should notify
their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with CREON.
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should
be exercised when CREON is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the
context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.
8.4
Pediatric Use
The short-term safety and efficacy of CREON were assessed in a single, randomized, double-blind, placebo-controlled,
crossover study of 32 patients with exocrine pancreatic insufficiency due to cystic fibrosis, including 12 patients between 12 and 18
years of age. The safety and efficacy in 12 to 18 year old patients in this study were similar to adult patients [see Adverse Reactions
(6.1) and Clinical Studies (14)].
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active
ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis
have been described in the medical literature and through clinical experience.
Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation
Consensus Conferences [see Dosage and Administration (2.1)]. Doses of other pancreatic enzyme products exceeding 6,000 lipase
units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years
of age [see Warnings and Precautions (5.1)].
10
OVERDOSAGE
There have been no reports of overdose in clinical trials with CREON, or in clinical trials or postmarketing surveillance with
other pancreatic enzyme products. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy
and colonic strictures [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. High doses of pancreatic enzyme
products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of
hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].
11
DESCRIPTION
CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands.
Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.
Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and
ether.
Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).
The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase.
CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol,
and triethyl citrate. The imprinting ink on the capsule contains dimethicone, 2-ethoxyethanol, shellac, soya lecithin, and titanium
dioxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have a Swedish-orange
opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue No. 2, gelatin, red iron oxide,
sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a brown opaque cap
with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron oxide, gelatin, red iron oxide, sodium
lauryl sulfate, titanium dioxide, and yellow iron oxide.
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have a Swedish-orange
opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain gelatin, red iron oxide, sodium lauryl
sulfate, titanium dioxide, and yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into
peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and
proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.
12.3
Pharmacokinetics
The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid. CREON is
expected to release most of the enzymes in vivo at a pH greater than 5.5. Pancreatic enzymes are not absorbed from the
gastrointestinal tract in appreciable amounts.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed.
14
CLINICAL STUDIES
The short-term safety and efficacy of CREON were evaluated in two studies conducted in 86 patients with exocrine pancreatic
insufficiency (EPI). Study 1 was conducted in 32 patients with EPI due to cystic fibrosis (CF); Study 2 was conducted in 54 patients
with EPI due to chronic pancreatitis or pancreatectomy.
14.1
Cystic Fibrosis
Study 1 was a randomized, double-blind, placebo-controlled, crossover study in 32 patients, ages 12 to 43 years, with exocrine
pancreatic insufficiency due to cystic fibrosis. The final analysis population was limited to 29 patients; 3 patients were excluded due to
protocol deviations. Patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching
placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients
consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment periods.
The primary efficacy endpoint was the mean difference in the coefficient of fat absorption (CFA) between CREON and
placebo treatment. The CFA was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat
ingestion were measured. Each patient’s CFA during placebo treatment was used as their no-treatment CFA value.
Mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean difference in CFA was 41
percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.
Subgroup analyses of the CFA results showed that mean change in CFA with CREON treatment was greater in patients with
lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were no differences
in response to CREON by age or gender, with similar responses to CREON observed in male and female patients, and in younger
(under 18 years of age) and older patients.
14.2
Chronic Pancreatitis or Pancreatectomy
Study 2 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages 32 to 75 years, with
EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to 52 patients; 2 patients were excluded
due to protocol violations. Ten patients had a history of pancreatectomy (7 were treated with CREON). In this study, patients received
placebo for 5 days (run-in period), followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this
was followed by randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with CFA
less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the double-blind period
was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). All patients consumed a high-fat
diet (greater than or equal to 100 grams of fat per day) during the treatment period.
The primary efficacy endpoint was the mean change in CFA from the run-in period to the end of the double-blind period. The
CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods, when both fat excretion and
fat ingestion were measured (Table 3).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3: Percent Change in CFA in Study 2 (Run-in Period to End of Double-Blind Period)
CREON
n = 24
Placebo
n = 28
CFA [%] empty cell
Run-in Period (Mean, SD)
54 (19)
57 (21)
End of Double-Blind Period (Mean, SD)
86 (6)
66 (20)
Change in CFA * [%]
Run-in Period to End of Double-Blind Period (Mean, SD)
32 (18)
9 (13)
Treatment Difference (95% CI)
21 (14, 28)
*p<0.0001
The mean percent change in CFA from the run-in period to the end of the double-blind period was 32% for CREON and 9% for
placebo (p<0.0001). Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower run-in
period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a history of total pancreatectomy
was treated with CREON in the study. That patient had a CFA of 26% during the run-in period and a CFA of 73% at the end of the
double-blind period. The remaining 6 patients with a history of partial pancreatectomy treated with CREON on the study had a mean
CFA of 42% during the run-in period and a mean CFA of 84% at the end of the double-blind period.
15
REFERENCES
1 Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of
fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684.
2 Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Journal of Pediatric
Gastroenterology Nutrition. 2002 Sep; 35: 246-259.
3 Stallings VA, Start LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children
and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic
Association. 2008; 108: 832-839.
4 Dominguez-Munoz JE, Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current Gastroenterology Reports. 2007;
9: 116-122.
5 Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346:
1247-1251.
6 FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in
children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.
16
HOW SUPPLIED/STORAGE AND HANDLING
CREON (pancrelipase) Delayed-Release Capsules
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1206” and a
blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
●
100 capsules (NDC 0032-1206-01)
●
250 capsules (NDC 0032-1206-07)
CREON (pancrelipase) Delayed-Release Capsules
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint “CREON 1212” and a
colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
●
100 capsules (NDC 0032-1212-01)
●
250 capsules (NDC 0032-1212-07)
CREON (pancrelipase) Delayed-Release Capsules
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1224” and a
colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
●
100 capsules (NDC 0032-1224-01)
●
250 capsules (NDC 0032-1224-07)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage and Handling
CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature excursions are
permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if exposed to higher temperature
and moisture conditions higher than 70%. AFTER OPENING, KEEP BOTTLE TIGHTLY CLOSED between uses to PROTECT
FROM MOISTURE.
Keep out of reach of children.
DO NOT CRUSH CREON delayed-release capsules or the capsule contents.
17
PATIENT COUNSELING INFORMATION
See Medication Guide
CREON is available in capsule strengths of:
● 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
● 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
●
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
Healthcare professionals should inform patients of the following important information about CREON.
17.1 Dosing and Administration
● Instruct patients and caregivers that CREON should only be taken as directed by their healthcare professional [see Dosage
and Administration (2)].
● Instruct patients and caregivers that CREON should always be taken with food [see Dosage and Administration (2)].
● Instruct patients who are unable to swallow intact capsules to sprinkle the contents of CREON on a small amount of acidic
soft food, such as applesauce, at room temperature. Instruct these patients to swallow the CREON-soft food mixture
immediately without crushing or chewing, and follow with water or juice to ensure complete ingestion and to avoid
irritation of the oral mucosa [see Dosage and Administration (2)].
● Tell patients that CREON or their contents should not be crushed or chewed as doing so could cause early release of
enzymes and/or loss of enzymatic activity [see Dosage and Administration (2)].
● Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during
treatment with CREON [see Use in Specific Populations (8.1)].
● Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast feeding during
treatment with CREON [see Use in Specific Populations (8.3)].
17.2
Fibrosing Colonopathy
Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000
lipase units/kg of body weight per meal have been associated with colonic strictures in children below the age of 12 years [see Dosage
and Administration (2)].
17.3
Allergic Reactions
Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to CREON develop
[see Warnings and Precautions (5.5)].
Manufactured by:
Abbott Products GmbH
Hannover, Germany
Marketed By:
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
1055216 6E
© 2010 Abbott Laboratories
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
n)
ŏ׳ ē
CREON® (kr
(pancrelipase)
Delayed-Release Capsules
Read this Medication Guide before you or your child start taking CREON and each time you or your child get a prescription refilled.
There may be new information. This information does not take the place of talking with your healthcare professional about your
medical condition or your treatment.
What is the most important information I should know about CREON?
●
CREON may increase your chance of having a rare bowel disorder called fibrosing colonopathy. This condition is serious and
may require surgery. The risk of having this condition may be reduced by following the dosing instructions that your healthcare
professional gave you. Call your healthcare professional right away if you have any unusual or severe stomach area
(abdominal) pain.
●
Take CREON exactly as prescribed. Do not take more or less CREON than directed by your healthcare professional.
What is CREON?
CREON is a prescription pancreatic enzyme medicine used to improve food digestion in people who cannot digest food
properly because they have exocrine pancreatic insufficiency. CREON contains a mixture of digestive enzymes (including lipases,
proteases, and amylases) from pig pancreas.
CREON is safe and effective in children.
What should I tell my healthcare professional before taking CREON?
Tell your healthcare professional if you:
●
are allergic to pork (pig) products.
●
have a history of intestinal blockage or a condition called fibrosing colonopathy.
●
have gout, kidney disease, or a condition called high blood uric acid (hyperuricemia).
●
have trouble swallowing capsules.
●
are pregnant or planning to become pregnant. It is not known if CREON will harm your unborn baby.
●
are breast-feeding or plan to breast-feed. It is not known if CREON passes into your breast milk. Tell your healthcare
professional about all the medicines you take, including prescription and nonprescription medicines, vitamins, and dietary or
herbal supplements.
Know the medicines you take. Keep a list of them and show it to your healthcare professional and pharmacist when you get a
new medicine.
How should I take CREON?
●
Take CREON exactly as instructed by your healthcare professional.
Infants (up to 12 months)
Contents of the capsule may be put directly in the infant’s mouth or in a small amount of applesauce and administered (or
given) just prior to feeding the infant breast milk or formula. Do not mix CREON capsule contents directly into formula or breast milk
prior to administration. Care should be taken to ensure that the entire administered dose is swallowed and not retained in the mouth, to
avoid irritation of the mouth.
Children and Adults
●
Always take CREON during a meal or a snack and follow it with sufficient fluid.
●
If you forget to take CREON, call your healthcare professional or wait until your next meal and take your usual number of
capsules. Do not make up for missed doses. Take your next dose at the usual time.
●
If you or your child takes more CREON than directed, call your healthcare professional right away.
●
Swallow CREON whole. Do not crush or chew the contents of the capsules.
If you have trouble swallowing capsules, you can add the contents of an open capsule directly onto your food. To do so,
carefully open the capsules and sprinkle the contents on a small amount of applesauce at room temperature as described below.
Swallow the soft food right away without chewing and follow with water or juice.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A. Hold the Usage Illustration
B. Carefully twist off
capsule upright
the top portion of
so that you can
the capsule over
read the word
the food you plan
CREON on the
to eat.
capsule. Usage Illustration
C. Sprinkle the Usage Illustration
D. Swallow the
contents of the
CREON-soft food
capsule onto
right away without
the soft food.
chewing and
Do not crush
follow with water
the contents of
or juice to make
the capsules.
sure the contents
of the capsules are
swallowed
completely. Usage Illustration
What are the possible side effects of CREON?
CREON may cause serious side effects, including:
●
CREON may increase your chance of having a rare bowel disorder called fibrosing colonopathy. See “What is the most
important information I should know about CREON?”
●
increase in blood uric acid levels, for example, worsening of gout, or painful, swollen joints. Call your healthcare professional
right away if you have any of these symptoms.
●
allergic reactions. For example, symptoms of an allergic reaction include: trouble with breathing, skin rashes, or swollen lips.
Call your healthcare professional right away if you have any of these symptoms.
The most common side effects include:
●
gassiness (flatulence)
●
stomach area (abdominal) pain
●
headache
●
dizziness
Tell your healthcare professional if you have any side effect that bothers you or that does not go away.
These are not all the side effects of CREON. Call your doctor for medical advice about side effects. You may report side
effects to the FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch. You may also report side effects to Solvay Pharmaceuticals, Inc.
at 1-800-241-1643.
How should I store CREON?
●
Store CREON at room temperature (up to 25°C or 77°F) for up to 12 weeks after the bottle is opened.
●
If you store CREON at temperatures greater than room temperature (up to 40°C or 104°F), throw away after 30 days.
●
Store CREON in the container you were given by the pharmacy.
●
Keep the bottle closed tightly.
●
Protect the bottle from moisture.
●
Keep CREON and all medicines out of reach of children.
General information about the safe and effective use of CREON
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CREON for a
condition for which it was not prescribed. Do not give CREON to other people to take, even if they have the same symptoms you
have. It may harm them.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Medication Guide summarizes the most important information about CREON. If you would like more information, talk to
your healthcare professional. You can ask your healthcare professional or pharmacist for information about CREON that is written for
healthcare professionals. For more information, go to www.creon-us.com or call toll-free [1-800-241-1643].
What are the ingredients in CREON?
Active Ingredient: pancrelipase
Inactive Ingredients: cetyl alcohol, dimethicone, gelatin, hypromellose phthalate, polyethylene glycol, red iron oxide, sodium lauryl
sulfate, titanium dioxide, triethyl citrate, and yellow iron oxide. In addition, the 6,000 strength contains FD&C Blue No. 2 and the
12,000 strength contains black iron oxide. The imprinting ink on the capsule contains dimethicone, 2-ethoxyethanol, shellac, soya
lecithin, and titanium dioxide.
Additional information about pancreatic enzymes
CREON and other pancreatic enzyme products are made from pancreatic organs of pigs used for food. There is a theoretical
risk of contracting a viral infection from pig-derived medicines, but no human illness has been reported.
The risk of fibrosing colonopathy, increased blood uric acid levels, and the theoretical risk of viral transmission is present with
all pancreatic enzyme products including CREON.
You should report any change in condition or illness to your healthcare professional.
© 2009 Solvay Pharmaceuticals, Inc.
Manufactured for Solvay Pharmaceuticals, Inc., Marietta, GA 30062, U.S.A.
1055216 1E Rev Apr 2009
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued April 2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:24.232380 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020725s003lbl.pdf', 'application_number': 20725, 'submission_type': 'SUPPL ', 'submission_number': 3} |
3,208 |
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CREON
safely and effectively. See full prescribing information for CREON.
CREON (pancrelipase) delayed-release capsules
Initial U.S. Approval: 2009
---------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage, Chronic Pancreatitis, Pancreatectomy (1)
4/2010
Dosage and Administration, Chronic Pancreatitis or
Pancreatectomy (2.2)
4/2010
---------------------------INDICATIONS AND USAGE-----------------------------
CREON is a combination of porcine-derived lipases, proteases, and amylases
indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. (1)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
CREON is not interchangeable with any other pancrelipase product. (2.1)
Do not crush or chew capsules and capsule contents. For infants or patients
unable to swallow intact capsules, the contents may be sprinkled on soft acidic
food, e.g., applesauce. (2.1) Dosing should not exceed the recommended
maximum dosage set forth by the Cystic Fibrosis Foundation Consensus
Conferences Guidelines. (2.2)
Infants (up to 12 months)
● Prior to each feeding, give 2,000 to 4,000 lipase units per 120 mL of
formula or breast feeding. (2.1)
● Do not mix CREON capsule contents directly into formula or breast milk
prior to administration. (2.1)
Children Older than 12 Months and Younger than 4 Years
● Begin with 1,000 lipase units/kg of body weight per meal for children less
than age 4 years to a maximum of 2,500 lipase units/kg of body weight per
meal (or less than or equal to 10,000 lipase units/kg of body weight per
day), or less than 4,000 lipase units/g fat ingested per day. (2.2)
Children 4 Years and Older and Adults
● Begin with 500 lipase units/kg of body weight per meal for those older than
age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal
(or less than or equal to 10,000 lipase units/kg of body weight per day), or
less than 4,000 lipase units/g fat ingested per day. (2.2)
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or
Pancreatectomy
● Individualize dosage based on clinical symptoms, the degree of steatorrhea
present and the fat content of the diet. (2.2)
2
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Administration
2.2
Dosage
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
5.2
Potential for Irritation to Oral Mucosa
5.3
Potential for Risk of Hyperuricemia
5.4
Potential Viral Exposure from the Product Source
5.5 Allergic Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
----------------------DOSAGE FORMS AND STRENGTHS-----------------
● Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000
USP units of amylase (3)
● Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000
USP units of amylase (3)
● Capsules: 24,000 USP units of lipase; 76,000 USP units of protease;
120,000 USP units of amylase (3)
----------------------------CONTRAINDICATIONS----------------------------
None (4)
-----------------------WARNINGS AND PRECAUTIONS---------------------
● Fibrosing colonopathy is associated with high-dose use of pancreatic
enzyme replacement in the treatment of cystic fibrosis patients. Exercise
caution when doses of CREON exceed 2,500 lipase units/kg of body
weight per meal (or greater than 10,000 lipase units/kg of body weight per
day). (5.1)
● To avoid irritation of oral mucosa, do not chew CREON or retain in the
mouth. (5.2)
● Exercise caution when prescribing CREON to patients with gout, renal
impairment, or hyperuricemia. (5.3)
● There is theoretical risk of viral transmission with all pancreatic enzyme
products including CREON. (5.4)
● Exercise caution when administering pancrelipase to a patient with a
known allergy to proteins of porcine origin. (5.5)
----------------------------ADVERSE REACTIONS----------------------------
● Adverse reactions occurring in at least 2 cystic fibrosis patients (greater
than or equal to 4%) receiving CREON are vomiting, dizziness, and
cough. (6.1)
● Adverse reactions that occurred in at least 1 chronic pancreatitis or
pancreatectomy patient (greater than or equal to 4%) receiving CREON are
hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence,
frequent bowel movements, and nasopharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Abbott
Laboratories at 1-800-241-1643 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: July 2010
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Cystic Fibrosis
14.2 Chronic Pancreatitis or Pancreatectomy
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1 Dosing and Administration
17.2 Fibrosing Colonopathy
17.3 Allergic Reactions
17.4 Pregnancy and Breast Feeding
*Sections or subsections omitted from the full prescribing information are not
listed
Page 1 of 13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.
2
DOSAGE AND ADMINISTRATION
CREON is not interchangeable with other pancrelipase products.
CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually
increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea
present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and
Administration (2.2) and Warnings and Precautions (5.1)].
2.1
Administration
Infants (up to 12 months)
CREON should be administered to infants immediately prior to each feeding, using a dosage of 2,000 to
4,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered
directly to the mouth or with a small amount of applesauce. Administration should be followed by breast milk or
formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish
efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid
irritation of the oral mucosa.
Children and Adults
CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents
should not be crushed or chewed. Capsules should be swallowed whole.
For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the
contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room
temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and
followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in
the mouth.
2.2
Dosage
Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic
Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the
recommendations of the Conferences provided in the following paragraphs. Patients may be dosed on a fat
ingestion-based or actual body weight-based dosing scheme.
Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency
due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
Infants (up to 12 months)
Infants may be given 2,000 to 4,000 lipase units per 120 mL of formula or per breast-feeding. Do not mix
CREON capsule contents directly into formula or breast milk prior to administration [see Dosage and
Administration (2.1)].
Children Older than 12 Months and Younger than 4 Years
Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age
4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase
units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Children 4 Years and Older and Adults
Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age
4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase
units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Page 2 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
The total daily dose should reflect approximately three meals plus two or three snacks per day.
Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients
because they weigh more but tend to ingest less fat per kilogram of body weight.
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy
The initial starting dose and increases in the dose per meal should be individualized based on clinical
symptoms, the degree of steatorrhea present, and the fat content of the diet.
In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at
least 100 g of fat per day [see Clinical Studies (14.2)]. Lower starting doses recommended in the literature are
consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the
Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose
for an individualized full meal should be given with each snack.
Limitations on Dosing
Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation
Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased
by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great
inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may
require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal,
further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than
10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be
effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses
greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of
fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently
receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either
immediately decreased or titrated downward to a lower range.
3
DOSAGE FORMS AND STRENGTHS
The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase. Each CREON capsule strength contains the specified
amounts of lipase, protease, and amylase as follows:
● 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have an
orange opaque cap with imprint “CREON 1206” and a blue opaque body.
● 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a
brown opaque cap with imprint “CREON 1212” and a colorless transparent body.
● 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have
an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 5, 6
Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic
enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic
fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in
children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some
patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing
Page 3 of 13
This label may not be the latest approved by FDA.
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95
colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than
96
2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less
97
than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.1)].
98
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of
99
body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat
100
measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than
101
6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or
102
titrated downward to a lower range.
103
5.2
Potential for Irritation to Oral Mucosa
104
Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or
105
chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating
106
resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and
107
Administration (2.2) and Patient Counseling Information (17.1)]. For patients who are unable to swallow intact
108
capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a
109
pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed
110
immediately and followed with water or juice to ensure complete ingestion.
111
5.3
Potential for Risk of Hyperuricemia
112
Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or
113
hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
114
5.4
Potential Viral Exposure from the Product Source
115
CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that
116
CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during
117
manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission
118
of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses
119
that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness
120
associated with the use of porcine pancreatic extracts have been reported.
121
5.5
Allergic Reactions
122
Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of
123
porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been
124
reported with other pancreatic enzyme products with different formulations of the same active ingredient
125
(pancrelipase). The risks and benefits of continued CREON treatment in patients with severe allergy should be taken
126
into consideration with the overall clinical needs of the patient.
127
6
ADVERSE REACTIONS
128
The most serious adverse reactions reported with different pancreatic enzyme products of the same active
129
ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and
130
allergic reactions [see Warnings and Precautions (5)].
131
6.1
Clinical Trials Experience
132
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
133
clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not
134
reflect the rates observed in practice.
135
The short-term safety of CREON was assessed in clinical trials conducted in 103 patients with exocrine
136
pancreatic insufficiency (EPI): 49 patients with EPI due to cystic fibrosis (CF) and 25 patients with EPI due to
137
chronic pancreatitis or pancreatectomy were treated with CREON.
138
Cystic Fibrosis
139
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies of 49 patients, ages 7
140
to 43 years, with EPI due to CF. Study 1 included 32 patients ages 12 to 43 years and Study 2 included 17 patients
141
ages 7 to 11 years. In these studies, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat
Page 4 of 13
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142
ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment
143
for an additional 5 to 6 days. The mean exposure to CREON during these studies was 5 days.
144
In Study 1, one patient experienced duodenitis and gastritis of moderate severity 16 days after completing
145
treatment with CREON. Transient neutropenia without clinical sequelae was observed as an abnormal laboratory
146
finding in one patient receiving CREON and a macrolide antibiotic.
147
In Study 2, adverse reactions that occurred in at least 2 patients (greater than or equal to 12%) treated with
148
CREON were vomiting and headache. Vomiting occurred in 2 patients treated with CREON and did not occur in
149
patients treated with placebo; headache occurred in 2 patients treated with CREON and did not occur in patients
150
treated with placebo.
151
The most common adverse reactions (greater than or equal to 4%) were vomiting, dizziness, and cough.
152
Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 4%) treated with
153
CREON at a higher rate than with placebo in Studies 1 and 2.
154
Table 1: Adverse Reactions Occurring in at Least 2 Patients (greater than or equal to 4%) in Cystic Fibrosis
155
(Studies 1 and 2)
Adverse Reaction
CREON Capsules
n = 49 (%)
Placebo
n = 47 (%)
Vomiting
3 (6)
1 (2)
Dizziness
2 (4)
1 (2)
Cough
2 (4)
0
156
Chronic Pancreatitis or Pancreatectomy
157
Study 3 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages
158
32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo
159
treatment during a 5-day run-in period followed by an intervening period of up to 16 days of investigator-directed
160
treatment with no restrictions on pancreatic enzyme replacement therapy. Patients were then randomized to receive
161
CREON or matching placebo for 7 days. The CREON dose was 72,000 lipase units per main meal (3 main meals)
162
and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this study was 6.8 days in the 25
163
patients that received CREON.
164
The most common adverse reactions reported during the study were related to glycemic control and were
165
reported more commonly during CREON treatment than during placebo treatment.
166
Table 2 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 4%) treated
167
with CREON at a higher rate than with placebo in Study 3.
168
Table 2: Adverse Reactions in at least 1 Patient (greater than or equal to 4%) in Chronic Pancreatitis or
169
Pancreatectomy (Study 3)
Adverse Reaction
CREON Capsules
n = 25 (%)
Placebo
n = 29 (%)
Hyperglycemia
2 (8)
2 (7)
Hypoglycemia
1 (4)
1 (3)
Abdominal Pain
1 (4)
1 (3)
Abnormal Feces
1 (4)
0
Flatulence
1 (4)
0
Frequent Bowel Movements
1 (4)
0
Nasopharyngitis
1 (4)
0
170
6.2
Postmarketing Experience
171
Postmarketing data from this formulation of CREON have been available since 2009. The following adverse
172
reactions have been identified during post approval use of this formulation of CREON. Because these reactions are
173
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency
174
or establish a causal relationship to drug exposure.
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175
Gastrointestinal disorders (including abdominal pain, diarrhea, flatulence, constipation and nausea), skin
176
disorders (including pruritus, urticaria and rash), blurred vision, myalgia, muscle spasm, and asymptomatic
177
elevations of liver enzymes have been reported with this formulation of CREON.
178
Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active
179
ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to
180
cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has
181
been described in the medical literature. The most serious adverse reactions included fibrosing colonopathy, distal
182
intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions
183
including anaphylaxis, asthma, hives, and pruritus.
184
7
DRUG INTERACTIONS
185
No drug interactions have been identified. No formal interaction studies have been conducted.
186
8
USE IN SPECIFIC POPULATIONS
187
8.1
Pregnancy
188
Teratogenic effects
189
Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not
190
known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect
191
reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of
192
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant
193
woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal
194
maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with
195
adverse pregnancy outcomes.
196
8.3
Nursing Mothers
197
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
198
milk, caution should be exercised when CREON is administered to a nursing woman. The risk and benefit of
199
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing
200
mother with exocrine pancreatic insufficiency.
201
8.4
Pediatric Use
202
The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo
203
controlled, crossover studies of 49 patients with exocrine pancreatic insufficiency due to cystic fibrosis, 25 of whom
204
were pediatric patients, Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included 17
205
children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar to
206
adult patients [see Adverse Reactions (6.1) and Clinical Studies (14)].
207
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting
208
of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic
209
insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.
210
Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis
211
Foundation Consensus Conferences [see Dosage and Administration (2.1)]. Doses of other pancreatic enzyme
212
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy
213
and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)].
214
10
OVERDOSAGE
215
There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation
216
of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and
217
colonic strictures [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. High doses of
218
pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with
219
caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].
Page 6 of 13
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220
11
DESCRIPTION
221
CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine
222
pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and
223
amylases.
224
Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble
225
in alcohol and ether.
226
Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in
227
diameter).
228
The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
229
Other active ingredients include protease and amylase.
230
CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate,
231
polyethylene glycol, and triethyl citrate. The imprinting ink on the capsule contains dimethicone, 2-ethoxyethanol,
232
shellac, soya lecithin, and titanium dioxide.
233
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have a
234
Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue
235
No. 2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
236
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a
237
brown opaque cap with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron
238
oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
239
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have a
240
Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain
241
gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
242
12
CLINICAL PHARMACOLOGY
243
12.1
Mechanism of Action
244
The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty
245
acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and
246
maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically
247
secreted by the pancreas.
248
12.3
Pharmacokinetics
249
The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid.
250
CREON is designed to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic
251
enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.
252
13
NONCLINICAL TOXICOLOGY
253
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
254
Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed.
255
14
CLINICAL STUDIES
256
The short-term safety and efficacy of CREON were evaluated in three studies conducted in 103 patients with
257
exocrine pancreatic insufficiency (EPI). Studies 1 and 2 were conducted in 49 patients with EPI due to cystic
258
fibrosis (CF); Study 3 was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.
259
14.1
Cystic Fibrosis
260
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to
261
43 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Study 1 included patients aged 12 to 43 years
262
(n = 32). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol
263
deviations. Study 2 included patients aged 7 to 11 years (n = 17). The final analysis population was limited to 16
264
patients; 1 patient withdrew consent prior to stool collection during treatment with CREON. In each study, patients
Page 7 of 13
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T
a
b
l
e
265
were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5
266
to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients
267
consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat)
268
during the treatment periods.
269
The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments,
270
when both fat excretion and fat ingestion were measured. Each patient’s CFA during placebo treatment was used as
271
their no-treatment CFA value.
272
In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean
273
difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.
274
In Study 2,mean CFA was 83% with CREON treatment compared to 47% with placebo treatment. The mean
275
difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.
276
Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON
277
treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher
278
no-treatment (placebo) CFA values. There were no differences in response to CREON by age or gender, with similar
279
responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older
280
patients.
281
The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both
282
treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated
283
(based on the assumption that proteins contain 16% nitrogen). Each patient’s CNA during placebo treatment was
284
used as their no-treatment CNA value.
285
In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment. The mean
286
difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.
287
In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment. The mean
288
difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.
289
14.2
Chronic Pancreatitis or Pancreatectomy
290
Study 3 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages
291
32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to
292
52 patients; 2 patients were excluded due to protocol violations. Ten patients had a history of pancreatectomy (7
293
were treated with CREON). In this study, patients received placebo for 5 days (run-in period), followed by
294
pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by
295
randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with
296
CFA less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the
297
double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2
298
snacks). All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the
299
treatment period.
300
The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods,
301
when both fat excretion and fat ingestion were measured. The mean change in CFA from the run-in period to the end
302
of the double-blind period in the CREON and Placebo groups is shown in Table 3.
303
Table 3: Change in CFA in Study 3 (Run-in Period to End of Double-Blind Period)
Page 8 of 13
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304
Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower
305
run-in period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a
306
history of total pancreatectomy was treated with CREON in the study. That patient had a CFA of 26% during the
307
run-in period and a CFA of 73% at the end of the double-blind period. The remaining 6 patients with a history of
308
partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a
309
mean CFA of 84% at the end of the double-blind period.
310
15
REFERENCES
311
1 Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in
312
the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684.
313
2 Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis.
314
Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259.
315
3 Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related
316
management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic
317
review. Journal of the American Dietetic Association. 2008; 108: 832-839.
318
4 Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current
319
Gastroenterology Reports. 2007; 9: 116-122.
320
5 Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study.
321
Lancet. 1995; 346: 1247-1251.
322
6 FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing
323
colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.
324
16
HOW SUPPLIED/STORAGE AND HANDLING
325
CREON (pancrelipase) Delayed-Release Capsules
326
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
327
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint
328
“CREON 1206” and a blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles
329
of:
330
●
100 capsules (NDC 0032-1206-01)
331
●
250 capsules (NDC 0032-1206-07)
332
CREON (pancrelipase) Delayed-Release Capsules
333
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
334
Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint
335
“CREON 1212” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in
336
bottles of:
337
●
100 capsules (NDC 0032-1212-01)
338
●
250 capsules (NDC 0032-1212-07)
339
CREON (pancrelipase) Delayed-Release Capsules
340
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
341
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint
342
“CREON 1224” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in
343
bottles of:
344
●
100 capsules (NDC 0032-1224-01)
345
●
250 capsules (NDC 0032-1224-07)
346
Storage and Handling
347
CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature
348
excursions are permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if
Page 9 of 13
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349
exposed to higher temperature and moisture conditions higher than 70%. After opening, keep bottle tightly closed
350
between uses to protect from moisture.
351
352
Do not crush CREON delayed-release capsules or the capsule contents.
353
17
PATIENT COUNSELING INFORMATION
354
[See Medication Guide]
355
17.1 Dosing and Administration
356
●
Instruct patients and caregivers that CREON should only be taken as directed by their healthcare
357
professional [see Dosage and Administration (2)].
358
●
Instruct patients and caregivers that CREON should always be taken with food [see Dosage and
359
Administration (2)].
360
●
Instruct patients who are unable to swallow intact capsules to sprinkle the contents of CREON on a
361
small amount of acidic soft food, such as applesauce, at room temperature. Instruct these patients to
362
swallow the CREON-soft food mixture immediately without crushing or chewing, and follow with water
363
or juice to ensure complete ingestion and to avoid irritation of the oral mucosa [see Dosage and
364
Administration (2)].
365
●
Tell patients that CREON or their contents should not be crushed or chewed as doing so could cause
366
early release of enzymes and/or loss of enzymatic activity [see Dosage and Administration (2)].
367
17.2
Fibrosing Colonopathy
368
Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme
369
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in
370
children below the age of 12 years [see Dosage and Administration (2)].
371
17.3
Allergic Reactions
372
Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to
373
CREON develop [see Warnings and Precautions (5.5)].
374
17.4 Pregnancy and Breast Feeding
375
●
Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming
376
pregnant during treatment with CREON [see Use in Specific Populations (8.1)].
377
●
Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast
378
feeding during treatment with CREON [see Use in Specific Populations (8.3)].
379
380
Manufactured by:
381
Abbott Products GmbH
382
Hannover, Germany
383
Marketed By:
384
Abbott Laboratories
385
North Chicago, IL 60064, U.S.A.
386
387
1055216 7E
388
© 2010 Abbott Laboratories
Page 10 of 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:24.393379 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020725s006lbl.pdf', 'application_number': 20725, 'submission_type': 'SUPPL ', 'submission_number': 6} |
2,292 |
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Genotropin
safely and effectively. See full prescribing information for Genotropin.
GENOTROPIN® (somatropin [rDNA origin] for injection)
Initial U.S. Approval: 1987
----------------------------RECENT MAJOR CHANGES--------------------------
Warnings and Precautions, Pancreatitis (5.14)
03/2011
Warnings and Precautions, Impaired Glucose Tolerance
and Diabetes Mellitus (5.4)
03/2011
----------------------------INDICATIONS AND USAGE---------------------------
GENOTROPIN is a recombinant human growth hormone indicated for:
• Pediatric: Treatment of children with growth failure due to growth hormone
deficiency (GHD), Prader-Willi syndrome, Small for Gestational Age, Turner
syndrome, and Idiopathic Short Stature (1.1)
• Adult: Treatment of adults with either adult onset or childhood onset GHD (1.2)
----------------------DOSAGE AND ADMINISTRATION-----------------------
GENOTROPIN should be administered subcutaneously (2)
• Pediatric GHD: 0.16 to 0.24 mg/kg/week (2.1)
• Prader-Willi Syndrome: 0.24 mg/kg/week (2.1)
• Small for Gestational Age: Up to 0.48 mg/kg/week (2.1)
• Turner Syndrome: 0.33 mg/kg/week (2.1)
• Idiopathic Short Stature: up to 0.47 mg/kg/week (2.1)
• Adult GHD: Either a non-weight based or a weight based dosing regimen may be
followed, with doses adjusted based on treatment response and IGF-I
concentrations (2.2)
• Non-weight based dosing: A starting dose of approximately 0.2mg/day (range,
0.15-0.30 mg/day) may be used without consideration of body weight, and
increased gradually every 1-2 months by increments of approximately 0.1-0.2
mg/day. (2.2)
• Weight based dosing: The recommended initial dose is not more than 0.04
mg/kg/week; the dose may be increased as tolerated to not more than 0.08
mg/kg/week at 4–8 week intervals. (2.2)
• GENOTROPIN cartridges are color-coded to correspond to a specific
GENOTROPIN PEN delivery device (2.3)
• Injection sites should always be rotated to avoid lipoatrophy (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
GENOTROPIN lyophilized powder in a two-chamber color-coded cartridge (3):
• 5 mg (green tip) and 12 mg (purple tip) (with preservative)
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-
chamber cartridge (without preservative):
• 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0
mg
-------------------------------CONTRAINDICATIONS------------------------------
• Acute Critical Illness (4.1, 5.1)
• Children with Prader-Willi syndrome who are severely obese or have
severe
respiratory impairment – reports of sudden death (4.2, 5.2)
• Active Malignancy (4.3)
• Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy (4.4)
• Children with closed epiphyses (4.5)
• Known hypersensitivity to somatropin or m-cresol (4.6)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Acute Critical Illness: Potential benefit of treatment continuation should
be
weighed against the potential risk (5.1).
• Prader-Willi syndrome in Children: Evaluate for signs of upper airway
obstruction and sleep apnea before initiation of treatment.
Discontinue treatment if these signs occur (5.2).
• Neoplasm: Monitor patients with preexisting tumors for progression or
recurrence. Increased risk of a second neoplasm in childhood cancer
survivors
treated with somatropin—in particular meningiomas in patients treated
with
radiation to the head for their first neoplasm (5.3).
• Impaired Glucose Tolerance and Diabetes Mellitus: May be
unmasked.
Periodically monitor glucose levels in all patients. Doses of concurrent
antihyperglycemic drugs in diabetics may require adjustment (5.4).
• Intracranial Hypertension: Exclude preexisting papilledema. May
develop
and is usually reversible after discontinuation or dose reduction (5.5).
• Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome –
especially
in adults): May occur frequently. Reduce dose as necessary (5.6).
• Hypopituitarism: Closely monitor other hormone replacement
therapies (5.7)
• Hypothyroidism: May first become evident or worsen (5.8).
• Slipped Capital Femoral Epiphysis: May develop. Evaluate children
with the
onset of a limp or hip/knee pain (5.9).
• Progression of Preexisting Scoliosis: May develop (5.10)
• Pancreatitis: Consider pancreatitis in patients with persistent severe
abdominal pain (5.14).
------------------------------ADVERSE REACTIONS-------------------------------
Other common somatropin-related adverse reactions include injection
site
reactions/rashes and lipoatrophy (6.1) and headaches (6.3).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1: May require
the
initiation of glucocorticoid replacement therapy. Patients treated with
glucocorticoid replacement for previously diagnosed hypoadrenalism
may
require an increase in their maintenance doses (7.1, 7.2).
• Glucocorticoid Replacement: Should be carefully adjusted (7.2)
• Cytochrome P450-Metabolized Drugs: Monitor carefully if used with
somatropin (7.3)
• Oral Estrogen: Larger doses of somatropin may be required in
women (7.4)
• Insulin and/or Oral/Injectable Hypoglycemic Agents: May require
adjustment (7.5)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 03/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Pediatric Patients
1.2 Adult Patients
2
DOSAGE AND ADMINISTRATION
2.1 Dosing of Pediatric Patients
2.2 Dosing of Adult Patients
2.3 Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1 Acute Critical Illness
4.2 Prader-Willi Syndrome in Children
4.3 Active Malignancy
4.4 Diabetic Retinopathy
4.5 Closed Epiphyses
4.6 Hypersensitivity
5
WARNINGS AND PRECAUTIONS
5.1 Acute Critical Illness
5.2 Prader-Willi Syndrome in Children
5.3 Neoplasms
5.4 Impaired Glucose Tolerance and Diabetes Mellitus
5.5 Intracranial Hypertension
5.6 Fluid Retention
5.7 Hypopituitarism
5.8 Hypothyroidism
5.9 Slipped Capital Femoral Epiphysis in Pediatric Patients
5.10 Progression of Preexisting Scoliosis in Pediatric Patients
5.11 Otitis Media and Cardiovascular Disorders in Turner Syndrome
5.12 Local and Systemic Reactions
5.13 Laboratory Tests
5.14 Pancreatitis
6
ADVERSE REACTIONS
6.1 Most Serious and/or Most Frequently Observed Adverse Reactions
6.2 Clinical Trials Experience
6.3 Post-Marketing Experience
Reference ID: 2946504
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
DRUG INTERACTIONS
12.1 Mechanism of Action
7.1 11 β-Hydroxysteroid Dehydrogenase Type 1
12.2 Pharmacodynamics
7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic
12.3 Pharmacokinetics
Glucocortioid Treatment
13 NONCLINICAL TOXICOLOGY
7.3 Cytochrome P450- Metabolized Drugs
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
7.4 Oral Estrogen
14 CLINICAL STUDIES
7.5 Insulin and/or Oral/Injectable Hypoglycemic Agents
14.1 Adult Growth Hormone Deficiency
8
USE IN SPECIFIC POPULATIONS
14.2 Prader-Willi Syndrome
8.1 Pregnancy
14.3 SGA
8.3 Nursing Mothers
14.4 Turner Syndrome
8.5 Geriatric Use
14.5 Idiopathic Short Stature
10 OVERDOSAGE
16 HOW SUPPLIED/STORAGE AND HANDLING
11 DESCRIPTION
17 PATIENT COUNSELING INFORMATION
12 CLINICAL PHARMACOLOGY
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Pediatric Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of
endogenous growth hormone.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome
(PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing (see CONTRAINDICATIONS).
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to
manifest catch-up growth by age 2 years.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure associated with Turner syndrome.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short
stature, defined by height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in
pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or
treated by other means.
1.2
Adult Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who
meet either of the following two criteria:
Adult Onset (AO): Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of
pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood Onset (CO): Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of
somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. According to current standards, confirmation of the diagnosis of adult
growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary
hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
2
DOSAGE AND ADMINISTRATION
The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN must not be injected intravenously.
Therapy with GENOTROPIN should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure
associated with growth hormone deficiency (GHD), Prader-Willi syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA) or
Idiopathic Short Stature (ISS), and adult patients with either childhood onset or adult onset GHD.
2.1
Dosing of Pediatric Patients
General Pediatric Dosing Information
The GENOTROPIN dosage and administration schedule should be individualized based on the growth response of each patient.
Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during
the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism,
undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).
Treatment with GENOTROPIN for short stature should be discontinued when the epiphyses are fused.
Pediatric Growth Hormone Deficiency (GHD)
Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.
Prader-Willi Syndrome
Generally, a dose of 0.24 mg/kg body weight/week is recommended.
Turner Syndrome
Generally, a dose of 0.33 mg/kg body weight/week is recommended.
2
Reference ID: 2946504
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Idiopathic Short Stature
Generally, a dose up to 0.47 mg/kg body weight/week is recommended.
Small for Gestational Agea
Generally, a dose of up to 0.48 mg/kg body weight/week is recommended.
a Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.48 mg/kg/week), especially in very short children (i.e., height SDS <–3),
and/or older/ pubertal children, and that a reduction in dosage (e.g., gradually towards 0.24 mg/kg/week) should be considered if substantial catch-up growth is
observed during the first few years of therapy. On the other hand, in younger SGA children (e.g., approximately <4 years) (who respond the best in general) with less
severe short stature (i.e., baseline height SDS values between -2 and -3), consideration should be given to initiating treatment at a lower dose (e.g., 0.24 mg/kg/week),
and titrating the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and adjust the somatropin dose as necessary.
2.2
Dosing of Adult Patients
Adult Growth Hormone Deficiency (GHD)
Either of two approaches to GENOTROPIN dosing may be followed: a non-weight based regimen or a weight based regimen.
Non-weight based — based on published consensus guidelines, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without
consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient
requirements based on the clinical response and serum insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of
adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and
between male and female patients.
Weight based — based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment is not more than 0.04
mg/kg/week. The dose may be increased according to individual patient requirements to not more than 0.08 mg/kg/week at 4–8 week intervals. Clinical response, side
effects, and determination of age- and gender-adjusted serum IGF-I concentrations should be used as guidance in dose titration.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger
individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment
goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
2.3
Preparation and Administration
The GENOTROPIN 5 and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green tip
to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
GENOTROPIN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.
GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.
3
DOSAGE FORMS AND STRENGTHS
GENOTROPIN lyophilized powder:
•
5 mg two-chamber cartridge (green tip, with preservative)
concentration of 5 mg/mL
•
12 mg two-chamber cartridge (purple tip, with preservative)
concentration of 12 mg/mL
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)
•
0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg
4
CONTRAINDICATIONS
4.1
Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery,
abdominal surgery or multiple accidental trauma, or those with acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult
patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses
5.3–8 mg/day) compared to those receiving placebo [see Warnings and Precautions (5.1)].
4.2
Prader-Willi Syndrome in Children
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe
respiratory impairment. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions (5.2)].
4.3
Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to
instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency may be an early sign
of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should
not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
4.4
Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
4.5
Closed Epiphyses
3
Reference ID: 2946504
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
4.6
Hypersensitivity
GENOTROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of
GENOTROPIN lyophilized powder contain m-cresol as a preservative. These products should not be used by patients with a known sensitivity to this preservative. The
GENOTROPIN MINIQUICK presentations are preservative-free (see HOW SUPPLIED). Localized reactions are the most common hypersensitivity reactions.
5
WARNINGS AND PRECAUTIONS
5.1
Acute Critical Illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those
with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4.1)]. The safety of continuing
somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the
potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk.
5.2
Prader-Willi Syndrome in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk
factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be
at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of
treatment with somatropin. If during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new
onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be
monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4.2)].
5.3
Neoplasms
Patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the
underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system
(CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients
treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm,
were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor
recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions.
5.4
Impaired Glucose Tolerance and Diabetes Mellitus
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose
tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. New-onset Type 2 diabetes mellitus has been reported. Therefore, glucose levels
should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or
a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during
somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral/injectable agents) may require adjustment when somatropin therapy is instituted in these
patients.
5.5 Intracranial Hypertension
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with
somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and
symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating
treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy
during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-
associated signs and symptoms have resolved. Patients with Turner syndrome and Prader-Willi syndrome may be at increased risk for the development of IH.
5.6
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent.
5.7
Hypopituitarism
Patients with hypopituitarism (multiple pituitary hormone deficiencies) should have their other hormonal replacement treatments closely monitored during somatropin
treatment.
5.8
Hypothyroidism
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome
have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central
(secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid
function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
5.9
Slipped Capital Femoral Epiphyses in Pediatric Patients
Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing
rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.
5.10 Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are
treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal
abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi
syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
5.11 Otitis Media and Cardiovascular Disorders in Turner Syndrome
Reference ID: 2946504
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing
disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be
monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
5.12 Local and Systemic Reactions
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site
[see Dosage and Administration. (2.3) ].
As with any protein, local or systemic allergic reactions may occur. Parents/Patients should be informed that such reactions are possible and that prompt medical
attention should be sought if allergic reactions occur.
5.13 Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.
5.14
Pancreatitis
Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children
compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis
should be considered in any somatropin–treated patient, especially a child, who develops persistent severe abdominal pain.
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most serious
b and/or most frequently observed
a adverse reactions during treatment with somatropin:
•
b Sudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep
apnea and unidentified respiratory infection [see Contraindications (4.2) and Warnings andPrecautions (5.2)]
•
b Intracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a
first neoplasm and somatropin [see Contraindications (4.3) and Warnings and Precautions (5.3)]
•
a,
b Glucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see
Warnings and Precautions (5.4)]
•
b Intracranial hypertension [see Warnings and Precautions (5.5)]
•
b Significant diabetic retinopathy [see Contraindications (4.4)]
•
b Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.8)]
•
b Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.9)]
•
aFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see
Warnings and Precautions (5.6)]
•
aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.7)]
•
aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings andPrecautions (5.11)]
•
b Pancreatitis [see Warnings and Precautions (5.14)]
6.2
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation
cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse
reaction rates observed in practice.
Clinical Trials in children with GHD
In clinical studies with GENOTROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning
associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild
hyperglycemia.
Clinical Trials in PWS
In two clinical studies with GENOTROPIN in pediatric patients with Prader-Willi syndrome, the following drug-related events were reported: edema, aggressiveness,
arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.
Clinical Trials in children with SGA
In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, the following clinically significant events were reported: mild
transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several
patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Anti-hGH antibodies were not detected in any
of the patients treated with GENOTROPIN.
Clinical Trials in children with Turner Syndrome
In two clinical studies with GENOTROPIN in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses
(influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint
pain.
Clinical Trials in children with Idiopathic Short Stature
In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract
infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies,
during Genotropin treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as
follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one
measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.
Clinical Trials in adults with GHD
In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including
peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during
therapy, and tended to be transient and/or responsive to dosage reduction.
Reference ID: 2946504
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Event
Double
Placebo
0–6 mo.
n = 572
% Patients
Blind Phase
GENOTROPIN
0–6 mo.
n = 573
% Patients
6–12 mo.
n = 504
% Patients
Open Label Phase
GENOTROPI
12–18 mo.
n = 63
% Patients
N
18–24 mo.
n = 60
% Patients
Swelling, peripheral
5.1
17.5*
5.6
0
1.7
Arthralgia
4.2
17.3*
6.9
6.3
3.3
Upper respiratory infection
14.5
15.5
13.1
15.9
13.3
Pain, extremities
5.9
14.7*
6.7
1.6
3.3
Edema, peripheral
2.6
10.8*
3.0
0
0
Paresthesia
1.9
9.6*
2.2
3.2
0
Headache
7.7
9.9
6.2
0
0
Stiffness of extremities
1.6
7.9*
2.4
1.6
0
Fatigue
3.8
5.8
4.6
6.3
1.7
Myalgia
1.6
4.9*
2.0
4.8
6.7
Back pain
4.4
2.8
3.4
4.8
5.0
*
Increased significantly when compared to placebo, P≤.025: Fisher´s Exact Test (one-sided)
Table 1 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also
presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.
Table 1
Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of
GENOTROPIN and Placebo, Grouped by Duration of Treatment
n
= number of patients receiving treatment during the indicated period.
% = percentage of patients who reported the event during the indicated period.
Post-Trial Extension Studies in Adults
In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had
predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving
GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other
adverse events that have been reported include generalized edema and hypoesthesia.
Anti-hGH Antibodies
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the
assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of
antibodies to GENOTROPIN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities
lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater
than 2 mg/mL, interference with the growth response was observed.
In 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN or other growth
hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously
treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining
413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There
was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.
Periplasmic Escherichia coli Peptides
Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients
treated with GENOTROPIN, but these appear to be of no clinical significance.
6.3
Post-Marketing Experience
Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure. The adverse events reported during post-marketing surveillance do not differ from those
listed/discussed above in Sections 6.1 and 6.2 in children and adults.
Leukemia has been reported in a small number of GHD children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is
uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation
therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia.
The risk for children with GHD, if any, remains to be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].
The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults),
gynecomastia (children), and pancreatitis (children and adults, see Warnings and Precautions [5.14]).
New-onset type 2 diabetes mellitus has been reported.
7
DRUG INTERACTIONS
7.1 11 β-Hydroxysteroid Dehydrogenase Type 1
Reference ID: 2946504
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and
adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol.
Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed
central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated
with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of
somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active
metabolites is dependent on the activity of 11βHSD-1.
7.2
Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocortioid Treatment
Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore,
glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both
hypoadrenalism and an inhibitory effect on growth.
7.3
Cytochrome P450-Metabolized Drugs
Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that
somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids,
anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450
liver enzymes. However, formal drug interaction studies have not been conducted.
7.4
Oral Estrogen
In patients on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see Dosage and Administration (2.2)].
7.5
Insulin and/or Oral/Injectable Hypoglycemic Agents
In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated
[see Warnings and Precautions (5.4)]).
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. Reproduction studies carried out with GENOTROPIN at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3
mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively,
based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving SC doses during gametogenesis and up to 7
days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in
males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day
(approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted.
In perinatal and postnatal studies in rats, GENOTROPIN doses of 0.3, 1, and 3.3 mg/kg/day produced growth-promoting effects in the dams but not in the fetuses.
Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on
gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offsprings due to GENOTROPIN. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
8.3
Nursing Mothers
There have been no studies conducted with GENOTROPIN in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when GENOTROPIN is administered to a nursing woman.
8.5
Geriatric Use
The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the
action of GENOTROPIN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for
older patients [see Dosage and Administration (2.2)].
10
OVERDOSAGE
Short-Term
Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid
retention.
Long-Term
Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [see Dosage
and Administration (2)].
11
DESCRIPTION
GENOTROPIN lyophilized powder contains somatropin [rDNA origin], which is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues
and a molecular weight of 22,124 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin).
GENOTROPIN is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone. GENOTROPIN is a sterile
white lyophilized powder intended for subcutaneous injection.
GENOTROPIN 5 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 5.8 mg, glycine 2.2 mg, mannitol 1.8 mg, sodium
dihydrogen phosphate anhydrous 0.32 mg, and disodium phosphate anhydrous 0.31 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and mannitol 45
mg in 1.14 mL water for injection. The GENOTROPIN 5 mg two-chambered cartridge contains 5.8 mg of somatropin. The reconstituted concentration is 5mg/ml . The
cartridge contains overfill to allow for delivery of 1ml containing the stated amount of GENOTROPIN – 5 mg.
GENOTROPIN 12mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 13.8 mg, glycine 2.3 mg, mannitol 14.0 mg,
sodium dihydrogen phosphate anhydrous 0.47 mg, and disodium phosphate anhydrous 0.46 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and
7
Reference ID: 2946504
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mannitol 32 mg in 1.13 mL water for injection. The GENOTROPIN 12 mg two-chambered cartridge contains 13.8 mg of somatropin. The reconstituted concentration is
12 mg/ml . The cartridge contains overfill to allow for delivery of 1ml containing the stated amount of GENOTROPIN – 12 mg.
GENOTROPIN MINIQUICK® is dispensed as a single-use syringe device containing a two-chamber cartridge. GENOTROPIN MINIQUICK is available as individual
doses of 0.2 mg to 2.0 mg in 0.2 mg increments. The front chamber contains recombinant somatropin 0.22 to 2.2 mg, glycine 0.23 mg, mannitol 1.14 mg, sodium
dihydrogen phosphate 0.05 mg, and disodium phosphate anhydrous 0.027 mg; the rear chamber contains mannitol 12.6 mg in water for injection 0.275 mL. The
reconstituted GENOTROPIN MINIQUICK two-chamber cartridge contains overfill to allow for delivery of 0.25 ml containing the stated amount of GENOTROPIN.
GENOTROPIN is a highly purified preparation. The reconstituted recombinant somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of
approximately 6.7. The concentration of the reconstituted solution varies by strength and presentation (see HOW SUPPLIED).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
In vitro, preclinical, and clinical tests have demonstrated that GENOTROPIN lyophilized powder is therapeutically equivalent to human growth hormone of pituitary
origin and achieves similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), have Prader-Willi syndrome
(PWS), were born small for gestational age (SGA), have Turner syndrome (TS), or have Idiopathic short stature (ISS), treatment with GENOTROPIN stimulates linear
growth. In patients with GHD or PWS, treatment with GENOTROPIN also normalizes concentrations of IGF-I (Insulin-like Growth Factor-I/Somatomedin C). In
adults with GHD, treatment with GENOTROPIN results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid
metabolism, and normalization of IGF-I concentrations.
In addition, the following actions have been demonstrated for GENOTROPIN and/or somatropin.
12.2
Pharmacodynamics
Tissue Growth
A. Skeletal Growth: GENOTROPIN stimulates skeletal growth in pediatric patients with GHD, PWS, SGA, TS, or ISS. The measurable increase in body
length after administration of GENOTROPIN results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role
in skeletal growth, are generally low in the serum of pediatric patients with GHD, PWS, or SGA, but tend to increase during treatment with GENOTROPIN.
Elevations in mean serum alkaline phosphatase concentration are also seen.
B.
Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as
compared with the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.
Protein Metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum
urea nitrogen, follows the initiation of therapy with GENOTROPIN.
Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN. Large doses of growth
hormone may impair glucose tolerance.
Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after
therapy with GENOTROPIN. Serum calcium is not significantly altered by GENOTROPIN. Growth hormone could increase calciuria.
Body Composition
Adult GHD patients treated with GENOTROPIN at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass
and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of GENOTROPIN is to modify body
composition, an effect that is maintained with continued treatment.
12.3
Pharmacokinetics
Absorption
Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically
available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been
observed in healthy adult male subjects.
In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35%
greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL,
respectively.
In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN.
The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.
Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between
injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.
There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.
Distribution
Reference ID: 2946504
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The mean volume of distribution of GENOTROPIN following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.
Metabolism
The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are
returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered
GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.
Excretion
The mean clearance of subcutaneously administered GENOTROPIN in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.
Special Populations
Pediatric: The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.
Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and
females.
Race: No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.
Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN in these patient populations.
Table 2
Mean SC Pharmacokinetic Parameters in Adult GHD Patients
Bioavaila
bility
(%)
(N=15)
Tmax
(hours)
(N=16)
CL/F
(L/hr x
kg)
(N=16)
Vss/F
(L/kg)
(N=16)
T1/2
(hours)
(N=16)
Mean
(± SD)
80.5
*
5.9
(± 1.65)
0.3
(± 0.11)
1.3
(± 0.80)
3.0
(± 1.44)
95% CI
70.5 –
92.1
5.0 – 6.7
0.2 – 0.4
0.9 – 1.8
2.2 – 3.7
Tmax = time of maximum plasma concentration T 1/2 = terminal half-life
CL/F = plasma clearance
SD = standard deviation
Vss/F = volume of distribution
CI = confidence interval
* The absolute bioavailability was estimated under the assumption that the
log-transformed data follow a normal distribution. The mean and standard
deviation of the log-transformed data were mean = 0.22 (± 0.241).
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with GENOTROPIN. No potential mutagenicity of GENOTROPIN was revealed in a battery of tests including
induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact
animals (bone marrow cells in rats). See PREGNANCY section for effect on fertility.
14
CLINICAL STUDIES
14.1
Adult Growth Hormone Deficiency (GHD)
GENOTROPIN lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6
month double-blind treatment period, during which 85 patients received GENOTROPIN and 87 patients received placebo, followed by an open-label treatment period
in which participating patients received GENOTROPIN for up to a total of 24 months. GENOTROPIN was administered as a daily SC injection at a dose of 0.04
mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.
Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving GENOTROPIN as compared with the
placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body
composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline
values after 12 months of treatment.
14.2
Prader-Willi Syndrome (PWS)
The safety and efficacy of GENOTROPIN in the treatment of pediatric patients with Prader-Willi syndrome (PWS) were evaluated in two randomized, open-label,
controlled clinical trials. Patients received either GENOTROPIN or no treatment for the first year of the studies, while all patients received GENOTROPIN during the
second year. GENOTROPIN was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group
received GENOTROPIN at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.48
mg/kg/week. In Study 2, the treatment group received GENOTROPIN at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group
received GENOTROPIN at a dose of 0.36 mg/kg/week.
Patients who received GENOTROPIN showed significant increases in linear growth during the first year of study, compared with patients who received no treatment
(see Table 3). Linear growth continued to increase in the second year, when both groups received treatment with GENOTROPIN.
Reference ID: 2946504
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3
Efficacy of GENOTROPIN in Pediatric Patients with Prader-Willi
Syndrome (Mean ± SD)
Study 1
Study 2
GENOTR
OPIN
(0.24
mg/kg/we
ek)
n=15
Untreated
Control
n=12
GENOTR
OPIN
(0.36
mg/kg/we
ek)
n=7
Untreated
Control
n=9
Linear growth
(cm)
Baseline height
112.7 ±
14.9
109.5 ±
12.0
120.3 ±
17.5
120.5 ±
11.2
Growth from
months 0 to 12
11.6* ± 2.3
5.0 ± 1.2
10.7* ± 2.3
4.3 ± 1.5
Height
Standard
Deviation Score
(SDS) for age
Baseline SDS
-1.6 ± 1.3
-1.8 ± 1.5
-2.6 ± 1.7
-2.1 ± 1.4
SDS at 12
months
-0.5† ± 1.3
-1.9 ± 1.4
-1.4† ± 1.5
-2.2 ± 1.4
*
p ≤ 0.001
†
p ≤ 0.002 (when comparing SDS change at 12 months)
Changes in body composition were also observed in the patients receiving GENOTROPIN (see Table 4). These changes included a decrease in the amount of fat mass,
and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no
treatment. Treatment with GENOTROPIN did not accelerate bone age, compared with patients who received no treatment.
Table 4
Effect of GENOTROPIN on Body Composition
in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
GENOTROPIN
n=14
Untreated Control
n=10
Fat mass (kg)
Baseline
12.3 ± 6.8
9.4 ± 4.9
Change from
months 0 to 12
-0.9* ± 2.2
2.3 ± 2.4
Lean body mass
(kg)
Baseline
15.6 ± 5.7
14.3 ± 4.0
Change from
months 0 to 12
4.7* ± 1.9
0.7 ± 2.4
Lean body
mass/Fat mass
Baseline
1.4 ± 0.4
1.8 ± 0.8
Change from
months 0 to 12
1.0* ± 1.4
-0.1 ± 0.6
Body weight (kg) †
Baseline
27.2 ± 12.0
23.2 ± 7.0
Change from
months 0 to 12
3.7‡ ± 2.0
3.5 ± 1.9
Reference ID: 2946504
10
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For current labeling information, please visit https://www.fda.gov/drugsatfda
*
p < 0.005
†
n=15 for the group receiving GENOTROPIN; n=12 for the
Control group
‡
n.s.
14.3
SGA
Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2
The safety and efficacy of GENOTROPIN in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled
clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either GENOTROPIN (two doses per study, most
often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received
GENOTROPIN.
Patients who received any dose of GENOTROPIN showed significant increases in growth during the first 24 months of study, compared with patients who received no
treatment (see Table 5). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children
treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown).
Table 5
Efficacy of GENOTROPIN in Children Born Small for Gestational Age
(Mean ± SD)
GENOTRO
PIN
(0.24
mg/kg/week)
n=76
GENOTRO
PIN
(0.48
mg/kg/week)
n=93
Untreated
Control
n=40
Height Standard
Deviation Score (SDS)
Baseline SDS
-3.2 ± 0.8
-3.4 ± 1.0
-3.1 ± 0.9
SDS at 24 months
-2.0 ± 0.8
-1.7 ± 1.0
-2.9 ± 0.9
Change in SDS from
baseline to month 24
1.2* ± 0.5
1.7*† ± 0.6
0.1 ± 0.3
*
p = 0.0001 vs Untreated Control group
†
p = 0.0001 vs group treated with GENOTROPIN 0.24 mg/kg/week
14.4
Turner Syndrome
Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of GENOTROPIN in Turner syndrome patients with short stature.
Turner syndrome patients were treated with GENOTROPIN alone or GENOTROPIN plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38
patients were treated with GENOTROPIN alone in the two studies. In Study 055, 22 patients were treated for 12 months, and in Study 092, 16 patients were treated for
12 months. Patients received GENOTROPIN at a dose between 0.13 to 0.33 mg/kg/week.
SDS for height velocity and height are expressed using either the Tanner (Study 055) or Sempé (Study 092) standards for age-matched normal children as well as the
Ranke standard (both studies) for age-matched, untreated Turner syndrome patients. As seen in Table 5, height velocity SDS and height SDS values were smaller at
baseline and after treatment with GENOTROPIN when the normative standards were utilized as opposed to the Turner syndrome standard.
Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and
height SDS) after treatment with GENOTROPIN (see Table 6). The linear growth response was greater in Study 055 wherein patients were treated with a larger dose of
GENOTROPIN.
Reference ID: 2946504
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6
Growth Parameters (mean ± SD) after 12 Months of Treatment with
GENOTROPIN
in Pediatric Patients with Turner Syndrome in Two Open Label Studies
GENOTROPIN
0.33 mg/kg/week
Study 055^ n=22
GENOTROPIN
0.13–0.23 mg/kg/week
Study 092# n=16
Height Velocity (cm/yr)
Baseline
4.1 ± 1.5
3.9 ± 1.0
Month 12
7.8 ± 1.6
6.1 ± 0.9
Change from baseline
(95% CI)
3.7 (3.0, 4.3)
2.2 (1.5, 2.9)
Height Velocity SDS
(Tanner^/Sempé#
Standards)
(n=20)
Baseline
-2.3 ± 1.4
-1.6 ± 0.6
Month 12
2.2 ± 2.3
0.7 ± 1.3
Change from baseline
(95% CI)
4.6 (3.5, 5.6)
2.2 (1.4, 3.0)
Height Velocity SDS
(Ranke Standard)
Baseline
-0.1 ± 1.2
-0.4 ± 0.6
Month 12
4.2 ± 1.2
2.3 ± 1.2
Change from baseline
(95% CI)
4.3 (3.5, 5.0)
2.7 (1.8, 3.5)
Height SDS
(Tanner^/Sempé#
Standards)
Baseline
-3.1 ± 1.0
-3.2 ± 1.0
Month 12
-2.7 ± 1.1
-2.9 ± 1.0
Change from baseline
(95% CI)
0.4 (0.3, 0.6)
0.3 (0.1, 0.4)
Height SDS
(Ranke Standard)
Baseline
-0.2 ± 0.8
-0.3 ± 0.8
Month 12
0.6 ± 0.9
0.1 ± 0.8
Change from baseline
(95% CI)
0.8 (0.7, 0.9)
0.5 (0.4, 0.5)
SDS = Standard Deviation Score
Ranke standard based on age-matched, untreated Turner syndrome patients
Tanner^/Sempé# standards based on age-matched normal children
p<0.05, for all changes from baseline
14.5
Idiopathic Short Stature
The long-term efficacy and safety of GENOTROPIN in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that
enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short
stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to
Genotropin or observation only and followed to final height. Two Genotropin doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47
mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD):
chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were
treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 7. GENOTROPIN therapy improved final height in
ISS children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to
untreated control subjects. A height gain of 1 SDS was observed in 10 % of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects
receiving 0.47 mg/kg/week
Table 7. Final height SDS results for pre-pubertal patients with ISS*
Untreated
(n=30)
GEN 0.033
(n=30)
GEN 0.067
(n=42)
GEN 0.033 vs.
Untreated
(95% CI)
GEN 0.067 vs.
Untreated
(95% CI)
Baseline height SDS
Final height SDS minus
baseline
Baseline predicted ht
Final height SDS minus
baseline predicted final
height SDS
0.41 (0.58)
0.23 (0.66)
0.95 (0.75)
0.73 (0.63)
1.36 (0.64)
1.05 (0.83)
+0.53 (0.20, 0.87)
p=0.0022
+0.60 (0.09, 1.11)
p=0.0217
+0.94 (0.63, 1.26)
p<0.0001
+0.90 (0.42, 1.39)
p=0.0004
*Mean (SD) are observed values.
Reference ID: 2946504
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
**Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS)
.
16
HOW SUPPLIED/STORAGE AND HANDLING
GENOTROPIN lyophilized powder is available in the following packages:
5 mg two-chamber cartridge (with preservative)
concentration of 5 mg/mL
For use with the GENOTROPIN PEN® 5 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER™ Growth Hormone Reconstitution Device.
Package of 1 NDC 0013-2626-81
12 mg two-chamber cartridge (with preservative)
concentration of 12 mg/mL
For use with the GENOTROPIN PEN 12 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER Growth Hormone Reconstitution Device.
Package of 1 NDC 0013-2646-81
GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)
After reconstitution, each GENOTROPIN MINIQUICK delivers 0.25 mL, regardless of strength. Available in the following strengths, each in a package of 7:
0.2 mg
NDC 0013-2649-02
0.4 mg
NDC 0013-2650-02
0.6 mg
NDC 0013-2651-02
0.8 mg
NDC 0013-2652-02
1.0 mg
NDC 0013-2653-02
1.2 mg
NDC 0013-2654-02
1.4 mg
NDC 0013-2655-02
1.6 mg
NDC 0013-2656-02
1.8 mg
NDC 0013-2657-02
2.0 mg
NDC 0013-2658-02
Storage and Handling
Except as noted below, store GENOTROPIN lyophilized powder under refrigeration at 2° to 8°C (36° to 46°F). Do not freeze. Protect from light.
The 5 mg and 12 mg cartridges of GENOTROPIN contain a diluent with a preservative. Thus, after reconstitution, they may be stored under refrigeration for up to 28
days.
The GENOTROPIN MINIQUICK Growth Hormone Delivery Device should be refrigerated prior to dispensing, but may be stored at or below 25°C (77°F) for up to
three months after dispensing. The diluent has no preservative. After reconstitution, the GENOTROPIN MINIQUICK may be stored under refrigeration for up to 24
hours before use. The GENOTROPIN MINIQUICK should be used only once and then discarded.
17
PATIENT COUNSELING INFORMATION
Patients being treated with GENOTROPIN (and/or their parents) should be informed about the potential benefits and risks associated with GENOTROPIN treatment [in
particular, see Adverse Reactions (6.1) for a listing of the most serious and/or most frequently observed adverse reactions associated with somatropin treatment in
children and adults]. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects.
Patients and caregivers who will administer GENOTROPIN should receive appropriate training and instruction on the proper use of GENOTROPIN from the physician
or other suitably qualified health care professional. A puncture-resistant container for the disposal of used syringes and needles should be strongly recommended.
Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles and syringes. This information
is intended to aid in the safe and effective administration of the medication.
GENOTROPIN is supplied in a two-chamber cartridge, with the lyophilized powder in the front chamber and a diluent in the rear chamber. A reconstitution device is
used to mix the diluent and powder. The two-chamber cartridge contains overfill in order to deliver the stated amount of GENOTROPIN
The GENOTROPIN 5 mg and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green
tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Follow the directions for reconstitution provided with each device. Do not shake; shaking may cause denaturation of the active ingredient.
Please see accompanying directions for use of the reconstitution and/or delivery device.
Reference ID: 2946504
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
Vetter Pharma-Fertigung GmbH & Co. KG
Ravensburg, Germany
Or
Vetter Pharma-Fertigung GmbH & Co. KG
Langenargen, Germany
Rx only company logo
LAB-0222-17.0
Revised March 2011
Reference ID: 2946504
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:24.517036 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020280s071lbl.pdf', 'application_number': 20280, 'submission_type': 'SUPPL ', 'submission_number': 71} |
3,209 |
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CREON
safely and effectively. See full prescribing information for CREON.
CREON (pancrelipase) delayed-release capsules
Initial U.S. Approval: 2009
---------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage, Chronic Pancreatitis, Pancreatectomy (1)
4/2010
Dosage and Administration, Chronic Pancreatitis or
Pancreatectomy (2.2)
4/2010
---------------------------INDICATIONS AND USAGE-----------------------------
CREON is a combination of porcine-derived lipases, proteases, and amylases
indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. (1)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
CREON is not interchangeable with any other pancrelipase product. (2.1)
Do not crush or chew capsules and capsule contents. For infants or patients
unable to swallow intact capsules, the contents may be sprinkled on soft acidic
food, e.g., applesauce. (2.1) Dosing should not exceed the recommended
maximum dosage set forth by the Cystic Fibrosis Foundation Consensus
Conferences Guidelines. (2.2)
Infants (up to 12 months)
● Prior to each feeding, give 2,000 to 4,000 lipase units per 120 mL of
formula or breast feeding. (2.1)
● Do not mix CREON capsule contents directly into formula or breast milk
prior to administration. (2.1)
Children Older than 12 Months and Younger than 4 Years
● Begin with 1,000 lipase units/kg of body weight per meal for children less
than age 4 years to a maximum of 2,500 lipase units/kg of body weight per
meal (or less than or equal to 10,000 lipase units/kg of body weight per
day), or less than 4,000 lipase units/g fat ingested per day. (2.2)
Children 4 Years and Older and Adults
● Begin with 500 lipase units/kg of body weight per meal for those older than
age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal
(or less than or equal to 10,000 lipase units/kg of body weight per day), or
less than 4,000 lipase units/g fat ingested per day. (2.2)
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or
Pancreatectomy
● Individualize dosage based on clinical symptoms, the degree of steatorrhea
present and the fat content of the diet. (2.2)
2
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Administration
2.2
Dosage
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
5.2
Potential for Irritation to Oral Mucosa
5.3
Potential for Risk of Hyperuricemia
5.4
Potential Viral Exposure from the Product Source
5.5 Allergic Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
----------------------DOSAGE FORMS AND STRENGTHS-----------------
● Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000
USP units of amylase (3)
● Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000
USP units of amylase (3)
● Capsules: 24,000 USP units of lipase; 76,000 USP units of protease;
120,000 USP units of amylase (3)
----------------------------CONTRAINDICATIONS----------------------------
None (4)
-----------------------WARNINGS AND PRECAUTIONS---------------------
● Fibrosing colonopathy is associated with high-dose use of pancreatic
enzyme replacement in the treatment of cystic fibrosis patients. Exercise
caution when doses of CREON exceed 2,500 lipase units/kg of body
weight per meal (or greater than 10,000 lipase units/kg of body weight per
day). (5.1)
● To avoid irritation of oral mucosa, do not chew CREON or retain in the
mouth. (5.2)
● Exercise caution when prescribing CREON to patients with gout, renal
impairment, or hyperuricemia. (5.3)
● There is theoretical risk of viral transmission with all pancreatic enzyme
products including CREON. (5.4)
● Exercise caution when administering pancrelipase to a patient with a
known allergy to proteins of porcine origin. (5.5)
----------------------------ADVERSE REACTIONS----------------------------
● Adverse reactions occurring in at least 2 cystic fibrosis patients (greater
than or equal to 4%) receiving CREON are vomiting, dizziness, and
cough. (6.1)
● Adverse reactions that occurred in at least 1 chronic pancreatitis or
pancreatectomy patient (greater than or equal to 4%) receiving CREON are
hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence,
frequent bowel movements, and nasopharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Abbott
Laboratories at 1-800-241-1643 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: August 2010
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Cystic Fibrosis
14.2 Chronic Pancreatitis or Pancreatectomy
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1 Dosing and Administration
17.2 Fibrosing Colonopathy
17.3 Allergic Reactions
17.4 Pregnancy and Breast Feeding
*Sections or subsections omitted from the full prescribing information are not
listed
Page 1 of 10
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.
2
DOSAGE AND ADMINISTRATION
CREON is not interchangeable with other pancrelipase products.
CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually
increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea
present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and
Administration (2.2) and Warnings and Precautions (5.1)].
2.1
Administration
Infants (up to 12 months)
CREON should be administered to infants immediately prior to each feeding, using a dosage of 2,000 to
4,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered
directly to the mouth or with a small amount of applesauce. Administration should be followed by breast milk or
formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish
efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid
irritation of the oral mucosa.
Children and Adults
CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents
should not be crushed or chewed. Capsules should be swallowed whole.
For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the
contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room
temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and
followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in
the mouth.
2.2
Dosage
Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic
Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the
recommendations of the Conferences provided in the following paragraphs. Patients may be dosed on a fat
ingestion-based or actual body weight-based dosing scheme.
Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency
due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
Infants (up to 12 months)
Infants may be given 2,000 to 4,000 lipase units per 120 mL of formula or per breast-feeding. Do not mix
CREON capsule contents directly into formula or breast milk prior to administration [see Dosage and
Administration (2.1)].
Children Older than 12 Months and Younger than 4 Years
Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age
4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase
units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Children 4 Years and Older and Adults
Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age
4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase
units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
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Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
The total daily dose should reflect approximately three meals plus two or three snacks per day.
Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients
because they weigh more but tend to ingest less fat per kilogram of body weight.
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy
The initial starting dose and increases in the dose per meal should be individualized based on clinical
symptoms, the degree of steatorrhea present, and the fat content of the diet.
In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at
least 100 g of fat per day [see Clinical Studies (14.2)]. Lower starting doses recommended in the literature are
consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the
Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose
for an individualized full meal should be given with each snack.
Limitations on Dosing
Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation
Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased
by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great
inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may
require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal,
further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than
10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be
effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses
greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of
fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently
receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either
immediately decreased or titrated downward to a lower range.
3
DOSAGE FORMS AND STRENGTHS
The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase. Each CREON capsule strength contains the specified
amounts of lipase, protease, and amylase as follows:
● 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have an
orange opaque cap with imprint “CREON 1206” and a blue opaque body.
● 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a
brown opaque cap with imprint “CREON 1212” and a colorless transparent body.
● 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have
an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 5, 6
Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic
enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic
fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in
children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some
patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing
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colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than
2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less
than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.1)].
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of
body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat
measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than
6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or
titrated downward to a lower range.
5.2
Potential for Irritation to Oral Mucosa
Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or
chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating
resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and
Administration (2.2) and Patient Counseling Information (17.1)]. For patients who are unable to swallow intact
capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a
pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed
immediately and followed with water or juice to ensure complete ingestion.
5.3
Potential for Risk of Hyperuricemia
Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or
hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
5.4
Potential Viral Exposure from the Product Source
CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that
CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during
manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission
of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses
that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness
associated with the use of porcine pancreatic extracts have been reported.
5.5
Allergic Reactions
Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of
porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been
reported with other pancreatic enzyme products with different formulations of the same active ingredient
(pancrelipase). The risks and benefits of continued CREON treatment in patients with severe allergy should be taken
into consideration with the overall clinical needs of the patient.
6
ADVERSE REACTIONS
The most serious adverse reactions reported with different pancreatic enzyme products of the same active
ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and
allergic reactions [see Warnings and Precautions (5)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The short-term safety of CREON was assessed in clinical trials conducted in 103 patients with exocrine
pancreatic insufficiency (EPI): 49 patients with EPI due to cystic fibrosis (CF) and 25 patients with EPI due to
chronic pancreatitis or pancreatectomy were treated with CREON.
Cystic Fibrosis
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies of 49 patients, ages 7
to 43 years, with EPI due to CF. Study 1 included 32 patients ages 12 to 43 years and Study 2 included 17 patients
ages 7 to 11 years. In these studies, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat
Page 4 of 10
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ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment
for an additional 5 to 6 days. The mean exposure to CREON during these studies was 5 days.
In Study 1, one patient experienced duodenitis and gastritis of moderate severity 16 days after completing
treatment with CREON. Transient neutropenia without clinical sequelae was observed as an abnormal laboratory
finding in one patient receiving CREON and a macrolide antibiotic.
In Study 2, adverse reactions that occurred in at least 2 patients (greater than or equal to 12%) treated with
CREON were vomiting and headache. Vomiting occurred in 2 patients treated with CREON and did not occur in
patients treated with placebo; headache occurred in 2 patients treated with CREON and did not occur in patients
treated with placebo.
The most common adverse reactions (greater than or equal to 4%) were vomiting, dizziness, and cough.
Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 4%) treated with
CREON at a higher rate than with placebo in Studies 1 and 2.
Table 1: Adverse Reactions Occurring in at Least 2 Patients (greater than or equal to 4%) in Cystic Fibrosis
(Studies 1 and 2)
Adverse Reaction
CREON Capsules
n = 49 (%)
Placebo
n = 47 (%)
Vomiting
3 (6)
1 (2)
Dizziness
2 (4)
1 (2)
Cough
2 (4)
0
Chronic Pancreatitis or Pancreatectomy
Study 3 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages
32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo
treatment during a 5-day run-in period followed by an intervening period of up to 16 days of investigator-directed
treatment with no restrictions on pancreatic enzyme replacement therapy. Patients were then randomized to receive
CREON or matching placebo for 7 days. The CREON dose was 72,000 lipase units per main meal (3 main meals)
and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this study was 6.8 days in the 25
patients that received CREON.
The most common adverse reactions reported during the study were related to glycemic control and were
reported more commonly during CREON treatment than during placebo treatment.
Table 2 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 4%) treated
with CREON at a higher rate than with placebo in Study 3.
Table 2: Adverse Reactions in at least 1 Patient (greater than or equal to 4%) in Chronic Pancreatitis or
Pancreatectomy (Study 3)
Adverse Reaction
CREON Capsules
n = 25 (%)
Placebo
n = 29 (%)
Hyperglycemia
2 (8)
2 (7)
Hypoglycemia
1 (4)
1 (3)
Abdominal Pain
1 (4)
1 (3)
Abnormal Feces
1 (4)
0
Flatulence
1 (4)
0
Frequent Bowel Movements
1 (4)
0
Nasopharyngitis
1 (4)
0
6.2
Postmarketing Experience
Postmarketing data from this formulation of CREON have been available since 2009. The following adverse
reactions have been identified during post approval use of this formulation of CREON. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
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Gastrointestinal disorders (including abdominal pain, diarrhea, flatulence, constipation and nausea), skin
disorders (including pruritus, urticaria and rash), blurred vision, myalgia, muscle spasm, and asymptomatic
elevations of liver enzymes have been reported with this formulation of CREON.
Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active
ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to
cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has
been described in the medical literature. The most serious adverse reactions included fibrosing colonopathy, distal
intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions
including anaphylaxis, asthma, hives, and pruritus.
7
DRUG INTERACTIONS
No drug interactions have been identified. No formal interaction studies have been conducted.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic effects
Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not
known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant
woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal
maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with
adverse pregnancy outcomes.
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when CREON is administered to a nursing woman. The risk and benefit of
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing
mother with exocrine pancreatic insufficiency.
8.4
Pediatric Use
The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo-
controlled, crossover studies of 49 patients with exocrine pancreatic insufficiency due to cystic fibrosis, 25 of whom
were pediatric patients, Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included 17
children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar to
adult patients [see Adverse Reactions (6.1) and Clinical Studies (14)].
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting
of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic
insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.
Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis
Foundation Consensus Conferences [see Dosage and Administration (2.1)]. Doses of other pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy
and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)].
10
OVERDOSAGE
There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation
of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and
colonic strictures [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. High doses of
pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with
caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].
Page 6 of 10
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11
DESCRIPTION
CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine
pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and
amylases.
Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble
in alcohol and ether.
Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in
diameter).
The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase.
CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate,
polyethylene glycol, and triethyl citrate. The imprinting ink on the capsule contains dimethicone, 2-ethoxyethanol,
shellac, soya lecithin, and titanium dioxide.
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have a
Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue
No. 2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a
brown opaque cap with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron
oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have a
Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain
gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty
acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and
maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically
secreted by the pancreas.
12.3
Pharmacokinetics
The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid.
CREON is designed to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic
enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed.
14
CLINICAL STUDIES
The short-term safety and efficacy of CREON were evaluated in three studies conducted in 103 patients with
exocrine pancreatic insufficiency (EPI). Studies 1 and 2 were conducted in 49 patients with EPI due to cystic
fibrosis (CF); Study 3 was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.
14.1
Cystic Fibrosis
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to
43 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Study 1 included patients aged 12 to 43 years
(n = 32). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol
deviations. Study 2 included patients aged 7 to 11 years (n = 17). The final analysis population was limited to 16
patients; 1 patient withdrew consent prior to stool collection during treatment with CREON. In each study, patients
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T
a
b
l
e
were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5
to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients
consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat)
during the treatment periods.
The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments,
when both fat excretion and fat ingestion were measured. Each patient’s CFA during placebo treatment was used as
their no-treatment CFA value.
In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean
difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.
In Study 2,mean CFA was 83% with CREON treatment compared to 47% with placebo treatment. The mean
difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.
Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON
treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher
no-treatment (placebo) CFA values. There were no differences in response to CREON by age or gender, with similar
responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older
patients.
The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both
treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated
(based on the assumption that proteins contain 16% nitrogen). Each patient’s CNA during placebo treatment was
used as their no-treatment CNA value.
In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment. The mean
difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.
In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment. The mean
difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.
14.2
Chronic Pancreatitis or Pancreatectomy
Study 3 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages
32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to
52 patients; 2 patients were excluded due to protocol violations. Ten patients had a history of pancreatectomy (7
were treated with CREON). In this study, patients received placebo for 5 days (run-in period), followed by
pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by
randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with
CFA less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the
double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2
snacks). All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the
treatment period.
The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods,
when both fat excretion and fat ingestion were measured. The mean change in CFA from the run-in period to the end
of the double-blind period in the CREON and Placebo groups is shown in Table 3.
Table 3: Change in CFA in Study 3 (Run-in Period to End of Double-Blind Period)
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Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower
run-in period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a
history of total pancreatectomy was treated with CREON in the study. That patient had a CFA of 26% during the
run-in period and a CFA of 73% at the end of the double-blind period. The remaining 6 patients with a history of
partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a
mean CFA of 84% at the end of the double-blind period.
15
REFERENCES
1 Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in
the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684.
2 Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis.
Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259.
3 Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related
management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic
review. Journal of the American Dietetic Association. 2008; 108: 832-839.
4 Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current
Gastroenterology Reports. 2007; 9: 116-122.
5 Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study.
Lancet. 1995; 346: 1247-1251.
6 FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing
colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.
16
HOW SUPPLIED/STORAGE AND HANDLING
CREON (pancrelipase) Delayed-Release Capsules
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint
“CREON 1206” and a blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles
of:
●
100 capsules (NDC 0032-1206-01)
●
250 capsules (NDC 0032-1206-07)
CREON (pancrelipase) Delayed-Release Capsules
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint
“CREON 1212” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in
bottles of:
●
100 capsules (NDC 0032-1212-01)
●
250 capsules (NDC 0032-1212-07)
CREON (pancrelipase) Delayed-Release Capsules
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint
“CREON 1224” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in
bottles of:
●
100 capsules (NDC 0032-1224-01)
●
250 capsules (NDC 0032-1224-07)
Storage and Handling
CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature
excursions are permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if
Page 9 of 10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
exposed to higher temperature and moisture conditions higher than 70%. After opening, keep bottle tightly closed
between uses to protect from moisture.
Do not crush CREON delayed-release capsules or the capsule contents.
17
PATIENT COUNSELING INFORMATION
[See Medication Guide]
17.1 Dosing and Administration
● Instruct patients and caregivers that CREON should only be taken as directed by their healthcare
professional. Patients should be advised that the total daily dose should not exceed 10,000 lipase units/kg
body weight/day unless clinically indicated. This needs to be especially emphasized for patients eating
multiple snacks and meals per day. Patients should be informed that if a dose is missed, the next dose
should be taken with the next meal or snack as directed. Doses should not be doubled [see Dosage and
Administration (2)].
● Instruct patients and caregivers that CREON should always be taken with food. Patients should be
advised that CREON delayed-release capsules and the capsule contents must not be crushed or chewed
as doing so could cause early release of enzymes and/or loss of enzymatic activity. Patients should
swallow the intact capsules with adequate amounts of liquid at mealtimes. If necessary, the capsule
contents can also be sprinkled on soft acidic foods [see Dosage and Administration (2)].
17.2
Fibrosing Colonopathy
Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in
children below the age of 12 years [see Dosage and Administration (2)].
17.3
Allergic Reactions
Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to
CREON develop [see Warnings and Precautions (5.5)].
17.4 Pregnancy and Breast Feeding
● Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming
pregnant during treatment with CREON [see Use in Specific Populations (8.1)].
● Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast
feeding during treatment with CREON [see Use in Specific Populations (8.3)].
Manufactured by:
Abbott Products GmbH
Hannover, Germany
Marketed By:
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
1055216 7E
© 2010 Abbott Laboratories
Page 10 of 10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:24.643779 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020725s007lbl.pdf', 'application_number': 20725, 'submission_type': 'SUPPL ', 'submission_number': 7} |
3,211 |
NDA 020725/S-011
Page 4
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CREON
safely and effectively. See full prescribing information for CREON.
CREON (pancrelipase) delayed-release capsules
Initial U.S. Approval: 2009
---------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage, Chronic Pancreatitis, Pancreatectomy (1)
4/2010
Dosage and Administration (2.2)
X/2011
Dosage and Administration, Infants (up to 12 months) (2.2)
X/2011
Dosage and Administration, Chronic Pancreatitis or
Pancreatectomy (2.2)
4/2010
---------------------------INDICATIONS AND USAGE-----------------------------
CREON is a combination of porcine-derived lipases, proteases, and amylases
indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. (1)
----------------------DOSAGE AND ADMINISTRATION------------------------
CREON is not interchangeable with any other pancrelipase product. (2.1)
Do not crush or chew capsules and capsule contents. For infants or patients
unable to swallow intact capsules, the contents may be sprinkled on soft acidic
food, e.g., applesauce. (2.1) Dosing should not exceed the recommended
maximum dosage set forth by the Cystic Fibrosis Foundation Consensus
Conferences Guidelines. (2.2)
Infants (up to 12 months)
● Prior to each feeding, infants may be given 3,000 lipase units (one capsule)
per 120 mL of formula or per breast-feeding. (2.1)
● Do not mix CREON capsule contents directly into formula or breast milk
prior to administration. (2.1)
Children Older than 12 Months and Younger than 4 Years
● Begin with 1,000 lipase units/kg of body weight per meal for children less
than age 4 years to a maximum of 2,500 lipase units/kg of body weight per
meal (or less than or equal to 10,000 lipase units/kg of body weight per
day), or less than 4,000 lipase units/g fat ingested per day. (2.2)
Children 4 Years and Older and Adults
● Begin with 500 lipase units/kg of body weight per meal for those older than
age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal
(or less than or equal to 10,000 lipase units/kg of body weight per day), or
less than 4,000 lipase units/g fat ingested per day. (2.2)
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or
Pancreatectomy
● Individualize dosage based on clinical symptoms, the degree of steatorrhea
present and the fat content of the diet. (2.2)
----------------------DOSAGE FORMS AND STRENGTHS------------------
● Capsules: 3,000 USP units of lipase; 9,500 USP units of protease; 15,000
USP units of amylase (3)
● Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000
USP units of amylase (3)
● Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000
USP units of amylase (3)
● Capsules: 24,000 USP units of lipase; 76,000 USP units of protease;
120,000 USP units of amylase (3)
-----------------------------CONTRAINDICATIONS----------------------------
None (4)
-----------------------WARNINGS AND PRECAUTIONS---------------------
● Fibrosing colonopathy is associated with high-dose use of pancreatic
enzyme replacement in the treatment of cystic fibrosis patients. Exercise
caution when doses of CREON exceed 2,500 lipase units/kg of body
weight per meal (or greater than 10,000 lipase units/kg of body weight per
day). (5.1)
● To avoid irritation of oral mucosa, do not chew CREON or retain in the
mouth. (5.2)
● Exercise caution when prescribing CREON to patients with gout, renal
impairment, or hyperuricemia. (5.3)
● There is theoretical risk of viral transmission with all pancreatic enzyme
products including CREON. (5.4)
● Exercise caution when administering pancrelipase to a patient with a
known allergy to proteins of porcine origin. (5.5)
-----------------------------ADVERSE REACTIONS-----------------------------
● Adverse reactions occurring in at least 2 cystic fibrosis patients (greater
than or equal to 4%) receiving CREON are vomiting, dizziness, and cough.
(6.1)
● Adverse reactions that occurred in at least 1 chronic pancreatitis or
pancreatectomy patient (greater than or equal to 4%) receiving CREON are
hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence,
frequent bowel movements, and nasopharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Abbott
Laboratories at 1-800-241-1643 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: June 2011
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 5
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Administration
2.2
Dosage
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Fibrosing Colonopathy
5.2 Potential for Irritation to Oral Mucosa
5.3 Potential for Risk of Hyperuricemia
5.4 Potential Viral Exposure from the Product Source
5.5
Allergic Reactions
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Cystic Fibrosis
14.2 Chronic Pancreatitis or Pancreatectomy
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
17.1 Dosing and Administration
17.2 Fibrosing Colonopathy
17.3 Allergic Reactions
17.4 Pregnancy and Breast Feeding
*Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 6
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic
fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.
2
DOSAGE AND ADMINISTRATION
CREON is not interchangeable with other pancrelipase products.
CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually
increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea
present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and
Administration (2.2) and Warnings and Precautions (5.1)].
2.1
Administration
Infants (up to 12 months)
CREON should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase
units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered directly to the
mouth or with a small amount of applesauce. Administration should be followed by breast milk or formula. Contents
of the capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be
taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral
mucosa.
Children and Adults
CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents
should not be crushed or chewed. Capsules should be swallowed whole.
For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the
contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room
temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and
followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in
the mouth.
2.2
Dosage
Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic
Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the
recommendations of the Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided
in the following paragraphs, except for infants. Although the Conferences recommend doses of 2,000 to 4,000 lipase
units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule. Therefore, the recommended
dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding.
Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.
Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency
due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
Infants (up to 12 months)
CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units
(one capsule) per 120 mL of formula or per breast-feeding. Do not mix CREON capsule contents directly into
formula or breast milk prior to administration [see Administration (2.1)].
Children Older than 12 Months and Younger than 4 Years
Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age
4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase
units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Reference ID: 2959088
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NDA 020725/S-011
Page 7
Children 4 Years and Older and Adults
Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age
4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase
units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
The total daily dose should reflect approximately three meals plus two or three snacks per day.
Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients
because they weigh more but tend to ingest less fat per kilogram of body weight.
Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy
The initial starting dose and increases in the dose per meal should be individualized based on clinical
symptoms, the degree of steatorrhea present, and the fat content of the diet.
In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at
least 100 g of fat per day [see Clinical Studies (14.2)]. Lower starting doses recommended in the literature are
consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the
Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose
for an individualized full meal should be given with each snack.
Limitations on Dosing
Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation
Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased
by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great
inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may
require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal,
further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than
10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be
effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses
greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of
fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently
receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either
immediately decreased or titrated downward to a lower range.
3
DOSAGE FORMS AND STRENGTHS
The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase. Each CREON capsule strength contains the specified
amounts of lipase, protease, and amylase as follows:
● 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase capsules have a
white opaque cap with imprint “CREON 1203” and a white opaque body.
● 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have an
orange opaque cap with imprint “CREON 1206” and a blue opaque body.
● 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a
brown opaque cap with imprint “CREON 1212” and a colorless transparent body.
● 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have
an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.
4
CONTRAINDICATIONS
None.
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 8
5
WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 5, 6
Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic
enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic
fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in
children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some
patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing
colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than
2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less
than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.1)].
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of
body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat
measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than
6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or
titrated downward to a lower range.
5.2
Potential for Irritation to Oral Mucosa
Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or
chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating
resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and
Administration (2.2) and Patient Counseling Information (17.1)]. For patients who are unable to swallow intact
capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a
pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed
immediately and followed with water or juice to ensure complete ingestion.
5.3
Potential for Risk of Hyperuricemia
Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or
hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
5.4
Potential Viral Exposure from the Product Source
CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that
CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during
manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission
of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses
that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness
associated with the use of porcine pancreatic extracts have been reported.
5.5
Allergic Reactions
Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of
porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been
reported with other pancreatic enzyme products with different formulations of the same active ingredient
(pancrelipase). The risks and benefits of continued CREON treatment in patients with severe allergy should be taken
into consideration with the overall clinical needs of the patient.
6
ADVERSE REACTIONS
The most serious adverse reactions reported with different pancreatic enzyme products of the same active
ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and
allergic reactions [see Warnings and Precautions (5)].
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 9
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The short-term safety of CREON was assessed in clinical trials conducted in 103 patients with exocrine
pancreatic insufficiency (EPI): 49 patients with EPI due to cystic fibrosis (CF) and 25 patients with EPI due to
chronic pancreatitis or pancreatectomy were treated with CREON.
Cystic Fibrosis
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies of 49 patients, ages 7
to 43 years, with EPI due to CF. Study 1 included 32 patients ages 12 to 43 years and Study 2 included 17 patients
ages 7 to 11 years. In these studies, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat
ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment
for an additional 5 to 6 days. The mean exposure to CREON during these studies was 5 days.
In Study 1, one patient experienced duodenitis and gastritis of moderate severity 16 days after completing
treatment with CREON. Transient neutropenia without clinical sequelae was observed as an abnormal laboratory
finding in one patient receiving CREON and a macrolide antibiotic.
In Study 2, adverse reactions that occurred in at least 2 patients (greater than or equal to 12%) treated with
CREON were vomiting and headache. Vomiting occurred in 2 patients treated with CREON and did not occur in
patients treated with placebo; headache occurred in 2 patients treated with CREON and did not occur in patients
treated with placebo.
The most common adverse reactions (greater than or equal to 4%) were vomiting, dizziness, and cough.
Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 4%) treated with
CREON at a higher rate than with placebo in Studies 1 and 2.
Table 1: Adverse Reactions Occurring in at Least 2 Patients (greater than or equal to 4%) in Cystic Fibrosis
(Studies 1 and 2)
Adverse Reaction
CREON Capsules
n = 49 (%)
Placebo
n = 47 (%)
Vomiting
3 (6)
1 (2)
Dizziness
2 (4)
1 (2)
Cough
2 (4)
0
Reference ID: 2959088
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Page 10
Chronic Pancreatitis or Pancreatectomy
Study 3 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages
32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo
treatment during a 5-day run-in period followed by an intervening period of up to 16 days of investigator-directed
treatment with no restrictions on pancreatic enzyme replacement therapy. Patients were then randomized to receive
CREON or matching placebo for 7 days. The CREON dose was 72,000 lipase units per main meal (3 main meals)
and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this study was 6.8 days in the 25
patients that received CREON.
The most common adverse reactions reported during the study were related to glycemic control and were
reported more commonly during CREON treatment than during placebo treatment.
Table 2 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 4%) treated
with CREON at a higher rate than with placebo in Study 3.
Table 2: Adverse Reactions in at least 1 Patient (greater than or equal to 4%) in Chronic Pancreatitis or
Pancreatectomy (Study 3)
Adverse Reaction
CREON Capsules
n = 25 (%)
Placebo
n = 29 (%)
Hyperglycemia
2 (8)
2 (7)
Hypoglycemia
1 (4)
1 (3)
Abdominal Pain
1 (4)
1 (3)
Abnormal Feces
1 (4)
0
Flatulence
1 (4)
0
Frequent Bowel Movements
1 (4)
0
Nasopharyngitis
1 (4)
0
6.2
Postmarketing Experience
Postmarketing data from this formulation of CREON have been available since 2009. The following adverse
reactions have been identified during post approval use of this formulation of CREON. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Gastrointestinal disorders (including abdominal pain, diarrhea, flatulence, constipation and nausea), skin
disorders (including pruritus, urticaria and rash), blurred vision, myalgia, muscle spasm, and asymptomatic
elevations of liver enzymes have been reported with this formulation of CREON.
Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active
ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to
cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has
been described in the medical literature. The most serious adverse reactions included fibrosing colonopathy, distal
intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions
including anaphylaxis, asthma, hives, and pruritus.
7
DRUG INTERACTIONS
No drug interactions have been identified. No formal interaction studies have been conducted.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic effects
Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not
known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant
woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal
Reference ID: 2959088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 11
maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with
adverse pregnancy outcomes.
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when CREON is administered to a nursing woman. The risk and benefit of
pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing
mother with exocrine pancreatic insufficiency.
8.4
Pediatric Use
The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind,
placebo-controlled, crossover studies of 49 patients with exocrine pancreatic insufficiency due to cystic fibrosis, 25
of whom were pediatric patients. Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included
17 children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar
to adult patients [see Adverse Reactions (6.1) and Clinical Studies (14)].
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting
of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic
insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.
Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis
Foundation Consensus Conferences [see Dosage and Administration (2.1)]. Doses of other pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy
and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)].
10
OVERDOSAGE
There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation
of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and
colonic strictures [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. High doses of
pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with
caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].
11
DESCRIPTION
CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine
pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and
amylases.
Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble
in alcohol and ether.
Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in
diameter).
The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
Other active ingredients include protease and amylase.
CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate,
polyethylene glycol, and triethyl citrate.
3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase capsules have a white
opaque cap with imprint “CREON 1203” and a white opaque body. The shells contain titanium dioxide and
hypromellose.
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase capsules have a
Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue
No. 2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 12
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase capsules have a
brown opaque cap with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron
oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase capsules have a
Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain
gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty
acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and
maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically
secreted by the pancreas.
12.3
Pharmacokinetics
The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid.
CREON is expected to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic
enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed.
14
CLINICAL STUDIES
The short-term safety and efficacy of CREON were evaluated in three studies conducted in 103 patients with
exocrine pancreatic insufficiency (EPI). Studies 1 and 2 were conducted in 49 patients with EPI due to cystic
fibrosis (CF); Study 3 was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.
14.1
Cystic Fibrosis
Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to
43 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Study 1 included patients aged 12 to 43 years
(n = 32). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol
deviations. Study 2 included patients aged 7 to 11 years (n = 17). The final analysis population was limited to 16
patients; 1 patient withdrew consent prior to stool collection during treatment with CREON. In each study, patients
were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5
to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients
consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat)
during the treatment periods.
The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments,
when both fat excretion and fat ingestion were measured. Each patient’s CFA during placebo treatment was used as
their no-treatment CFA value.
In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean
difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.
In Study 2, mean CFA was 83% with CREON treatment compared to 47% with placebo treatment. The mean
difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.
Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON
treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher
no-treatment (placebo) CFA values. There were no differences in response to CREON by age or gender, with similar
responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older
patients.
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CREON
Placebo
n = 24
n = 28
CFA [%]
Run-in Period (Mean, SD)
54 (19)
57 (21)
End of Double-Blind Period (Mean, SD)
86 (6)
66 (20)
Change in CFA * [%]
Run-in Period to End of Double-Blind Period (Mean, SD)
32 (18)
9 (13)
Treatment Difference (95% CI)
21 (14, 28)
*p<0.0001
NDA 020725/S-011
Page 13
The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both
treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated
(based on the assumption that proteins contain 16% nitrogen). Each patient’s CNA during placebo treatment was
used as their no-treatment CNA value.
In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment. The mean
difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.
In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment. The mean
difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.
14.2
Chronic Pancreatitis or Pancreatectomy
Study 3 was a randomized, double-blind, placebo-controlled, parallel group study of 54 adult patients, ages
32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to
52 patients; 2 patients were excluded due to protocol violations. Ten patients had a history of pancreatectomy (7
were treated with CREON). In this study, patients received placebo for 5 days (run-in period), followed by
pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by
randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with
CFA less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the
double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2
snacks). All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the
treatment period.
The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods,
when both fat excretion and fat ingestion were measured. The mean change in CFA from the run-in period to the end
of the double-blind period in the CREON and Placebo groups is shown in Table 3.
Table 3: Change in CFA in Study 3 (Run-in Period to End of Double-Blind Period)
Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower
run-in period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a
history of total pancreatectomy was treated with CREON in the study. That patient had a CFA of 26% during the
run-in period and a CFA of 73% at the end of the double-blind period. The remaining 6 patients with a history of
partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a
mean CFA of 84% at the end of the double-blind period.
15
REFERENCES
1 Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in
the context of fibrosing colonopathy. Journal of Pediatrics. 1995; 127: 681-684.
2 Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis.
Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246-259.
3 Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related
management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic
review. Journal of the American Dietetic Association. 2008; 108: 832-839.
4 Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current
Gastroenterology Reports. 2007; 9: 116-122.
Reference ID: 2959088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 14
5 Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study.
Lancet. 1995; 346: 1247-1251.
6 FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme supplements and fibrosing
colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289.
16
HOW SUPPLIED/STORAGE AND HANDLING
CREON (pancrelipase) Delayed-Release Capsules
3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase
Each CREON capsule is available as a two-piece hypromellose capsule with a white opaque cap with imprint
“CREON 1203” and a white opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles
of:
●
70 capsules (NDC 0032-1203-70)
CREON (pancrelipase) Delayed-Release Capsules
6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint
“CREON 1206” and a blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles
of:
●
100 capsules (NDC 0032-1206-01)
●
250 capsules (NDC 0032-1206-07)
CREON (pancrelipase) Delayed-Release Capsules
12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint
“CREON 1212” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in
bottles of:
●
100 capsules (NDC 0032-1212-01)
●
250 capsules (NDC 0032-1212-07)
CREON (pancrelipase) Delayed-Release Capsules
24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint
“CREON 1224” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in
bottles of:
●
100 capsules (NDC 0032-1224-01)
●
250 capsules (NDC 0032-1224-07)
Storage and Handling
CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature
excursions are permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if
exposed to higher temperature and moisture conditions higher than 70%. After opening, keep bottle tightly closed
between uses to protect from moisture.
Bottles of CREON 3,000 USP units of lipase must be stored and dispensed in the original container.
Do not crush CREON delayed-release capsules or the capsule contents.
17
PATIENT COUNSELING INFORMATION
[See Medication Guide]
Reference ID: 2959088
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NDA 020725/S-011
Page 15
17.1
Dosing and Administration
● Instruct patients and caregivers that CREON should only be taken as directed by their healthcare
professional. Patients should be advised that the total daily dose should not exceed 10,000 lipase units/kg
body weight/day unless clinically indicated. This needs to be especially emphasized for patients eating
multiple snacks and meals per day. Patients should be informed that if a dose is missed, the next dose
should be taken with the next meal or snack as directed. Doses should not be doubled [see Dosage and
Administration (2)].
● Instruct patients and caregivers that CREON should always be taken with food. Patients should be
advised that CREON delayed-release capsules and the capsule contents must not be crushed or chewed
as doing so could cause early release of enzymes and/or loss of enzymatic activity. Patients should
swallow the intact capsules with adequate amounts of liquid at mealtimes. If necessary, the capsule
contents can also be sprinkled on soft acidic foods [see Dosage and Administration (2)].
17.2
Fibrosing Colonopathy
Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme
products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in
children below the age of 12 years [see Dosage and Administration (2)].
17.3
Allergic Reactions
Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to
CREON develop [see Warnings and Precautions (5.5)].
17.4
Pregnancy and Breast Feeding
● Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming
pregnant during treatment with CREON [see Use in Specific Populations (8.1)].
● Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast
feeding during treatment with CREON [see Use in Specific Populations (8.3)].
MANUFACTURED BY:
ABBOTT PRODUCTS GMBH
HANNOVER, GERMANY
MARKETED BY:
ABBOTT LABORATORIES
NORTH CHICAGO, IL 60064, U.S.A.
055216 10E REV JUNE 2011
© 2011 ABBOTT LABORATORIES
1
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 16
MEDICATION GUIDE
(pancrelipase)
Delayed-Release Capsules
Read this Medication Guide before you start taking CREON and each time you get a
refill. There may be new information. This information does not take the place of
talking to your doctor about your medical condition or treatment.
What is the most important information I should know about CREON?
CREON may increase your chance of having a rare bowel disorder called fibrosing
colonopathy. This condition is serious and may require surgery. The risk of having
this condition may be reduced by following the dosing instructions that your doctor
gave you. Call your doctor right away if you have any unusual or severe:
● stomach area (abdominal) pain
● bloating
● trouble passing stool (having bowel movements)
● nausea, vomiting, or diarrhea
Take CREON exactly as prescribed. Do not take more or less CREON than directed
by your doctor.
What is CREON?
CREON is a prescription medicine used to treat people who cannot digest food
normally because their pancreas does not make enough enzymes due to cystic
fibrosis, swelling of the pancreas that lasts a long time (chronic pancreatitis),
removal of some or all of the pancreas (pancreatectomy), or other conditions.
CREON may help your body use fats, proteins, and sugars from food.
CREON contains a mixture of digestive enzymes including lipases, proteases, and
amylases from pig pancreas.
What should I tell my doctor before taking CREON?
Before taking CREON, tell your doctor about all your medical conditions,
including if you:
● are allergic to pork (pig) products
● have a history of intestinal blockage of your intestines, or scarring or
thickening of your bowel wall (fibrosing colonopathy)
● have gout, kidney disease, or high blood uric acid (hyperuricemia)
● have trouble swallowing capsules
● have any other medical condition
● are pregnant or plan to become pregnant. It is not known if CREON will harm
your unborn baby.
● are breast-feeding or plan to breast-feed. It is not known if CREON passes
into your breast milk.
n)
ŏ׳ ē
CREON® (kr
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Page 17
Tell your doctor about all the medicines you take, including prescription and
nonprescription medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them and show it to your doctor and
pharmacist when you get a new medicine.
How should I take CREON?
● Take CREON exactly as your doctor tells you.
● You should not switch CREON with any other pancreatic enzyme product
without first talking to your doctor.
● Do not take more capsules in a day than the number your doctor tells you to
take (total daily dose).
● Always take CREON with a meal or snack and enough liquid to swallow
CREON completely. If you eat a lot of meals or snacks in a day, be careful
not to go over your total daily dose.
● Your doctor may change your dose based on the amount of fatty foods you
eat or based on your weight.
● Do not crush or chew CREON capsules or its contents, and do not
hold the capsule or capsule contents in your mouth. Crushing, chewing
or holding the CREON capsules in your mouth may cause irritation in your
mouth or change the way CREON works in your body.
Giving CREON to infants (children up to 12 months)
1. Give CREON right before each feeding of formula or breast milk.
2. Do not mix CREON capsule contents directly into formula or breast milk.
3. Open the capsules and sprinkle the contents directly into your infant’s mouth
or mix the contents in a small amount of room temperature acidic soft food
such as applesauce. These foods should be the kind found in baby food jars
that you buy at the store, or other food recommended by your doctor.
4. If you sprinkle the CREON on food, give the CREON and food mixture to your
child right away. Do not store CREON that is mixed with food.
5. Give your child enough liquid to completely swallow the CREON contents or
the CREON and food mixture.
6. Look in your child’s mouth to make sure that all of the medicine has been
swallowed.
Giving CREON to children and adults
1. Swallow CREON capsules whole and take them with enough liquid to swallow
them right away.
2. If you have trouble swallowing capsules, open the capsules and sprinkle the
contents on a small amount of room temperature acidic food such as
applesauce. Ask your doctor about other foods you can mix with CREON.
3. If you sprinkle CREON on food, swallow it right after you mix it and drink
enough water or juice to make sure the medicine is swallowed completely.
Do not store CREON that is mixed with food.
4. If you forget to take CREON, call your doctor or wait until your next meal and
take your usual number of capsules. Take your next dose at your usual time.
Do not make up for missed doses.
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 18
What are the possible side effects of CREON?
CREON may cause serious side effects, including:
● See “What is the most important information I should know about
CREON?”
● Irritation of the inside of your mouth. This can happen if CREON is not
swallowed completely.
● Increase in blood uric acid levels. This may cause worsening of
swollen, painful joints (gout) caused by an increase in your blood
uric acid levels.
● Allergic reactions including trouble with breathing, skin rashes, or
swollen lips.
Call your doctor right away if you have any of these symptoms.
The most common side effects of CREON include:
● Blood sugar increase (hyperglycemia) or decrease (hypoglycemia)
● Pain in your stomach (abdominal area)
● Frequent or abnormal bowel movements
● Gas
● Vomiting
● Dizziness
● Sore throat and cough
Other Possible Side Effects:
CREON and other pancreatic enzyme products are made from the pancreas of pigs,
the same pigs people eat as pork. These pigs may carry viruses. Although it has
never been reported, it may be possible for a person to get a viral infection from
taking pancreatic enzyme products that come from pigs.
Tell your doctor if you have any side effect that bothers you or that does not go
away.
These are not all the side effects of CREON. For more information, ask your doctor
or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to the FDA at 1-800-FDA-1088.
You may also report side effects to Abbott Laboratories at 1-800-241-1643.
How should I store CREON?
● Store CREON at room temperature below 77°F (25°C). Avoid heat.
● You may store CREON at a temperature between 77°F to 104°F (25°C to 40°C)
for up to 30 days. Throw away any CREON stored at these temperatures for
more than 30 days.
● Keep CREON in a dry place and in the original container.
● After opening the bottle, keep it closed tightly between uses to protect from
moisture.
Keep CREON and all medicines out of the reach of children.
Reference ID: 2959088
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 020725/S-011
Page 19
General information about CREON
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use CREON for a condition for which it was not prescribed.
Do not give CREON to other people to take, even if they have the same symptoms
you have. It may harm them.
This Medication Guide summarizes the most important information about CREON. If
you would like more information, talk to your doctor. You can ask your doctor or
pharmacist for information about CREON that is written for healthcare
professionals. For more information, go to www.creon-us.com or call toll-free [1
800-241-1643].
What are the ingredients in CREON?
Active Ingredient: lipase, protease, amylase
Inactive Ingredients: cetyl alcohol, dimethicone, hypromellose phthalate,
polyethylene glycol, and triethyl citrate.
The shells of the CREON 6,000 USP units of lipase, 12,000 USP units of lipase, and
24,000 USP units of lipase strengths contain: gelatin, red iron oxide, sodium lauryl
sulfate, titanium dioxide, and yellow iron oxide.
In addition:
The shells for the CREON 3,000 USP units of lipase contain titanium dioxide and
hypromellose.
The shells of the 6,000 USP units of lipase strength capsules contain FD&C Blue No.
2.
The shells of the 12,000 USP units of lipase strength capsules contain black iron
oxide.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Manufactured for:
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
1055216 10E Rev May 2011
© 2011 Abbott Laboratories
Rev June/2011
Reference ID: 2959088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:24.781761 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020725s011lbl.pdf', 'application_number': 20725, 'submission_type': 'SUPPL ', 'submission_number': 11} |
3,938 | custom-source | 2025-02-12T13:43:24.803320 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-986SE3003_NovoLog_prntlbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 3} |
|
3,939 | NDA 20-986/S-011
Final Draft
Page 1
NNPI submission date: 11/26/02
NovoLog®
1
Insulin aspart (rDNA origin) Injection
2
3
4
DESCRIPTION
5
NovoLog® (insulin aspart [rDNA origin] injection) is a human insulin analog that is a rapid-
6
acting, parenteral blood glucose-lowering agent. NovoLog is homologous with regular human
7
insulin with the exception of a single substitution of the amino acid proline by aspartic acid in
8
position B28, and is produced by recombinant DNA technology utilizing Saccharomyces
9
cerevisiae (baker's yeast) as the production organism. Insulin aspart has the empirical formula
10
C256H381N65079S6 and a molecular weight of 5825.8.
11
12
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
13
Figure 1. Structural formula of insulin aspart.
14
15
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart (B28
16
asp regular human insulin analog) 100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL,
17
metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25
18
mg/mL, and sodium chloride 0.58 mg/mL. NovoLog has a pH of 7.2-7.6. Hydrochloric acid
19
10% and/or sodium hydroxide 10% may be added to adjust pH.
20
21
CLINICAL PHARMACOLOGY
22
Mechanism of Action
23
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins, including
24
NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose by
25
facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
26
from the liver.
27
28
In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-
29
lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is
30
more rapid in onset and of shorter duration, compared to regular human insulin, due to its
31
faster absorption after subcutaneous injection (see Figure 2 and Figure 3).
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-011
Final Draft
Page 2
NNPI submission date: 11/26/02
33
Pharmacokinetics
34
The single substitution of the amino acid proline with aspartic acid at position B28 in
35
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
36
insulin. NovoLog is therefore more rapidly absorbed after subcutaneous injection compared to
37
regular human insulin.
38
39
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of action, and
40
a shorter duration of action than regular human insulin after subcutaneous injection (see Figure
41
2 and Figure 3). The relative bioavailability of NovoLog compared to regular human insulin
42
indicates that the two insulins are absorbed to a similar extent.
43
44
45
46
Figure 2. Serial mean serum free insulin concentration collected up to 6 hours following a
47
single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
48
injected immediately before a meal in 22 patients with Type 1 diabetes.
49
50
In studies in healthy volunteers (total n=l07) and patients with Type 1 diabetes (total n=40),
51
NovoLog consistently reached peak serum concentrations approximately twice as fast as
52
regular human insulin. The median time to maximum concentration in these trials was 40 to
53
50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial
54
in patients with Type 1 diabetes, NovoLog and regular human insulin, both administered
55
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
56
82.1 and 35.9 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of
57
insulin aspart have not been established in patients with Type 2 diabetes.
58
The intra-individual variability in time to maximum serum insulin concentration for healthy
59
male volunteers was significantly less for NovoLog than for regular human insulin. The
60
clinical significance of this observation has not been established.
61
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences between
62
NovoLog and regular human insulin described above, were observed independent of the
63
injection site (abdomen, thigh, or upper arm). Differences in pharmacokinetics between
64
| custom-source | 2025-02-12T13:43:24.953344 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20986SE8-011_novolog_lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 11} |
3,942 | NDA 20-986/S-024
Final DRAFT
Page 1
Novo Nordisk submission date: 7/26/04
NovoLog®
1
Insulin aspart (rDNA origin) Injection
2
3
4
DESCRIPTION
5
NovoLog® (insulin aspart [rDNA origin] injection) is a human insulin analog that is a rapid-
6
acting, parenteral blood glucose-lowering agent. NovoLog is homologous with regular human
7
insulin with the exception of a single substitution of the amino acid proline by aspartic acid in
8
position B28, and is produced by recombinant DNA technology utilizing Saccharomyces
9
cerevisiae (baker's yeast) as the production organism. Insulin aspart has the empirical formula
10
C256H381N65079S6 and a molecular weight of 5825.8.
11
12
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
13
Figure 1. Structural formula of insulin aspart.
14
15
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart (B28
16
asp regular human insulin analog) 100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL,
17
metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25
18
mg/mL, and sodium chloride 0.58 mg/mL. NovoLog has a pH of 7.2-7.6. Hydrochloric acid
19
10% and/or sodium hydroxide 10% may be added to adjust pH.
20
21
CLINICAL PHARMACOLOGY
22
Mechanism of Action
23
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins, including
24
NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose by
25
facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
26
from the liver.
27
28
In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-
29
lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is
30
more rapid in onset and of shorter duration, compared to regular human insulin, due to its
31
faster absorption after subcutaneous injection (see Figure 2 and Figure 3).
32
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 2
Novo Nordisk submission date: 7/26/04
Pharmacokinetics
34
The single substitution of the amino acid proline with aspartic acid at position B28 in
35
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
36
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared
37
to regular human insulin.
38
39
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of action, and
40
a shorter duration of action than regular human insulin after subcutaneous injection (see
41
Figure 2 and Figure 3). The relative bioavailability of NovoLog compared to regular human
42
insulin indicates that the two insulins are absorbed to a similar extent.
43
44
45
46
Figure 2. Serial mean serum free insulin concentration collected up to 6 hours following a
47
single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
48
injected immediately before a meal in 22 patients with Type 1 diabetes.
49
50
In studies in healthy volunteers (total n=l07) and patients with Type 1 diabetes (total n=40),
51
NovoLog consistently reached peak serum concentrations approximately twice as fast as
52
regular human insulin. The median time to maximum concentration in these trials was 40 to
53
50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial
54
in patients with Type 1 diabetes, NovoLog and regular human insulin, both administered
55
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
56
82.1 and 35.9 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of
57
insulin aspart have not been established in patients with Type 2 diabetes.
58
The intra-individual variability in time to maximum serum insulin concentration for healthy
59
male volunteers was significantly less for NovoLog than for regular human insulin. The
60
clinical significance of this observation has not been established.
61
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences between
62
NovoLog and regular human insulin described above, were observed independent of the
63
injection site (abdomen, thigh, or upper arm). Differences in pharmacokinetics between
64
NovoLog® and regular human insulin are not associated with differences in overall glycemic
65
control.
66
0
20
40
60
80
0
1
2
3
4
5
6
Free serum insulin (mU/L)
Time (h)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 3
Novo Nordisk submission date: 7/26/04
67
Distribution and Elimination - NovoLog has a low binding to plasma proteins, 0-9%, similar
68
to regular human insulin. After subcutaneous administration in normal male volunteers
69
(n=24), NovoLog was more rapidly eliminated than regular human insulin with an average
70
apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
71
72
Pharmacodynamics
73
Studies in normal volunteers and patients with diabetes demonstrated that NovoLog has a
74
more rapid onset of action than regular human insulin.
75
In a 6-hour study in patients with Type 1 diabetes (n=22), the maximum glucose-lowering
76
effect of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 3).
77
The duration of action for NovoLog is 3 to 5 hours compared to 5 to 8 hours for regular human
78
insulin. The time course of action of insulin and insulin analogs such as NovoLog may vary
79
considerably in different individuals or within the same individual. The parameters of
80
NovoLog activity (time of onset, peak time and duration) as designated in Figure 3 should be
81
considered only as general guidelines. The rate of insulin absorption and consequently the
82
onset of activity is known to be affected by the site of injection, exercise, and other variables
83
(see PRECAUTIONS, General). Differences in pharmacodynamics between NovoLog® and
84
regular human insulin are not associated with differences in overall glycemic control.
85
86
87
88
Figure 3. Serial mean serum glucose collected up to 6 hours following a single pre-meal dose
89
of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately
90
before a meal in 22 patients with Type 1 diabetes.
91
92
Special Populations
93
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
94
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
95
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with Type 1 diabetes. The
96
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents
97
with Type 1 diabetes between NovoLog and regular human insulin were similar to those in
98
healthy adult subjects and adults with Type 1 diabetes.
99
50
100
150
200
250
300
0
1
2
3
4
5
6
Serum glucose (mg/dL)
Time (h)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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100
Geriatrics - The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog
101
has not been studied.
102
103
Gender - In healthy volunteers, no difference in insulin aspart levels was seen between men
104
and women when body weight differences were taken into account. There was no significant
105
difference in efficacy noted (as assessed by HbAlc) between genders in a trial in patients with
106
Type 1 diabetes.
107
108
Obesity - In a study of 23 patients with type 1 diabetes and a wide range of body mass index
109
(BMI, 22-39 kg/m2), the pharmacokinetic parameters, AUC and Cmax, of NovoLog® were
110
generally unaffected by BMI. Clearance of NovoLog® was reduced by 28% in patients with
111
BMI >32 compared to patients with BMI <23 when a single dose of 0.1 U/kg NovoLog® was
112
administered. However, only 3 patients with BMI <23 were studied.
113
114
Ethnic Origin - The effect of ethnic origin on the pharmacokinetics of NovoLog has not been
115
studied.
116
117
Renal Impairment - Some studies with human insulin have shown increased circulating levels
118
of insulin in patients with renal failure. A single subcutaneous dose of NovoLog® was
119
administered in a study of 18 patients with creatinine clearance values ranging from normal to
120
<30 mL/min and not requiring hemodialysis. No apparent effect of creatinine clearance values
121
on AUC and Cmax of NovoLog® was found. However, only 2 patients with severe renal
122
impairment were studied (<30 mL/min). Careful glucose monitoring and dose adjustments of
123
insulin, including NovoLog, may be necessary in patients with renal dysfunction (see
124
PRECAUTIONS, Renal Impairment).
125
126
Hepatic Impairment - Some studies with human insulin have shown increased circulating
127
levels of insulin in patients with liver failure. In an open-label, single-dose study of 24
128
patients with Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic
129
impairment), no correlation was found between the degree of hepatic failure and any
130
NovoLog® pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of
131
insulin, including NovoLog, may be necessary in patients with hepatic dysfunction (see
132
PRECAUTIONS, Hepatic Impairment).
133
134
Pregnancy - The effect of pregnancy on the pharmacokinetics and glucodynamics of
135
NovoLog has not been studied (see PRECAUTIONS, Pregnancy).
136
137
Smoking - The effect of smoking on the pharmacokinetics/pharmacodynamics of NovoLog has
138
not been studied.
139
140
CLINICAL STUDIES
141
To evaluate the safety and efficacy of NovoLog in patients with Type 1 diabetes, two
142
six-month, open-label, active-control (NovoLog vs. Novolin® R) studies were conducted (see
143
Table 1). NovoLog was administered by subcutaneous injection immediately prior to meals
144
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
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and regular human insulin was administered by subcutaneous injection 30 minutes before
145
meals. NPH insulin was administered as the basal insulin in either single or divided daily
146
doses. Changes in HbA1c, the rates of hypoglycemia (as determined from the number of
147
events requiring intervention from a third party), and the incidence of ketosis were clinically
148
comparable for the two treatment regimens. The mean total daily doses of insulin were greater
149
(1-3 U/day) in the NovoLog-treated patients compared to patients who received regular human
150
insulin. This difference was primarily due to basal insulin requirements. To achieve
151
improved glycemic control, some patients required more than three doses of meal-related
152
insulin and/or more than one dose of basal insulin (see Table 1). No serum glucose
153
measurements were obtained in these studies.
154
155
To evaluate the safety and efficacy of NovoLog in patients with Type 2 diabetes, one six-
156
month, open-label, active-control (NovoLog vs. Novolin R) study was conducted (see Table
157
1). NovoLog was administered by subcutaneous injection immediately prior to meals and
158
regular human insulin was administered by subcutaneous injection 30 minutes before meals.
159
NPH insulin was administered as the basal insulin in either single or divided daily doses.
160
Changes in HbAlc and the rates of hypoglycemia (as determined from the number of events
161
requiring intervention from a third party) were clinically comparable for the two treatment
162
regimens. The mean total daily dose of insulin was greater (2 U/day) in the NovoLog-treated
163
patients compared to patients who received regular human insulin. This difference was
164
primarily due to basal insulin requirements. To achieve improved glycemic control, some
165
patients required more than three doses of meal-related insulin and/or more than one dose of
166
basal insulin (see Table 1).
167
168
Table 1. Results of two six-month, active-control, open-label trials in patients with Type 1
169
diabetes (Studies A and B) and one six-month, active-control, open-label trial in patients with
170
Type 2 diabetes (Study C).
171
172
Mean HbA1c (%)
% of Patients Using Various
Numbers of Insulin Injections /
Day2
Rapid-acting
Basal
Study
Treatment (n)
Baseline
Month
6
Hypoglycemia1
(events / month
/ patient)
1 - 2
3
4 - 5
1
2
NovoLog (n=694)
8.0
7.9
0.06
3
75
22
54
46
A
Novolin R (n=346)
8.0
8.0
0.06
6
75
19
63
37
NovoLog (n=573)
7.9
7.8
0.08
4
90
6
94
6
B
Novolin R (n=272)
8.0
7.9
0.06
4
91
4
93
7
NovoLog (n=90)
8.1
7.7
0.02
4
93
4
97
4
C
Novolin R (n=86)
7.8
7.8
0.01
2
93
5
93
7
1 Events requiring intervention from a third party during the last three months of treatment
173
2 Percentages are rounded to the nearest whole number
174
175
To evaluate the use of NovoLog by subcutaneous infusion with an external pump, two open-
176
label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) compared NovoLog
177
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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versus Velosulin (buffered regular human insulin) in patients with Type 1 diabetes. Changes in
178
HbA1c and rates of hypoglycemia were comparable. Patients with Type 2 diabetes were also
179
studied in an open-label, parallel design trial (16 weeks [n=127]) using NovoLog by
180
subcutaneous infusion compared to pre-prandial injection (in conjunction with basal NPH
181
injections). Reductions in HbA1c and rates of hypoglycemia were comparable. (See
182
INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, Mixing of Insulins,
183
Information for Patients, DOSAGE AND ADMINISTRATION, and RECOMMENDED
184
STORAGE.)
185
186
INDICATIONS AND USAGE
187
NovoLog is indicated for the treatment of adult patients with diabetes mellitus, for the control
188
of hyperglycemia. Because NovoLog has a more rapid onset and a shorter duration of activity
189
than human regular insulin, NovoLog given by injection should normally be used in regimens
190
with an intermediate or long-acting insulin. NovoLog may also be infused subcutaneously by
191
external insulin pumps. (See WARNINGS, PRECAUTIONS [especially Usage in Pumps],
192
Information for Patients [especially For Patients Using Pumps], Mixing of Insulins, DOSAGE
193
AND ADMINISTRATION, RECOMMENDED STORAGE.)
194
195
CONTRAINDICATIONS
196
NovoLog is contraindicated during episodes of hypoglycemia and in patients hypersensitive to
197
NovoLog or one of its excipients.
198
199
WARNINGS
200
NovoLog differs from regular human insulin by a more rapid onset and a shorter
201
duration of activity. Because of the fast onset of action, the injection of NovoLog should
202
immediately be followed by a meal. Because of the short duration of action of NovoLog,
203
patients with diabetes also require a longer-acting insulin to maintain adequate glucose
204
control. Glucose monitoring is recommended for all patients with diabetes and is
205
particularly important for patients using external pump infusion therapy.
206
207
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog.
208
As with all insulins, the timing of hypoglycemia may differ among various insulin
209
formulations.
210
211
Any change of insulin dose should be made cautiously and only under medical
212
supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH,
213
analog), species (animal, human), or method of manufacture (rDNA versus animal-
214
source insulin) may result in the need for a change in dosage.
215
216
Insulin Pumps: When used in an external insulin pump for subcutaneous infusion,
217
NovoLog should not be diluted or mixed with any other insulin. Physicians and patients
218
should carefully evaluate information on pump use in the NovoLog physician and patient
219
package inserts and in the pump manufacturer's manual (e.g. NovoLog-specific
220
information should be followed for in-use time, frequency of changing infusion sets, or
221
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 7
Novo Nordisk submission date: 7/26/04
other details specific to NovoLog usage, because NovoLog-specific information may
222
differ from general pump manual instructions).
223
224
Pump or infusion set malfunctions or insulin degradation can lead to hyperglycemia and
225
ketosis in a short time because of the small subcutaneous depot of insulin. This is
226
especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed
227
through skin and have shorter duration of action. These differences may be particularly
228
relevant when patients are switched from multiple injection therapy or infusion with
229
buffered regular insulin. Prompt identification and correction of the cause of
230
hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection may
231
be required. (See PRECAUTIONS, Mixing of Insulins, Information for Patients,
232
DOSAGE AND ADMINISTRATION, and RECOMMENDED STORAGE.)
233
234
PRECAUTIONS
235
General
236
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated
237
with the use of all insulins. Because of differences in the action of NovoLog and other
238
insulins, care should be taken in patients in whom such potential side effects might be
239
clinically relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using
240
potassium-lowering drugs or patients taking drugs sensitive to serum potassium level).
241
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects
242
associated with the use of all insulins.
243
As with all insulin preparations, the time course of NovoLog action may vary in different
244
individuals or at different times in the same individual and is dependent on site of injection,
245
blood supply, temperature, and physical activity.
246
Adjustment of dosage of any insulin may be necessary if patients change their physical
247
activity or their usual meal plan. Insulin requirements may be altered during illness,
248
emotional disturbances, or other stresses.
249
250
Hypoglycemia - As with all insulin preparations, hypoglycemic reactions may be associated
251
with the administration of NovoLog. Rapid changes in serum glucose levels may induce
252
symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early
253
warning symptoms of hypoglycemia may be different or less pronounced under certain
254
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such
255
as beta-blockers, or intensified diabetes control (see PRECAUTIONS, Drug Interactions).
256
Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior
257
to patients’ awareness of hypoglycemia.
258
259
Renal Impairment - As with other insulins, the dose requirements for NovoLog® may be
260
reduced in patients with renal impairment (see CLINICAL PHARMACOLOGY,
261
Pharmacokinetics).
262
263
Hepatic Impairment - As with other insulins, the dose requirements for NovoLog® may be
264
reduced in patients with hepatic impairment (see CLINICAL PHARMACOLOGY,
265
Pharmacokinetics).
266
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
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Novo Nordisk submission date: 7/26/04
267
Allergy - Local Allergy - As with other insulin therapy, patients may experience redness,
268
swelling, or itching at the site of injection. These minor reactions usually resolve in a few
269
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In
270
some instances, these reactions may be related to factors other than insulin, such as irritants in
271
a skin cleansing agent or poor injection technique.
272
Systemic Allergy - Less common, but potentially more serious, is generalized allergy to
273
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
274
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
275
allergy, including anaphylactic reaction, may be life threatening.
276
Localized reactions and generalized myalgias have been reported with the use of metacresol as
277
an injectable excipient.
278
In controlled clinical trials using injection therapy, allergic reactions were reported in 3 of 735
279
patients (0.4%) who received regular human insulin and 10 of 1394 patients (0.7%) who
280
received NovoLog. During these and other trials, 3 of 2341 patients treated with NovoLog
281
were discontinued due to allergic reactions.
282
283
Antibody Production - Increases in levels of anti-insulin antibodies that react with both human
284
insulin and insulin aspart have been observed in patients treated with NovoLog®. The
285
number of patients treated with insulin aspart experiencing these increases is greater than the
286
number among those treated with human regular insulin. Data from a 12-month controlled
287
trial in patients with Type 1 diabetes suggest that the increase in these antibodies is transient.
288
The differences in antibody levels between the human regular insulin and insulin aspart
289
treatment groups observed at 3 and 6 months were no longer evident at 12 months. The
290
clinical significance of these antibodies is not known. They do not appear to cause
291
deterioration in HbA1c or to necessitate increases in insulin dose.
292
293
Pregnancy and Lactation
294
Female patients should be advised to tell their physician if they intend to become, or if they
295
become pregnant. Information is not available on the use of NovoLog during pregnancy or
296
lactation.
297
298
Usage in Pumps
299
300
Pumps:
301
NovoLog is recommended for use in Disetronic H-TRON series, MiniMed 500 series, and
302
other equivalent pumps.
303
304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 9
Novo Nordisk submission date: 7/26/04
Reservoirs and infusion sets:
305
NovoLog is recommended for use in any reservoir and infusion sets that are compatible with
306
insulin and the specific pump. In-vitro studies have shown that pump malfunction, loss of
307
metacresol, and insulin degradation, may occur when NovoLog is maintained in a pump
308
system for more than 48 hours. Reservoirs and infusion sets should be changed at least every
309
48 hours.
310
311
NovoLog in clinical use should not be exposed to temperatures greater than 37oC (98.6oF).
312
NovoLog should not be mixed with other insulins or with a diluent when it is used in the
313
pump. (See WARNINGS, PRECAUTIONS, Mixing of Insulins, Information for Patients,
314
DOSAGE AND ADMINISTRATION, and RECOMMENDED STORAGE.)
315
316
Information for Patients
317
318
For all patients:
319
Patients should be informed about potential risks and advantages of NovoLog therapy
320
including the possible side effects. Patients should also be offered continued education and
321
advice on insulin therapies, injection technique, life-style management, regular glucose
322
monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo-
323
and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of
324
dose, instruction in the use of injection or subcutaneous infusion devices, and proper storage
325
of insulin. Patients should be informed that frequent, patient-performed blood glucose
326
measurements are needed to achieve optimal glycemic control and avoid both hyper- and
327
hypoglycemia.
328
329
Female patients should be advised to tell their physician if they intend to become, or if they
330
become pregnant. Information is not available on the use of NovoLog during pregnancy or
331
lactation (see PRECAUTIONS, Pregnancy).
332
333
For patients using pumps
334
Patients using external pump infusion therapy should be trained in intensive insulin therapy
335
with multiple injections and in the function of their pump and pump accessories.
336
337
Pumps:
338
NovoLog is recommended for use in Disetronic H-TRON series, MiniMed 500 series, and
339
other equivalent pumps
340
341
Reservoirs and infusion sets:
342
NovoLog is recommended for use in any reservoir and infusion sets that are compatible with
343
insulin and the specific pump. Please see recommended reservoir and infusion sets in the
344
pump manual.
345
346
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
347
(metacresol), reservoirs, infusion sets, and injection site should be changed at least every
348
48 hours.
349
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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350
351
Insulin exposed to temperatures higher than 37oC (98.6oF) should be discarded. The
352
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
353
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are
354
erythematous, pruritic, or thickened should be reported to medical personnel, and a new site
355
selected because continued infusion may increase the skin reaction and/or alter the absorption
356
of NovoLog. Pump or infusion set malfunctions or insulin degradation can lead to
357
hyperglycemia and ketosis in a short time because of the small subcutaneous depot of insulin.
358
This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed
359
through skin and have shorter duration of action. These differences are particularly relevant
360
when patients are switched from infused buffered regular insulin or multiple injection therapy.
361
Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary.
362
Problems include pump malfunction, infusion set occlusion, leakage, disconnection or
363
kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may
364
occur. If these problems cannot be promptly corrected, patients should resume therapy with
365
subcutaneous insulin injection and contact their physician. (See WARNINGS,
366
PRECAUTIONS, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and
367
RECOMMENDED STORAGE.)
368
369
Laboratory Tests
370
As with all insulin therapy, the therapeutic response to NovoLog should be monitored by
371
periodic blood glucose tests. Periodic measurement of glycosylated hemoglobin is
372
recommended for the monitoring of long-term glycemic control.
373
374
Drug Interactions
375
A number of substances affect glucose metabolism and may require insulin dose adjustment
376
and particularly close monitoring.
377
• The following are examples of substances that may increase the blood-glucose-lowering
378
effect and susceptibility to hypoglycemia: oral antidiabetic products, ACE inhibitors,
379
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene,
380
salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.
381
• The following are examples of substances that may reduce the blood-glucose-lowering
382
effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
383
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin,
384
thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives).
385
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the
386
blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which
387
may sometimes be followed by hyperglycemia.
388
• In addition, under the influence of sympatholytic medicinal products such as beta-
389
blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be
390
reduced or absent (see CLINICAL PHARMACOLOGY).
391
392
Mixing of Insulins
393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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• A clinical study in healthy male volunteers (n=24) demonstrated that mixing NovoLog
394
with NPH human insulin immediately before injection produced some attenuation in the
395
peak concentration of NovoLog, but that the time to peak and the total bioavailability of
396
NovoLog were not significantly affected. If NovoLog is mixed with NPH human insulin,
397
NovoLog should be drawn into the syringe first. The injection should be made
398
immediately after mixing. Because there are no data on the compatibility of NovoLog and
399
crystalline zinc insulin preparations, NovoLog should not be mixed with these
400
preparations.
401
• The effects of mixing NovoLog with insulins of animal source or insulin preparations
402
produced by other manufacturers have not been studied (see WARNINGS).
403
• Mixtures should not be administered intravenously.
404
• When used in external subcutaneous infusion pumps for insulin, NovoLog should not be
405
mixed with any other insulins or diluent.
406
407
Carcinogenicity, Mutagenicity, Impairment of Fertility
408
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
409
carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
410
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times
411
the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively).
412
At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in
413
females when compared to untreated controls. The incidence of mammary tumors for
414
NovoLog was not significantly different than for regular human insulin. The relevance of
415
these findings to humans is not known. NovoLog was not genotoxic in the following tests:
416
Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood
417
lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo
418
UDS test in rat liver hepatocytes. In fertility studies in male and female rats, at subcutaneous
419
doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on
420
U/body surface area), no direct adverse effects on male and female fertility, or general
421
reproductive performance of animals was observed.
422
423
Pregnancy - Teratogenic Effects - Pregnancy Category C
424
There are no adequate well-controlled clinical studies of the use of NovoLog in pregnant
425
women. NovoLog should be used during pregnancy only if the potential benefit justifies the
426
potential risk to the fetus.
427
428
It is essential for patients with diabetes or history of gestational diabetes to maintain good
429
metabolic control before conception and throughout pregnancy. Insulin requirements may
430
decrease during the first trimester, generally increase during the second and third trimesters,
431
and rapidly decline after delivery. Careful monitoring of glucose control is essential in such
432
patients.
433
434
Subcutaneous reproduction and teratology studies have been performed with NovoLog and
435
regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
436
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
437
The effects of NovoLog did not differ from those observed with subcutaneous regular human
438
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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Page 12
Novo Nordisk submission date: 7/26/04
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
439
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
440
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
441
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0
442
U/kg/day, based on U/body surface area). The effects are probably secondary to maternal
443
hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50
444
U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the
445
human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose
446
of 1.0 U/kg/day for rabbits, based on U/body surface area.
447
448
Nursing Mothers
449
It is unknown whether insulin aspart is excreted in human milk. Many drugs, including
450
human insulin, are excreted in human milk. For this reason, caution should be exercised when
451
NovoLog is administered to a nursing mother.
452
453
Pediatric Use
454
Safety and effectiveness of NovoLog in children have not been studied.
455
456
Geriatric Use
457
Of the total number of patients (n= 1,375) treated with NovoLog in 3 human insulin-controlled
458
clinical studies, 2.6% (n=36) were 65 years of age or over. Half of these patients had Type 1
459
diabetes (18/1285) and half had Type 2 (18/90) diabetes. The HbA1c response to NovoLog,
460
as compared to human insulin, did not differ by age, particularly in patients with Type 2
461
diabetes. Additional studies in larger populations of patients 65 years of age or over are
462
needed to permit conclusions regarding the safety of NovoLog in elderly compared to younger
463
patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of
464
NovoLog action have not been performed.
465
466
467
ADVERSE REACTIONS
468
Clinical trials comparing NovoLog with regular human insulin did not demonstrate a
469
difference in frequency of adverse events between the two treatments.
470
Adverse events commonly associated with human insulin therapy include the following:
471
Body as Whole - Allergic reactions (see PRECAUTIONS, Allergy).
472
Skin and Appendages - Injection site reaction, lipodystrophy, pruritus, rash (see
473
PRECAUTIONS, Allergy; Information for Patients, Usage in Pumps).
474
Other – Hypoglycemia, Hyperglycemia and ketosis (see WARNINGS and PRECAUTIONS).
475
In controlled clinical trials, small, but persistent elevations in alkaline phosphatase result were
476
observed in some patients treated with NovoLog. The clinical significance of this finding is
477
unknown.
478
479
OVERDOSAGE
480
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
481
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose.
482
Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes
483
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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Novo Nordisk submission date: 7/26/04
with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
484
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation
485
may be necessary because hypoglycemia may recur after apparent clinical recovery.
486
487
DOSAGE AND ADMINISTRATION
488
NovoLog should generally be given immediately before a meal (start of meal within 5 to 10
489
minutes after injection) because of its fast onset of action. The dosage of
490
NovoLog should be individualized and determined, based on the physician's advice, in
491
accordance with the needs of the patient. The total daily individual insulin requirement is
492
usually between 0.5 to1.0 units/kg/day. When used in a meal-related subcutaneous injection
493
treatment regimen, 50 to 70% of total insulin requirements may be provided by NovoLog and
494
the remainder provided by an intermediate-acting or long-acting insulin. When used in
495
external insulin infusion pumps, the initial programming of the pump is based on the total
496
daily insulin dose of the previous regimen. Although there is significant interpatient
497
variability, approximately 50% of the total dose is given as meal-related boluses of NovoLog
498
and the remainder as basal infusion. Because of NovoLog’s comparatively rapid onset and
499
short duration of glucose lowering activity, some patients may require more basal insulin and
500
more total insulin to prevent pre-meal hyperglycemia when using NovoLog than when using
501
human regular insulin. Additional basal insulin injections, or higher basal rates in external
502
subcutaneous infusion pumps may be necessary. NovoLog in the reservoir and infusion
503
sets, and the injection site must be changed at least every 48 hours.
504
NovoLog should be administered by subcutaneous injection in the abdominal wall, the thigh,
505
or the upper arm, or by continuous subcutaneous infusion in the abdominal wall. Injection
506
sites and infusion sites should be rotated within the same region. As with all insulins, the
507
duration of action will vary according to the dose, injection site, blood flow, temperature, and
508
level of physical activity.
509
Parenteral drug products should be inspected visually for particulate matter and discoloration
510
prior to administration, whenever solution and container permit. Never use any NovoLog if it
511
has become viscous (thickened) or cloudy; use it only if it is clear and colorless. NovoLog
512
should not be used after the printed expiration date.
513
514
HOW SUPPLIED
515
NovoLog is available in the following package sizes: each presentation containing 100 Units
516
of insulin aspart per mL (U-100).
517
10 mL vials
NDC 0169-7501-11
518
3 mL PenFill® cartridges*
NDC 0169-3303-12
519
3 mL NovoLog FlexPen® Prefilled syringe
NDC 0169-6339-10
520
3 mL NovoLog InnoLet® Prefilled syringe
NDC 0169-xxxx-xx
521
522
* NovoLog PenFill cartridges are for use with NovoFine® disposable needles and the
523
following Novo Nordisk 3 mL PenFill cartridge compatible insulin delivery devices:
524
NovoPen®3, NovoPen Junior, Innovo®, and InDuo®.
525
NovoLog FlexPen Prefilled syringes are for use with NovoFine disposable needles.
526
RECOMMENDED STORAGE
527
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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NovoLog in unopened vials, cartridges, NovoLog FlexPen, and NovoLog InnoLet Prefilled
528
syringes should be stored between 2o and 8oC (36o to 46oF). Do not freeze. Do not use
529
NovoLog if it has been frozen or exposed to temperatures that exceed 37oC (98.6oF). After
530
a vial, cartridge, or Prefilled syringe has been punctured, it may be kept at temperatures below
531
30oC (86oF) for up to 28 days, but should not be exposed to excessive heat or sunlight. Opened
532
vials may be refrigerated. Cartridges should not be refrigerated after insertion into the Novo
533
Nordisk 3 mL PenFill® cartridge compatible insulin delivery devices. The infusion set (tubing
534
and needle) should be changed at least every 48 hours.
535
536
NovoLog in the reservoir should be discarded after at least every 48 hours of use or after
537
exposure to temperatures that exceed 37oC (98.6oF).
538
539
Not in-use (unopened)
Room Temperature
(below 30◦ C)
Not in-use (unopened)
Refrigerated
In-use (opened) Room
Temperature (below 30◦ C)
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days (Do not refrigerate)
3 mL NovoLog
FlexPen
28 days
Until expiration date
28 days (Do not refrigerate)
3 mL NovoLog
InnoLet
28 days
Until expiration date
28 days (Do not refrigerate)
540
541
Rx only
542
543
Date of Issue: XX xx, 2004
544
8-XXXX-XX-XXX-X
545
546
Manufactured For Novo Nordisk Pharmaceuticals Inc., Princeton, New Jersey 08540
547
Manufactured By Novo Nordisk A/S, 2880 Bagsvaerd, Denmark
548
549
550
www.novonordisk-us.com
551
552
NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, Innovo®, InnoLet®, and NovoFine®
553
are trademarks of Novo Nordisk A/S
554
InDuo® is a trademark of LifeScan, Inc., a Johnson & Johnson company.
555
H-TRON™ is a trademark of Disetronic Medical Systems, Inc.
556
557
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
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Page 1
Novo Nordisk submission date: 7/26/04
1
Information For The Patient
2
NovoLog® (Insulin aspart [rDNA origin] Injection)
3
3 mL PenFill® Disposable Cartridge (300 units per cartridge)
4
10 mL Vial (1000 units per vial)
5
100 units/mL (U-100)
6
7
• What is the most important information I should know about NovoLog?
8
• For all NovoLog users
9
• For pump users
10
• What is NovoLog?
11
• Who should not use NovoLog?
12
• What should I know about using insulin?
13
• What should I know about using NovoLog?
14
• What should I avoid when using NovoLog?
15
• What are the possible side effects of NovoLog?
16
• How should I store NovoLog?
17
• General advice
18
• Injection and pump infusion instructions
19
• How should I inject NovoLog?
20
• Using Vials
21
• Using Cartridges
22
• How should I infuse NovoLog with an external subcutaneous insulin infusion
23
pump?
24
• How should I mix insulins?
25
26
Read this information carefully before you begin treatment. Read the information you
27
get whenever you get more medicine. There may be new information. This information
28
does not take the place of talking with your doctor about your medical condition or your
29
treatment. If you have any questions about NovoLog® (NO-voe-log), ask your doctor.
30
Only your doctor can determine if NovoLog® is right for you.
31
32
What is the most important information I should know about NovoLog?
33
34
For All NovoLog Users
35
• NovoLog (NO-voe-log) is different from regular human insulin and buffered regular
36
human insulin (Velosulin). It works faster (rapid onset of action) and will not work as
37
long (shorter duration of action) as regular human insulin or buffered regular human
38
insulin (Velosulin).
39
40
• Because the onset of action is fast, you should eat a meal 5 to10 minutes after a
41
NovoLog injection or NovoLog bolus infusion dose given by an external pump. (A
42
bolus is a large dose.) Eating right after the dose will reduce the risk of low blood
43
sugar (hypoglycemia).
44
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 2
Novo Nordisk submission date: 7/26/04
• The shorter duration of NovoLog’s action means that you may need to use an
46
intermediate or longer-acting insulin (basal insulin) or higher basal rates of NovoLog
47
insulin infusion in the pump. This will give the best glucose control and will help you
48
avoid hyperglycemia (high blood sugar) and ketoacidosis (too much acid [low pH] in
49
your body).
50
51
• Glucose monitoring is recommended for all patients who use insulin.
52
53
If you use NovoLog by injection, you may need to increase some or all of the following:
54
• your total dose of insulin
55
• your dose of intermediate or long-acting insulin (for example, NPH)
56
• the number of injections of basal insulin
57
58
If you infuse NovoLog into the skin (subcutaneous tissue) by pump, you may need to
59
increase some or all of the following:
60
• your total insulin dose
61
• the basal infusion dose
62
• the proportion of total insulin given as a basal infusion
63
64
Age and exposure to heat affect the stability of NovoLog and its preservative. Also,
65
NovoLog does not work well after it has been frozen. Therefore, do not use old insulin or
66
insulin that has been exposed to temperature extremes. Hyperglycemia may be a sign that
67
the insulin is no longer working and needs to be replaced.
68
69
Do not mix NovoLog:
70
• with any other insulins when used in a pump
71
• with Lantus (insulin glargine [rDNA origin] injection) when used with injections
72
by syringe
73
(You may, however, mix NovoLog with NPH when used with injections by syringe.
74
See: How should I mix insulins?)
75
76
For Pump Users
77
• Glucose monitoring is very important for patients using external pump subcutaneous
78
infusion therapy. You should be aware that pump or infusion set malfunctions that
79
result in inadequate insulin infusion can quickly lead to hyperglycemia and ketosis.
80
Accordingly, problems with the infusion pump, the flow of insulin, or the quality of
81
the insulin should be identified and corrected as quickly as possible. There is only a
82
small amount of insulin infused into the skin with a pump. The faster absorption
83
through the skin of rapid-acting insulin analogs and shorter duration of action may
84
give you less time to identify and correct the problem than with buffered regular
85
insulin.
86
87
• Therefore, you should dose with insulin from a new vial of NovoLog if unexplained
88
hyperglycemia or pump alarms do not respond to all of the following:
89
• a repeat dose (injection or bolus) of NovoLog
90
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 3
Novo Nordisk submission date: 7/26/04
• a change in the infusion set, including the NovoLog in the reservoir
91
• a change in the infusion site
92
93
If these measures do not work, you may need to resume skin (subcutaneous)
94
injections with syringes or insulin pens. Continue to monitor your glucose and
95
ketones. If problems continue, you must contact your doctor.
96
97
• When NovoLog is used in an external subcutaneous insulin infusion pump, you
98
should use only recommended pumps. Reservoirs, infusion sets, and injection site
99
should be changed at least every 48 hours. In addition, the reservoir, the infusion set,
100
and infusion site should be changed:
101
• with unexpected hyperglycemia or ketosis
102
• when the alarm sounds, as specified by your pump manual
103
• if the insulin or pump has been exposed to temperatures over 98.6oF (37oC), such
104
as in a sauna, with long showers, or on a hot day
105
• if the insulin or pump could have absorbed radiant heat, for example from
106
sunlight, that would heat the insulin to over 98.6oF (37oC). Dark colored pump
107
cases or sport covers can increase this type of heat. The location where the pump
108
is worn may also affect the temperature
109
110
Patients who develop “pump bumps” (skin reactions at the infusion site) may need to
111
change infusion sites more often than every 48 hours.
112
113
For your safety, read the section “What are the possible side effects of NovoLog?” to
114
review the symptoms of low blood sugar (hypoglycemia) and high blood sugar
115
(hyperglycemia).
116
117
What is NovoLog?
118
NovoLog is a clear, colorless, sterile solution for injection or infusion under the skin
119
(subcutaneously). NovoLog is a human-made form of insulin to lower your blood sugar
120
faster than human regular insulin. Because the insulin is human-made by recombinant
121
DNA technology (rDNA) and is chemically different from the insulin made by the human
122
body, it is called an insulin analog. The active ingredient in NovoLog is insulin aspart.
123
The concentration of insulin aspart is 100 units per milliliter, or U100. NovoLog also
124
contains: glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate,
125
and sodium chloride. Hydrochloric acid and/or sodium hydroxide may be added to adjust
126
the pH. These ingredients help to preserve or stabilize NovoLog insulin. The pH
127
(balance between acid and alkaline conditions) is important to the stability of NovoLog.
128
Increases in temperature can affect the stability of NovoLog, so it may not work well.
129
130
Who should not use NovoLog?
131
Do not use NovoLog if:
132
• your blood sugar (glucose) is too low (hypoglycemia)
133
• you do not plan to eat right after your injection or infusion
134
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 4
Novo Nordisk submission date: 7/26/04
• you are allergic to insulin aspart or any of the ingredients contained in NovoLog
135
(check with your doctor if you are not sure)
136
137
The effects of NovoLog on an unborn child or on a nursing baby are unknown.
138
Therefore, tell your doctor if you plan to become pregnant or breast feed, or if you
139
become pregnant. You may need to use another medicine.
140
141
Tell your doctor about all medicines and supplements that you are using. Some
142
medicines, including non-prescription medicines and dietary supplements, may affect
143
your diabetes.
144
145
What should I know about using insulin?
146
• Make any change of insulin cautiously and only under medical supervision. Changes
147
in the strength, manufacturer, type (for example: Regular, NPH, Lente®), species
148
(beef, pork, beef-pork, human) or method of manufacture (recombinant [rDNA] or
149
animal source insulin) may cause a need for a change in the timing or dose of the new
150
insulin.
151
• Glucose monitoring will help you and your health care provider adjust dosages.
152
• Always carry a quick source of sugar, such as candy or glucose tablets, to treat low
153
blood sugars (hypoglycemia).
154
• Always carry identification that states that you have diabetes.
155
156
What should I know about using NovoLog?
157
See the end of this Patient Information for instructions for using NovoLog in
158
injections and pumps.
159
160
• NovoLog starts working 10 to 20 minutes after injection or infusion. The greatest
161
blood sugar lowering effect is between 1 and 3 hours after injection or infusion. This
162
blood sugar lowering lasts for 3 to 5 hours. (The time periods are only general
163
guidelines.)
164
165
• Because the onset of action is rapid, you should eat a meal within 5to10 minutes after
166
a NovoLog injection or a NovoLog bolus dose from an external pump to avoid low
167
blood sugar (hypoglycemia).
168
169
• The shorter duration of NovoLog’s action means that you may need to use an
170
intermediate or longer-acting insulin (basal insulin) or higher basal rates of NovoLog
171
insulin infusion in the pump. This will help you avoid hyperglycemia and
172
ketoacidosis.
173
174
• Do not inject or infuse in skin that has become reddened or bumpy or thickened after
175
infusion or injection. Insulin absorption in these areas may not be the same as that in
176
normal skin, and may change the onset and duration of insulin action.
177
178
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 5
Novo Nordisk submission date: 7/26/04
• Use NovoLog only if it appears clear and colorless. Do not use NovoLog if it appears
179
cloudy, thickened, or colored, or if it contains solid particles.
180
181
What should I avoid while using NovoLog?
182
• Drinking alcohol may lead to hypoglycemia.
183
• Do not miss meals after injections of NovoLog or bolus infusions of NovoLog.
184
185
What are the possible side effects of NovoLog?
186
Insulins can cause hypoglycemia (low blood sugar), hyperglycemia (high blood sugar),
187
allergy, and skin reactions.
188
189
Hypoglycemia (low blood sugar). This is the most common side effect. It occurs when
190
there is a conflict between the amount of carbohydrates (source of glucose) from your
191
food, the amount of glucose used by your body, and the amount and timing of insulin
192
dosing. Therefore, hypoglycemia can occur with:
193
• The wrong insulin dose. This can happen with any of the following:
194
• too much insulin is injected
195
• the bolus dose of insulin infusion is set too high
196
• the basal infusion dose is set too high
197
• the pump does not work right, delivering too much insulin
198
• Medicines that directly lower glucose or increase sensitivity to insulin. This can
199
happen with oral (taken by mouth) antidiabetes drugs, sulfa antibiotics (for
200
infections), ACE inhibitors (for blood pressure and heart failure), salicylates,
201
including aspirin and NSAIDS (for pain), some antidepressants, and with other
202
medicines.
203
• Medical conditions that limit the body’s glucose reserve, lengthen the time
204
insulin stays in the body, or that increase sensitivity to insulin. These conditions
205
include diseases of the adrenal glands, the pituitary, the thyroid gland, the liver, and
206
the kidney.
207
• Not enough carbohydrate (sugar or starch) intake. This can happen if:
208
• a meal or snack is missed or delayed
209
• you have vomiting or diarrhea that decreases the amount of glucose absorbed by
210
your body
211
• alcohol interferes with carbohydrate metabolism
212
• Too much glucose use by the body. This can happen from:
213
• too much exercise
214
• higher than normal metabolism rates due to fever or an overactive thyroid
215
216
Hypoglycemia can be mild or severe. Its onset may be rapid. Patients with very good
217
(tight) glucose control, patients with diabetic neuropathy (nerve problems), or patients
218
using some Beta-blockers (used for high blood pressure and heart conditions) may have
219
few warning symptoms before severe hypoglycemia develops. Hypoglycemia may reduce
220
your ability to drive a car or use mechanical equipment without risk of injury to yourself
221
or others. Severe hypoglycemia can cause temporary or permanent harm to your heart or
222
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 6
Novo Nordisk submission date: 7/26/04
brain. It may cause unconsciousness, seizures, or death. Symptoms of hypoglycemia
223
include:
224
• anxiety, irritability, restlessness, trouble concentrating, personality changes, mood
225
changes, or other abnormal behavior
226
• tingling in your hands, feet, lips, or tongue
227
• dizziness, light-headedness, or drowsiness
228
• nightmares or trouble sleeping
229
• headache
230
• blurred vision or slurred speech
231
• palpitations (rapid heart beat)
232
• sweating
233
• tremor (shaking) or unsteady gait (walking)
234
235
Mild to moderate hypoglycemia can be treated by eating or drinking carbohydrates (milk,
236
orange juice, sugar candies, or glucose tablets). More severe or continuing hypoglycemia
237
may require the help of another person or emergency medical personnel. Patients who are
238
unable to take sugar by mouth or who are unconscious may need treatment with a
239
glucagon injection or glucose given intravenously (in the vein).
240
241
Talk with your doctor about severe, continuing, or frequent hypoglycemia, and
242
hypoglycemia for which you had few warning symptoms.
243
244
Hyperglycemia (high blood sugar) is another common side effect. It also occurs when
245
there is a conflict between the amount of carbohydrates (source of glucose) from your
246
food, the amount of glucose used by your body, and the amount and timing of insulin
247
dosing. Therefore, hyperglycemia can occur with:
248
• The wrong insulin dose. This can happen from any of the following:
249
• too little or no insulin is injected
250
• the bolus dose of insulin infusion is set too low
251
• the basal infusion dose is set too low
252
• the pump or catheter system does not work right, delivering too little insulin
253
• the insulin’s ability to lower glucose is changed by incorrect storage (freezing,
254
excessive heat), or usage after the expiration date
255
• Medicines that directly increase glucose or decrease sensitivity to insulin. This
256
can happen, for example, with thiazide water pills (used for blood pressure),
257
corticosteroids, birth control pills, and protease inhibitors (used for AIDS).
258
• Medical conditions that increase the body’s production of glucose or decrease
259
sensitivity to insulin. These medical conditions include fevers, infections, heart
260
attacks, and stress.
261
• Too much carbohydrate intake. This can happen if you
262
• eat larger meals
263
• eat more often
264
• increase the proportion of carbohydrate in your meals
265
266
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 7
Novo Nordisk submission date: 7/26/04
Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA)
267
or very high glucose levels (hyperosmolar coma) and result in unconsciousness and
268
death. Although DKA occurs most often in patients with Type 1 diabetes, it can occur in
269
patients with Type 2 diabetes who become severely ill. Urine or blood tests will show
270
acetone, ketones, and high levels of glucose. Hyperosmolar coma occurs most often in
271
patients with Type 2 diabetes. Urine and blood tests will show very high levels of
272
glucose.
273
Glucose monitoring is very important for patients using external pump infusion therapy.
274
You should be aware that pump or infusion set malfunctions that result in inadequate
275
insulin infusion can quickly lead to hyperglycemia and ketosis. Accordingly, problems
276
with the infusion pump, the flow of insulin, or the quality of the insulin should be
277
identified and corrected as quickly as possible. The faster absorption of rapid-acting
278
insulin analogs through the skin and shorter duration of action may give you less time to
279
identify and correct the problem.
280
Because some patients experience few symptoms of hyperglycemia and ketosis, it is
281
important to monitor your glucose several times a day. Symptoms of hyperglycemia
282
include:
283
• confusion or drowsiness
284
• fruity smelling breath
285
• rapid, deep breathing
286
• increased thirst
287
• decreased appetite, nausea, or vomiting
288
• abdominal (stomach area) pain
289
• rapid heart rate
290
• increased urination and dehydration (too little fluid in your body)
291
292
Mild hyperglycemia can be treated by extra doses of insulin and drinking fluids
293
(rehydration). Patients using pumps should check pump function and replace the insulin
294
in the reservoir-syringe, as well as change the tubing and catheter and the infusion site.
295
Patients using pumps may need to resume insulin injections with syringes or
296
injection pens. Glucose and acetone-ketone levels should be monitored more often until
297
they return to normal. More severe or continuing hyperglycemia requires prompt
298
evaluation and treatment by your health care provider.
299
300
Allergy can be serious. Generalized allergy is an uncommon, but possibly life-
301
threatening, reaction to insulin products. Symptoms include:
302
• itchy rash over the entire body
303
• shortness of breath or wheezing
304
• confusion
305
• low blood pressure
306
• rapid heart beat
307
• sweating
308
If you think you are having a generalized allergic reaction, get emergency medical
309
help right away.
310
311
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 8
Novo Nordisk submission date: 7/26/04
Allergic reactions at the injection site (itching, redness, hardness, or swelling) are more
312
common than generalized allergy. They may need several days or weeks to clear up.
313
Pump patients with site reactions may need to change their infusion sites more often than
314
every 48 hours. Patients should avoid injection or infusion of insulin into skin areas that
315
have reactions. Tell your doctor about such reactions, because they can become more
316
severe, or they may change the absorption of insulin.
317
318
Lipodystrophy is a common change in the fat below the injection site. These changes
319
include loss of fat (depressions in the skin called lipoatrophy) or thickening of the tissue
320
under the skin (lipohypertrophy). Pump patients with lipodystrophy may need to change
321
their infusion sites more often than every 48 hours. Patients should avoid injection or
322
infusion of insulin into skin areas that have these reactions. Tell your doctor about such
323
reactions because they can become more severe, or they may change the absorption of
324
insulin.
325
326
How should I store NovoLog?
327
• NovoLog can be damaged by high temperatures. Therefore, be sure to protect it
328
from high air temperatures, heat from the sun, saunas, long showers, and other heat
329
sources. This is especially important if you use a pump or an insulin pen, because
330
you carry these devices with you and they may be exposed to different temperatures
331
as you go about your daily activities. Throw NovoLog away if it has been in
332
temperatures greater than 98.6°F (37°C).
333
334
• Unopened NovoLog should be stored in a refrigerator but not in the freezer and
335
protected from light. Even if it has been refrigerated and protected from sunlight and
336
unopened, it should not be used after the expiration date on the label and the carton.
337
Unopened vials and cartridges can be stored unrefrigerated at temperatures below
338
86oF (30oC) and protected from light for up to 28 days.
339
340
• Punctured vials and cartridges can be stored unrefrigerated at temperatures below
341
86oF (30oC) and protected from light for up to 28 days. Punctured vials may be
342
stored in the refrigerator. Cartridges inserted into their NovoPen® 3 device should not
343
be stored in the refrigerator.
344
345
• The NovoLog in the pump reservoir and the complete infusion set (reservoir,
346
tubing, catheter-needle) should be replaced at least every 48 hours. Replacement
347
should be more often than every 48 hours if you have hyperglycemia, the pump alarm
348
sounds, or the insulin flow is blocked (occlusion).
349
350
• Never use NovoLog if it has been stored improperly.
351
352
General advice
353
This leaflet summarizes the most important information about NovoLog. If you would
354
like more information, talk with your doctor. You can ask your pharmacist or doctor for
355
information about NovoLog that is written for health professionals.
356
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 9
Novo Nordisk submission date: 7/26/04
357
Injection and pump infusion instructions
358
• NovoLog comes in 10 mL (milliliter) vials or in 3 mL cartridges. NovoLog can be
359
withdrawn from vials with syringes for injection or for insertion into the reservoirs of
360
external subcutaneous infusion pumps (Disetronic H-TRON® series, MiniMed 500
361
series, or other pumps recommended by your doctor.)
362
• Doses of insulin are measured in units. NovoLog is available as a U-100 insulin.
363
One milliliter (mL) of U-100 contains 100 units of insulin aspart (1 mL=1 cc). Only
364
U-100 type syringes should be used for injection to ensure proper dosing.
365
• Disposable syringes and needles are sterile if the package is sealed. They should be
366
used only once and thrown away properly, to protect others from harm.
367
• NovoLog PenFill® cartridges are for use with NovoFine® disposable needles and the
368
following Novo Nordisk 3 mL PenFill® compatible insulin delivery devices:
369
NovoPen® 3, NovoPen® Junior, Innovo®, and InDuo®. Never share needles.
370
371
How should I inject NovoLog?
372
373
Using Vials
374
1. The vial and the insulin should be inspected. The insulin should be clear and colorless.
375
The tamper-resistant cap should be in place to be removed by you. If the cap had been
376
removed before your first use of the vial, or if the insulin is cloudy or colored, you
377
should return the vial to the pharmacy. Do not use it.
378
2. Both the injection site and your hands should be cleaned with soap and water or with
379
alcohol. The injection site should be dry before you inject.
380
3. The rubber stopper should be wiped with an alcohol wipe.
381
4. The plunger of the syringe should be pulled back until the black tip is at the level for
382
the number of units to be injected.
383
5. Insert the needle of the syringe through the rubber stopper of the vial. Push in the
384
syringe plunger completely to put air into the vial.
385
6. Turn the vial upside-down with the needle-syringe still attached, and pull the plunger
386
back a few units past the correct dose.
387
7. Remove any air bubbles by flicking the syringe and squirting air bubbles out the
388
needle. Continue pushing the plunger until you have the correct dose.
389
8. Lift the vial off the syringe.
390
9. Inject NovoLog into the subcutaneous (under the skin) tissue (not into muscle or
391
blood vessels) in the abdomen, thighs, upper arms, or buttocks. Pinch the skin fold
392
between your fingers and push the needle straight into the pinched skin. Because
393
insulin absorption and activity can be affected by the site you choose, you should
394
discuss the injection site with your doctor.
395
10. Release the pinched skin and push the plunger in completely. Keep the needle in the
396
skin for a few seconds before withdrawing the syringe.
397
11. Press the injection site for a few seconds to reduce bleeding. Do not rub.
398
12. To avoid needle sticks, throw away the syringe and needle without recapping. Discuss
399
sterile technique and proper disposal of your used insulin supplies with your doctor.
400
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 10
Novo Nordisk submission date: 7/26/04
401
Using Cartridges
402
1. The cartridge and the insulin should be inspected. The insulin should be clear and
403
colorless. The tamper-resistant foil should be in place to be removed by you. If the
404
foil had been punctured or removed before your first use of the cartridge or if the
405
insulin is cloudy or colored, you should return the cartridge to the pharmacy. Do not
406
use it.
407
2. Both the injection site and your hands should be cleaned with soap and water or with
408
alcohol. The injection site should be dry before you inject. Do not use skin that is
409
reddened, itchy, or thickened as an infusion site.
410
3. Insert a 3 mL cartridge in the pen-device barrel. Attach a new needle to the end of the
411
cartridge and turn the pen device upside-down so that any air bubbles can be
412
eliminated by flicking the pen device and squirting air bubbles out the needle. (This
413
should eliminate extra air for all future doses from that cartridge. However, the needle
414
will need to be changed for each dose.)
415
4. Set the dose to be delivered by twisting the top of the pen-device until the correct
416
number appears in the window.
417
5. Inject NovoLog into the subcutaneous (under the skin) tissue (not into muscle or
418
blood vessels) in the abdomen, thighs, upper arms, or buttocks. Pinch the skin fold
419
between your fingers and push the needle straight into the pinched skin. Because
420
insulin absorption and activity can be affected by the site you choose, you should
421
discuss the injection site with your doctor.
422
6. Release the pinched skin. Inject the dose by pressing the flat plunger button on the
423
top of the pen-device. Keep the needle in the skin for a few seconds before
424
withdrawing the pen-device.
425
7. Press the injection site for a few seconds to reduce bleeding. Do not rub.
426
8. Throw away the disposable needle without recapping to avoid needle sticks. Discuss
427
sterile technique and proper disposal of your used insulin supplies with your doctor.
428
429
How should I infuse NovoLog with an external subcutaneous insulin infusion pump?
430
431
NovoLog is recommended for use with the Disetronic H-TRON®series, MiniMed 500
432
series, or other pumps recommended by your doctor.
433
434
1. Inspect your insulin as you would for an injection. The insulin should be clear and
435
colorless and without particles. The tamper-resistant cap should be in place to be
436
removed by you. If the cap had been removed before your first use of the vial or if the
437
insulin is cloudy or colored, you should return the vial to the pharmacy. Do not use it.
438
2. Both the infusion site and your hands should be cleaned with soap and water or with
439
alcohol. The infusion site should be dry before you insert the catheter-needle and
440
tubing. Do not use skin that is reddened, itchy, bumpy or thickened as an infusion site
441
because the onset and duration of NovoLog action may not be the same as that in
442
normal skin.
443
3. Fill the reservoir-syringe with 2 days worth of NovoLog plus about 25 extra units to
444
prime the pump and fill up the dead space of the infusion tubing.
445
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 11
Novo Nordisk submission date: 7/26/04
4. Remove air bubbles from the reservoir according to the pump manufacturers’
446
instructions.
447
5. Attach the infusion set to the reservoir. Make sure the connection is tight. Prime the
448
infusion set until you see a drop of insulin coming out of the infusion needle-catheter.
449
Flick the tubing to remove air bubbles. Follow the pump manufacturers’ instructions
450
for additional priming.
451
6. Prime the needle-catheter and insert the infusion set into the skin according to the
452
pump manufacturer.
453
7. Program the pump for mealtime NovoLog boluses and NovoLog basal insulin
454
infusion according to instructions from your doctor and the manufacturer of your
455
pump equipment.
456
8. Change the infusion site, the insulin reservoir, the tubing, the catheter-needle, and the
457
insulin every 48 hours or less, even if you have not used all of the insulin. This will
458
help ensure that NovoLog and the pump works well. (See “What is the most
459
important information I should know about NovoLog?”)
460
9. Change the infusion site, the insulin reservoir, the tubing, the catheter-needle, and the
461
insulin if you experience a pump alarm, catheter blockage, hyperglycemia, or if your
462
pump insulin has been exposed to heat greater than 98.6oF (37oC). (See “What is the
463
most important information I should know about NovoLog?”) Hyperglycemia
464
identified with glucose monitoring may be the first indication of a problem with the
465
pump, infusion set, or NovoLog. Hyperglycemia in the absence of an alarm still
466
requires you to investigate because pump alarms are designed to detect back-pressure
467
and occlusion. The alarms may not detect all the changes to NovoLog that could
468
result in hyperglycemia. You may need to resume subcutaneous insulin injections if
469
the cause of the problem cannot be promptly identified or fixed. (See
470
“Hyperglycemia” under “What are the possible side effects of NovoLog?”)
471
Remember that long stretches of tubing increase the risk for kinking and expose the
472
insulin in the tubing to more variations in temperature.
473
474
These instructions give you specific information for use of NovoLog in external
475
subcutaneous infusion pumps, but are not a substitute for pump education.
476
477
How should I mix insulins?
478
479
NovoLog should be mixed only when syringe injections are used. NovoLog can be
480
mixed with NPH human insulin immediately before use. The NovoLog should be drawn
481
into the syringe before the NPH. Mixing with other insulins has not been studied.
482
NovoLog should not be mixed with Lantus® (insulin glargine [rDNA origin]
483
injection). Mixed insulins should NEVER be used in a pump or for intravenous
484
infusion.
485
486
1. Add together the doses of NPH and NovoLog. The total dose will determine the final
487
volume in the syringe after drawing up both insulins into the syringe.
488
2. Roll the NPH vial between your hands until the liquid is equally cloudy throughout.
489
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air into the
490
NPH vial and then remove the needle without withdrawing or touching any of the
491
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-024
Final DRAFT
Page 12
Novo Nordisk submission date: 7/26/04
NPH insulin. (Transferring NPH to the NovoLog vial will contaminate the NovoLog
492
vial and may change how quickly it works.)
493
4. Draw into the syringe the same amount of air as the NovoLog dose. Inject this air into
494
the NovoLog vial. With the needle in place, turn the vial upside-down and withdraw
495
the correct dose of NovoLog. The tip of the needle must be in the NovoLog to get the
496
full dose and not an air dose.
497
5. Insert the needle into the NPH vial. Turn the NPH vial upside down with the syringe-
498
needle still in it. Withdraw the correct dose of NPH.
499
6. Inject immediately to reduce changes in how quickly the insulin works.
500
501
502
Helpful information for people with diabetes is published by the American Diabetes
503
Association, 1660 Duke Street, Alexandria, VA 22314
504
505
For information contact:
506
Novo Nordisk Pharmaceuticals Inc.,
507
100 College Road West
508
Princeton, New Jersey 08540
509
1-800-727-6500
510
www.novonordisk-us.com
511
512
Manufactured by
513
Novo Nordisk A/S
514
2880 Bagsvaerd, Denmark
515
516
License under U.S. Patent No. 5,618,913 and Des. 347,894
517
518
NovoLog®, PenFill, NovoPen, Innovo®, NovoFine, and Lente are trademarks of
519
Novo Nordisk A/S.
520
Lantus® is a trademark of Aventis Pharmaceuticals Inc.
521
H-TRON™ is a trademark of Disetronic Medical Systems, Inc.
522
InDuoTM is a trademark of LifeScan, Inc., a Johnson & Johnson company.
523
524
525
Date of Issue: XX xx, 2004
526
527
8-XXXX-XX-XXX-X
528
529
Printed in Denmark
530
531
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:25.581464 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20986s024lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 24} |
3,941 | NDA 20-986/S-023
Page 1
NNPI Submission date 4/6/04
NovoLog®
1
Insulin aspart (rDNA origin) Injection
2
3
4
DESCRIPTION
5
NovoLog® (insulin aspart [rDNA origin] injection) is a human insulin analog that is a rapid-
6
acting, parenteral blood glucose-lowering agent. NovoLog is homologous with regular human
7
insulin with the exception of a single substitution of the amino acid proline by aspartic acid in
8
position B28, and is produced by recombinant DNA technology utilizing Saccharomyces
9
cerevisiae (baker's yeast) as the production organism. Insulin aspart has the empirical formula
10
C256H381N65079S6 and a molecular weight of 5825.8.
11
12
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
13
Figure 1. Structural formula of insulin aspart.
14
15
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart (B28
16
asp regular human insulin analog) 100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL,
17
metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25
18
mg/mL, and sodium chloride 0.58 mg/mL. NovoLog has a pH of 7.2-to 7.6. Hydrochloric
19
acid 10% and/or sodium hydroxide 10% may be added to adjust pH.
20
21
CLINICAL PHARMACOLOGY
22
Mechanism of Action
23
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins, including
24
NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose by
25
facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
26
from the liver.
27
28
In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-
29
lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is
30
more rapid in onset and of shorter duration, compared to regular human insulin, due to its
31
faster absorption after subcutaneous injection (see Figure 2 and Figure 3).
32
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 2
NNPI Submission date 4/6/04
Pharmacokinetics
34
The single substitution of the amino acid proline with aspartic acid at position B28 in
35
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
36
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared
37
to regular human insulin.
38
39
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of action, and
40
a shorter duration of action than regular human insulin after subcutaneous injection (see
41
Figure 2 and Figure 3). The relative bioavailability of NovoLog compared to regular human
42
insulin indicates that the two insulins are absorbed to a similar extent.
43
44
45
46
Figure 2. Serial mean serum free insulin concentration collected up to 6 hours following a
47
single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
48
injected immediately before a meal in 22 patients with Type 1 diabetes.
49
50
In studies in healthy volunteers (total n=l07) and patients with Type 1 diabetes (total n=40),
51
NovoLog consistently reached peak serum concentrations approximately twice as fast as
52
regular human insulin. The median time to maximum concentration in these trials was 40 to
53
50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial
54
in patients with Type 1 diabetes, NovoLog and regular human insulin, both administered
55
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
56
82.1 and 35.9 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of
57
insulin aspart have not been established in patients with Type 2 diabetes.
58
The intra-individual variability in time to maximum serum insulin concentration for healthy
59
male volunteers was significantly less for NovoLog than for regular human insulin. The
60
clinical significance of this observation has not been established.
61
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences between
62
NovoLog and regular human insulin described above, were observed independent of the
63
injection site (abdomen, thigh, or upper arm). Differences in pharmacokinetics between
64
NovoLog and regular human insulin are not associated with differences in overall glycemic
65
control.
66
0
20
40
60
80
0
1
2
3
4
5
6
Free serum insulin (mU/L)
Time (h)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 3
NNPI Submission date 4/6/04
67
Distribution and Elimination - NovoLog has a low binding to plasma proteins, 0-9%, similar
68
to regular human insulin. After subcutaneous administration in normal male volunteers
69
(n=24), NovoLog was more rapidly eliminated than regular human insulin with an average
70
apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
71
72
Pharmacodynamics
73
Studies in normal volunteers and patients with diabetes demonstrated that NovoLog has a
74
more rapid onset of action than regular human insulin.
75
In a 6-hour study in patients with Type 1 diabetes (n=22), the maximum glucose-lowering
76
effect of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 3).
77
The duration of action for NovoLog is 3 to 5 hours compared to 5 to 8 hours for regular human
78
insulin. The time course of action of insulin and insulin analogs such as NovoLog may vary
79
considerably in different individuals or within the same individual. The parameters of
80
NovoLog activity (time of onset, peak time and duration) as designated in Figure 3 should be
81
considered only as general guidelines. The rate of insulin absorption and consequently the
82
onset of activity is known to be affected by the site of injection, exercise, and other variables
83
(see PRECAUTIONS, General). Differences in pharmacodynamics between NovoLog and
84
regular human insulin are not associated with differences in overall glycemic control.
85
86
87
88
Figure 3. Serial mean serum glucose collected up to 6 hours following a single pre-meal dose
89
of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately
90
before a meal in 22 patients with Type 1 diabetes.
91
92
Special Populations
93
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
94
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
95
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with Type 1 diabetes. The
96
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents
97
with Type 1 diabetes between NovoLog and regular human insulin were similar to those in
98
healthy adult subjects and adults with Type 1 diabetes.
99
50
100
150
200
250
300
0
1
2
3
4
5
6
Serum glucose (mg/dL)
Time (h)
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100
Geriatrics - The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog
101
has not been studied.
102
103
Gender - In healthy volunteers, no difference in insulin aspart levels was seen between men
104
and women when body weight differences were taken into account. There was no significant
105
difference in efficacy noted (as assessed by HbAlc) between genders in a trial in patients with
106
Type 1 diabetes.
107
108
Obesity - In a study of 23 patients with type 1 diabetes and a wide range of body mass index
109
(BMI, 22-39 kg/m2), the pharmacokinetic parameters, AUC and Cmax, of NovoLog were
110
generally unaffected by BMI. Clearance of NovoLog was reduced by 28% in patients with
111
BMI >32 compared to patients with BMI <23 when a single dose of 0.1 U/kg NovoLog was
112
administered. However, only 3 patients with BMI <23 were studied.
113
114
Ethnic Origin - The effect of ethnic origin on the pharmacokinetics of NovoLog has not been
115
studied.
116
117
Renal Impairment - Some studies with human insulin have shown increased circulating levels
118
of insulin in patients with renal failure. A single subcutaneous dose of NovoLog was
119
administered in a study of 18 patients with creatinine clearance values ranging from normal to
120
<30 mL/min and not requiring hemodialysis. No apparent effect of creatinine clearance values
121
on AUC and Cmax of NovoLog was found. However, only 2 patients with severe renal
122
impairment were studied (<30 mL/min). Careful glucose monitoring and dose adjustments of
123
insulin, including NovoLog, may be necessary in patients with renal dysfunction (see
124
PRECAUTIONS, Renal Impairment).
125
126
Hepatic Impairment - Some studies with human insulin have shown increased circulating
127
levels of insulin in patients with liver failure. In an open-label, single-dose study of 24
128
patients with Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic
129
impairment), no correlation was found between the degree of hepatic failure and any NovoLog
130
pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of insulin,
131
including NovoLog, may be necessary in patients with hepatic dysfunction (see
132
PRECAUTIONS, Hepatic Impairment).
133
134
Pregnancy - The effect of pregnancy on the pharmacokinetics and pharmacodynamics of
135
NovoLog has not been studied (see PRECAUTIONS, Pregnancy).
136
137
Smoking - The effect of smoking on the pharmacokinetics/pharmacodynamics of NovoLog has
138
not been studied.
139
140
CLINICAL STUDIES
141
To evaluate the safety and efficacy of NovoLog in patients with Type 1 diabetes, two
142
six-month, open-label, active-control (NovoLog vs. Novolin® R) studies were conducted (see
143
Table 1). NovoLog was administered by subcutaneous injection immediately prior to meals
144
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and regular human insulin was administered by subcutaneous injection 30 minutes before
145
meals. NPH insulin was administered as the basal insulin in either single or divided daily
146
doses. Changes in HbA1c, the rates of hypoglycemia (as determined from the number of
147
events requiring intervention from a third party), and the incidence of ketosis were clinically
148
comparable for the two treatment regimens. The mean total daily doses of insulin were greater
149
(1-3 U/day) in the NovoLog-treated patients compared to patients who received regular human
150
insulin. This difference was primarily due to basal insulin requirements. To achieve
151
improved glycemic control, some patients required more than three doses of meal-related
152
insulin and/or more than one dose of basal insulin (see Table 1). No serum glucose
153
measurements were obtained in these studies.
154
155
To evaluate the safety and efficacy of NovoLog in patients with Type 2 diabetes, one six-
156
month, open-label, active-control (NovoLog vs. Novolin R) study was conducted (see Table
157
1). NovoLog was administered by subcutaneous injection immediately prior to meals and
158
regular human insulin was administered by subcutaneous injection 30 minutes before meals.
159
NPH insulin was administered as the basal insulin in either single or divided daily doses.
160
Changes in HbAlc and the rates of hypoglycemia (as determined from the number of events
161
requiring intervention from a third party) were clinically comparable for the two treatment
162
regimens. The mean total daily dose of insulin was greater (2 U/day) in the NovoLog-treated
163
patients compared to patients who received regular human insulin. This difference was
164
primarily due to basal insulin requirements. To achieve improved glycemic control, some
165
patients required more than three doses of meal-related insulin and/or more than one dose of
166
basal insulin (see Table 1).
167
168
Table 1. Results of two six-month, active-control, open-label trials in patients with Type 1
169
diabetes (Studies A and B) and one six-month, active-control, open-label trial in patients with
170
Type 2 diabetes (Study C).
171
172
Mean HbA1c (%)
% of Patients Using Various
Numbers of Insulin Injections /
Day2
Rapid-acting
Basal
Study
Treatment (n)
Baseline
Month
6
Hypoglycemia1
(events / month
/ patient)
1 - 2
3
4 - 5
1
2
NovoLog (n=694)
8.0
7.9
0.06
3
75
22
54
46
A
Novolin R (n=346)
8.0
8.0
0.06
6
75
19
63
37
NovoLog (n=573)
7.9
7.8
0.08
4
90
6
94
6
B
Novolin R (n=272)
8.0
7.9
0.06
4
91
4
93
7
NovoLog (n=90)
8.1
7.7
0.02
4
93
4
97
4
C
Novolin R (n=86)
7.8
7.8
0.01
2
93
5
93
7
1 Events requiring intervention from a third party during the last three months of treatment
173
2 Percentages are rounded to the nearest whole number
174
175
To evaluate the use of NovoLog by subcutaneous infusion with an external pump, two open-
176
label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) compared NovoLog
177
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versus Velosulin (buffered regular human insulin) in patients with Type 1 diabetes. Changes in
178
HbA1c and rates of hypoglycemia were comparable. Patients with Type 2 diabetes were also
179
studied in an open-label, parallel design trial (16 weeks [n=127]) using NovoLog by
180
subcutaneous infusion compared to pre-prandial injection (in conjunction with basal NPH
181
injections). Reductions in HbA1c and rates of hypoglycemia were comparable (see
182
INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, Mixing of Insulins,
183
Information for Patients, DOSAGE AND ADMINISTRATION, and RECOMMENDED
184
STORAGE).
185
186
INDICATIONS AND USAGE
187
NovoLog is indicated for the treatment of adult patients with diabetes mellitus, for the control
188
of hyperglycemia. Because NovoLog has a more rapid onset and a shorter duration of activity
189
than human regular insulin, NovoLog given by injection should normally be used in regimens
190
with an intermediate or long-acting insulin. NovoLog may also be infused subcutaneously by
191
external insulin pumps (see WARNINGS, PRECAUTIONS [especially Usage in Pumps],
192
Information for Patients [especially For Patients Using Pumps], Mixing of Insulins, DOSAGE
193
AND ADMINISTRATION, RECOMMENDED STORAGE).
194
195
CONTRAINDICATIONS
196
NovoLog is contraindicated during episodes of hypoglycemia and in patients hypersensitive to
197
NovoLog or one of its excipients.
198
199
WARNINGS
200
NovoLog differs from regular human insulin by a more rapid onset and a shorter
201
duration of activity. Because of the fast onset of action, the injection of NovoLog should
202
immediately be followed by a meal. Because of the short duration of action of NovoLog,
203
patients with diabetes also require a longer-acting insulin to maintain adequate glucose
204
control. Glucose monitoring is recommended for all patients with diabetes and is
205
particularly important for patients using external pump infusion therapy.
206
207
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog.
208
As with all insulins, the timing of hypoglycemia may differ among various insulin
209
formulations.
210
211
Any change of insulin dose should be made cautiously and only under medical
212
supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH,
213
analog), species (animal, human), or method of manufacture (rDNA versus animal-
214
source insulin) may result in the need for a change in dosage.
215
216
Insulin Pumps: When used in an external insulin pump for subcutaneous infusion,
217
NovoLog should not be diluted or mixed with any other insulin. Physicians and patients
218
should carefully evaluate information on pump use in the NovoLog physician and patient
219
package inserts and in the pump manufacturer's manual (e.g. NovoLog-specific
220
information should be followed for in-use time, frequency of changing infusion sets, or
221
other details specific to NovoLog usage, because NovoLog-specific information may
222
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differ from general pump manual instructions). Pump or infusion set malfunctions or
223
insulin degradation can lead to hyperglycemia and ketosis in a short time because of the
224
small subcutaneous depot of insulin. This is especially pertinent for rapid-acting insulin
225
analogs that are more rapidly absorbed through skin and have shorter duration of
226
action. These differences may be particularly relevant when patients are switched from
227
multiple injection therapy or infusion with buffered regular insulin. Prompt
228
identification and correction of the cause of hyperglycemia or ketosis is necessary.
229
Interim therapy with subcutaneous injection may be required (see PRECAUTIONS,
230
Mixing of Insulins, Information for Patients, DOSAGE AND ADMINISTRATION, and
231
RECOMMENDED STORAGE).
232
233
PRECAUTIONS
234
General
235
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated
236
with the use of all insulins. Because of differences in the action of NovoLog and other
237
insulins, care should be taken in patients in whom such potential side effects might be
238
clinically relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using
239
potassium-lowering drugs or patients taking drugs sensitive to serum potassium level).
240
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects
241
associated with the use of all insulins.
242
As with all insulin preparations, the time course of NovoLog action may vary in different
243
individuals or at different times in the same individual and is dependent on site of injection,
244
blood supply, temperature, and physical activity.
245
Adjustment of dosage of any insulin may be necessary if patients change their physical
246
activity or their usual meal plan. Insulin requirements may be altered during illness,
247
emotional disturbances, or other stresses.
248
249
Hypoglycemia - As with all insulin preparations, hypoglycemic reactions may be associated
250
with the administration of NovoLog. Rapid changes in serum glucose levels may induce
251
symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early
252
warning symptoms of hypoglycemia may be different or less pronounced under certain
253
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such
254
as beta-blockers, or intensified diabetes control (see PRECAUTIONS, Drug Interactions).
255
Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior
256
to patients’ awareness of hypoglycemia.
257
258
Renal Impairment - As with other insulins, the dose requirements for NovoLog may be
259
reduced in patients with renal impairment (see CLINICAL PHARMACOLOGY,
260
Pharmacokinetics).
261
262
Hepatic Impairment - As with other insulins, the dose requirements for NovoLog may be
263
reduced in patients with hepatic impairment (see CLINICAL PHARMACOLOGY,
264
Pharmacokinetics).
265
266
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Allergy - Local Allergy - As with other insulin therapy, patients may experience redness,
267
swelling, or itching at the site of injection. These minor reactions usually resolve in a few
268
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In
269
some instances, these reactions may be related to factors other than insulin, such as irritants in
270
a skin cleansing agent or poor injection technique.
271
Systemic Allergy - Less common, but potentially more serious, is generalized allergy to
272
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
273
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
274
allergy, including anaphylactic reaction, may be life threatening.
275
Localized reactions and generalized myalgias have been reported with the use of cresol as an
276
injectable excipient.
277
In controlled clinical trials using injection therapy, allergic reactions were reported in 3 of 735
278
patients (0.4%) who received regular human insulin and 10 of 1394 patients (0.7%) who
279
received NovoLog. During these and other trials, 3 of 2341 patients treated with NovoLog
280
were discontinued due to allergic reactions.
281
282
Antibody Production - Increases in levels of anti-insulin antibodies that react with both human
283
insulin and insulin aspart have been observed in patients treated with NovoLog. The number
284
of patients treated with insulin aspart experiencing these increases is greater than the number
285
among those treated with human regular insulin. Data from a 12-month controlled trial in
286
patients with Type 1 diabetes suggest that the increase in these antibodies is transient. The
287
differences in antibody levels between the human regular insulin and insulin aspart treatment
288
groups observed at 3 and 6 months were no longer evident at 12 months. The clinical
289
significance of these antibodies is not known. They do not appear to cause deterioration in
290
HbA1c or to necessitate increases in insulin dose.
291
292
Pregnancy and Lactation
293
Female patients should be advised to tell their physician if they intend to become, or if they
294
become pregnant. Information is not available on the use of NovoLog during pregnancy or
295
lactation.
296
297
Usage in Pumps
298
NovoLog is recommended for use in Disetronic H-TRON® plus V100 with Disetronic 3.15
299
plastic cartridges and Classic or Tender infusion sets; MiniMed Models 505, 506, or 507 with
300
MiniMed 3 mL syringes and Polyfin® or Sof-set® infusion sets.
301
302
In-vitro studies have shown that pump malfunction, loss of cresol, and insulin degradation,
303
may occur with the use of NovoLog for more than two days at 37oC (98.6oF) in infusion sets
304
and reservoirs. NovoLog in clinical use should not be exposed to temperatures greater than
305
37oC (98.6oF). NovoLog should not be mixed with other insulins or with a diluent when it
306
is used in the pump (see WARNINGS, PRECAUTIONS, Mixing of Insulins, Information for
307
Patients, DOSAGE AND ADMINISTRATION, and RECOMMENDED STORAGE).
308
309
310
Information for Patients
311
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312
For all patients:
313
Patients should be informed about potential risks and advantages of NovoLog therapy
314
including the possible side effects. Patients should also be offered continued education and
315
advice on insulin therapies, injection technique, life-style management, regular glucose
316
monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo-
317
and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of
318
dose, instruction in the use of injection or subcutaneous infusion devices, and proper storage
319
of insulin. Patients should be informed that frequent, patient-performed blood glucose
320
measurements are needed to achieve optimal glycemic control and avoid both hyper- and
321
hypoglycemia.
322
323
Female patients should be advised to tell their physician if they intend to become, or if they
324
become pregnant. Information is not available on the use of NovoLog during pregnancy or
325
lactation (see PRECAUTIONS, Pregnancy).
326
327
For patients using pumps
328
Patients using external pump infusion therapy should be trained in intensive insulin therapy
329
with multiple injections and in the function of their pump and pump accessories. NovoLog is
330
recommended for use with Disetronic H-TRON plus V100 with Disetronic 3.15 plastic
331
cartridges and Classic or Tender infusion sets; MiniMed Models 505, 506, and 507 with
332
MiniMed 3 mL syringes and Polyfin or Sof-set infusion sets. The use of NovoLog in quick-
333
release infusion sets and cartridge adapters has not been assessed.
334
335
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
336
(metacresol), the infusion sets (reservoir syringe, tubing, and catheter) and the NovoLog
337
in the reservoir should be replaced, and a new infusion site selected every 48 hours or
338
less. Insulin exposed to temperatures higher than 37oC (98.6oF) should be discarded. The
339
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
340
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are
341
erythematous, pruritic, or thickened should be reported to medical personnel, and a new site
342
selected because continued infusion may increase the skin reaction and/or alter the absorption
343
of NovoLog.
344
345
Pump or infusion set malfunctions or insulin degradation can lead to hyperglycemia and
346
ketosis in a short time because of the small subcutaneous depot of insulin. This is especially
347
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have
348
shorter duration of action. These differences are particularly relevant when patients are
349
switched from infused buffered regular insulin or multiple injection therapy. Prompt
350
identification and correction of the cause of hyperglycemia or ketosis is necessary. Problems
351
include pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and
352
degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur. If these
353
problems cannot be promptly corrected, patients should resume therapy with subcutaneous
354
insulin injection and contact their physician (see WARNINGS, PRECAUTIONS, Mixing of
355
Insulins, DOSAGE AND ADMINISTRATION, and RECOMMENDED STORAGE).
356
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357
Laboratory Tests
358
As with all insulin therapy, the therapeutic response to NovoLog should be monitored by
359
periodic blood glucose tests. Periodic measurement of glycosylated hemoglobin is
360
recommended for the monitoring of long-term glycemic control.
361
362
Drug Interactions
363
A number of substances affect glucose metabolism and may require insulin dose adjustment
364
and particularly close monitoring.
365
• The following are examples of substances that may increase the blood-glucose-lowering
366
effect and susceptibility to hypoglycemia: oral antidiabetic products, ACE inhibitors,
367
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene,
368
salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.
369
• The following are examples of substances that may reduce the blood-glucose-lowering
370
effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
371
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin,
372
thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives).
373
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the
374
blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which
375
may sometimes be followed by hyperglycemia.
376
• In addition, under the influence of sympatholytic medicinal products such as beta-
377
blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be
378
reduced or absent (see CLINICAL PHARMACOLOGY).
379
380
Mixing of Insulins
381
• A clinical study in healthy male volunteers (n=24) demonstrated that mixing NovoLog
382
with NPH human insulin immediately before injection produced some attenuation in the
383
peak concentration of NovoLog, but that the time to peak and the total bioavailability of
384
NovoLog were not significantly affected. If NovoLog is mixed with NPH human insulin,
385
NovoLog should be drawn into the syringe first. The injection should be made
386
immediately after mixing. Because there are no data on the compatibility of NovoLog and
387
crystalline zinc insulin preparations, NovoLog should not be mixed with these
388
preparations.
389
• The effects of mixing NovoLog with insulins of animal source or insulin preparations
390
produced by other manufacturers have not been studied (see WARNINGS).
391
• Mixtures should not be administered intravenously.
392
• When used in external subcutaneous infusion pumps for insulin, NovoLog should not be
393
mixed with any other insulins or diluent.
394
395
Carcinogenicity, Mutagenicity, Impairment of Fertility
396
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
397
carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
398
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times
399
the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively).
400
At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in
401
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females when compared to untreated controls. The incidence of mammary tumors for
402
NovoLog was not significantly different than for regular human insulin. The relevance of
403
these findings to humans is not known. NovoLog was not genotoxic in the following tests:
404
Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood
405
lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo
406
UDS test in rat liver hepatocytes. In fertility studies in male and female rats, at subcutaneous
407
doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on
408
U/body surface area), no direct adverse effects on male and female fertility, or general
409
reproductive performance of animals was observed.
410
411
Pregnancy - Teratogenic Effects - Pregnancy Category C
412
There are no adequate well-controlled clinical studies of the use of NovoLog in pregnant
413
women. NovoLog should be used during pregnancy only if the potential benefit justifies the
414
potential risk to the fetus.
415
416
It is essential for patients with diabetes or history of gestational diabetes to maintain good
417
metabolic control before conception and throughout pregnancy. Insulin requirements may
418
decrease during the first trimester, generally increase during the second and third trimesters,
419
and rapidly decline after delivery. Careful monitoring of glucose control is essential in such
420
patients.
421
422
Subcutaneous reproduction and teratology studies have been performed with NovoLog and
423
regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
424
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
425
The effects of NovoLog did not differ from those observed with subcutaneous regular human
426
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
427
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
428
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
429
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0
430
U/kg/day, based on U/body surface area). The effects are probably secondary to maternal
431
hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50
432
U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the
433
human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose
434
of 1.0 U/kg/day for rabbits, based on U/body surface area.
435
436
Nursing Mothers
437
It is unknown whether insulin aspart is excreted in human milk. Many drugs, including
438
human insulin, are excreted in human milk. For this reason, caution should be exercised when
439
NovoLog is administered to a nursing mother.
440
441
Pediatric Use
442
Safety and effectiveness of NovoLog in children have not been studied.
443
444
Geriatric Use
445
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Of the total number of patients (n= 1,375) treated with NovoLog in 3 human insulin-controlled
446
clinical studies, 2.6% (n=36) were 65 years of age or over. Half of these patients had Type 1
447
diabetes (18/1285) and half had Type 2 (18/90) diabetes. The HbA1c response to NovoLog,
448
as compared to human insulin, did not differ by age, particularly in patients with Type 2
449
diabetes. Additional studies in larger populations of patients 65 years of age or over are
450
needed to permit conclusions regarding the safety of NovoLog in elderly compared to younger
451
patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of
452
NovoLog action have not been performed.
453
454
455
ADVERSE REACTIONS
456
Clinical trials comparing NovoLog with regular human insulin did not demonstrate a
457
difference in frequency of adverse events between the two treatments.
458
Adverse events commonly associated with human insulin therapy include the following:
459
Body as Whole - Allergic reactions (see PRECAUTIONS, Allergy).
460
Skin and Appendages - Injection site reaction, lipodystrophy, pruritus, rash (see
461
PRECAUTIONS, Allergy; Information for Patients, Usage in Pumps).
462
Other – Hypoglycemia, Hyperglycemia and ketosis (see WARNINGS and PRECAUTIONS).
463
In controlled clinical trials, small, but persistent elevations in alkaline phosphatase result were
464
observed in some patients treated with NovoLog. The clinical significance of this finding is
465
unknown.
466
467
OVERDOSAGE
468
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
469
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose.
470
Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes
471
with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
472
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation
473
may be necessary because hypoglycemia may recur after apparent clinical recovery.
474
475
DOSAGE AND ADMINISTRATION
476
NovoLog should generally be given immediately before a meal (start of meal within 5- to 10
477
minutes after injection) because of its fast onset of action. The dosage of
478
NovoLog should be individualized and determined, based on the physician's advice, in
479
accordance with the needs of the patient. The total daily individual insulin requirement is
480
usually between 0.5- to 1.0 units/kg/day. When used in a meal-related subcutaneous injection
481
treatment regimen, 50- to 70% of total insulin requirements may be provided by NovoLog and
482
the remainder provided by an intermediate-acting or long-acting insulin. When used in
483
external insulin infusion pumps, the initial programming of the pump is based on the total
484
daily insulin dose of the previous regimen. Although there is significant interpatient
485
variability, approximately 50% of the total dose is given as meal-related boluses of NovoLog
486
and the remainder as basal infusion. Because of NovoLog’s comparatively rapid onset and
487
short duration of glucose lowering activity, some patients may require more basal insulin and
488
more total insulin to prevent pre-meal hyperglycemia when using NovoLog than when using
489
human regular insulin. Additional basal insulin injections, or higher basal rates in external
490
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 13
NNPI Submission date 4/6/04
subcutaneous infusion pumps may be necessary. Infusion sets and the insulin in the infusion
491
sets must be changed every 48 hours or sooner to assure the activity of NovoLog and
492
proper pump function (see WARNINGS, PRECAUTIONS, Information for Patients).
493
494
NovoLog should be administered by subcutaneous injection in the abdominal wall, the thigh,
495
or the upper arm, or by continuous subcutaneous infusion in the abdominal wall. Injection
496
sites and infusion sites should be rotated within the same region. As with all insulins, the
497
duration of action will vary according to the dose, injection site, blood flow, temperature, and
498
level of physical activity.
499
Parenteral drug products should be inspected visually for particulate matter and discoloration
500
prior to administration, whenever solution and container permit. Never use any NovoLog if it
501
has become viscous (thickened) or cloudy; use it only if it is clear and colorless. NovoLog
502
should not be used after the printed expiration date.
503
504
HOW SUPPLIED
505
NovoLog is available in the following package sizes: each presentation containing 100 Units
506
of insulin aspart per mL (U-100).
507
10 mL vials
NDC 0169-7501-11
508
3 mL PenFill® cartridges*
NDC 0169-3303-12
509
3 mL NovoLog FlexPen® Prefilled syringe NDC 0169-6339-10
510
3 mL NovoLog InnoLet® Prefilled syringe NDC 0169-xxxx-xx
511
512
* NovoLog PenFill cartridges are for use with NovoFine® disposable needles and the
513
following 3 mL PenFill cartridge compatible delivery devices: NovoPen 3, NovoPen Junior,
514
Innovo® and InDuo®.
515
NovoLog FlexPen and NovoLog InnoLet Prefilled syringes are for use with NovoFine
516
disposable needles.
517
518
RECOMMENDED STORAGE
519
NovoLog in unopened vials, cartridges, and NovoLog FlexPen and NovoLog InnoLet
520
Prefilled syringes should be stored between 2o and 8oC (36o to 46oF). Do not freeze. Do not
521
use NovoLog if it has been frozen or exposed to temperatures that exceed 37oC (98.6oF).
522
After a vial, cartridge, or Prefilled syringe has been punctured, it may be kept at temperatures
523
below 30oC (86oF) for up to 28 days, but should not be exposed to excessive heat or sunlight.
524
Opened vials may be refrigerated. Cartridges should not be refrigerated after insertion into the
525
Novo Nordisk 3 mL PenFill cartridge compatible insulin delivery devices.
526
527
Not in-use (unopened)
Room Temperature
(below 30◦C)
Not in-use (unopened)
Refrigerated
In-use (opened) Room
Temperature (below 30◦C)
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days (Do not refrigerate)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 14
NNPI Submission date 4/6/04
3 mL NovoLog
Flex Pen
28 days
Until expiration date
28 days (Do not refrigerate)
3 mL NovoLog
InnoLet
28 days
Until expiration date
28 days (Do not refrigerate)
528
529
530
Infusion sets (reservoirs, tubing, and catheters) and the NovoLog in the reservoir should be
531
discarded after no more than 48 hours of use or after exposure to temperatures that exceed
532
37oC (98.6oF).
533
534
Rx only
535
536
Date of Issue: [insert date]
537
8-XXXX-XX-XXX-X
538
539
Manufactured For Novo Nordisk Pharmaceuticals Inc., Princeton, New Jersey 08540
540
www.novonordisk-us.com
541
Manufactured By Novo Nordisk A/S, 2880 Bagsvaerd, Denmark
542
543
NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, Innovo®, InnoLet®, and NovoFine®
544
are trademarks of Novo Nordisk A/S
545
InDuo® is a trademark of LifeScan, Inc., a Johnson & Johnson company.
546
Polyfin® and Sof-set® are trademarks of Medtronic MiniMed, Inc.
547
H-TRON® is a trademark of Disetronic Medical Systems, Inc.
548
549
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 1
NNPI submission date: 4/6/04
1
Information For The Patient
2
NovoLog® InnoLet® (Insulin aspart [rDNA origin] Injection) 3 mL Prefilled
3
Syringe
4
100 units/mL (U-100)
5
6
• What is the most important information I should know about NovoLog?
7
• What is NovoLog?
8
• Who should not use NovoLog?
9
• What should I know about using insulin?
10
• What should I know about using NovoLog?
11
• What should I avoid when using NovoLog?
12
• What are the possible side effects of NovoLog?
13
• How should I store NovoLog?
14
• General advice
15
• How do I prepare NovoLog InnoLet before I give an injection?
16
• How do I give an injection using NovoLog InnoLet?
17
18
Read this information carefully before you begin treatment. Read the information you
19
get whenever you get more medicine. There may be new information. This information
20
does not take the place of talking with your doctor about your medical condition or your
21
treatment. If you have any questions about NovoLog® (NO-voe-log), ask your doctor.
22
Only your doctor can determine if NovoLog® is right for you.
23
24
What is the most important information I should know about NovoLog?
25
26
• Because NovoLog starts lowering blood glucose more quickly and will not work as
27
long as human regular insulin, you should give NovoLog injection 5 to 10 minutes
28
before you eat.
29
• Because NovoLog does not work as long as human regular insulin, you may need to
30
add an intermediate-acting or longer-acting insulin (basal insulin) to give the best
31
glucose control.
32
• Glucose monitoring is recommended for all patients who use insulin.
33
34
Age and exposure to heat affect the stability of NovoLog and its preservative. Also,
35
NovoLog does not work after it has been frozen. Therefore, do not use old insulin or
36
insulin that has been exposed to high temperature (greater than 37◦C [98.6◦F]) or frozen.
37
Hyperglycemia may be a sign that the insulin is no longer working and needs to be
38
replaced.
39
40
For your safety, read the section “What are the possible side effects of NovoLog?” to
41
review the symptoms of low blood sugar (hypoglycemia) and high blood sugar
42
(hyperglycemia).
43
44
What is NovoLog?
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 2
NNPI submission date: 4/6/04
NovoLog is a clear, colorless, sterile solution for injection under the skin
46
(subcutaneously). Because NovoLog is made by recombinant DNA (rDNA) technology
47
and is chemically different from the insulin made by the human body, it is called an
48
insulin analog. The active ingredient in NovoLog is insulin aspart. The concentration of
49
insulin aspart is 100 units per milliliter, or U100. NovoLog also contains: glycerin,
50
phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, and sodium chloride.
51
Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. These
52
ingredients help to preserve or stabilize NovoLog. The pH (balance between acid and
53
alkaline conditions) is important to the stability of NovoLog.
54
55
Who should not use NovoLog?
56
Do not use NovoLog if:
57
• your blood sugar (glucose) is too low (hypoglycemia).
58
• you do not plan to eat right after your injection.
59
• you are allergic to insulin aspart or any of the ingredients mentioned above in “What
60
is NovoLog?”. Check with your doctor if you are not sure.
61
62
The effects of NovoLog on an unborn child or on a nursing baby are unknown.
63
Therefore, tell your doctor if you plan to become pregnant or breast feed, or if you
64
become pregnant.
65
Tell your doctor about all medicines and supplements that you are using. Some
66
medicines, including non-prescription medicines and dietary supplements, may affect
67
your diabetes.
68
69
What should I know about using insulin?
70
• Any change of insulin should be made cautiously and only under medical
71
supervision. Changes in the strength, manufacturer, type (for example: Regular, NPH,
72
Lente®), species (beef, pork, beef-pork, human) or method of manufacture
73
(recombinant [rDNA] or animal source insulin) may result in the need for a change in
74
the timing or dosage of the new insulin.
75
• Glucose monitoring will help you and your health care provider adjust the dosages.
76
• Always carry a quick source of sugar, such as candy or glucose tablets, to treat low
77
blood sugars (hypoglycemia).
78
• Always carry identification that states that you have diabetes.
79
80
What should I know about using NovoLog?
81
See the end of this Information For The Patient for instructions about preparing
82
and giving the injection.
83
84
• NovoLog starts working 10- to 20 minutes after injection. The greatest blood sugar
85
lowering effect is between 1 and 3 hours after injection. This blood sugar lowering
86
lasts for 3 to 5 hours. (The time periods are only general guidelines.)
87
88
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 3
NNPI submission date: 4/6/04
• If you switch to NovoLog from a different insulin product, you may require a change
89
in dosage from that used with other insulin products. If an adjustment is needed, it
90
may occur with the first dose or during the first several weeks or months.
91
92
• Do not inject in skin that has become reddened or bumpy or thickened after injection.
93
Insulin absorption in these areas may not be the same as that in normal skin, and may
94
change the onset and duration of insulin action.
95
96
• Use NovoLog only if it appears clear and colorless. Do not use NovoLog if it appears
97
cloudy, thickened, or colored, or if it contains solid particles.
98
99
What should I avoid while using NovoLog?
100
• Drinking alcohol may lead to hypoglycemia.
101
• Do not miss meals after injections of NovoLog.
102
103
What are the possible side effects of NovoLog?
104
NovoLog, like other insulin products, can cause hypoglycemia (low blood sugar),
105
hyperglycemia (high blood sugar), allergy, and skin reactions.
106
107
Hypoglycemia (low blood sugar) is the most common side effect. Hypoglycemia occurs
108
when there is too much insulin, or not enough food in your body, or the amount and
109
timing of insulin dosing is incorrect. Therefore, hypoglycemia can occur with:
110
• Excessive (too much) insulin. This can happen if too much insulin is injected.
111
• Medicines that directly lower glucose or increase sensitivity to insulin. This can
112
happen with oral (taken by mouth) antidiabetes drugs, sulfa antibiotics (for
113
infections), ACE inhibitors (for blood pressure and heart failure), salicylates,
114
including aspirin and NSAIDS (for pain), some antidepressants, and with other
115
medicines.
116
• Medical conditions that limit the body’s glucose reserve, lengthen the time
117
insulin stays in the body, or that increase sensitivity to insulin. These conditions
118
include diseases of the adrenal glands, the pituitary, the thyroid gland, the liver, and
119
the kidney.
120
• Not enough carbohydrate (sugar or starch) intake. This can happen if:
121
• a meal or snack is missed or delayed
122
• you have vomiting or diarrhea that decreases the amount of glucose absorbed by
123
your body
124
• alcohol interferes with carbohydrate metabolism
125
• Too much glucose use by the body. This can happen from:
126
• too much exercise
127
• higher than normal metabolism rates due to fever or an overactive thyroid
128
129
Hypoglycemia can be mild or severe. Its onset may be rapid. Patients with very good
130
(tight) glucose control, patients with diabetic neuropathy (nerve problems), or patients
131
using some Beta-blockers (used for high blood pressure and heart conditions) may have
132
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 4
NNPI submission date: 4/6/04
few warning symptoms before severe hypoglycemia develops. Hypoglycemia may reduce
133
your ability to drive a car or use mechanical equipment without risk of injury to yourself
134
or others. Severe hypoglycemia can cause temporary or permanent harm to your heart or
135
brain. It may cause unconsciousness, seizures, or death. Symptoms of hypoglycemia
136
include:
137
• anxiety, irritability, restlessness, trouble concentrating, personality changes, mood
138
changes, or other abnormal behavior
139
• tingling in your hands, feet, lips, or tongue
140
• dizziness, light-headedness, or drowsiness
141
• nightmares or trouble sleeping
142
• headache
143
• blurred vision or slurred speech
144
• palpitations (rapid heart beat)
145
• sweating
146
• tremor (shaking) or unsteady gait (walking)
147
148
Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates (milk,
149
orange juice, sugar candies, or glucose tablets). More severe or continuing hypoglycemia
150
may require the help of another person or emergency medical personnel. Patients who are
151
unable to take sugar by mouth or who are unconscious may need treatment with a
152
glucagon injection or glucose given intravenously (in the vein).
153
154
Talk with your doctor about severe, continuing, or frequent hypoglycemia, and
155
hypoglycemia for which you had few warning symptoms.
156
157
Hyperglycemia (high blood sugar) is another common side effect. Hyperglycemia also
158
occurs when there is too little insulin, or too much food in your body, or the amount and
159
timing of insulin dosing is incorrect. Therefore, hyperglycemia can occur with:
160
• Insufficient (too little) insulin. This can happen from any of the following:
161
• too little or no insulin is injected.
162
• the insulin’s ability to lower glucose is changed by incorrect storage (freezing,
163
excessive heat), or usage after the expiration date.
164
• Medicines that directly increase glucose or decrease sensitivity to insulin. This
165
can happen, for example, with thiazide diuretics (water pills used for blood pressure),
166
corticosteroids, birth control pills, and protease inhibitors (used for AIDS).
167
• Medical conditions that increase the body’s production of glucose or decrease
168
sensitivity to insulin. These medical conditions include surgery, fevers, infections,
169
heart attacks, and stress.
170
• Too much carbohydrate intake. This can happen if you
171
• eat larger meals
172
• eat more often
173
• increase the proportion of carbohydrate in your meals
174
175
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 5
NNPI submission date: 4/6/04
Hyperglycemia can be mild or severe. Hyperglycemia can progress to diabetic
176
ketoacidosis (DKA) or very high glucose levels (hyperosmolar coma) and result in
177
unconsciousness and death. Although diabetic acidosis occurs most often in patients
178
with Type 1 diabetes, it can occur in patients with Type 2 diabetes who become severely
179
ill. Urine or blood tests will show acetone, ketones, and high levels of glucose.
180
Hyperosmolar coma occurs most often in patients with Type 2 diabetes. Urine and blood
181
tests will show very high levels of glucose.
182
Because some patients experience few symptoms of hyperglycemia and ketosis, it is
183
important to monitor your glucose several times a day. Symptoms of hyperglycemia
184
include:
185
• confusion or drowsiness
186
• fruity smelling breath
187
• rapid, deep breathing
188
• increased thirst
189
• decreased appetite, nausea, or vomiting
190
• abdominal (stomach area) pain
191
• rapid heart rate
192
• increased urination and dehydration (too little fluid in your body)
193
194
Mild hyperglycemia is treated by drinking fluids (rehydration) and taking extra doses of
195
insulin. Glucose and acetone-ketone levels should be monitored more often until they
196
return to normal. More severe or continuing hyperglycemia requires prompt
197
evaluation and treatment by your health care provider.
198
199
Allergy can be serious. Generalized allergy is an uncommon, but possibly life-
200
threatening, reaction to insulin products. Symptoms include:
201
• itchy rash over the entire body
202
• shortness of breath or wheezing
203
• confusion
204
• low blood pressure
205
• rapid heart beat
206
• sweating
207
If you think you are having a generalized allergic reaction, get emergency medical
208
help right away.
209
210
Allergic reactions at the injection site (itching, redness, hardness, or swelling) are more
211
common than generalized allergy. They may need several days or weeks to clear up.
212
Avoid injection of insulin into skin areas that have reactions. Tell your doctor about such
213
reactions, because they can become more severe, or they may change the absorption of
214
insulin.
215
216
Lipodystrophy is a common change in the fat below the injection site. These changes
217
include loss of fat (depressions in the skin called lipoatrophy) or thickening of the tissue
218
under the skin (lipohypertrophy). Avoid injection or infusion of insulin into skin areas
219
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 6
NNPI submission date: 4/6/04
that have these reactions. Tell your doctor about such reactions because they can become
220
more severe, or they may change the absorption of insulin.
221
222
How should I store NovoLog?
223
• NovoLog can be damaged by high temperatures. Therefore, be sure to protect it
224
from high temperatures, heat from the sun, saunas, long showers, and other heat
225
sources. This is especially important if you use NovoLog InnoLet because you carry
226
this device with you and it may be exposed to different temperatures as you go about
227
your daily activities. Throw away NovoLog InnoLet if it has been exposed to
228
temperatures greater than 37°C (98.6°F).
229
230
• Unopened NovoLog should be stored in a refrigerator but not in the freezer. Do not
231
use NovoLog if it has been frozen. Keep unused NovoLog InnoLet in the carton so
232
that they will stay clean and protected from light. If unopened NovoLog InnoLet is
233
stored at room temperature below 30oC (86oF) and protected from direct heat and
234
sunlight, you can use it for up to 28 days.
235
236
• After starting to use insulin, do not refrigerate NovoLog InnoLet in use (the rubber
237
stopper has been punctured). However, keep it as cool as possible at room
238
temperature (below 30oC [86oF]) and away from direct heat and sunlight for up to 28
239
days.
240
241
• Never use NovoLog InnoLet if it has been stored improperly.
242
243
• Never use NovoLog InnoLet after the expiration date printed on the label or carton.
244
245
• Throw away unrefrigerated NovoLog InnoLet after 28 days, even if they still
246
contain insulin.
247
248
Not in-use (unopened)
Room Temperature
(below 30◦C)
Not in-use (unopened)
Refrigerated
In-use (opened) Room
Temperature (below 30◦C)
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days (Do not refrigerate)
3 mL NovoLog
Flex Pen
28 days
Until expiration date
28 days (Do not refrigerate)
3 mL NovoLog
InnoLet
28 days
Until expiration date
28 days (Do not refrigerate)
249
250
General advice
251
• NovoLog is available in:
252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 7
NNPI submission date: 4/6/04
i.
10 mL vials
253
ii.
3 mL PenFill cartridges for use with insulin Pen
254
iii.
3 mL NovoLog FlexPen Prefilled syringes
255
iv.
3 mL NovoLog InnoLet Prefilled syringes
256
v.
For use with external insulin infusion pump
257
258
• This leaflet summarizes the most important information about NovoLog. If you
259
would like more information, talk with your doctor. You can ask your pharmacist
260
or doctor for additional information about NovoLog.
261
262
How do I prepare NovoLog InnoLet before I give an injection?
263
264
• Never attach a disposable needle on your NovoLog InnoLet Prefilled syringe
265
until you are ready to give an injection. Remove it immediately after each
266
injection. Follow the directions for use of this syringe on the reverse side of this
267
insert.
268
• NovoLog InnoLet Prefilled syringes may contain a small amount of air. To
269
prevent an injection of air and to make sure correct dose of insulin is given, an air
270
shot must be done before each injection. See Using the disposable NovoLog
271
InnoLet Prefilled Syringe for the instructions on how to do an air shot.
272
273
How do I give an injection using NovoLog InnoLet?
274
275
1. Thighs, upper arms, buttocks, abdomen are acceptable areas for an insulin injection.
276
Do not change the injection areas without consulting your physician. Do not inject
277
into a muscle unless your physician has advised it. You should never inject insulin
278
into a vein.
279
2. The actual point of injection should be changed each time. Injection sites should be
280
about an inch apart. The injection site should be clean and dry. Pinch up skin area
281
to be injected and hold it firmly.
282
3. Hold the device upright and push the needle quickly and firmly into the pinched-up
283
area. Release the skin and push the push-button all the way in to inject insulin
284
beneath the skin. To ensure that all the insulin is injected, keep the needle in the skin
285
for at least 6 seconds after injection with your thumb on the push-button. If slight
286
bleeding occurs, press lightly with a dry cotton swab for a few seconds – DO NOT
287
RUB.
288
4. After the injection, remove the needle without replacing the cap. Hold the NovoLog
289
InnoLet firmly while you unscrew the NovoFine disposable needle. The NovoFine
290
disposable needle must be removed immediately after each injection without
291
replacing the cap. If the NovoFine disposable needle is not removed, some liquid
292
may leak out of the NovoLog InnoLet.
293
5. Used NovoFine disposable needles should be placed in sharps containers (such as red
294
biohazard containers), hard plastic containers (such as detergent bottles), or metal
295
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-986/S-023
Page 8
NNPI submission date: 4/6/04
containers (such as an empty coffee can). Such containers should be sealed and
296
disposed of properly.
297
298
299
300
301
302
303
Helpful information is published by The American Diabetes Association, 1660 Duke
304
Street, Alexandria, VA 22314, for people with diabetes.
305
306
For information contact:
307
Novo Nordisk Pharmaceuticals Inc.,
308
100 College Road West
309
Princeton, New Jersey 08540
310
1-800-727-6500
311
www.novonordisk-us.com
312
313
Manufactured by
314
Novo Nordisk A/S
315
2880 Bagsvaerd, Denmark
316
317
License under U.S. Patent No. xxx and Des. xxx
318
319
NovoLog® InnoLet®, NovoFine®, and PenFill are trademarks of Novo Nordisk A/S.
320
321
Date of Issue: [tbd]
322
323
8-XXXX-XX-XXX-X
324
325
Printed in Denmark
326
327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9 of 14
Patient package insert
Using the disposable NovoLog InnoLet Prefilled Syringe
328
NovoLog InnoLet is a disposable dial-a-dose insulin delivery system able to deliver 1 to a
329
maximum of 50 units. The dose can be adjusted in increments of 1 unit. NovoLog
330
InnoLet is designed for use with NovoFine® single-use needles. NovoLog InnoLet is not
331
recommended for the blind or visually impaired patients without the assistance of a
332
sighted individual trained in the proper use of the product.
333
334
Please read these instructions completely before using this device.
335
336
337
338
PREPARING THE NOVOLOG INNOLET:
339
a. Pull off the cap.
340
b. Wipe the rubber stopper with an alcohol swab.
341
342
Stopper
Device
Reservoir
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10 of 14
Patient package insert
343
344
1A. Remove the protective tab from the disposable needle and screw the needle onto the
345
NovoLog InnoLet (see diagram 1A). Never place a disposable needle on your NovoLog
346
InnoLet until you are ready to give an injection. Remove the needle immediately after
347
use. If the needle is not removed, some liquid may leak from the NovoLog InnoLet.
348
349
350
351
352
353
1B. Giving the air shot before each injection:
354
Small amounts of air may collect in the needle and insulin reservoir during normal use.
355
To avoid injecting air and to ensure proper dosing, dial 2 units by turning the dose
356
selector clockwise. Hold the NovoLog InnoLet with the needle pointing up and tap the
357
insulin reservoir gently with your finger so any air bubbles collect in the top of the
358
reservoir. Remove both the plastic outer and inner needle cap.
359
360
With the needle pointing up, press the push button as far as it will go and the dose
361
selector returns to zero. See if a drop of insulin appears at the needle tip (see diagram
362
1B). If not, repeat the procedure until insulin appears. Before the first use of NovoLog
363
InnoLet, you may need to perform up to 6 air shots to get a droplet of insulin at the
364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 11 of 14
Patient package insert
needle tip. If you need to make more than 6 air shots, do not use the syringe, and contact
365
Novo Nordisk at 1-800-727-6500. A small air bubble may remain but it will not be
366
injected because the operating mechanism prevents the reservoir from being completely
367
emptied.
368
369
2. SETTING THE DOSE
370
371
372
373
Always check that the push button is fully depressed and the dose selector is set at 0.
374
Hold the NovoLog InnoLet in front of you and dial the dose selector clockwise to set the
375
required dose. Do not put your hand over the push button when dialing the dose. If the
376
button is not allowed to rise freely, insulin will be pushed out of the needle. You will
377
hear a click for every single unit dialed. Do not rely on this click for setting your dose. If
378
you have set a wrong dose, simply dial the dose selector forward or backwards until the
379
right number of units has been set. You cannot set a dose larger than the number of units
380
left in the reservoir. 50 units is the maximum dose.
381
382
3. GIVING THE INJECTION
383
384
Use the injection technique recommended by your doctor or health care professionals.
385
386
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 12 of 14
Patient package insert
387
388
389
Check that you have set the proper dose and depress the push button as far as it will go.
390
Make sure not to block the dose selector while injecting, as the dose selector must be
391
allowed to return to zero when you press the push button. When depressing the push
392
button you may hear a clicking sound. Do not rely on this clicking sound as a means of
393
confirming your dose.
394
395
After the injection, the needle should remain under the skin for at least 6 seconds.
396
Keep the push button fully depressed until the needle is withdrawn from the skin. This
397
will ensure that the full dose has been delivered. If blood appears after you pull the
398
needle from your skin, press the injection site lightly with a finger. Do not rub the area.
399
400
Do not recap the needle. Remove the used needle and dispose of it in a puncture-
401
resistant container. Used syringes, needles, or lancets should be placed in sharps
402
containers (such as red biohazard containers), hard plastic containers (such as detergent
403
bottles), or metal containers (such as an empty coffee can). Such containers should be
404
sealed and disposed of properly.
405
406
It is important that you use a new needle for each injection. Health care
407
professionals, relatives, and other caregivers, should follow general precautionary
408
measures for removal and disposal of needles to eliminate the risk of unintended
409
needle penetration.
410
411
LATER (SUBSEQUENT) INJECTIONS
412
413
It is important that you use a new needle for each injection.
414
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 13 of 14
Patient package insert
Always check that the push button is fully depressed and the dose selector is at zero
415
before using the NovoLog InnoLet again. If not, turn the dose selector until the push
416
button is completely down. Then proceed as stated in steps 1-3.
417
418
The numbers on the insulin reservoir can be used to estimate the amount of insulin left in
419
the NovoLog InnoLet. Do not use these numbers to measure the insulin dose. You
420
cannot set a dose greater than the number of units remaining in the reservoir.
421
422
423
4. FUNCTION CHECK
424
425
426
427
If your disposable NovoLog InnoLet is not working properly, follow this procedure:
428
429
- Screw on a new NovoFine needle
430
- Give an air shot as described in section 1B
431
- Put the outer needle cap onto the needle
432
- Dispense 20 units into the outer needle cap, holding the NovoLog InnoLet with the
433
needle pointing down.
434
435
The insulin should fill the lower part of the cap (as shown in diagram 4). If the
436
disposable NovoLog InnoLet has released too much, or too little insulin, repeat the test.
437
If it happens again, do not use your disposable NovoLog InnoLet and contact Novo
438
Nordisk® at 1-800-727-6500.
439
Dispose of the used NovoLog InnoLet carefully without the needle attached.
440
441
442
5. IMPORTANT NOTES
443
• If you need to perform more than 6 air shots before the first use of the NovoLog
444
InnoLet to get a droplet of insulin at the needle tip, do not use it.
445
• Remember to perform an air shot before each injection. See diagram 1B.
446
• Care should be taken not to drop your NovoLog InnoLet or subject it to impact.
447
• Remember to keep the NovoLog InnoLet with you. Don’t leave it in a car or other
448
location where it can get too hot or too cold.
449
• NovoLog InnoLet is designed for use with NovoFine disposable needles.
450
• Do NOT attach a disposable needle on the NovoLog InnoLet until you are ready to
451
use it. Remove the needle right after use without recapping.
452
• Throw away used needles properly, so other people will not be harmed. Used
453
NovoFine disposable needles should be placed in sharps containers (such as red
454
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 14 of 14
Patient package insert
biohazard containers), hard plastic containers (such as detergent bottles), or metal
455
containers (such as an empty coffee can). Such containers should be sealed and
456
disposed of properly.
457
• Throw away the used NovoLog InnoLet carefully, without the needle attached.
458
• Always carry a spare NovoLog InnoLet with you in case your NovoLog InnoLet is
459
damaged or lost.
460
• To avoid possible transmission of disease, do not let anyone else use your NovoLog
461
InnoLet, even if they attach a new needle.
462
• Novo Nordisk is not responsible for harm due to using this insulin delivery system
463
with products not recommended by Novo Nordisk.
464
•
Keep this NovoLog InnoLet out of the reach of children.
465
466
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:25.950153 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20986scp023_novolog_lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 23} |
3,940 | 2
8
8-xxxx-31-
xxx-x
Code centre line
Code: 100% Direction
Length: Max 29 mm (100%)
22-503-30
Exp. Date/Control:
RA Labelling & Graphics
Carton: 22-503-30-30X
Current 1.0
Lacquer free area:
Lacquerform: 30048-2
Colour: PMS 280C
+ Black + PMS 151C
+ PMS 289C
100 units/mL (U-100)
5×3 mL Prefilled Insulin Syringes
Rx only
For use with NovoFine® disposable needles or
other products specifically recommended by
Novo Nordisk.
Keep in a cold place. Avoid freezing.
Protect from light.
Warning
Any change of insulin should be made cautiously and
only under medical supervision.
NovoLog® FlexPen® Prefilled Syringe is for single person
use only.
See accompanying literature for dosage.
Needles not included.
For parenteral use.
Each mL contains 100 Units of insulin aspart; glycerin, 16 mg;
phenol,1.50 mg; metacresol, 1.72 mg; zinc, 19.6 µg;
disodium hydrogen phosphate dihydrate, 1.25 mg and
sodium chloride, 0.58 mg.
NovoLog® FlexPen® and NovoFine® are trademarks of
Novo Nordisk A/S. U.S. patent No. 4,973,318
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by:
Novo Nordisk A/S
DK 2880 Bagsvaerd, Denmark
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100) 5×3 mL Prefilled Insulin Syringes
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100) 5×3 mL Prefilled Insulin Syringes
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100) 5×3 mL Prefilled Insulin Syringes
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
NDC 0169-6339-10
List 633910
NovoLog_FlexPen_carton5.qxd 06-10-2004 17:29 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100) 1×3 mL Prefilled Insulin Syringes
Rx only
Sample. Not for resale
For use with NovoFine® disposable needles or other
products specifically recommended by Novo Nordisk.
Keep in a cold place. Avoid freezing.
Protect from light.
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by:
Novo Nordisk A/S
DK 2880 Bagsvaerd, Denmark
Warning
Any change of insulin should be made cautiously and only under
medical supervision.
NovoLog® FlexPen® Prefilled Syringe is for single person use only.
See accompanying literature for dosage.
Needles not included.
For parenteral use.
Each mL contains 100 Units of insulin aspart; glycerin, 16 mg;
phenol, 1.50 mg; metacresol, 1.72 mg; zinc, 19.6 µg; disodium
hydrogen phosphate dihydrate, 1.25 mg and sodium chloride, 0.58
mg.
NovoLog® FlexPen® and NovoFine® are trademarks of
Novo Nordisk A/S. U.S. patent No. 4,973,318
Exp. Date/Control:
22-508-37
RA Labelling & Graphics
Carton: 22-508-37-30X
Current 1.0
Lacqerform: 30080-2
Lacqer free area:
Colour: PMS 280C
+ PMS 289C + PMS 151C
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100)
1×3 mL Prefilled Insulin Syringes
Code centre line
Code: 100% Direction
Length Max 29 mm (100%)
8 mm
1 mm
8-xxxx-31-xxx-x
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100) 1×3 mL Prefilled Insulin Syringes
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
100 units/mL (U-100) 1×3 mL Prefilled Insulin Syringes
NDC 0169-6339-90
List 633990
NovoLog_FlexPen_carton1.qxd 06-10-2004 17:27 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exp. Date/
Control:
8-xxxx-31-xxx-x
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
Rx only
NDC 0169-6339-90
List 633990
100 units/mL
3 mL Prefilled Insulin Syringe
Overlap
Lakfrit område
ved tiltryk
og overlap
RA Labelling & Graphics
Label: 48x61-20X
Current 1.0
Lacquer area:
Lacquerform: 20005-1
Colour: White colour under
Colour band and Product band
indicated by yellow
+ PMS 285C + Black + PMS 151C
Center for
prod. name
NovoLog®
FlexPen® Prefilled Syringe
Insulin aspart Injection (rDNA origin)
RSS Barcode
NovoLog_FlexPen_label.qxd 06-10-2004 18:15 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exp. Date/
Control:
RA Labelling & Graphics
Carton: 22-480-26-30X
Current 1.0
Machinepack
5 pieces 3 ml Penfill
US
Lacquerform: 30055-1
Lacquer free area:
Colour: PMS 280C + Black
+ PMS 151C
1 8
Code centre line
Code: 100% Direction
Length: Max 29 mm (100%)
22-480-26
3 mL cartridges
100 units/mL (U-100)
5 cartridges per package
For use with 3 mL PenFill cartridge
compatible delivery devices*
Keep in a cold place.
Avoid freezing.
Protect from light.
Rx only
8-xxxx-31-xxx-x
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
Questions or Comments?
Call 1-800-727-6500
(Se habla español) or write:
Novo Nordisk Pharmaceuticals, Inc.
100 College Road West
Princeton, NJ 08540
www.novonordisk-us.com
Manufactured by
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Each mL contains 100 Units of insulin aspart; glycerin, 16 mg;
phenol, 1.50 mg; metacresol, 1.72 mg; zinc, 19.6 µg; disodium
hydrogen phosphate dihydrate, 1.25 mg and sodium chloride,
0.58 mg.
*3 mL PenFill cartridge compatible delivery devices: NovoPen® 3,
NovoPen® Junior, Innovo®, InDuo®
NovoLog®, PenFill®, Innovo® and NovoPen® are trademarks
owned by Novo Nordisk A/S. InDuo® is a trademark of
LifeScan, Inc., a Johnson & Johnson company.
Warning
Any change of insulin should be made cautiously
and only under medical supervision.
PenFill® cartridge is for single person use only.
See accompanying literature for dosage.
For parenteral use.
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
3 mL cartridges 100 units/mL (U-100)
5 cartridges per package
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
3 mL cartridges 100 units/mL (U-100)
5 cartridges per package
Rx only
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
3 mL cartridges 100 units/mL (U-100)
5 cartridges per package
NDC 0169-3303-12
List 330312
NovoLog_Penfill_carton5.qxd 06-10-2004 18:17 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RA Labelling & Graphics
Carton: 22-479-41
Edition: 2002-03-301-3
3 ml Penfill - 1 piece US
Lacquerform: 30090-1
Lacquer free area:
Colour: PMS 280C
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
8 mm
2 mm
Code end
Code 200% Direction
Length: Max 29 mm (100%)
NDC 0169-3303-91
List 330391
Questions or Comments?
Call 1-800-727-6500
(Se habla español) or write:
Novo Nordisk
Pharmaceuticals, Inc.
100 College Road West
Princeton, NJ 08540
www.novonordisk-us.com
Manufactured by:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Each mL contains 100 Units of insulin aspart; glycerin, 16 mg; phenol, 1.50 mg;
metacresol, 1.72 mg; zinc, 19.6 µg; disodium hydrogen phosphate dihydrate,
1.25 mg and sodium chloride, 0.58 mg.
NovoLog®, PenFill®, Innovo® and NovoPen® are trademarks owned by
Novo Nordisk A/S.
InDuo™ is a trademark of LifeScan, Inc., a Johnson & Johnson company
*3 mL PenFill® cartridge compatible delivery devices: NovoPen® 3,
Innovo®, InDuo™
Warning
Any change of insulin should be
made cautiously
and only under medical supervision.
PenFill® cartridge is for single person
use only.
See accompanying literature for dosage.
For parenteral use.
3 mL cartridge 100 units/mL (U-100)
1 cartridge per package
For use with 3 mL PenFill® cartridge
compatible delivery devices*
Keep in a cold place. Avoid freezing. Protect from light. Rx only
Sample. Not for resale
Exp. Date/Control:
22-479-41
8-xxxx-31-xxx-x
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
3 mL cartridges 100 units/mL (U-100)
1 cartridge per package
Sample. Not for Resale
Rx only
3 mL cartridges 100 units/mL (U-100)
1 cartridge per package
NovoLog_Penfill_carton1.qxd 06-10-2004 18:05 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8-xxxx-
31-xxx-x
Exp. Date/
Control:
Label: 53x44
Current 1.0
US
Colour: White tint is indicated
by yellow+ Black + PMS 151C
White tint under colour band,
RSS code and product name
(only the frame)
Overlap
White
White tint block
under colour band
Code start
Code: 100% Direction
Length: Max. 21 mm (100%)
NovoLog®
PenFill®
Insulin aspart Injection (rDNA origin)
3 mL 100 units/mL
Rx only
For information contact:
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
List 330312
NDC 0169-3303-12
RSS Barcode
NovoLog_Penfill_label.qxd 06-10-2004 18:20 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1 8
Code centre line
Code: 100% Direction
Length: Max 22 mm (100%)
RA Labelling & Graphics
Carton: 22-202-53-30X
Current 1.0
Machinepack S10 HN
USA DESIGN
Lacquerform: 30053-1
Lacquer free area:
Colour: PMS 280C + Black
+ PMS 151C
Exp. Date/Control:
8-XXXX-31-XXX-X
10 mL 100 units/mL
Rx only
U-100
Sample. Not for resale
22-202-53
NovoLog®
Insulin aspart Injection
(rDNA origin)
For information contact:
Novo Nordisk
Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
10 mL 100 units/mL
Rx only
U-100
Keep in a cold place. Avoid freezing. Protect from light.
Warning: Any change of insulin should be made cautiously and
only under medical supervision (see package insert).
See accompanying literature for dosage.
For parenteral use.
Each mL contains 100 Units of insulin aspart; glycerin, 16 mg;
phenol, 1.50 mg; metacresol, 1.72 mg; zinc, 19.6 µg; disodium
hydrogen phosphate dihydrate, 1.25 mg and sodium chloride,
0.58 mg.
NovoLog® is a trademark owned by Novo Nordisk A/S
10 mL 100 units/mL
Rx only
U-100
NovoLog®
Insulin aspart Injection
(rDNA origin)
NovoLog®
Insulin aspart Injection
(rDNA origin)
NDC 0169-7501-11
List 750111
NovoLog_10mlsample_carton.qxd 06-10-2004 17:53 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1 8
Code centre line
Code: 100% Direction
Length: Max 22 mm (100%)
RA Labelling & Graphics
Carton: 22-202-53-30X
Current 1.0
Machinepack S10 HN
USA DESIGN
Lacquerform: 30053-1
Lacquer free area:
Colour: PMS 280C + Black
+ PMS 151C
Exp. Date/Control:
8-XXXX-31-XXX-X
10 mL 100 units/mL
Rx only
U-100
22-202-53
NovoLog®
Insulin aspart Injection
(rDNA origin)
For information contact:
Novo Nordisk
Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
10 mL 100 units/mL
Rx only
U-100
Keep in a cold place. Avoid freezing. Protect from light.
Warning: Any change of insulin should be made cautiously and
only under medical supervision (see package insert).
See accompanying literature for dosage.
For parenteral use.
Each mL contains 100 Units of insulin aspart; glycerin, 16 mg;
phenol, 1.50 mg; metacresol, 1.72 mg; zinc, 19.6 µg; disodium
hydrogen phosphate dihydrate, 1.25 mg and sodium chloride,
0.58 mg.
NovoLog® is a trademark owned by Novo Nordisk A/S
10 mL 100 units/mL
Rx only
U-100
NovoLog®
Insulin aspart Injection
(rDNA origin)
NovoLog®
Insulin aspart Injection
(rDNA origin)
NDC 0169-7501-11
List 750111
NovoLog_10ml_carton.qxd 06-10-2004 18:14 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exp. Date/Control:
Code end
Code: 100% Direction
Length: Max 25 mm (100%)
White tint block with luminicens
10 mL 100 units/mL (U-100)
Important: see insert
Keep in a cold place
Avoid freezing
Rx only
Novo Nordisk
Pharmaceuticals Inc.
Princeton, NJ 08540
1-800-727-6500
Manufactured by
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
8-XXXX-31-XXX-X
RA Labelling & Graphics
Label: 81x30-20X
Current 1.0
Colour:
White tint is indicated by yellow
+ Black + PMS 151C
White with silber under RSS code
indicated only by: PMS 427C
NovoLog®
Insulin aspart Injection
(rDNA origin)
NDC 0169-7501-11
List 750111
RSS Barcode
NovoLog_10ml_label.qxd 06-10-2004 18:14 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
8
8-XXXX-31-
XXX-X
Code centre line
Code: 100% Direction
Length: Max 29 mm (100%)
22-503-30
Exp. Date/Control:
RA Labelling & Graphics
Carton: 22-503-30-30X
Current 1.0
Lacquer free area:
Lacquerform: 30048-2
Colour: PMS 280C
+ Black + PMS 289C
+ PMS 648C
100 units/mL (U-100)
5×3 mL Prefilled Insulin Syringes
Rx only
For use with NovoFine® disposable needles or
other products specifically recommended by
Novo Nordisk.
Keep in a cold place. Avoid freezing.
Protect from light.
Warning
Any change of insulin should be made cautiously and
only under medical supervision.
NovoLog® Mix 70/30 FlexPen® Prefilled syringe is for
single person use only.
See accompanying literature for dosage.
Needles not included.
For parenteral use.
Each ml contains 100 Units of insulin aspart; mannitol,
36.4 mg; phenol, 1.50 mg;
metacresol, 1.72 mg; zinc, 19.6 µg; disodium
hydrogen phosphate dihydrate,1.25 mg, sodium chloride,
0.58 mg, and protamine sulfate 0.33 mg.
NovoLog® Mix 70/30 FlexPen® Prefilled Syringe and
NovoFine® are trademarks of Novo Nordisk® A/S.
U.S. patent No. 4,973,318
Novo Nordisk Pharmaceuticals Inc.
Princeton, NJ 08540
www.novonordisk-us.com
1-800-727-6500
Manufactured by:
Novo Nordisk A/S
DK 2880 Bagsvaerd, Denmark
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 5×3 mL Prefilled Insulin Syringes
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 5×3 mL Prefilled Insulin Syringes
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 5×3 mL Prefilled Insulin Syringes
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
NDC 0169-3696-19
List 369619
NovoLog Mix_FlexPen_carton5.qxd 06-10-2004 19:21 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100)
1×3 mL Prefilled Insulin Syringes
Rx only
Sample. Not for resale
Novo Nordisk
Pharmaceuticals Inc.
Princeton, NJ 08540
www.novonordisk-us.com
1-800-727-6500
Manufactured by:
Novo Nordisk A/S
DK 2880 Bagsvaerd,
Denmark
Warning
Any change of insulin should be made cautiously and only under
medical supervision.
NovoLog® Mix 70/30 FlexPen® Prefilled syringe is for single person use
only.
See accompanying literature for dosage. Needles not included.
For parenteral use.
Each ml contains 100 Units of insulin aspart; mannitol, 36.4 mg; phenol,
1.50 mg; metacresol, 1.72 mg; zinc, 19.6 µg; disodium hydrogen
phosphate dihydrate, 1.25 mg, sodium chloride, 0.58 mg, and protamine
sulfate 0.33 mg.
NovoLog® Mix 70/30 FlexPen® and NovoFine® are trademarks of
Novo Nordisk® A/S. U.S. patent No. 4,973,318
Exp. Date/Control:
22-508-37
RA Labelling & Graphics
Carton: 22-508-37-30X
Current 1.0
Lacqerform: 30080-2
Lacqer free area:
Colour: PMS 280C
+ PMS 289C + PMS 648C
+ Black
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100)
1×3 mL Prefilled Insulin Syringes
Code centre line
Code: 100% Direction
Length Max 29 mm (100%)
8 mm
1 mm
8-xxxx-31-xxx-x
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 1×3 mL Prefilled Insulin Syringes
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 1×3 mL Prefilled Insulin Syringes
NDC 0169-3696-90
List 369690
For use with NovoFine® disposable
needles or other products specifically
recommended by Novo Nordisk.
Keep in a cold place. Avoid freezing.
Protect from light.
NovoLog Mix_FlexPen_carton1.qxd 06-10-2004 19:18 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exp. Date/
Control:
8-xxxx-31-xxx-x
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540. 1-800-727-6500
Rx only
NDC 0169-3696-19 List 369619
100 units/mL
3 mL Prefilled Insulin Syringe
Overlap
Lakfrit område
ved tiltryk
og overlap
RA Labelling & Graphics
Label: 48x61-20X
Current 1.0
Lacquer area:
Lacquerform: 20005-1
Colour: White tint is indicated
by yellow + PMS 285C
+ PMS 648C + Black
White tint under Colour band,
Product band and RSS Code
Center for
prod. name
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
70% insulin aspart protamine
suspension and 30% insulin
aspart injection, (rDNA origin)
RSS Barcode
NovoLog Mix_FlexPen_label.qxd 06-10-2004 19:05 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exp. Date/
Control:
RA Labelling & Graphics
Carton: 22-480-26-30X
Current 1.0
Machinepack
5 pieces 3 ml Penfill US
Lacquerform: 30055-1
Lacquer free area:
Colour: PMS 280C
1 8
Code centre line
Code: 100% Direction
Length: Max 29 mm (100%)
22-480-26
100 units/mL (U-100) 5×3 mL cartridges
3 mL Cartridges
For use with 3 mL PenFill® cartridge compatible delivery devices*
Store at 2°C - 8°C (36°F - 46°F)
Avoid freezing
Protect from light
Rx only
8-xxxx-31-xxx-x
NovoLog® Mix 70/30
PenFill®
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
Questions or Comments?
Call 1-800-727-6500
(Se habla español) or write:
Novo Nordisk
Pharmaceuticals, Inc.
100 College Road, West
Princeton, NJ 08540
www.novonordisk-us.com
Manufactured by:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Warning
Any change of insulin should be made cautiously
and only under medical supervision.
PenFill® cartridge is for single person use only.
See accompanying literature for dosage.
For parenteral use.
Each mL contains 100 Units of insulin aspart; mannitol, 36.4 mg; phenol, 1.50 mg;
metacresol, 1.72 mg; zinc, 19.6 µg; disodium hydrogen phosphate dihydrate, 1.25 mg;
sodium chloride, 0.58 mg and protamine sulfate 0.33 mg.
*3 mL PenFill® cartridge compatible delivery devices: NovoPen® 3, Innovo®, InDuo™
NovoLog®, PenFill®, NovoPen® and Innovo® are trademarks owned by
Novo Nordisk A/S
InDuo™ is a trademark of LifeScan, Inc., a Johnson & Johnson company
NDC 0169-3682-13
NovoLog® Mix 70/30
PenFill®
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 5×3 mL cartridges
3 mL Cartridges
NovoLog® Mix 70/30
PenFill®
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 5×3 mL cartridges
3 mL Cartridges
NovoLog® Mix 70/30
PenFill®
70% insulin aspart protamine suspension and
30% insulin aspart injection, (rDNA origin)
100 units/mL (U-100) 5×3 mL cartridges
3 mL Cartridges
NDC 0169-3682-13
List 368213
NovoLog Mix_Penfill_carton5.qxd 06-10-2004 19:26 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8-xxxx-
31-xxx-x
Exp. Date/
Control:
Label size: 53x44 mm
Colour: White tint under
Colour band and Product
band indicated by yellow
+ Black + PMS 648C
Overlap
White
White tint block
under colour band
Code start
Code: 100% Direction
Length: Max. 21 mm (100%)
NovoLog® Mix 70/30
PenFill®
70% insulin aspart protamine
suspension and 30% insulin aspart
injection, (rDNA origin)
100 units/mL (U-100) 3 mL
Rx only
For information contact:
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
List 368213
NDC 0169-3682-13
RSS Barcode
NovoLog Mix_Penfill_label.qxd 06-10-2004 19:24 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1 8
Code centre line
Code: 100% Direction
Length: Max 22 mm (100%)
RA Labelling & Graphics
Carton: 22-202-53-304
Current 1.0
Maskinpak S10 HN
US DESIGN
Lacquerform: 30053-1
Lacquer free area:
Colour: PMS 280C
+ Black + PMS 648C
Exp. Date/Control:
8-XXXX-31-XXX-X
100 units/mL 10 mL
Rx only
U-100
22-202-53
NovoLog® Mix 70/30
70% insulin aspart protamine
suspension and 30% insulin
aspart injection, (rDNA origin)
For information contact:
Novo Nordisk
Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Store at 2°-8°C (36°-46°F)
Avoid freezing. Protect from light.
Warning: Any change of insulin should be made cautiously and
only under medical supervision (see package insert).
For parenteral use.
Each mL contains 100 Units of insulin aspart; mannitol 36.4 mg,
phenol 1.50 mg, metacresol 1.72 mg, zinc 19.6 µg,
disodium hydrogen phosphate dihydrate 1.25 mg, sodium chloride
0.58 mg, and protamine sulfate 0.33 mg.
NovoLog® is a trademark owned by Novo Nordisk® A/S
100 units/mL 10 mL
Rx only
U-100
NovoLog® Mix 70/30
70% insulin aspart protamine
suspension and 30% insulin
aspart injection, (rDNA origin)
NDC 0169-3685-12
List 368512
100 units/mL 10 mL
Rx only
U-100
NovoLog® Mix 70/30
70% insulin aspart protamine
suspension and 30% insulin
aspart injection, (rDNA origin)
NovoLog Mix_10ml_carton.qxd 06-10-2004 18:56 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exp. Date/Control:
Code end
Code: 100% Direction
Length: Max 25 mm (100%)
White tint block with luminicens
100 units/mL (U-100) 10 mL
Important: see insert
Store at 2°-8°C (36°-46°F)
Avoid freezing. Rx only
Novo Nordisk
Pharmaceuticals, Inc.
Princeton, NJ 08540
1-800-727-6500
Manufactured by
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
8-XXXX-31-XXX-X
RA Labelling & Graphics
Label: 81x30-202
Current 1.0
US DESIGN
Colour:
Ground-tint White indicated
by yellow + Black + PMS 648C
NovoLog®
Mix 70/30
70% insulin aspart protamine
suspension and 30% insulin
aspart injection, (rDNA origin)
NDC 0169-3685-92
List 368592
RSS Barcode
NovoLog Mix_10ml_label.qxd 06-10-2004 18:58 Side 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:26.020781 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20986s019,21172s013lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 19} |
3,943 | Page 1 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
NovoLog®
Insulin aspart (rDNA origin) Injection
DESCRIPTION
NovoLog® (insulin aspart [rDNA origin] injection) is a human insulin analog that is a rapid-
acting, parenteral blood glucose-lowering agent. NovoLog is homologous with regular human
insulin with the exception of a single substitution of the amino acid proline by aspartic acid in
position B28, and is produced by recombinant DNA technology utilizing Saccharomyces
cerevisiae (baker's yeast) as the production organism. Insulin aspart has the empirical formula
C256H381N65079S6 and a molecular weight of 5825.8.
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart (B28
asp regular human insulin analog) 100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL,
metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25
mg/mL, and sodium chloride 0.58 mg/mL. NovoLog has a pH of 7.2-7.6. Hydrochloric acid
10% and/or sodium hydroxide 10% may be added to adjust pH.
CLINICAL PHARMACOLOGY
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins, including
NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose by
facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-
lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is
more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Figure 2 and Figure 3).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared
to regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects between
18 and 40 years of age received an intravenous infusion of either NovoLog or regular human
insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two
groups with mean values of 1.22 l/h/kg for the NovoLog group and 1.24 l/h/kg for the regular
human insulin group.
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of action, and
a shorter duration of action than regular human insulin after subcutaneous injection (see
Figure 2 and Figure 3). The relative bioavailability of NovoLog compared to regular human
insulin indicates that the two insulins are absorbed to a similar extent.
Figure 2. Serial mean serum free insulin concentration collected up to 6 hours following a
single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
injected immediately before a meal in 22 patients with Type 1 diabetes.
In studies in healthy volunteers (total n=l07) and patients with Type 1 diabetes (total n=40),
NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to
50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial
in patients with Type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82.1 and 35.9 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of
insulin aspart have not been established in patients with Type 2 diabetes.
0
20
40
60
80
0
1
2
3
4
5
6
Free serum insulin (mU/L)
Time (h)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
The intra-individual variability in time to maximum serum insulin concentration for healthy
male volunteers was significantly less for NovoLog than for regular human insulin. The
clinical significance of this observation has not been established.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences between
NovoLog and regular human insulin described above, were observed independent of the
injection site (abdomen, thigh, or upper arm). Differences in pharmacokinetics between
NovoLog and regular human insulin are not associated with differences in overall glycemic
control.
Distribution and Elimination - NovoLog has a low binding to plasma proteins, 0-9%, similar
to regular human insulin. After subcutaneous administration in normal male volunteers
(n=24), NovoLog was more rapidly eliminated than regular human insulin with an average
apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset of action than regular human insulin.
In a 6-hour study in patients with Type 1 diabetes (n=22), the maximum glucose-lowering
effect of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 3).
The duration of action for NovoLog is 3 to 5 hours compared to 5 to 8 hours for regular human
insulin. The time course of action of insulin and insulin analogs such as NovoLog may vary
considerably in different individuals or within the same individual. The parameters of
NovoLog activity (time of onset, peak time and duration) as designated in Figure 3 should be
considered only as general guidelines. The rate of insulin absorption and consequently the
onset of activity is known to be affected by the site of injection, exercise, and other variables
(see PRECAUTIONS, General). Differences in pharmacodynamics between NovoLog and
regular human insulin are not associated with differences in overall glycemic control.
Figure 3. Serial mean serum glucose collected up to 6 hours following a single pre-meal dose
of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately
before a meal in 22 patients with Type 1 diabetes.
50
100
150
200
250
300
0
1
2
3
4
5
6
Serum glucose
Time (h)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
A double-blind, randomized, two-way cross-over study with 16 patients with Type 1 diabetes
demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile that
was similar to that after intravenous infusion with regular human insulin (see Figure 4).
Figure 4. Mean blood glucose profiles following intravenous infusion of NovoLog (hatched
curve) and regular human insulin (solid curve) in 16 patients with Type 1 diabetes. R
represents the time of autonomic reaction.
Special Populations
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with Type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents
with Type 1 diabetes between NovoLog and regular human insulin were similar to those in
healthy adult subjects and adults with Type 1 diabetes.
Geriatrics - The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog
has not been studied.
Gender - In healthy volunteers, no difference in insulin aspart levels was seen between men
and women when body weight differences were taken into account. There was no significant
difference in efficacy noted (as assessed by HbAlc) between genders in a trial in patients with
Type 1 diabetes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Obesity - In a study of 23 patients with type 1 diabetes and a wide range of body mass index
(BMI, 22-39 kg/m2), the pharmacokinetic parameters, AUC and Cmax, of NovoLog were
generally unaffected by BMI. Clearance of NovoLog was reduced by 28% in patients with
BMI >32 compared to patients with BMI <23 when a single dose of 0.1 U/kg NovoLog was
administered. However, only 3 patients with BMI <23 were studied.
Ethnic Origin - The effect of ethnic origin on the pharmacokinetics of NovoLog has not been
studied.
Renal Impairment - Some studies with human insulin have shown increased circulating levels
of insulin in patients with renal failure. A single subcutaneous dose of NovoLog was
administered in a study of 18 patients with creatinine clearance values ranging from normal to
<30 mL/min and not requiring hemodialysis. No apparent effect of creatinine clearance values
on AUC and Cmax of NovoLog was found. However, only 2 patients with severe renal
impairment were studied (<30 mL/min). Careful glucose monitoring and dose adjustments of
insulin, including NovoLog, may be necessary in patients with renal dysfunction (see
PRECAUTIONS, Renal Impairment).
Hepatic Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. In an open-label, single-dose study of 24
patients with Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic
impairment), no correlation was found between the degree of hepatic failure and any NovoLog
pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of insulin,
including NovoLog, may be necessary in patients with hepatic dysfunction (see
PRECAUTIONS, Hepatic Impairment).
Pregnancy - The effect of pregnancy on the pharmacokinetics and pharmacodynamics of
NovoLog has not been studied (see PRECAUTIONS, Pregnancy).
Smoking - The effect of smoking on the pharmacokinetics/pharmacodynamics of NovoLog has
not been studied.
CLINICAL STUDIES
To evaluate the safety and efficacy of NovoLog in patients with Type 1 diabetes, two
six-month, open-label, active-control (NovoLog vs. Novolin® R) studies were conducted (see
Table 1). NovoLog was administered by subcutaneous injection immediately prior to meals
and regular human insulin was administered by subcutaneous injection 30 minutes before
meals. NPH insulin was administered as the basal insulin in either single or divided daily
doses. Changes in HbA1c, the rates of hypoglycemia (as determined from the number of
events requiring intervention from a third party), and the incidence of ketosis were clinically
comparable for the two treatment regimens. The mean total daily doses of insulin were greater
(1-3 U/day) in the NovoLog-treated patients compared to patients who received regular human
insulin. This difference was primarily due to basal insulin requirements. No serum glucose
measurements were obtained in these studies.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
To evaluate the safety and efficacy of NovoLog in patients with Type 2 diabetes, one six-
month, open-label, active-control (NovoLog vs. Novolin R) study was conducted (see Table
1). NovoLog was administered by subcutaneous injection immediately prior to meals and
regular human insulin was administered by subcutaneous injection 30 minutes before meals.
NPH insulin was administered as the basal insulin in either single or divided daily doses.
Changes in HbAlc and the rates of hypoglycemia (as determined from the number of events
requiring intervention from a third party) were clinically comparable for the two treatment
regimens.
Table 1. Results of two six-month, active-control, open-label trials in patients with Type 1
diabetes (Studies A and B) and one six-month, active-control, open-label trial in patients with
Type 2 diabetes (Study C).
Mean HbA1c (%)
% of Patients Using Various
Numbers of Insulin Injections /
Day2
Rapid-acting
Basal
Study
Treatment (n)
Baseline
Month
6
Hypoglycemia1
(events / month
/ patient)
1 - 2
3
4 - 5
1
2
NovoLog (n=694)
8.0
7.9
0.06
3
75
22
54
46
A
Novolin R (n=346)
8.0
8.0
0.06
6
75
19
63
37
NovoLog (n=573)
7.9
7.8
0.08
4
90
6
94
6
B
Novolin R (n=272)
8.0
7.9
0.06
4
91
4
93
7
NovoLog (n=90)
8.1
7.7
0.02
4
93
4
97
4
C
Novolin R (n=86)
7.8
7.8
0.01
2
93
5
93
7
1 Events requiring intervention from a third party during the last three months of treatment
2 Percentages are rounded to the nearest whole number
To evaluate the use of NovoLog by subcutaneous infusion with an external pump, two open-
label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) compared NovoLog
versus Velosulin (buffered regular human insulin) in patients with Type 1 diabetes. Changes in
HbA1c and rates of hypoglycemia were comparable. Patients with Type 2 diabetes were also
studied in an open-label, parallel design trial (16 weeks [n=127]) using NovoLog by
subcutaneous infusion compared to pre-prandial injection (in conjunction with basal NPH
injections). Reductions in HbA1c and rates of hypoglycemia were comparable. (See
INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, Mixing of Insulins,
Information for Patients, DOSAGE AND ADMINISTRATION, and RECOMMENDED
STORAGE.)
INDICATIONS AND USAGE
NovoLog is indicated for the treatment of patients with diabetes mellitus, for the control of
hyperglycemia. Because NovoLog has a more rapid onset and a shorter duration of activity
than human regular insulin, NovoLog given by injection should normally be used in regimens
with an intermediate or long-acting insulin. NovoLog may also be infused subcutaneously by
external insulin pumps. NovoLog may be administered intravenously under proper medical
supervision in a clinical setting for glycemic control. (See WARNINGS, PRECAUTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
[especially Usage in Pumps], Information for Patients [especially For Patients Using Pumps],
Mixing of Insulins, DOSAGE AND ADMINISTRATION, RECOMMENDED STORAGE.)
CONTRAINDICATIONS
NovoLog is contraindicated during episodes of hypoglycemia and in patients hypersensitive to
NovoLog or one of its excipients.
WARNINGS
NovoLog differs from regular human insulin by a more rapid onset and a shorter
duration of activity. Because of the fast onset of action, the injection of NovoLog should
immediately be followed by a meal. Because of the short duration of action of NovoLog,
patients with diabetes also require a longer-acting insulin to maintain adequate glucose
control. Glucose monitoring is recommended for all patients with diabetes and is
particularly important for patients using external pump infusion therapy.
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog.
As with all insulins, the timing of hypoglycemia may differ among various insulin
formulations.
Any change of insulin dose should be made cautiously and only under medical
supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH,
analog), species (animal, human), or method of manufacture (rDNA versus animal-
source insulin) may result in the need for a change in dosage.
Insulin Pumps: When used in an external insulin pump for subcutaneous infusion,
NovoLog should not be diluted or mixed with any other insulin. Physicians and patients
should carefully evaluate information on pump use in the NovoLog physician and patient
package inserts and in the pump manufacturer's manual (e.g. NovoLog-specific
information should be followed for in-use time, frequency of changing infusion sets, or
other details specific to NovoLog usage, because NovoLog-specific information may
differ from general pump manual instructions).
Pump or infusion set malfunctions or insulin degradation can lead to hyperglycemia and
ketosis in a short time because of the small subcutaneous depot of insulin. This is
especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed
through skin and have shorter duration of action. These differences may be particularly
relevant when patients are switched from multiple injection therapy or infusion with
buffered regular insulin. Prompt identification and correction of the cause of
hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection may
be required. (See PRECAUTIONS, Mixing of Insulins, Information for Patients,
DOSAGE AND ADMINISTRATION, and RECOMMENDED STORAGE.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 8 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
PRECAUTIONS
General
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated
with the use of all insulins. Because of differences in the action of NovoLog and other
insulins, care should be taken in patients in whom such potential side effects might be
clinically relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using
potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Insulin
stimulates potassium movement into the cells, possibly leading to hypokalemia that left
untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Since
intravenously administered insulin has a rapid onset of action, increased attention to
hypoglycemia and hypokalemia is necessary. Therefore, glucose and potassium levels must
be monitored closely when NovoLog or any other insulin is administered intravenously.
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects
associated with the use of all insulins. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual
and is dependent on site of injection, blood supply, temperature, and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical
activity or their usual meal plan. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Hypoglycemia - As with all insulin preparations, hypoglycemic reactions may be associated
with the administration of NovoLog. Rapid changes in serum glucose levels may induce
symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early
warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such
as beta-blockers, or intensified diabetes control (see PRECAUTIONS, Drug Interactions).
Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior
to patients’ awareness of hypoglycemia.
Renal Impairment - As with other insulins, the dose requirements for NovoLog may be
reduced in patients with renal impairment (see CLINICAL PHARMACOLOGY,
Pharmacokinetics).
Hepatic Impairment - As with other insulins, the dose requirements for NovoLog may be
reduced in patients with hepatic impairment (see CLINICAL PHARMACOLOGY,
Pharmacokinetics).
Allergy - Local Allergy - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of injection. These minor reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In
some instances, these reactions may be related to factors other than insulin, such as irritants in
a skin cleansing agent or poor injection technique.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Systemic Allergy - Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
allergy, including anaphylactic reaction, may be life threatening.
Localized reactions and generalized myalgias have been reported with the use of cresol as an
injectable excipient.
In controlled clinical trials using injection therapy, allergic reactions were reported in 3 of 735
patients (0.4%) who received regular human insulin and 10 of 1394 patients (0.7%) who
received NovoLog. During these and other trials, 3 of 2341 patients treated with NovoLog
were discontinued due to allergic reactions.
Antibody Production - Increases in levels of anti-insulin antibodies that react with both human
insulin and insulin aspart have been observed in patients treated with NovoLog. The number
of patients treated with insulin aspart experiencing these increases is greater than the number
among those treated with human regular insulin. Data from a 12-month controlled trial in
patients with Type 1 diabetes suggest that the increase in these antibodies is transient. The
differences in antibody levels between the human regular insulin and insulin aspart treatment
groups observed at 3 and 6 months were no longer evident at 12 months. The clinical
significance of these antibodies is not known. They do not appear to cause deterioration in
HbA1c or to necessitate increases in insulin dose.
Pregnancy and Lactation
Female patients should be advised to tell their physician if they intend to become, or if they
become pregnant. Information is not available on the use of NovoLog during lactation (see
PREGNANCY-TERATOGENIC EFFECTS-PREGNANCY CATEGORY).
Usage in Pumps
NovoLog is recommended for use in pump systems suitable for insulin infusion as listed
below.
Pumps:
Disetronic H-TRON series, MiniMed 500 series and other equivalent pumps.
Reservoirs and infusion sets:
NovoLog is recommended for use in any reservoir and infusion sets that are compatible with
insulin and the specific pump. In-vitro studies have shown that pump malfunction, loss of
cresol, and insulin degradation, may occur when NovoLog is maintained in a pump system for
more than 48 hours. Reservoirs and infusion sets should be changed at least every 48 hours.
NovoLog in clinical use should not be exposed to temperatures greater than 37°C (98.6°F).
NovoLog should not be mixed with other insulins or with a diluent when it is used in the
pump. (See WARNINGS, PRECAUTIONS, Mixing of Insulins, Information for Patients,
DOSAGE AND ADMINISTRATION, and RECOMMENDED STORAGE.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Information for Patients
For all patients:
Patients should be informed about potential risks and advantages of NovoLog therapy
including the possible side effects. Patients should also be offered continued education and
advice on insulin therapies, injection technique, life-style management, regular glucose
monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo-
and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of
dose, instruction in the use of injection or subcutaneous infusion devices, and proper storage
of insulin. Patients should be informed that frequent, patient-performed blood glucose
measurements are needed to achieve optimal glycemic control and avoid both hyper- and
hypoglycemia.
Female patients should be advised to tell their physician if they intend to become, or if they
become pregnant. Information is not available on the use of NovoLog during lactation (see
PREGNANCY-TERATOGENIC EFFECTS-PREGNANCY CATEGORY).
For patients using pumps:
Patients using external pump infusion therapy should be trained in intensive insulin therapy
with multiple injections and in the function of their pump and pump accessories.
Pumps:
NovoLog is recommended for use in Disetronic H-TRON series, MiniMed 500 series and
other equivalent pumps
Reservoirs and infusion sets:
NovoLog is recommended for use in any reservoir and infusion sets that are compatible with
insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), reservoirs, infusion sets, and injection site should be changed at least every
48 hours.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are
erythematous, pruritic, or thickened should be reported to medical personnel, and a new site
selected because continued infusion may increase the skin reaction and/or alter the absorption
of NovoLog. Pump or infusion set malfunctions or insulin degradation can lead to
hyperglycemia and ketosis in a short time because of the small subcutaneous depot of insulin.
This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed
through skin and have shorter duration of action. These differences are particularly relevant
when patients are switched from infused buffered regular insulin or multiple injection therapy.
Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 11 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Problems include pump malfunction, infusion set occlusion, leakage, disconnection or
kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may
occur. If these problems cannot be promptly corrected, patients should resume therapy with
subcutaneous insulin injection and contact their physician. (See WARNINGS,
PRECAUTIONS, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and
RECOMMENDED STORAGE.)
Laboratory Tests
As with all insulin therapy, the therapeutic response to NovoLog should be monitored by
periodic blood glucose tests. Periodic measurement of glycosylated hemoglobin is
recommended for the monitoring of long-term glycemic control. When NovoLog is
administered intravenously, glucose and potassium levels must be closely monitored to avoid
potentially fatal hypoglycemia and hypokalemia.
Drug Interactions
A number of substances affect glucose metabolism and may require insulin dose adjustment
and particularly close monitoring.
• The following are examples of substances that may increase the blood-glucose-lowering
effect and susceptibility to hypoglycemia: oral antidiabetic products, ACE inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene,
salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.
• The following are examples of substances that may reduce the blood-glucose-lowering
effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin,
thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives).
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the
blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which
may sometimes be followed by hyperglycemia.
• In addition, under the influence of sympatholytic medicinal products such as beta-
blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be
reduced or absent (see CLINICAL PHARMACOLOGY).
Mixing of Insulins
• A clinical study in healthy male volunteers (n=24) demonstrated that mixing NovoLog
with NPH human insulin immediately before injection produced some attenuation in the
peak concentration of NovoLog, but that the time to peak and the total bioavailability of
NovoLog were not significantly affected. If NovoLog is mixed with NPH human insulin,
NovoLog should be drawn into the syringe first. The injection should be made
immediately after mixing. Because there are no data on the compatibility of NovoLog and
crystalline zinc insulin preparations, NovoLog should not be mixed with these
preparations.
• The effects of mixing NovoLog with insulins of animal source or insulin preparations
produced by other manufacturers have not been studied (see WARNINGS).
• Mixtures should not be administered intravenously.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 12 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
• When used in external subcutaneous infusion pumps for insulin, NovoLog should not
be mixed with any other insulins or diluent.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times
the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively).
At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in
females when compared to untreated controls. The incidence of mammary tumors for
NovoLog was not significantly different than for regular human insulin. The relevance of
these findings to humans is not known. NovoLog was not genotoxic in the following tests:
Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood
lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo
UDS test in rat liver hepatocytes. In fertility studies in male and female rats, at subcutaneous
doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on
U/body surface area), no direct adverse effects on male and female fertility, or general
reproductive performance of animals was observed.
Pregnancy - Teratogenic Effects - Pregnancy Category B
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. This background risk is increased in pregnancies complicated by
hyperglycemia and may be decreased with good metabolic control. It is essential for patients
with diabetes or history of gestational diabetes to maintain good metabolic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first
trimester, generally increase during the second and third trimesters, and rapidly decline after
delivery. Careful monitoring of glucose control is essential in such patients.
An open-label, randomized study compared the safety and efficacy of NovoLog versus human
insulin in the treatment of pregnant women with Type 1 diabetes (322 exposed pregnancies
(NovoLog: 157, human insulin: 165)). Two-thirds of the enrolled patients were already
pregnant when they entered the study. Since only one-third of the patients enrolled before
conception, the study was not large enough to evaluate the risk of congenital malformations.
Mean HbA1c of ~ 6% was observed in both groups during pregnancy, and there was no
significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog and
regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 13 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
U/kg/day, based on U/body surface area). The effects are probably secondary to maternal
hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50
U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the
human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose
of 1.0 U/kg/day for rabbits, based on U/body surface area.
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Many drugs, including
human insulin, are excreted in human milk. For this reason, caution should be exercised when
NovoLog is administered to a nursing mother.
Pediatric Use
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n = 283)
age 6 to 18 years compared the following treatment regimens: NovoLog (n = 187) or Novolin
R (n = 96). NPH insulin was administered as the basal insulin. NovoLog achieved glycemic
control comparable to Novolin R, as measured by change in HbA1c. The incidence of
hypoglycemia was similar for both treatment groups. NovoLog and regular human insulin
have also been compared in children with type 1 diabetes (n=26) age 2 to 6 years. As
measured by end-of-treatment HbA1c and fructosamine, glycemic control with NovoLog was
comparable to that obtained with regular human insulin. As observed in the 6 to 18 year old
pediatric population, the rates of hypoglycemia were similar in both treatment groups.
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 human insulin-controlled
clinical studies, 2.6% (n=36) were 65 years of age or over. Half of these patients had Type 1
diabetes (18/1285) and half had Type 2 (18/90) diabetes. The HbA1c response to NovoLog,
as compared to human insulin, did not differ by age, particularly in patients with Type 2
diabetes. Additional studies in larger populations of patients 65 years of age or over are
needed to permit conclusions regarding the safety of NovoLog in elderly compared to younger
patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of
NovoLog action have not been performed.
ADVERSE REACTIONS
Clinical trials comparing NovoLog with regular human insulin did not demonstrate a
difference in frequency of adverse events between the two treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as Whole - Allergic reactions (see PRECAUTIONS, Allergy).
Skin and Appendages - Injection site reaction, lipodystrophy, pruritus, rash (see
PRECAUTIONS, Allergy; Information for Patients, Usage in Pumps).
Other – Hypoglycemia, Hyperglycemia and ketosis (see WARNINGS and PRECAUTIONS).
In controlled clinical trials, small, but persistent elevations in alkaline phosphatase result were
observed in some patients treated with NovoLog. The clinical significance of this finding is
unknown.
OVERDOSAGE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 14 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Excess insulin may cause hypoglycemia and hypokalemia, particularly during IV
administration. Hypoglycemia may occur as a result of an excess of insulin relative to food
intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated
with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
DOSAGE AND ADMINISTRATION
NovoLog should generally be given immediately before a meal (start of meal within 5 to10
minutes after injection) because of its fast onset of action. The dosage of
NovoLog should be individualized and determined, based on the physician's advice, in
accordance with the needs of the patient. The total daily insulin requirement may vary and is
usually between 0.5 to1.0 units/kg/day. When used in a meal-related subcutaneous injection
treatment regimen, 50 to 70% of total insulin requirements may be provided by NovoLog and
the remainder provided by an intermediate-acting or long-acting insulin. Because of
NovoLog’s comparatively rapid onset and short duration of glucose lowering activity, some
patients may require more basal insulin and more total insulin to prevent pre-meal
hyperglycemia when using NovoLog than when using human regular insulin.
When used in external insulin infusion pumps, the initial programming of the pump is based
on the total daily insulin dose of the previous regimen. Although there is significant
interpatient variability, approximately 50% of the total dose is given as meal-related boluses
of NovoLog and the remainder as basal infusion. Additional basal insulin injections, or higher
basal rates in external subcutaneous infusion pumps may be necessary. NovoLog in the
reservoir and infusion sets, and the injection site must be changed at least every 48
hours.
NovoLog should be administered by subcutaneous injection in the abdominal wall, the thigh,
or the upper arm, or by continuous subcutaneous infusion in the abdominal wall. Injection
sites and infusion sites should be rotated within the same region. As with all insulins, the
duration of action will vary according to the dose, injection site, blood flow, temperature, and
level of physical activity.
Intravenous administration of NovoLog is possible under medical supervision with close
monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia.
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems with the infusion fluids 0.9% sodium chloride, 5% dextrose,
or 10% dextrose with 40 mmol/l potassium chloride using polypropylene infusion bags.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog to a concentration of
1:10 (equivalent to U-10) or 1:2 (equivalent to U-50).
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use any NovoLog if it
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 15 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
has become viscous (thickened) or cloudy; use it only if it is clear and colorless. NovoLog
should not be used after the printed expiration date.
HOW SUPPLIED
NovoLog is available in the following package sizes: each presentation containing 100 Units
of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill® cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen® Prefilled syringe
NDC 0169-6339-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery devices, with or without the addition of a NovoPen® 3 PenMate®,
and NovoFine® disposable needles.
RECOMMENDED STORAGE
NovoLog in unopened vials, cartridges, and NovoLog FlexPen Prefilled syringes should be
stored between 2° and 8°C (36° to 46°F). Do not freeze. Do not use NovoLog if it has been
frozen or exposed to temperatures that exceed 37°C (98.6°F). After a vial, cartridge, or
Prefilled syringe has been punctured, it may be kept at temperatures below 30°C (86°F) for up
to 28 days, but should not be exposed to excessive heat or sunlight. Opened vials may be
refrigerated. Cartridges should not be refrigerated after insertion into the Novo Nordisk 3 mL
PenFill cartridge compatible insulin delivery devices. The infusion set (tubing and needle)
should be changed at least every 48 hours.
NovoLog in the reservoir should be discarded after at least every 48 hours of use or after
exposure to temperatures that exceed 37°C (98.6°F).
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use (unopened)
Refrigerated
In-use (opened) Room
Temperature (below 30°C)
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days (Do not refrigerate)
3 mL NovoLog
FlexPen
28 days
Until expiration date
28 days (Do not refrigerate)
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION are stable at
room temperature for 24 hours. A certain amount of insulin will be initially adsorbed to the
material of the infusion bag.
NovoLog diluted with Insulin Diluting Medium for NovoLog may remain in patient use at
temperatures below 30°C (86°F) for 28 days.
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 16 of 16; NDA 20-986/S-037
Proposed Physician Insert
Version 10.4; Submitted 12-JAN-2007
NovoLog® Physician Insert
Date of Issue: January 12, 2007
Version 12
© Novo Nordisk A/S 2002-2006
Manufactured For Novo Nordisk Inc., Princeton, New Jersey 08540
Manufactured By Novo Nordisk A/S, 2880 Bagsvaerd, Denmark
www.novonordisk-us.com
NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, PenMate®, and NovoFine® are
trademarks of Novo Nordisk A/S.
H-TRON® is a trademark of Disetronic Medical Systems, Inc.
NovoLog® is covered by US Patent Nos 5,618,913, 5,866,538, and other patents pending.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 1, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
Information For The Patient
1
NovoLog® FlexPen®
2
3
Insulin aspart (recombinant DNA origin) Injection
in a 3 mL Prefilled Syringe
4
5
100 units/mL (U-100)
6
7
Read this leaflet carefully before using NovoLog®. Read the information you get
8
when you refill your NovoLog prescription because there may be new
9
information. This leaflet does not take the place of complete discussions with
10
your health care provider. If you have questions about NovoLog or about
11
diabetes, talk with your health care provider.
12
13
14
What is the most important information I should know about
15
NovoLog?
16
17
1. NovoLog® is different than human regular insulin because it starts to
18
work faster (rapid onset of action) and will not work as long (shorter
19
duration of action) in your body as human regular insulin. You should
20
eat a meal within 5 to 10 minutes after your injection of NovoLog to
21
reduce the risk of low blood sugar (hypoglycemia). The shorter
22
duration of action of NovoLog means that if you have Type 1 diabetes,
23
you may need to change your dose of total insulin or your dose of basal
24
intermediate or long-acting insulin (e.g., NPH). You may also need to
25
change the number of injections of basal insulin. You also may need to
26
use a longer-acting insulin to give the best glucose control. Any
27
change in dosage should be made under the supervision of your health
28
care provider and carefully monitored.
29
30
2. Any change of insulin should be made cautiously and only under
31
medical supervision. Changes in strength, manufacturer, type (e.g.,
32
Regular, NPH, Lente®), species (beef, pork, beef-pork, human), or
33
method of manufacture (rDNA versus animal-source insulin) may result
34
in the need for a change in the timing or dose of NovoLog or the longer-
35
acting insulin, or both. Patients taking NovoLog may require a change
36
in dose from that used with other insulins. If an adjustment is needed, it
37
may occur with the first dose or during the first several weeks or
38
months.
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
40
For your safety, read the section “What are the possible side effects of
41
insulins?” for symptoms of low blood sugar (hypoglycemia) and high blood
42
sugar (hyperglycemia).
43
44
45
What is NovoLog?
46
47
NovoLog is a human insulin analogue that lowers your blood sugar faster than
48
human regular insulin. NovoLog is a clear, colorless, sterile solution for injection
49
under the skin (subcutaneously). The active ingredient in NovoLog is insulin
50
aspart. Insulin aspart is identical to human insulin except for one amino acid,
51
which has been changed in the insulin molecule. Insulin aspart is produced by
52
recombinant DNA technology.
53
54
NovoLog also contains: glycerin, phenol, metacresol, zinc, disodium hydrogen
55
phosphate dihydrate, and sodium chloride. Hydrochloric acid and/or sodium
56
hydroxide may be added to adjust the pH.
57
58
The concentration of NovoLog is 100 units of insulin aspart per milliliter (U 100).
59
60
NovoLog FlexPen syringes are for single person use only.
61
62
63
What is diabetes, and how is insulin used to treat diabetes?
64
65
Insulin is normally produced by the pancreas, a gland that lies behind the
66
stomach. Without insulin, glucose is trapped in the bloodstream and cannot
67
enter the cells of the body. Glucose is a simple sugar made from the food you
68
eat. Some people who do not make any, or enough, of their own insulin, or who
69
cannot use the insulin they do make, must take insulin by injection to control the
70
amount of glucose in their blood (their blood glucose levels). Treatment for
71
diabetes may involve injections of insulin, injections of insulin combined with an
72
oral (taken by mouth) antidiabetic medicine, or an oral antidiabetic medicine
73
alone.
74
75
Each case of diabetes is different and requires direct and continued medical
76
supervision. Your health care provider has told you the type, strength and
77
amount of insulin you should use and the time(s) when you should inject it.
78
Your health care provider has also discussed a diet and exercise schedule with
79
you. Contact your health care provider if you have any problems or if you have
80
questions.
81
82
83
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
What types of insulin are available?
84
85
There are 3 types of insulin: animal insulins, human insulins, and insulin
86
analogs. Animal insulins may vary in animal source and how pure they are.
87
Human insulin is identical in structure to the insulin produced by the human
88
pancreas, and thus differs from animal insulins. Insulin analogs differ slightly
89
from human insulin in their chemical structure and are synthetic. Insulin analogs
90
differ in time of action from human insulin because the rate of absorption after
91
injection under the skin (subcutaneous) is different. However, they work the
92
same way as human insulin once they are absorbed. The animal insulins differ
93
slightly from human insulin in their chemical structure. Your health care provider
94
has prescribed the insulin that is right for you; be sure you have purchased the
95
correct insulin and check it carefully before you use it.
96
97
98
Who should not use NovoLog?
99
100
Do not take NovoLog if:
101
• Your blood sugar (glucose) is too low (hypoglycemia).
102
• You are allergic to insulin aspart or any of the ingredients contained in
103
NovoLog (check with your health care provider or pharmacist if you are not
104
sure).
105
• You are not planning to eat immediately following your injection.
106
107
Tell your health care provider or diabetes educator if you plan to become pregnant or
108
breast feed, or if you become pregnant. NovoLog has not been tested for use in women
109
who are nursing.
110
111
Tell your health care provider or diabetes educator about all medicines and supplements
112
that you are using. Some medicines, including non-prescription medicines and dietary
113
supplements, may affect your diabetes.
114
115
What should I know about insulin use?
116
117
• A change in the type, strength or species of insulin could require a dosage
118
adjustment. Any change in insulin should be made under medical
119
supervision.
120
• Monitor your glucose levels as directed by your health care provider.
121
You may have learned how to test your blood or urine for glucose. It is
122
important to do these tests regularly and to record the results for review with
123
your health care provider or diabetes educator.
124
• Always carry a quick source of sugar such as candy, mints, or glucose
125
tablets.
126
• Always carry identification that states that you have diabetes.
127
• Always ask your health care provider or pharmacist before taking any drug.
128
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
129
Always consult your health care provider if you have any questions about
130
your condition or the use of insulin.
131
132
What should I know about NovoLog use?
133
134
Inject NovoLog immediately before a meal.
135
• The effects of NovoLog will start within 10 to 20 minutes after the injection is
136
made.
137
• The maximum effect will be between 1 and 3 hours after the injection is
138
made.
139
• The effect will last for 3 to 5 hours after the injection.
140
141
Due to this shorter duration of action, NovoLog is usually taken in combination
142
with intermediate or longer-acting insulins. The effects of insulin may be different
143
for different people. Even in the same person, the effects may vary from day to
144
day. Because of this variation, the time periods listed here are general
145
guidelines only. See the section “How should I give a NovoLog® FlexPen
146
Prefilled syringe injection” at the end of this Information For The Patient for
147
detailed instructions.
148
149
What can affect how much insulin I need?
150
151
Illness
152
Even if you have an acute illness, especially with vomiting or fever, continue
153
taking your insulin. If possible, stay on your regular diet. If you have trouble
154
eating, drink fruit juices, regular soft drinks, or clear soups. If you can, eat small
155
amounts of bland foods. Test your urine for glucose and ketones and, if
156
possible, test your blood glucose. Note the results and contact your health care
157
provider for possible insulin dose adjustment. If you have severe and continued
158
vomiting, get emergency medical care.
159
160
Travel
161
If you are traveling across more than two time zones, consult your health care
162
provider about adjusting your insulin schedule.
163
164
Exercise
165
Exercise may lower your body’s need for insulin during and for some time after
166
physical activity. Exercise may also speed up the effect of a NovoLog dose,
167
especially if the exercise involves the area of the injection site. Discuss with your
168
health care provider how you should adjust your treatment to account for
169
exercise.
170
171
Usage in Pregnancy
172
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
It is especially important to maintain good control of your diabetes during
173
pregnancy. Pay special attention to your diet, exercise, and insulin regimens. If
174
you are planning to have a baby, are pregnant, or are nursing a baby, consult
175
your health care provider or diabetes educator. NovoLog has not been tested for
176
use in women who are nursing.
177
178
Use with other Medicines
179
Insulin requirements may increase or decrease when taken in combination with
180
other medicines. Drugs such as birth control pills, niacin, corticosteroids, or
181
thyroid replacement therapy may increase insulin requirements. Drugs such as
182
antidiabetic medicines, salicylates (for example, aspirin), sulfa antibiotics, and
183
certain antidepressants may decrease insulin requirements. Your health care
184
provider is aware of other medicines that may affect your diabetes control.
185
Always discuss any medicines you are taking with your health care provider.
186
187
Beta blocking agents (used for the treatment of certain heart conditions and high
188
blood pressure) may mask the symptoms of hypoglycemia or may increase or
189
decrease the effects of NovoLog. ACE inhibitors (used for the treatment of
190
certain heart conditions and high blood pressure) may increase the effects of
191
NovoLog.
192
193
Drinking alcohol may lead to hypoglycemia.
194
195
What are the possible side effects of insulins?
196
197
Hypoglycemia (Insulin Reaction)
198
Insulin reaction (hypoglycemia) is the most common side effect of insulins.
199
Hypoglycemia occurs when the blood glucose falls very low. The first symptoms
200
of an insulin reaction usually begin suddenly. Hypoglycemia can be caused by:
201
1.
missing or delaying meals
202
2.
taking too much insulin
203
3.
exercising or working more than usual
204
4.
an infection or illness (especially with diarrhea, vomiting, or fever)
205
5.
a change in the body’s need for insulin
206
6.
diseases of the adrenal, pituitary, or thyroid gland, or progression of kidney
207
or liver disease
208
7.
interactions with other drugs that lower blood glucose, such as oral
209
hypoglycemics, salicylates (for example, aspirin), sulfa antibiotics, and
210
certain antidepressants
211
8.
drinking alcoholic beverages
212
213
Symptoms of mild to moderate hypoglycemia may occur suddenly and can
214
include:
215
•
sweating
216
•
dizziness
217
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
•
palpitation
218
•
tremor
219
•
restlessness
220
•
tingling in the hands, feet, lips, or tongue
221
•
lightheadedness
222
•
trouble concentrating
223
•
headache
224
•
drowsiness
225
•
sleep problems
226
•
anxiety
227
•
blurred vision
228
•
slurred speech
229
•
depression
230
•
irritability
231
•
abnormal behavior
232
•
unsteady movement
233
•
personality changes
234
235
If you drink or eat something right away (a glass of milk or orange juice, or
236
several sugar candies), you can often stop symptoms from getting worse. If
237
symptoms continue, call your health care provider right away-- hypoglycemia can
238
lead to unconsciousness. If hypoglycemia causes loss of consciousness, you
239
must have emergency medical care right away. If you have had repeated
240
hypoglycemic reactions or if hypoglycemia has led to a loss of consciousness,
241
contact your health care provider. Severe hypoglycemia can result in temporary
242
or permanent harm to your heart function, brain function, or death.
243
244
In certain cases, the type and strength of the warning symptoms of
245
hypoglycemia may change. This may happen especially with very tight
246
glucose control or in patients with diabetic nerve problems (neuropathy). If
247
you do not recognize early warning symptoms, you may not be able to take steps
248
to avoid more serious hypoglycemia. Symptoms of severe hypoglycemia can
249
include disorientation, unconsciousness, or seizures. Hypoglycemia can result in
250
death. Be alert for all of the various types of symptoms that can indicate
251
hypoglycemia. Patients who develop hypoglycemia without early warning
252
symptoms should monitor their blood glucose frequently, especially before
253
activities such as driving. If the blood glucose is below your normal fasting
254
glucose, you should eat or drink sugar-containing foods to treat your
255
hypoglycemia.
256
257
Patients should always carry a quick source of sugar, such as candy, mints, or
258
glucose tablets. More severe hypoglycemia may require the help of another
259
person. Patients who are unable to take sugar orally or who are unconscious
260
require an injection of glucagon or should be treated with intravenous glucose at
261
a medical facility.
262
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
263
Learn to recognize your own symptoms of hypoglycemia. If you are uncertain
264
about these symptoms, you should monitor your blood glucose frequently to help
265
you learn to recognize the symptoms that you experience with hypoglycemia. If
266
you have frequent episodes of hypoglycemia or have trouble recognizing the
267
symptoms, consult your health care provider to discuss possible changes in
268
therapy, meal plan, and exercise programs to help you avoid hypoglycemia.
269
270
Hyperglycemia and Diabetic Acidosis
271
Hyperglycemia (too much glucose in the blood) may develop if your body has too
272
little insulin. Hyperglycemia can be brought about by any of the following:
273
1. Not taking your insulin or taking less than the health care provider has
274
prescribed
275
2. Eating significantly more than your meal plan suggests
276
3. Developing a fever, infection, or other significant stressful situation
277
278
In patients with insulin-dependent diabetes (Type 1 diabetes), continued
279
hyperglycemia can result in diabetic acidosis. The first symptoms of diabetic
280
acidosis usually come on slowly, over a period of hours or days. Symptoms
281
include a drowsy feeling, flushed face, thirst, loss of appetite, and fruity odor on
282
the breath. With acidosis, urine tests show large amounts of glucose and
283
acetone. More severe symptoms are heavy breathing and a rapid pulse. If
284
uncorrected, continued hyperglycemia or diabetic acidosis can lead to nausea,
285
vomiting, dehydration, loss of consciousness, or death. Therefore, it is important
286
that you obtain medical help right away.
287
288
Allergy
289
Generalized Allergy: An uncommon, but potentially serious reaction to insulins,
290
is generalized allergy, which may cause a rash over the whole body, shortness of
291
breath, wheezing, reduced blood pressure, fast pulse, or sweating. Severe
292
cases of generalized allergy may be life threatening. If you think you are
293
having a generalized allergic reaction, notify a health care provider right
294
away.
295
296
Local Allergy: Patients sometimes develop redness, swelling, and itching at the
297
site of injection. This condition, called “local allergy,” usually clears up in a few
298
days to a few weeks. Sometimes, this condition may be related to factors other
299
than insulin, such as irritants in skin cleansing agents or poor injection technique.
300
If you have a local reaction, contact your health care provider.
301
302
Lipodystrophy
303
Sometimes, getting insulin subcutaneously can result in lipoatrophy (depression
304
in the skin) or lipohypertrophy (enlargement or thickening of tissue at the injection
305
site). If you notice either of these conditions, consult your health care provider.
306
A change in your injection technique may help reduce the problem.
307
308
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 8, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
Always consult your health care provider if you have any questions about
309
your condition or the use of insulin.
310
311
How should I store NovoLog?
312
313
• Store insulin in a refrigerator, but not in the freezer. Do not use NovoLog
314
FlexPen Prefilled syringe if it has been frozen. Keep unused NovoLog
315
FlexPen Prefilled syringes in the carton so that they will stay clean and
316
protected from light.
317
• The NovoLog FlexPen Prefilled syringe that you are currently using can be
318
kept unrefrigerated for 28 days, as long as it is kept as cool as possible
319
(below 86°F [30°C]). Keep away from direct heat and light. Throw away
320
unrefrigerated NovoLog FlexPen Prefilled syringes after 28 days, even if they
321
still contain NovoLog.
322
• Do not use NovoLog if it appears cloudy, thickened, slightly colored, or if solid
323
particles are visible. Use it only if it is clear and colorless.
324
• Never use NovoLog after the expiration date printed on the label and carton.
325
326
General advice about prescription medicines
327
328
Do not share your medicine with other persons. It may harm them. If you have
329
any questions about diabetes or NovoLog, ask you health care provider. Your
330
pharmacist or health care provider can give you the written information about
331
NovoLog that is written for health care professionals.
332
333
How should I give a NovoLog FlexPen Prefilled syringe
334
injection?
335
336
Never share your NovoLog® FlexPen Prefilled syringe and needles.
337
Sharing may cause infections. Disposable needles are for single use. Use
338
the disposable needle once and throw it away properly, to protect others
339
from harm.
340
341
Caution
342
If you do not follow the instructions and advice in this leaflet about antiseptic
343
measures for avoiding germs, you may develop infections, most commonly, at
344
the injection site.
345
346
How do I prepare the injection?
347
348
Do not use NovoLog after the expiration date printed on the label and
349
carton.
350
351
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
• Never place a single-use needle on your insulin delivery device until you are
352
ready to give an injection. Remove the needle after you complete the
353
injection and throw it away properly, so it will not harm others.
354
• To use this syringe, follow the directions on the back of this leaflet for using
355
this syringe.
356
• NovoLog FlexPen Prefilled syringes may contain a small amount of air. To
357
prevent an injection of air and to inject a full dose of insulin, you must do an
358
air shot before each injection. Directions for performing an air shot are on the
359
back of this leaflet.
360
361
How do I give the injection?
362
363
Use the injection technique recommended by your health care provider.
364
365
1. Do not inject insulin into your muscle unless your health care provider has
366
advised it. Never inject insulin into a vein.
367
2. The following areas are suitable for subcutaneous (under the skin) insulin
368
injection: thighs, upper arms, buttocks, and abdomen. Do not change areas
369
without consulting your health care provider because the insulin absorption
370
and duration of action may vary. Absorption rate of the insulin affects the
371
insulin’s onset and duration of action. The actual point of injection on your
372
body should be changed each time. Injection sites should be about an inch
373
apart, in the same area of your body.
374
3. Clean your hands with soap and water. Clean the injection site with soap and
375
water or with alcohol. The injection site on your body should be clean and
376
dry.
377
4. Pinch up the skin area to be injected and hold it firmly.
378
5. Hold your device like a pencil and push the needle quickly and firmly into the
379
pinched-up skin. If it goes straight in, it will probably sting less.
380
6. Release your skin and push the button on your device all the way in. This
381
injects the insulin beneath your skin. After the injection the needle should
382
remain under the skin for at least 6 seconds. Keep the push button fully
383
depressed until the needle is withdrawn from the skin. This will ensure that
384
the full dose has been delivered.
385
7. After injecting the insulin and ensuring all of the insulin is injected, pull the
386
needle out.
387
8. Press gently over the injection site for several seconds - do not rub. If slight
388
bleeding occurs, press lightly with a dry cotton swab for a few seconds - do
389
not rub.
390
9. Remove the needle from the NovoLog® FlexPen® Prefilled syringe. Do not
391
reuse needles. Throw away used needles in a responsible manner so
392
they will not harm others. For example, you can use a hard-walled
393
container, such as a liquid laundry detergent bottle for this purpose.
394
395
Date of Issue:
396
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
397
Novo Nordisk®, NovoLog®, Novolin®, FlexPen®, PenFill®, NovoPen®, and NovoFine®are
398
trademarks owned by Novo Nordisk A/S.
399
400
Helpful information for people with diabetes is published by American Diabetes Association, 1660
401
Duke Street, Alexandria, VA 22314
402
403
For information contact:
404
Novo Nordisk Inc.
405
100 College Road West
406
Princeton, New Jersey 08540
407
1-800-727-6500
408
www.novonordisk-us.com
409
Manufactured by
410
Novo Nordisk A/S
411
DK-2880 Bagsvaerd, Denmark
412
413
NovoLog® is covered by U.S. Patent Nos. 5,618,913, 5,866,538 and other patents pending.
414
415
416
Printed in Denmark
417
418
8-xxxx-xx-xxx-x
419
420
421
Second page of the insert:
422
423
NovoLog® FlexPen® Prefilled syringe directions for use
424
425
NovoLog FlexPen Prefilled syringe is a disposable dial-a-dose insulin delivery system able to
426
deliver from 1 to a maximum of 60 units. The dose can be adjusted in 1 unit increments.
427
NovoLog FlexPen Prefilled syringe is designed for use with NovoFine® single use needles or
428
other products specifically recommended by Novo Nordisk. NovoLog FlexPen Prefilled syringe is
429
not recommended for the blind or severely visually impaired without the assistance of a sighted
430
individual trained in the proper use of the product.
431
432
Please read these instructions completely before using this device.
433
434
435
436
437
438
439
440
441
442
443
Residual
scale
window
Device Cap
Residual scale
Dosage
indicator
window
Push
button
12
units
Dose
selector
NovoFine®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 11, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
444
445
446
1. PREPARING THE SYRINGE
447
Pull off the cap.
448
Wipe the rubber stopper with an alcohol swab.
449
450
451
452
A. Remove the protective tab from the disposable needle and screw the needle onto
453
theFlexPen. Never place a disposable needle on your FlexPen until you are ready to give an
454
injection. Remove the needle right after use. If the needle is not removed, some liquid may leak
455
from the FlexPen.
456
B. Pull off the outer and inner needle caps.
457
458
Giving the airshot before each injection:
459
Small amounts of air may collect in the needle and insulin reservoir during normal use.
460
To avoid injecting air and to ensure proper dosing, hold the syringe with the needle pointing
461
up and tap the syringe gently with your finger so any air bubbles collect in the top of the
462
reservoir. Remove both the plastic outer cap and the needle cap.
463
464
Inner needle cap
Outer
needle
cap
Needle
Protective
tab
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 12, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
465
C. Dial 2 units.
466
D. Holding the syringe with the needle pointing up, tap the reservoir gently with your finger a few
467
times. Still with the needle pointing up, press the push button as far as it will go and see if a drop
468
of insulin appears at the needle tip. If not, repeat the procedure until insulin appears. Before the
469
first use of each NovoLog FlexPen you may need to perform up to 6 airshots to get a droplet of
470
insulin at the needle tip. If you need to make more than 6 airshots, do not use the syringe, and
471
contact Novo Nordisk. A small air bubble may remain but it will not be injected because the
472
operating mechanism prevents the reservoir from being completely emptied.
473
474
2. SETTING THE DOSE
475
476
E. Check that the dose selector is set at 0. Dial the number of units you need to inject. The
477
dose can be corrected either up or down by turning the dose selector in either direction. When
478
dialing back be careful not to push the push button as insulin will come out. You cannot set a
479
dose larger than the number of units left in the reservoir.
480
481
3. GIVING THE INJECTION
482
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 13, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
483
484
485
Use the injection technique recommended by your doctor.
486
487
F. Deliver the dose by pressing the push button all the way in. Be careful only to push the push
488
button when injecting.
489
G. After the injection the needle should remain under the skin for at least 6 seconds. Keep the
490
push button fully depressed until the needle is withdrawn from the skin. This will ensure that the
491
full dose has been delivered.
492
493
To avoid needlesticks, do not recap the needle. Throw away the needle safely after each
494
injection.
495
496
It is important that you use a new needle for each injection. Health care professionals,
497
relatives and other care givers should follow general precautionary measures for removal
498
and disposal of needles to eliminate the risk of unintended needle penetration.
499
500
501
For more information see
502
How do I give the injection on the reverse side of this insert.
503
504
4. SUBSEQUENTINJECTIONS
505
It is important that you use a new needle for each injection. Follow the directions in steps 1
506
– 3.
507
508
The numbers on the insulin reservoir can be used to estimate the amount of insulin left in the
509
syringe. Do not use these numbers to measure the insulin dose.
510
You cannot set a dose greater than the number of units remaining in the reservoir.
511
512
5. FUNCTION CHECK
513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 14, S-037
Proposed Patient Insert (FlexPen™)
Version 1.1 Submitted 12-JAN-2007
514
If your NovoLog FlexPen is not working properly, follow this procedure:
515
516
- Screw on a new NovoFine needle
517
- Give an airshot as described in sections C to D
518
- Put the outer needle cap onto the needle
519
- Dispense 20 units into the outer needle cap, holding the pen with the needle pointing
520
downwards.
521
522
The insulin should fill the lower part of the cap (as shown in figure H). If NovoLog FlexPen has
523
released too much or too little insulin, repeat the test. If it happens again, contact Novo Nordisk
524
and do not use your NovoLog FlexPen.
525
Dispose of the used NovoLog FlexPen carefully without the needle attached.
526
527
6. IMPORTANT NOTES
528
•
If you need to perform more than 6 airshots before the first use of NovoLog FlexPen syringe
529
to get a droplet of insulin at the needle tip, do not use the FlexPen.
530
•
Remember to perform an air shot before each injection. See figures C and D.
531
•
Take care not to drop the FlexPen.
532
•
Remember to keep the NovoLog FlexPen syringe with you; don’t leave it in a car or other
533
location where extremes of temperature can occur.
534
•
NovoLog FlexPen syringe is designed for use with NovoFine disposable needles or other
535
products specifically recommended by Novo Nordisk.
536
•
Never place a disposable needle on this syringe until you are ready to use it. Remove the
537
needle immediately after use.
538
•
Throw away used needles in a responsible manner, so others will not be harmed.
539
•
Throw away the used syringe, without the needle attached.
540
•
Always carry a spare NovoLog FlexPen syringe with you in case your FlexPen is damaged or
541
lost.
542
•
Novo Nordisk cannot be held responsible for adverse reactions occurring as a consequence
543
of using this insulin delivery system with products that are not recommended by Novo
544
Nordisk.
545
•
Keep this syringe out of the reach of children.
546
547
548
H
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 1 S-037
Proposed Patient Insert PenFill®/Vial
Version 4.1; Submitted 12-JAN-2007
1
Information For The Patient
2
NovoLog® (Insulin aspart [rDNA origin] Injection)
3
3 mL PenFill® Disposable Cartridge (300 units per cartridge)
4
10 mL Vial (1000 units per vial)
5
100 units/mL (U-100)
6
7
• What is the most important information I should know about NovoLog?
8
• For all NovoLog users
9
• For pump users
10
• What is NovoLog?
11
• Who should not use NovoLog?
12
• What should I know about using insulin?
13
• What should I know about using NovoLog?
14
• What should I avoid when using NovoLog?
15
• What are the possible side effects of NovoLog?
16
• How should I store NovoLog?
17
• General advice
18
• Injection and pump infusion instructions
19
• How should I inject NovoLog?
20
• Using Vials
21
• Using Cartridges
22
• How should I infuse NovoLog with an external subcutaneous insulin infusion
23
pump?
24
• How should I mix insulins?
25
26
Read this information carefully before you begin treatment. Read the information you
27
get whenever you get more medicine. There may be new information. This information
28
does not take the place of talking with your doctor about your medical condition or your
29
treatment. If you have any questions about NovoLog (NO-voe-log), ask your doctor.
30
Only your doctor can determine if NovoLog is right for you.
31
32
What is the most important information I should know about NovoLog?
33
34
For All NovoLog Users
35
• NovoLog (NO-voe-log) is different from regular human insulin and buffered regular
36
human insulin (Velosulin). It works faster (rapid onset of action) and will not work as
37
long (shorter duration of action) as regular human insulin or buffered regular human
38
insulin (Velosulin).
39
40
• Because the onset of action is fast, you should eat a meal 5 to10 minutes after a
41
NovoLog injection or NovoLog bolus infusion dose given by an external pump. (A
42
bolus is a large dose.) Eating right after the dose will reduce the risk of low blood
43
sugar (hypoglycemia).
44
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 S-037
Proposed Patient Insert PenFill®/Vial
Version 4.1; Submitted 12-JAN-2007
• The shorter duration of NovoLog’s action means that you may need to use an
46
intermediate or longer-acting insulin (basal insulin) or higher basal rates of NovoLog
47
insulin infusion in the pump. This will give the best glucose control and will help you
48
avoid hyperglycemia (high blood sugar) and ketoacidosis (too much acid [low pH] in
49
your body).
50
51
• Glucose monitoring is recommended for all patients who use insulin.
52
53
If you use NovoLog by injection, you may need to increase some or all of the following:
54
• your total dose of insulin
55
• your dose of intermediate or long-acting insulin (for example, NPH)
56
• the number of injections of basal insulin
57
58
If you infuse NovoLog into the skin (subcutaneous tissue) by pump, you may need to
59
increase some or all of the following:
60
• your total insulin dose
61
• the basal infusion dose
62
• the proportion of total insulin given as a basal infusion
63
64
Age and exposure to heat affect the stability of NovoLog and its preservative. Also,
65
NovoLog does not work well after it has been frozen. Therefore, do not use old insulin or
66
insulin that has been exposed to temperature extremes. Hyperglycemia may be a sign that
67
the insulin is no longer working and needs to be replaced.
68
69
Do not mix NovoLog:
70
• with any other insulins when used in a pump
71
• with Lantus® (insulin glargine [rDNA origin] injection) when used with injections
72
by syringe
73
(You may, however, mix NovoLog with NPH when used with injections by syringe.
74
See: How should I mix insulins?)
75
76
For Pump Users
77
• Glucose monitoring is very important for patients using external pump subcutaneous
78
infusion therapy. You should be aware that pump or infusion set malfunctions that
79
result in inadequate insulin infusion can quickly lead to hyperglycemia and ketosis.
80
Accordingly, problems with the infusion pump, the flow of insulin, or the quality of
81
the insulin should be identified and corrected as quickly as possible. There is only a
82
small amount of insulin infused into the skin with a pump. The faster absorption
83
through the skin of rapid-acting insulin analogs and shorter duration of action may
84
give you less time to identify and correct the problem than with buffered regular
85
insulin.
86
87
• Therefore, you should dose with insulin from a new vial of NovoLog if unexplained
88
hyperglycemia or pump alarms do not respond to all of the following:
89
• a repeat dose (injection or bolus) of NovoLog
90
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• a change in the infusion set, including the NovoLog in the reservoir
91
• a change in the infusion site
92
93
If these measures do not work, you may need to resume skin (subcutaneous)
94
injections with syringes or insulin pens. Continue to monitor your glucose and
95
ketones. If problems continue, you must contact your doctor.
96
97
• When NovoLog is used in an external subcutaneous insulin infusion pump, you
98
should use only recommended pumps. Reservoirs, infusion sets, and injection site
99
should be changed at least every 48 hours. In addition, the reservoir, the infusion set,
100
and infusion site should be changed:
101
• with unexpected hyperglycemia or ketosis
102
• when the alarm sounds, as specified by your pump manual
103
• if the insulin or pump has been exposed to temperatures over 98.6°F (37°C), such
104
as in a sauna, with long showers, or on a hot day
105
• if the insulin or pump could have absorbed radiant heat, for example from
106
sunlight, that would heat the insulin to over 98.6°F (37°C). Dark colored pump
107
cases or sport covers can increase this type of heat. The location where the pump
108
is worn may also affect the temperature
109
110
Patients who develop “pump bumps” (skin reactions at the infusion site) may need to
111
change infusion sites more often than every 48 hours.
112
113
For your safety, read the section “What are the possible side effects of NovoLog?” to
114
review the symptoms of low blood sugar (hypoglycemia) and high blood sugar
115
(hyperglycemia).
116
117
What is NovoLog?
118
NovoLog is a clear, colorless, sterile solution for injection or infusion under the skin
119
(subcutaneously). NovoLog is a human-made form of insulin to lower your blood sugar
120
faster than human regular insulin. Because the insulin is human-made by recombinant
121
DNA technology (rDNA) and is chemically different from the insulin made by the human
122
body, it is called an insulin analog. The active ingredient in NovoLog is insulin aspart.
123
The concentration of insulin aspart is 100 units per milliliter, or U100. NovoLog also
124
contains: glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate,
125
and sodium chloride. Hydrochloric acid and/or sodium hydroxide may be added to adjust
126
the pH. These ingredients help to preserve or stabilize NovoLog insulin. The pH
127
(balance between acid and alkaline conditions) is important to the stability of NovoLog.
128
Increases in temperature can affect the stability of NovoLog, so it may not work well.
129
130
Who should not use NovoLog?
131
Do not use NovoLog if:
132
• your blood sugar (glucose) is too low (hypoglycemia)
133
• you do not plan to eat right after your injection or infusion
134
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• you are allergic to insulin aspart or any of the ingredients contained in NovoLog
135
(check with your doctor if you are not sure)
136
137
Tell your health care provider or diabetes educator if you plan to become pregnant or
138
breast feed, or if you become pregnant. NovoLog has not been tested for use in women
139
who are nursing.
140
141
Tell your health care provider or diabetes educator about all medicines and supplements
142
that you are using. Some medicines, including non-prescription medicines and dietary
143
supplements, may affect your diabetes.
144
145
What should I know about using insulin?
146
• Make any change of insulin cautiously and only under medical supervision. Changes
147
in the strength, manufacturer, type (for example: Regular, NPH, Lente®), species
148
(beef, pork, beef-pork, human) or method of manufacture (recombinant [rDNA] or
149
animal source insulin) may cause a need for a change in the timing or dose of the new
150
insulin.
151
• Glucose monitoring will help you and your health care provider adjust dosages.
152
• Always carry a quick source of sugar, such as candy or glucose tablets, to treat low
153
blood sugars (hypoglycemia).
154
• Always carry identification that states that you have diabetes.
155
156
What should I know about using NovoLog?
157
See the end of this Patient Information for instructions for using NovoLog in
158
injections and pumps.
159
160
• NovoLog starts working 10 to 20 minutes after injection or infusion. The greatest
161
blood sugar lowering effect is between 1 and 3 hours after injection or infusion. This
162
blood sugar lowering lasts for 3 to 5 hours. (The time periods are only general
163
guidelines.)
164
165
• Because the onset of action is rapid, you should eat a meal within 5 to10 minutes after
166
a NovoLog injection or a NovoLog bolus dose from an external pump to avoid low
167
blood sugar (hypoglycemia).
168
169
• The shorter duration of NovoLog’s action means that you may need to use an
170
intermediate or longer-acting insulin (basal insulin) or higher basal rates of NovoLog
171
insulin infusion in the pump. This will help you avoid hyperglycemia and
172
ketoacidosis.
173
174
• Do not inject or infuse in skin that has become reddened or bumpy or thickened after
175
infusion or injection. Insulin absorption in these areas may not be the same as that in
176
normal skin, and may change the onset and duration of insulin action.
177
178
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• Use NovoLog only if it appears clear and colorless. Do not use NovoLog if it appears
179
cloudy, thickened, or colored, or if it contains solid particles.
180
181
What should I avoid while using NovoLog?
182
• Drinking alcohol may lead to hypoglycemia.
183
• Do not miss meals after injections of NovoLog or bolus infusions of NovoLog.
184
185
What are the possible side effects of NovoLog?
186
Insulins can cause hypoglycemia (low blood sugar), hyperglycemia (high blood sugar),
187
allergy, and skin reactions.
188
189
Hypoglycemia (low blood sugar). This is the most common side effect. It occurs when
190
there is a conflict between the amount of carbohydrates (source of glucose) from your
191
food, the amount of glucose used by your body, and the amount and timing of insulin
192
dosing. Therefore, hypoglycemia can occur with:
193
• The wrong insulin dose. This can happen with any of the following:
194
• too much insulin is injected
195
• the bolus dose of insulin infusion is set too high
196
• the basal infusion dose is set too high
197
• the pump does not work right, delivering too much insulin
198
• Medicines that directly lower glucose or increase sensitivity to insulin. This can
199
happen with oral (taken by mouth) antidiabetes drugs, sulfa antibiotics (for
200
infections), ACE inhibitors (for blood pressure and heart failure), salicylates,
201
including aspirin and NSAIDS (for pain), some antidepressants, and with other
202
medicines.
203
• Medical conditions that limit the body’s glucose reserve, lengthen the time
204
insulin stays in the body, or that increase sensitivity to insulin. These conditions
205
include diseases of the adrenal glands, the pituitary, the thyroid gland, the liver, and
206
the kidney.
207
• Not enough carbohydrate (sugar or starch) intake. This can happen if:
208
• a meal or snack is missed or delayed
209
• you have vomiting or diarrhea that decreases the amount of glucose absorbed by
210
your body
211
• alcohol interferes with carbohydrate metabolism
212
• Too much glucose use by the body. This can happen from:
213
• too much exercise
214
• higher than normal metabolism rates due to fever or an overactive thyroid
215
216
Hypoglycemia can be mild or severe. Its onset may be rapid. Patients with very good
217
(tight) glucose control, patients with diabetic neuropathy (nerve problems), or patients
218
using some Beta-blockers (used for high blood pressure and heart conditions) may have
219
few warning symptoms before severe hypoglycemia develops. Hypoglycemia may reduce
220
your ability to drive a car or use mechanical equipment without risk of injury to yourself
221
or others. Severe hypoglycemia can cause temporary or permanent harm to your heart or
222
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Proposed Patient Insert PenFill®/Vial
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brain. It may cause unconsciousness, seizures, or death. Symptoms of hypoglycemia
223
include:
224
• anxiety, irritability, restlessness, trouble concentrating, personality changes, mood
225
changes, or other abnormal behavior
226
• tingling in your hands, feet, lips, or tongue
227
• dizziness, light-headedness, or drowsiness
228
• nightmares or trouble sleeping
229
• headache
230
• blurred vision or slurred speech
231
• palpitations (rapid heart beat)
232
• sweating
233
• tremor (shaking) or unsteady gait (walking)
234
235
Mild to moderate hypoglycemia can be treated by eating or drinking carbohydrates (milk,
236
orange juice, sugar candies, or glucose tablets). More severe or continuing hypoglycemia
237
may require the help of another person or emergency medical personnel. Patients who are
238
unable to take sugar by mouth or who are unconscious may need treatment with a
239
glucagon injection or glucose given intravenously (in the vein).
240
241
Talk with your doctor about severe, continuing, or frequent hypoglycemia, and
242
hypoglycemia for which you had few warning symptoms.
243
244
Hyperglycemia (high blood sugar) is another common side effect. It also occurs when
245
there is a conflict between the amount of carbohydrates (source of glucose) from your
246
food, the amount of glucose used by your body, and the amount and timing of insulin
247
dosing. Therefore, hyperglycemia can occur with:
248
• The wrong insulin dose. This can happen from any of the following:
249
• too little or no insulin is injected
250
• the bolus dose of insulin infusion is set too low
251
• the basal infusion dose is set too low
252
• the pump or catheter system does not work right, delivering too little insulin
253
• the insulin’s ability to lower glucose is changed by incorrect storage (freezing,
254
excessive heat), or usage after the expiration date
255
• Medicines that directly increase glucose or decrease sensitivity to insulin. This
256
can happen, for example, with thiazide water pills (used for blood pressure),
257
corticosteroids, birth control pills, and protease inhibitors (used for AIDS).
258
• Medical conditions that increase the body’s production of glucose or decrease
259
sensitivity to insulin. These medical conditions include fevers, infections, heart
260
attacks, and stress.
261
• Too much carbohydrate intake. This can happen if you
262
• eat larger meals
263
• eat more often
264
• increase the proportion of carbohydrate in your meals
265
266
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Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA)
267
or very high glucose levels (hyperosmolar coma) and result in unconsciousness and
268
death. Although DKA occurs most often in patients with Type 1 diabetes, it can occur in
269
patients with Type 2 diabetes who become severely ill. Urine or blood tests will show
270
acetone, ketones, and high levels of glucose. Hyperosmolar coma occurs most often in
271
patients with Type 2 diabetes. Urine and blood tests will show very high levels of
272
glucose.
273
Glucose monitoring is very important for patients using external pump infusion therapy.
274
You should be aware that pump or infusion set malfunctions that result in inadequate
275
insulin infusion can quickly lead to hyperglycemia and ketosis. Accordingly, problems
276
with the infusion pump, the flow of insulin, or the quality of the insulin should be
277
identified and corrected as quickly as possible. The faster absorption of rapid-acting
278
insulin analogs through the skin and shorter duration of action may give you less time to
279
identify and correct the problem.
280
Because some patients experience few symptoms of hyperglycemia and ketosis, it is
281
important to monitor your glucose several times a day. Symptoms of hyperglycemia
282
include:
283
• confusion or drowsiness
284
• fruity smelling breath
285
• rapid, deep breathing
286
• increased thirst
287
• decreased appetite, nausea, or vomiting
288
• abdominal (stomach area) pain
289
• rapid heart rate
290
• increased urination and dehydration (too little fluid in your body)
291
292
Mild hyperglycemia can be treated by extra doses of insulin and drinking fluids
293
(rehydration). Patients using pumps should check pump function and replace the insulin
294
in the reservoir-syringe, as well as change the tubing and catheter and the infusion site.
295
Patients using pumps may need to resume insulin injections with syringes or
296
injection pens. Glucose and acetone-ketone levels should be monitored more often until
297
they return to normal. More severe or continuing hyperglycemia requires prompt
298
evaluation and treatment by your health care provider.
299
300
Allergy can be serious. Generalized allergy is an uncommon, but possibly life-
301
threatening, reaction to insulin products. Symptoms include:
302
• itchy rash over the entire body
303
• shortness of breath or wheezing
304
• confusion
305
• low blood pressure
306
• rapid heart beat
307
• sweating
308
If you think you are having a generalized allergic reaction, get emergency medical
309
help right away.
310
311
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Allergic reactions at the injection site (itching, redness, hardness, or swelling) are more
312
common than generalized allergy. They may need several days or weeks to clear up.
313
Pump patients with site reactions may need to change their infusion sites more often than
314
every 48 hours. Patients should avoid injection or infusion of insulin into skin areas that
315
have reactions. Tell your doctor about such reactions, because they can become more
316
severe, or they may change the absorption of insulin.
317
318
Lipodystrophy is a common change in the fat below the injection site. These changes
319
include loss of fat (depressions in the skin called lipoatrophy) or thickening of the tissue
320
under the skin (lipohypertrophy). Pump patients with lipodystrophy may need to change
321
their infusion sites more often than every 48 hours. Patients should avoid injection or
322
infusion of insulin into skin areas that have these reactions. Tell your doctor about such
323
reactions because they can become more severe, or they may change the absorption of
324
insulin.
325
326
How should I store NovoLog?
327
• NovoLog can be damaged by high temperatures. Therefore, be sure to protect it
328
from high air temperatures, heat from the sun, saunas, long showers, and other heat
329
sources. This is especially important if you use a pump or an insulin pen, because
330
you carry these devices with you and they may be exposed to different temperatures
331
as you go about your daily activities. Throw NovoLog away if it has been in
332
temperatures greater than 98.6°F (37°C).
333
334
• Unopened NovoLog should be stored in a refrigerator but not in the freezer and
335
protected from light. Even if it has been refrigerated and protected from sunlight and
336
unopened, it should not be used after the expiration date on the label and the carton.
337
Unopened vials and cartridges can be stored unrefrigerated at temperatures below
338
86°F (30°C) and protected from light for up to 28 days.
339
340
• Punctured vials and cartridges can be stored unrefrigerated at temperatures below
341
86°F (30°C) and protected from light for up to 28 days. Punctured vials may be
342
stored in the refrigerator. Cartridges inserted into their NovoPen® 3 device should not
343
be stored in the refrigerator.
344
345
• The NovoLog in the pump reservoir and the complete infusion set (reservoir,
346
tubing, catheter-needle) should be replaced at least every 48 hours. Replacement
347
should be more often than every 48 hours if you have hyperglycemia, the pump alarm
348
sounds, or the insulin flow is blocked (occlusion).
349
350
• Never use NovoLog if it has been stored improperly.
351
352
General advice
353
This leaflet summarizes the most important information about NovoLog. If you would
354
like more information, talk with your doctor. You can ask your pharmacist or doctor for
355
information about NovoLog that is written for health professionals.
356
This label may not be the latest approved by FDA.
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Page 9 S-037
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357
Injection and pump infusion instructions
358
• NovoLog comes in 10 mL (milliliter) vials or in 3 mL cartridges. NovoLog can be
359
withdrawn from vials with syringes for injection or for insertion into the reservoirs of
360
external subcutaneous infusion pumps (Disetronic H-TRON® series, MiniMed 500
361
series, or other pumps recommended by your doctor.)
362
• Doses of insulin are measured in units. NovoLog is available as a U-100 insulin.
363
One milliliter (mL) of U-100 contains 100 units of insulin aspart (1 mL=1 cc). Only
364
U-100 type syringes should be used for injection to ensure proper dosing.
365
• Disposable syringes and needles are sterile if the package is sealed. They should be
366
used only once and thrown away properly, to protect others from harm.
367
• NovoLog PenFill® cartridges are for use with NovoFine® disposable needles and the
368
following Novo Nordisk 3 mL PenFill compatible insulin delivery devices:
369
NovoPen® 3, NovoPen Junior, Innovo®, and InDuo®. Never share needles.
370
371
How should I inject NovoLog?
372
373
Using Vials
374
1. The vial and the insulin should be inspected. The insulin should be clear and colorless.
375
The tamper-resistant cap should be in place to be removed by you. If the cap had been
376
removed before your first use of the vial, or if the insulin is cloudy or colored, you
377
should return the vial to the pharmacy. Do not use it.
378
2. Both the injection site and your hands should be cleaned with soap and water or with
379
alcohol. The injection site should be dry before you inject.
380
3. The rubber stopper should be wiped with an alcohol wipe.
381
4. The plunger of the syringe should be pulled back until the black tip is at the level for
382
the number of units to be injected.
383
5. Insert the needle of the syringe through the rubber stopper of the vial. Push in the
384
syringe plunger completely to put air into the vial.
385
6. Turn the vial upside-down with the needle-syringe still attached, and pull the plunger
386
back a few units past the correct dose.
387
7. Remove any air bubbles by flicking the syringe and squirting air bubbles out the
388
needle. Continue pushing the plunger until you have the correct dose.
389
8. Lift the vial off the syringe.
390
9. Inject NovoLog into the subcutaneous (under the skin) tissue (not into muscle or
391
blood vessels) in the abdomen, thighs, upper arms, or buttocks. Pinch the skin fold
392
between your fingers and push the needle straight into the pinched skin. Because
393
insulin absorption and activity can be affected by the site you choose, you should
394
discuss the injection site with your doctor.
395
10. Release the pinched skin and push the plunger in completely. Keep the needle in the
396
skin for a few seconds before withdrawing the syringe.
397
11. Press the injection site for a few seconds to reduce bleeding. Do not rub.
398
12. To avoid needle sticks, throw away the syringe and needle without recapping. Discuss
399
sterile technique and proper disposal of your used insulin supplies with your doctor.
400
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10 S-037
Proposed Patient Insert PenFill®/Vial
Version 4.1; Submitted 12-JAN-2007
401
Using Cartridges
402
1. The cartridge and the insulin should be inspected. The insulin should be clear and
403
colorless. The tamper-resistant foil should be in place to be removed by you. If the
404
foil had been punctured or removed before your first use of the cartridge or if the
405
insulin is cloudy or colored, you should return the cartridge to the pharmacy. Do not
406
use it.
407
2. Both the injection site and your hands should be cleaned with soap and water or with
408
alcohol. The injection site should be dry before you inject. Do not use skin that is
409
reddened, itchy, or thickened as an infusion site.
410
3. Insert a 3 mL cartridge in the pen-device barrel. Attach a new needle to the end of the
411
cartridge and turn the pen device upside-down so that any air bubbles can be
412
eliminated by flicking the pen device and squirting air bubbles out the needle. (This
413
should eliminate extra air for all future doses from that cartridge. However, the needle
414
will need to be changed for each dose.)
415
4. Set the dose to be delivered by twisting the top of the pen-device until the correct
416
number appears in the window.
417
5. Inject NovoLog into the subcutaneous (under the skin) tissue (not into muscle or
418
blood vessels) in the abdomen, thighs, upper arms, or buttocks. Pinch the skin fold
419
between your fingers and push the needle straight into the pinched skin. Because
420
insulin absorption and activity can be affected by the site you choose, you should
421
discuss the injection site with your doctor.
422
6. Release the pinched skin. Inject the dose by pressing the flat plunger button on the
423
top of the pen-device. Keep the needle in the skin for a few seconds before
424
withdrawing the pen-device.
425
7. Press the injection site for a few seconds to reduce bleeding. Do not rub.
426
8. Throw away the disposable needle without recapping to avoid needle sticks. Discuss
427
sterile technique and proper disposal of your used insulin supplies with your doctor.
428
429
How should I infuse NovoLog with an external subcutaneous insulin infusion pump?
430
431
NovoLog is recommended for use with the Disetronic H-TRON series, MiniMed 500
432
series, or other pumps recommended by your doctor.
433
434
1. Inspect your insulin as you would for an injection. The insulin should be clear and
435
colorless and without particles. The tamper-resistant cap should be in place to be
436
removed by you. If the cap had been removed before your first use of the vial or if the
437
insulin is cloudy or colored, you should return the vial to the pharmacy. Do not use it.
438
2. Both the infusion site and your hands should be cleaned with soap and water or with
439
alcohol. The infusion site should be dry before you insert the catheter-needle and
440
tubing. Do not use skin that is reddened, itchy, bumpy or thickened as an infusion site
441
because the onset and duration of NovoLog action may not be the same as that in
442
normal skin.
443
3. Fill the reservoir-syringe with 2 days worth of NovoLog plus about 25 extra units to
444
prime the pump and fill up the dead space of the infusion tubing.
445
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Page 11 S-037
Proposed Patient Insert PenFill®/Vial
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4. Remove air bubbles from the reservoir according to the pump manufacturers’
446
instructions.
447
5. Attach the infusion set to the reservoir. Make sure the connection is tight. Prime the
448
infusion set until you see a drop of insulin coming out of the infusion needle-catheter.
449
Flick the tubing to remove air bubbles. Follow the pump manufacturers’ instructions
450
for additional priming.
451
6. Prime the needle-catheter and insert the infusion set into the skin according to the
452
pump manufacturer.
453
7. Program the pump for mealtime NovoLog boluses and NovoLog basal insulin
454
infusion according to instructions from your doctor and the manufacturer of your
455
pump equipment.
456
8. Change the infusion site, the insulin reservoir, the tubing, the catheter-needle, and the
457
insulin every 48 hours or less, even if you have not used all of the insulin. This will
458
help ensure that NovoLog and the pump works well. (See “What is the most
459
important information I should know about NovoLog?”)
460
9. Change the infusion site, the insulin reservoir, the tubing, the catheter-needle, and the
461
insulin if you experience a pump alarm, catheter blockage, hyperglycemia, or if your
462
pump insulin has been exposed to heat greater than 98.6oF (37oC). (See “What is the
463
most important information I should know about NovoLog?”) Hyperglycemia
464
identified with glucose monitoring may be the first indication of a problem with the
465
pump, infusion set, or NovoLog. Hyperglycemia in the absence of an alarm still
466
requires you to investigate because pump alarms are designed to detect back-pressure
467
and occlusion. The alarms may not detect all the changes to NovoLog that could
468
result in hyperglycemia. You may need to resume subcutaneous insulin injections if
469
the cause of the problem cannot be promptly identified or fixed. (See
470
“Hyperglycemia” under “What are the possible side effects of NovoLog?”)
471
Remember that long stretches of tubing increase the risk for kinking and expose the
472
insulin in the tubing to more variations in temperature.
473
474
These instructions give you specific information for use of NovoLog in external
475
subcutaneous infusion pumps, but are not a substitute for pump education.
476
477
How should I mix insulins?
478
479
NovoLog should be mixed only when syringe injections are used. NovoLog can be
480
mixed with NPH human insulin immediately before use. The NovoLog should be drawn
481
into the syringe before the NPH. Mixing with other insulins has not been studied.
482
NovoLog should not be mixed with Lantus (insulin glargine [rDNA origin]
483
injection). Mixed insulins should NEVER be used in a pump or for intravenous
484
infusion.
485
486
1. Add together the doses of NPH and NovoLog. The total dose will determine the final
487
volume in the syringe after drawing up both insulins into the syringe.
488
2. Roll the NPH vial between your hands until the liquid is equally cloudy throughout.
489
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air into the
490
NPH vial and then remove the needle without withdrawing or touching any of the
491
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 12 S-037
Proposed Patient Insert PenFill®/Vial
Version 4.1; Submitted 12-JAN-2007
NPH insulin. (Transferring NPH to the NovoLog vial will contaminate the NovoLog
492
vial and may change how quickly it works.)
493
4. Draw into the syringe the same amount of air as the NovoLog dose. Inject this air into
494
the NovoLog vial. With the needle in place, turn the vial upside-down and withdraw
495
the correct dose of NovoLog. The tip of the needle must be in the NovoLog to get the
496
full dose and not an air dose.
497
5. Insert the needle into the NPH vial. Turn the NPH vial upside down with the syringe-
498
needle still in it. Withdraw the correct dose of NPH.
499
6. Inject immediately to reduce changes in how quickly the insulin works.
500
501
502
Helpful information for people with diabetes is published by the American Diabetes
503
Association, 1660 Duke Street, Alexandria, VA 22314
504
505
For information contact:
506
Novo Nordisk Inc.,
507
100 College Road West
508
Princeton, New Jersey 08540
509
1-800-727-6500
510
www.novonordisk-us.com
511
512
Manufactured by
513
Novo Nordisk A/S
514
2880 Bagsvaerd, Denmark
515
516
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
517
pending.
518
519
NovoLog®, PenFill®, NovoPen®, Innovo®, NovoFine®, and Lente® are trademarks of
520
Novo Nordisk A/S.
521
Lantus® is a trademark of Aventis Pharmaceuticals Inc.
522
H-TRON® is a trademark of Disetronic Medical Systems, Inc.
523
InDuo® is a trademark of LifeScan, Inc., a Johnson & Johnson company.
524
525
526
Date of Issue
527
528
8-XXXX-XX-XXX-X
529
530
Printed in Denmark
531
532
533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:26.172765 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020986s037lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 37} |
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Novopen Illustration
Introduction
Read the Patient Instructions for Use that comes with NovoPen
4 before you start using it and each time you get a refill. There
may be new information. This leaflet does not take the place of
talking with your healthcare provider about your medical
condition or your treatment.
NovoPen 4 is an insulin pen that can deliver insulin doses from 1
to 60 units, in increments of 1 unit. NovoPen 4 is designed to be
used with PenFill 3 mL insulin cartridges and NovoFine
disposable needles.
NovoFine disposable needles are for one time use only.
You should read the instructions in this manual even if you have
used NovoPen 4 or other Novo Nordisk delivery systems before.
NovoPen 4 should not be used by people who are blind or have
visual problems without the help of a person who has good
eyesight and who is trained to use the NovoPen 4 the right way.
Getting Ready
Make sure you have the following items:
• NovoPen 4
• alcohol swabs
• PenFill 3 mL insulin cartridge
• NovoFine disposable needle Novopen Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Usage Illustration
Preparing your NovoPen 4
Before you start to prepare your injection, check the label to
make sure that you are taking the right type of insulin (such as
Novolin R, Novolin N, Novolin 70/30, or NovoLog).
A. Pull off the cap. See Figure A.
B. Unscrew and remove the cartridge holder from the
mechanical part. See Figure B.
C. Push in the piston rod, by gently pressing the piston rod head
(see Figure C1) in until it stops and looks like Figure C2.
Please note when NovoPen 4 is apart while removing the PenFill
cartridge, the piston rod can move back and forth without
pressing it.
If you use more than one kind of insulin, you should use a
separate delivery device for each product. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
D. Use a new PenFill cartridge.
To remove the PenFill cartridge from its wrapper, push the
cartridge through the foil side of the packaging (see Figure D1).
Before use, check that the PenFill cartridge is full and intact and
with no cracks. If not, do not use it.
How to prepare (resuspend) the insulin if the PenFill cartridge
contains an insulin suspension (white and cloudy insulin) such
as Novolin 70/30 or Novolin N you must:
Before inserting a 3 mL cartridge into your NovoPen 4 for
the first time:,
o Roll the PenFill cartridge between your hands 10 times.
These steps should be done with the 3 mL PenFill
cartridge in a flat (horizontal) position (see Figure D2)
o Then turn the PenFill cartridge up and down between
positions A and B (see Figure D3) so the glass ball
moves from one end of the cartridge to the other. Do
this at least 10 times. Repeat the rolling and turning
steps until the insulin looks white and cloudy. Mixing is
easier when the insulin is at room temperature.
After the first use of the 3 mL PenFill cartridge
o With the cartridge in the NovoPen 4, turn it upside
down between positions A and B (see Figure D3
above), so that the glass ball moves from one end of
the 3 mL PenFill cartridge to the other. Do this until all
of the insulin looks white and cloudy.
o Before you inject your insulin:
make sure there is at least 12 units of insulin left in
the cartridge this helps to make sure that the
remaining insulin is evenly mixed. If there is less
than 12 units left in the cartridge, use a new 3 mL
PenFill cartridge. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each PenFill 3 mL cartridge contains a total of 300 units of
insulin. There are five cartridges in a box. Each PenFill cartridge
is for only one person to use.
DO NOT share your NovoPen 4 with other people even if they
have diabetes. Sharing the PenFill cartridge can spread
disease.
Use only a new PenFill 3 mL cartridge when loading the
NovoPen 4. Never load a partially filled PenFill cartridge. Never
try to refill a used PenFill 3 mL cartridge.
E. Insert the PenFill cartridge into the cartridge holder, colored
cap first. See Figure E.
You can see the PenFill cartridge scale in the cartridge window.
The cartridge holder has a scale with marks showing about how
much insulin is left in the PenFill cartridge.
F. Screw the mechanical part together with the cartridge holder
until you hear or feel a click. See Figure F1.
Before each injection, check the amount of insulin left in the
PenFill cartridge:
If the rear rubber stopper cannot be seen in the cartridge
window, you have enough insulin for mixing left in the PenFill
cartridge. See Figure F2.
If the rear rubber stopper can be seen in the cartridge holder
window, you do not have enough insulin left in the PenFill
cartridge and must use a new PenFill 3 mL cartridge. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Wipe the rubber stopper with an alcohol swab. See Figure F3.
G. Remove the protective tab from a NovoFine disposable
needle. Screw the needle tightly onto the colored cap. See
Figure G.
Always use a new NovoFine disposable needle for each
injection.
Never place a NovoFine disposable needle on your NovoPen 4
until you are ready to do an air shot and take your injection.
H. Pull off the outer needle cap. Carefully pull off the inner
needle cap and throw it away. See Figure H1. A droplet of
insulin may appear at the needle tip. This is normal.
Do not bend or damage the needle. To lessen the risk of
unexpected needle sticks, never put the inner needle cap back
on the needle.
Always take off the needle after each injection and store the
NovoPen 4 without a needle attached. This prevents
contamination, infection, leakage of insulin, and will ensure
accurate dosing.
Do an “Air Shot” before each injection
Before each injection a small amount of air may collect in the
PenFill cartridge. To avoid injecting air and ensure proper
dosing, you must do an air shot before each injection.
Before starting the air shot, the dose indicator window must
show zero (0) see Figure H2.
Set the NovoPen 4 for the air shot: Usage IllustrationUsage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
I. Make sure that a NovoFine disposable needle is attached.
See Figure I.
J. Pull out the dose button, if it is not already pulled out. See
Figure J.
K. Turn the dose button to select:
4 units with a new PenFill cartridge. 4 units are selected
when the number 4 lines up with the dose indicator. See
Figure K.
OR
1 unit with a cartridge already in use. 1 unit is selected
when the number 1 lines up with the dose indicator. See
Figure K.
1 increment is equal to 1 unit.
The even numbers are shown. The odd numbers are indicated
by the lines between the even numbers.
L. Hold your NovoPen 4 with the needle pointing up.
Tap the PenFill cartridge holder gently with your finger a few
times to make any air bubbles collect at the top of the cartridge.
See Figure L. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
M. Keep the needle pointing up, press the dose button all the
way in, until you hear or feel a click. The display will return to 0.
A drop of insulin must appear at the needle tip. See Figure M. If
you do not see a drop of insulin at the needle tip, repeat steps I
to L until you see a drop of insulin at the needle tip. You may
need to do this up to 6 times. If you do not see a drop of insulin
after 6 times, do not use the NovoPen 4 and call Novo Nordisk
at 1-800-727-6500.
It is very important that a drop of insulin is seen at the needle tip
before you take your injection. This will ensure accurate dosing.
A small air bubble may remain in the PenFill cartridge. This is
normal it will not affect your dose and will not be injected.
Select your dose
Be sure to do an air shot before giving an injection.
N. Pull out the dose button, if it is not already pulled out. See
Figure N.
O. Turn the dose button to the number of units you need to
inject. The pointer should line up with your dose that is needed.
Remember that 60 units is the maximum dose you can take in
one injection. See Figure O.
If you select a different dose than you need, turn the dose button
until the correct dose lines up with the dose indicator.
If you need more than 60 units, you must divide your dose into
two injections. Inject the 60 units first and then make a new
injection with the remaining number of units needed to complete
your dose. For example, to inject 65 units you must inject 60
units first and then make a new injection with 5 units of insulin to
complete your dose. Always use a new disposable needle for
each injection. See Figure O.
Give your injection
Give the injection exactly as shown to you by your healthcare
provider.
P. Insert the needle into your skin. Inject the dose by pressing
the dose button all the way in, until you hear or feel a click.
Check the dose indicator window to make sure it shows zero (0).
See Figure P. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Q. Keep the NovoFine needle in the skin for at least 6 seconds.
See Figure Q
This will make sure that the full insulin dose has is given.
Be careful only to press the dose button to inject the insulin.
Turning the dose button will not inject insulin.
R. Take the needle out of your skin. You have completed your
injection and the selected insulin dose has been given. The
display will show 0. If zero (0) does not appear, you did not get
the full dose. See Figure R.
After you take the needle out of your skin, you may see a few
drops of insulin at the needle tip. This is normal and has no
effect on the dose you just received.
If your injection is given by another person, this person must be
careful when removing and disposing of needles to prevent
accidental needle stick injury.
After the injection
The NovoFine disposable needle must be removed immediately
after each injection without replacing the cap.
Do not recap the needle. Recapping can lead to a needle stick
injury. Remove the needle from the NovoPen 4 after each
injection. This helps to prevent infection, leakage of insulin, and
will help to make sure you inject the right dose of insulin.
S. Carefully remove the needle (see Figure S), put the needle
and any empty PenFill cartridge in a sharps container, or some
type of hard plastic or metal container with a screw top such as a
detergent bottle or empty coffee can. These containers should
be sealed and thrown away the right way. Check with your
healthcare provider about the right way to throw away used
needles and syringes. There may be local or state laws about
how to throw away used needles. Do not throw away used
needles in household trash or recycling bins.
Always replace the pen cap after each use.
Put the pen cap on the NovoPen 4 and store the NovoPen 4
without the needle attached. This helps to ensure sterility,
prevent leakage of insulin, and will help to make sure you inject
the right dose of insulin with your next injection. Usage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Change the PenFill cartridge
When the PenFill cartridge is almost empty:
T. The cartridge scale on the PenFill cartridge holder shows the
approximate number of insulin units left in the PenFill cartridge
as in Figure A. Do not use the cartridge scale to measure the
amount of insulin to be injected. See Figure T.
U. If the PenFill cartridge has less than 60 units in it, the exact
number of units left can be read in the display. To do this, pull
out the dose button, if it is not already pulled out, and turn it until
it stops. The number of units left will line up with the dose
indicator as seen in Figure B. If the dose indicator is positioned
between two lines, adjust to the lower of the two dose amounts.
You can not select a dose larger than the number of units left in
the PenFill cartridge. See Figure U.
Do not force the dose button to turn as this can damage your
NovoPen 4.
Insulin suspension (white and cloudy insulin):
V. Do not try to inject an insulin suspension (white and cloudy
insulin) if the rubber stopper (plunger) is below the white line on
the holder as in Figure V. The glass ball inside the PenFill
cartridge must have enough space to mix the insulin.
If you need more insulin than the amount left in the PenFill
cartridge, you can:
Inject the amount of insulin left in the PenFill cartridge,
making a note of the number of units you inject or replace the
used PenFill cartridge with a new one for your full dose.
To change the PenFill cartridge see Figure T to U.
Always attach a new NovoFine needle.
Do an airshot as described in Figure I to M.
Select and inject the number of insulin units needed to
complete your dose.
Storage
Storage and handling
Be careful when handling your NovoPen 4, do not drop it and
avoid knocking it against hard surfaces.
Always remove the needle and replace the pen cap after each
use. Usage IllustrationUsage IllustrationUsage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Protect your NovoPen 4 against direct sunlight, water, dust and
dirt.
When a PenFill cartridge is inserted in the NovoPen 4, store
your NovoPen 4 at 59oF to 86°F (15oC to 30°C) for the amount
of days listed in the PenFill “Information for the Patient” leaflet
for the type of insulin you are using.
The expiration date printed on the PenFill cartridge is for
unused PenFill cartridges stored in the refrigerator. Never use
the PenFill cartridge after the expiration date on the PenFill
cartridge or on the box.
For information on storing PenFill cartridges, see the
Information For The Patient leaflet that comes in the PenFill
cartridge box.
Keep your NovoPen 4 in the case supplied when possible.
Maintenance
Cleaning and maintenance
You can clean the outside of your NovoPen 4 by wiping it with
a damp cloth.
Do not soak in water, wash or lubricate your NovoPen 4, this
may damage it.
Clean off dirt and dust with a dry cloth.
Important Things to Know
Always keep a spare insulin delivery system in case your
NovoPen 4 is lost or damaged.
Keep your NovoPen 4, PenFill cartridges, and NovoFine
needles out of the reach of children.
Keep the NovoPen 4 away from areas where temperatures
may get too hot or too cold such as a car or refrigerator.
Use a separate insulin delivery device if you are using more
than one type of insulin in PenFill cartridges.
Novo Nordisk is not responsible for harm due to using the
NovoPen 4 with products other than PenFill 3 mL insulin
cartridges, and NovoFine single use disposable needles.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Warranty
Do not try to repair a faulty NovoPen 4.
If you think your NovoPen 4 is not working the right way, contact
Novo Nordisk at 1-800-727-6500.
The LOT number of your NovoPen 4 it is located on the
mechanical part as illustrated in the inside cover.
For assistance or further information, write to:
Novo Nordisk Inc.
Customer Care
100 College Road West
Princeton, NJ 08540
Or call: 1-800-727-6500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Quick Guide Usage Illustration
Preparing NovoPen 4
Pull off the cap. Unscrew and remove the cartridge holder from
the mechanical part. See Figure 1.
Push in the piston rod, by pressing the piston rod head in until it
stops and looks like Figure 2.
If you are using an insulin suspension (white and cloudy insulin),
always mix (resuspend) it before use. See the NovoPen 4
Instruction Manual for details on how to mix (resuspend) the
insulin.
Insert the PenFill cartridge into the cartridge holder, the color-
coded cap goes in first. See Figure 3. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Screw NovoPen 4 together (see Figure 4).
Wipe the front rubber stopper with an alcohol swab and screw
on a new NovoFine disposable needle. Pull off the outer and
inner needle caps. Dispose of the needle caps. See Figure 5.
Do an “Air Shot” before each injection
Always do an airshot before each injection.
Pull out the dose button, if it is not already pulled out, and turn it
to select: See Figure 6.
4 units with a new PenFill cartridge
OR
1 unit with a cartridge already in use
Hold your NovoPen 4 with the needle facing upwards.
Tap the cartridge holder gently with your finger a few times to
make any air bubbles collect at the top of the cartridge. See
Figure 7.
Press the dose button all the way in, until you hear or feel a
click. The display will return to (0) See Figure 8. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A drop of insulin must appear at the needle tip. See Figure 9.
If you do not see a drop of insulin, repeat steps in Figures 5 to 7
until you see a drop of insulin. You may need to do this up to 6
times. If you do not see a drop of insulin after 6 times, do not
use the NovoPen 4 and call Novo Nordisk at 1-800-727-6500.
Select your dose
Pull out the dose button, if it is not already pulled out, and turn
the dose button until your needed dose lines up with the dose
indicator. See Figure 10.
If you select a different dose than you need, turn the dose button
until the correct dose lines up with the dose indicator.
Give your injection
Give the injection exactly as shown to you by your healthcare
provider.
To inject, press the dose button completely in, until you hear or
feel a click. Turning the dose button will not inject insulin.
Leave the needle under the skin for at least 6 seconds. See
Figure 11. Take the needle out of your skin, your selected dose
has been given. Remove and dispose of the needle (follow the
detailed instructions in the NovoPen 4 Instruction Manual).
Put the pen cap back on. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Front of carton:
List: XXXXXX
NovoPen® 4
Dial-A-Dose
Insulin Delivery Pen
CONTAINS ONE NOVOPEN 4
Designed for use with PenFill 3 mL cartridges and NovoFine disposable needles
Side Flap of Carton:
NovoPen® 4
Dial-A-Dose
Insulin Delivery Pen
List: XXXXXXX
Lot
Side Flap of Carton:
NovoPen 4
Dial-A-Dose
Insulin Delivery Pen
Convenient Carrying Case Enclosed
The NovoPen 4 is designed for use with PenFill 3 mL cartridges and NovoFine
disposable needles.
Needles and cartridges not included.
Back of Carton:
For information contact:
Novo Nordisk Inc.
Princeton, NJ 08540
www.novonordisk-us.com
Manufactured in Denmark by Novo Nordisk A/S
2880 Bagvaerd, Denmark
NovoPen 4 is covered under US Patent No. 5,693,027, US
Patent No. 6,663,602, US Patent No. 7,241,278, and other patents pending.
Novo Nordisk, NovoPen, NovoFine, NovoLog, PenFill, and Novolin are registered
trademarks of Novo Nordisk A/S.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:26.428505 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019938s064,019959s067,019991s068,020986s055lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 55} |
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog®
safely and effectively. See full prescribing information for NovoLog.
NovoLog (insulin aspart [rDNA origin] injection) solution for subcutaneous
use
Initial U.S. Approval: 2000
·······································INDICATIONS AND USAGE········································
• NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
··································DOSAGE AND ADMINISTRATION································
• The dosage of NovoLog must be individualized.
• Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
• Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
• Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL to
1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags.
NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium
chloride (2.4).
·······························DOSAGE FORMS AND STRENGTHS································
Each presentation contains 100 Units of insulin aspart per mL (U-100)
• 10 mL vials (3)
• 3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
• 3 mL NovoLog FlexPen (3)
········································CONTRAINDICATIONS··············································
• Do not use during episodes of hypoglycemia (4).
• Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
··································WARNINGS AND PRECAUTIONS······························
• Hypoglycemia is the most common adverse effect of insulin therapy. Glucose
monitoring is recommended for all patients with diabetes. Any change of
insulin dose should be made cautiously and only under medical supervision
(5.1, 5.2).
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of diabetes mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Mixing of Insulins
5.9 Continuous Subcutaneous Insulin Infusion by External Pump
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
• Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.3).
• Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.4, 5.5).
• Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.6).
········································ADVERSE REACTIONS···········································
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
···········································DRUG INTERACTIONS·······································
• The following may increase the blood-glucose-lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide
antibiotics (7).
• The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral
contraceptives), atypical antipsychotics (7).
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or
weaken the blood-glucose-lowering effect of insulin (7).
• Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia (7).
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine, and
reserpine (7).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
•
Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: [3/2008]
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17
PATIENT COUNSELING INFORMATION
17.1 Physician Instructions
17.2 Patients Using Pumps
17.3 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
Medtronic Paradigm® 512 and 712
MiniMed 508
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
10 mL vials
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
3 mL NovoLog FlexPen
4
CONTRAINDICATIONS
NovoLog is contraindicated
during episodes of hypoglycemia
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.3
Hypokalemia
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
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5.4
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Clinical Pharmacology (12.3)].
5.5
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Clinical Pharmacology (12.3)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.7
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.8
Mixing of Insulins
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
Insulin mixtures should not be administered intravenously.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.2)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9) and How
Supplied/Storage and Handling (16.2), Patient Counseling Information (17)].
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
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Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL,with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during postapproval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during postapproval use [see Patient Counseling Information (17)].
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For current labeling information, please visit https://www.fda.gov/drugsatfda
7
DRUG INTERACTIONS
A number of substances affect glucose metabolism and may require insulin dose
adjustment and particularly close monitoring.
The following are examples of substances that may increase the blood-glucose
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide),
sulfonamide antibiotics.
The following are examples of substances that may reduce the blood-glucose
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
atypical antipsychotics.
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
the blood-glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
products such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
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insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age, particularly in patients with type 2 diabetes.
Additional studies in larger populations of patients 65 years of age or over are needed to permit
conclusions regarding the safety of NovoLog in elderly compared to younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog
action have not been performed.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
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NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8. Molecular Structure
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset of action than regular human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 2). The
duration of action for NovoLog is 3 to 5 hours. The time course of action of insulin and insulin
analogs such as NovoLog may vary considerably in different individuals or within the same
individual. The parameters of NovoLog activity (time of onset, peak time and duration) as
designated in Figure 2 should be considered only as general guidelines. The rate of insulin
absorption and onset of activity is affected by the site of injection, exercise, and other variables
[see Warnings and Precautions (5.1)].
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Graph
Figure 2. Serial mean serum glucose collected up to 6 hours following a single
pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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Mean Blood Glucose (mg/dL)
Gr
aph
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to
regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the
regular human insulin group.
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of
action, and a shorter duration of action than regular human insulin after subcutaneous injection
(see Figure 2 and Figure 4). The relative bioavailability of NovoLog compared to regular human
insulin indicates that the two insulins are absorbed to a similar extent.
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Graph
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single pre-meal dose of NovoLog (solid curve) or regular human insulin
(hatched curve) injected immediately before a meal in 22 patients with type 1
diabetes.
In studies in healthy volunteers (total n=l07) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin
aspart have not been established in patients with type 2 diabetes.
The intra-individual variability in time to maximum serum insulin concentration for
healthy male volunteers was significantly less for NovoLog than for regular human insulin. The
clinical significance of this observation has not been established.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
Specific Populations
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Gender - In healthy volunteers, no difference in insulin aspart levels was seen between
men and women when body weight differences were taken into account. There was no
significant difference in efficacy noted (as assessed by HbAlc) between genders in a trial in
patients with type 1 diabetes.
Obesity - A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.
Renal Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal (N=6) creatinine clearance
(CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50
ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment.
In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax
of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog,
may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4)].
Hepatic Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter.
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5)].
The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c ,Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.3 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (0.4, 0.3)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or sunlight. Opened vials may be refrigerated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen Prefilled Syringes:
Once a cartridge or a NovoLog FlexPen is punctured, it should be kept at temperatures
below 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight. A
NovoLog FlexPen or cartridge in use must NOT be stored in the refrigerator. Keep the NovoLog
FlexPen and all PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog
FlexPen and PenFill cartridges can be used until the expiration date printed on the label if they
are stored in a refrigerator. Keep unused NovoLog FlexPen and PenFill cartridges in the carton
so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen without a needle attached. This prevents
contamination and/or infection, or leakage of insulin, and will ensure accurate dosing.
Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges and NovoLog FlexPen Prefilled
syringe
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30°C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage of NovoLog in Infusion Fluids
Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling (17.3)]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.2
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
Medtronic Paradigm® 512 and 712
MiniMed 508
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.3 FDA Approved Patient Labeling
Rx only
Date of Issue:
Version
®
NovoLog , NovoPen® 3, PenFill®, Novolin®, FlexPen®, PenMate®, and NovoFine® are
trademarks of Novo Nordisk A/S.
®
NovoLog is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and other patents
pending.
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and other patents
pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured By Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark
Manufactured For Novo Nordisk Inc., Princeton, New Jersey 08540
www.novonordisk-us.com
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] Injection)
Important:
Know your insulin. Do not change the type of insulin you use unless told to do
so by your healthcare provider. The amount of insulin you take as well as the
best time for you to take your insulin may need to change if you take a different
type of insulin.
Make sure you know the type and strength of insulin prescribed for you.
Read the Patient Information that comes with NovoLog before you start taking it
and each time you get a refill. There may be new information. This leaflet does
not take the place of talking with your healthcare provider about your diabetes or
your treatment. Make sure you know how to manage your diabetes. Ask your
healthcare provider if you have any questions about managing your diabetes.
What is NovoLog?
NovoLog is a man-made insulin that is used to control high blood sugar in adults
and children with diabetes mellitus.
Who should not use NovoLog?
Do not take NovoLog if:
•
Your blood sugar is too low (hypoglycemia)
•
You are allergic to anything in NovoLog. See the end of this leaflet
for a complete list of ingredients in NovoLog. Check with your
healthcare provider if you are not sure.
Tell your healthcare provider:
•
about all of your medical conditions. Medical conditions can affect
your insulin needs and your dose of NovoLog.
•
if you are pregnant or breastfeeding. You and your healthcare
provider should talk about the best way to manage your diabetes
while you are pregnant or breastfeeding. NovoLog has not been
studied in nursing women.
•
about all medicines you take, including prescriptions and non
prescription medicines, vitamins and herbal supplements. Your
NovoLog dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show
your healthcare providers when you get a new medicine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take NovoLog?
Only use NovoLog if it appears clear and colorless. There may be air bubbles.
This is normal. If it looks cloudy, thickened, or colored, or if it contains solid
particles do not use it and call Novo Nordisk at 1-800-727-6500.
NovoLog comes in:
•
10 mL vials (small bottles) for use with syringe
•
3 mL PenFill® cartridges for use with the Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices and NovoFine®
disposable needles. The cartridge delivery device can be used with a
NovoPen® 3 PenMate®
•
3 mL NovoLog FlexPen®
Read the instructions for use that come with your NovoLog product. Talk
to your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject NovoLog before you start taking it.
•
Take NovoLog exactly as prescribed. You should eat a meal within
5 to 10 minutes after using NovoLog to avoid low blood sugar.
•
NovoLog is a fast-acting insulin. The effects of NovoLog start
working 10 to 20 minutes after injection or bolus pump infusion.
•
Do not inject NovoLog if you do not plan to eat right after your
injection or bolus pump infusion.
•
The greatest blood sugar lowering effect is between 1 and 3 hours
after the injection or infusion. This blood sugar lowering lasts for 3 to
5 hours.
•
While using NovoLog you may have to change your total dose of
insulin, your dose of longer-acting insulin, or the number of injections
of longer-acting insulin you use. Pump users given NovoLog may
need to change the amount of total insulin given as a basal infusion.
•
Do not mix NovoLog:
o with any other insulins when used in a pump
o with any insulins other than NPH when used with injections
by syringe
If your doctor recommends diluting NovoLog, follow your doctor’s
instructions exactly so that you know:
• How to make NovoLog more dilute (that is, a smaller number of
units of NovoLog for a given amount of liquid) and
• How to use this more dilute form of NovoLog. Do not use dilute
insulin in a pump.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Inject NovoLog into the skin of your stomach area, upper arms,
buttocks or upper legs. NovoLog may affect your blood sugar
levels sooner if you inject it into the skin of your stomach area. Never
inject NovoLog into a vein or into a muscle.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the exact same spot for each injection.
•
If you take too much NovoLog, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia)
by drinking or eating something sugary right away (fruit juice, sugar
candies, or glucose tablets). It is important to treat low blood sugar
(hypoglycemia) right away because it could get worse and you could
pass out (become unconscious). If you pass out you will need help
from another person or emergency medical services right away, and
will need treatment with a glucagon injection or treatment at a
hospital. See “What are the possible side effects of NovoLog?” for
more information on low blood sugar (hypoglycemia).
•
If you forget to take your dose of NovoLog, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death. Follow
your healthcare provider’s instructions for treating high blood sugar.
Know your symptoms of high blood sugar which may include:
•
increased thirst
• fruity smell on the breath
•
frequent urination
• high amounts of sugar and
•
drowsiness
ketones in your urine
•
loss of appetite
• nausea, vomiting (throwing up)
•
a hard time
or stomach pain
breathing
•
Check you r blood su gar levels. Ask your healthcare provider what
your blood sugars should be and when you should check your blood
sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
diet
change in
•
stress
• change in physical activity or
•
icines you
other med
exercise
take
What should I avoid while using NovoLog ?
•
Alcohol. Alcohol, including beer and wine, may affect your blood
sugar when you take NovoLog.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Driving and operating machinery. You may have difficulty
concentrating or reacting if you have low blood sugar (hypoglycemi a).
Be careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright to drive if you often have:
• low blood sugar
• decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog?
•
low b lo d sugar (hypoglycemia). Symptoms of low blood sugar
o
may in lu de:
c
•
sweating
•
trouble concentrating or
•
dizziness or
confusion
lightheadedness
•
blurred vision
•
shakiness
•
slurred speech
•
hunger
•
anxiety, irritability or
•
fast heart beat
mood changes
•
tingling of lips and
•
headache
tongue
Severe low blood sugar can cause unconsciousness (passing out),
seizures, and death. Know your symptoms of low blood sugar.
Follow your healthcare prov ider’s instructions for treating low blood
sugar. Talk to your healthcare provider if low blood sugar is a
problem for you.
•
Serious allergic reaction (whole body reaction). Get medical
help right away, if you develop a rash over your whole body, h ave
trouble breathing, a fast heartbeat, or sweating.
•
Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions or they are serious talk to your healthcare
provider. You may need to stop using NovoLog and use a differen t
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
•
Skin thickens or pits at the injection site (lipod ystrophy).
Change (rotate) where you inject your insulin to help to prevent these
skin changes from happening. Do not inject insulin into this type of
skin.
•
Swelling of your hands and feet.
•
Vision changes
•
Low potassium in your blood (hypokalemia)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Weight gain
These are not all of the possible side effects from NovoLog. Ask your
health are provider or pha
c
rmacist for more information.
Call your doctor for medical advice about side effects. Yo u may report side
effects to FDA at 1-80 0-FDA-1088.
How should I store NovoLog?
All Unopened NovoLog:
•
Keep all unopened NovoLog in the refrigerator between 36° to
46°F (2° to 8°C).
•
Do not freeze. Do not use NovoLog if it has been frozen.
•
Keep unopened NovoLog in the carton to protect from light.
NovoLog in use:
•
Vials.
• Keep in the refrigerator or at room temperature belo w 86°F
(30°C) for up to 28 days.
• Keep vials away from direct heat or light.
• Throw away an opened vial after 28 days of use, even if there is
insulin left in the vial.
• Do not draw up NovoLog into a syringe and store for later use
• Unopened vials can be used until the expiration date on the
NovoLog label, if the medicine has been stored in a refrigerator.
•
PenFill Cartridges or NovoLog FlexPen Prefilled syringe.
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store a PenFill cartridge or NovoLog FlexPen Prefilled
syringe that you are using in the refrigerator.
• Keep PenFill cartridges and NovoLog FlexPen Prefilled syringe
away from direct heat or light.
• Throw away a used PenFill cartridge or NovoLog FlexPen
Prefilled syringes after 28 days, even if there is insulin left in the
cartridge or syringe.
•
NovoLog in the pump reservoir and the complete external pump
infusion set
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• The infusion set and the infusion site should be changed at
least every 3 days. The insulin in the reservoir should be
changed at least every 6 days even if you have not used all of
the insulin. Change the infusion set and the infusion site more
often than every 3 days if you have high blood sugar
(hyperglycemia), the pump alarm sounds, or the insulin flow is
blocked (occlusion).
General advice about NovoLog
Medicines are sometimes prescribed for conditions that are not mentioned in the
patient leaflet. Do not use NovoLog for a condition for which it was not
prescribed. Do not give NovoLog to other people, even if they have the same
symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog. If you
would like more information about N ovoLog or diabetes, talk with your healthcare
provider. You can ask your healthcare provider or pharmacist for information
about NovoLog that is written for healthcare professionals. Call 1-800-727-6500
or visit www.novonordisk-us.com for more information.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1701 N Beauregard Street Alexandria, VA 22311 and on
www.diabetes.org.
NovoLog ingredients include:
• insulin aspart
• zinc
• glycerin
• disodium hydrogen phosphate dihydrate
• phenol
• sodium chloride
• metacresol
• water for injection
All NovoLog vials, PenFill cartridges and NovoLog FlexPen Prefilled syringes are
latex free.
Date of Issu e:
Version: 7
®
®
®
NovoLog , PenFill®, FlexPen®, NovoPen , NovoFine , PenMate®, are
trademarks of Novo Nordisk A/S.
®
NovoLog is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and
other patents pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
NovoLog® 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing
and giving your insulin injection.
Never re-use syringes and needles.
How should I use the NovoLog vial?
1. Check to make sure that you have the correct type of insulin. This is
especially important if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be clear and colorless. The
tamper-resistant cap should be in place before the first use. If the cap had
been removed before your first use of the vial, or if the insulin is cloudy or
colored, do not use it and call Novo Nordisk at 1-800-727-6500
3. Wash your hands with soap and water. If you clean your injection site with an
alcohol swab, let the injection site dry before you inject. Talk with your
healthcare provider about how to rotate injection sites and how to give an
injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber
stopper with an alcohol wipe.
5. Do not roll or shake the vial. Shaking right before the dose is drawn into the
syringe may cause bubbles or froth. This can cause you to draw up the wrong
dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for
the number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger
all the way in to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a
few units beyond correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the
air bubbles to the top. Then slowly push the plunger to the marking for your
correct dose. This process should move any air bubbles present in the
syringe back into the vial.
10.Check to make sure you have the right dose of NovoLog in the syringe.
11.Pull the syringe out of the vial’s rubber stopper.
12.Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important
to ask your doctor if you did not receive instructions on pinching the skin.
Insert the needle into the pinched skin. Press the plunger of the syringe to
inject the insulin. When you are finished injecting the insulin, pull the needle
out of your skin. You may see a drop of NovoLog at the needle tip. This is
normal and has no effect on the dose you just received. If you see blood after
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
you take the needle out of your skin, press the injection site lightly with a
piece of gauze or an alcohol wipe. Do not rub the area.
13.After your injection, do not recap the needle. Place used syringes, needles
and used insulin vials in a disposable puncture-resistant sharps container, or
some type of hard plastic or metal container with a screw on cap such as a
detergent bottle or coffee can.
14.Ask your healthcare provider about the right way to throw away used syringes
and needles. There may be state or local laws about the right way to throw
away used syringes and needles. Do not throw away used needles and
syringes in household trash or recycle.
How should I mix insulins?
NovoLog should be mixed only when injections with syringes are used. NovoLog
can be mixed with NPH human insulin right before use. The NovoLog should be
drawn into the syringe before you draw up the NPH insulin. NovoLog should
not be mixed with any other insulin except NPH.
1. Add together the doses (total number of units) of NPH and NovoLog that you
need to inject. The total dose will determine the final amount (volume) in the
syringe after drawing up both insulins into the syringe. For example, if you
need 5 units of NPH and 2 units of NovoLog, the total dose of insulin in the
syringe would be 7 units.
2. Roll the NPH vial between your hands until the liquid is equally cloudy
throughout.
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air
into the NPH vial and then remove the needle from the vial but do not
withdraw any of the NPH insulin. (Transferring NPH to the NovoLog vial will
contaminate the NovoLog vial and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the NovoLog dose. Inject this
air into the NovoLog vial. With the needle in place, turn the vial upside down
and withdraw the correct dose of NovoLog. The tip of the needle must be in
the NovoLog to get the full dose and not an air dose.
5. After withdrawing the needle from the NovoLog vial, insert the needle into the
NPH vial. Turn the NPH vial upside down with the syringe and needle still in
it. Withdraw the correct dose of NPH.
6. Inject right away to avoid changes in how quickly the insulin works.
How do I use NovoLog in a pump?
Checking your blood sugar is very important for patients using pumps.
Pump or infusion set problems can result in you not getting enough
insulin. This can quickly cause you to have high blood sugar and diabetic
ketoacidosis.
Use insulin from a new vial of NovoLog if unexplained high blood sugar or
pump alarms do not respond to all of the following:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o a repeat dose (injection or bolus) of NovoLog
o a change in the infusion set, including the NovoLog in the reservoir
o a change in the infusion site
If these measures do not work, you may need to go back to injecting
NovoLog with syringes, or insulin pens. Continue to monitor your blood
sugars and ketones. If problems continue, you must contact your
healthcare provider.
When NovoLog is used in pumps, use only pumps that are
recommended by your healthcare provider. The infusion set and
infusion site should be changed at least every 3 days. The insulin in the
reservoir should be changed at least every 6 days even if you have not
used all of the insulin. The reservoir, the infusion set, and infusion site
should also be changed:
o with unexpected high blood sugar
o when the alarm sounds (see your pump manual)
o if the insulin or pump has been exposed to temperatures over
98.6°F (37°C), such as in a sauna, with long showers, or on an
unusually hot day.
o if the insulin or pump could have absorbed heat, for example from
sunlight, that would heat the insulin to over 98.6°F (37°C). Dark
colored pump cases or sport covers can increase this type of heat.
The location where the pump is worn may also affect the
temperature
Patients who develop local skin reactions may need to change infusion sites
more often than every 3 days.
Use only insulin pumps that have been specially tested with NovoLog. Follow
your healthcare provider or pharmacist instructions for which insulin pumps may
be used.
Check with your healthcare provider or pharmacist to see if your pump and
infusion set can be used with NovoLog.
1. Check to make sure that you have the right type of insulin.
2. Look at the vial and insulin. The insulin should be clear and colorless. The
tamper-resistant cap should be in place before the first use. If the cap had
been removed before your first use, or if the insulin is cloudy or colored,
do not use it and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water.
4. Fill the reservoir-syringe with 2 days worth of NovoLog plus about 25 extra
units to prime the pump and the infusion tubing.
5. Remove air bubbles from the reservoir by following the pump
manufacturers’ instructions.
6. Attach the infusion set to the reservoir. Make sure the connection is tight.
Prime the infusion set until you see a drop of insulin coming out of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
infusion needle-catheter. Follow the pump manufacturers’ instructions for
priming and removing air bubbles.
7. Clean your insertion site with an alcohol swab and let the site dry before
you insert the needle-catheter. Talk with your healthcare provider about
how to rotate insertion sites and how to insert the needle-catheter into the
skin.
8. Insert the needle-catheter into the skin, remove the needle and prime the
catheter according to the pump manufacturers’ instructions. Do not insert
the needle-catheter into skin that is reddened, itchy, bumpy, or thickened.
9. Program the pump for mealtime NovoLog boluses and NovoLog basal
insulin infusion according to instructions from your healthcare provider and
the manufacturer of your pump equipment.
10.Change the infusion site and infusion set at least every 3 days, and
change the insulin in the reservoir at least every 6 days even if you have
not used all of the insulin. This will help ensure that NovoLog and the
pump work well.
11.Change the infusion site, the infusion set, the insulin reservoir and the
insulin if you experience a pump alarm, catheter blockage, high blood
sugars, or if your pump insulin has been exposed to heat greater than
98.6oF (37oC).
12.If you have high blood sugar (hyperglycemia) when you check your blood
sugar, this may be the first sign of a problem with the pump, infusion set,
or NovoLog. If you have high blood sugar without a pump alarm, you must
still check the pump because alarms may not detect all the changes to
NovoLog that could result in high blood sugar. You may need to start
insulin injections with syringes if the cause of the problem cannot be found
quickly or fixed. Long lengths of infusion-set tubing increase the risk for
kinking and expose the insulin in the tubing to more changes in
temperature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:26.911536 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020986s045lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 45} |
3,945 | Page 1 of 23 Submitted 14Mar08
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog®
safely and effectively. See full prescribing information for NovoLog.
NovoLog (insulin aspart [rDNA origin] injection) solution for subcutaneous
use
Initial U.S. Approval: 2000
·······································INDICATIONS AND USAGE········································
• NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1)
··································DOSAGE AND ADMINISTRATION································
• The dosage of NovoLog must be individualized.
• Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2)
• Use in pumps: Change the NovoLog in the reservoir, the infusion set, and the
infusion set insertion site at least every 48 hours. NovoLog should not be
mixed with other insulins or with a diluent when it is used in the pump. (2.3)
• Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL to
1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags.
NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium
chloride. (2.4)
·······························DOSAGE FORMS AND STRENGTHS································
Each presentation contains 100 Units of insulin aspart per mL (U-100)
• 10 mL vials (3)
• 3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
• 3 mL NovoLog FlexPen Prefilled syringe (3)
········································CONTRAINDICATIONS··············································
• Do not use during episodes of hypoglycemia (4)
• Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
··································WARNINGS AND PRECAUTIONS······························
• Hypoglycemia is the most common adverse effect of insulin therapy. Glucose
monitoring is recommended for all patients with diabetes. Any change of
insulin dose should be made cautiously and only under medical supervision.
(5.1, 5.2).
•
Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.3).
•
Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.4, 5.5)
•
Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog.(5.7)
········································ADVERSE REACTIONS···········································
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
···········································DRUG INTERACTIONS·······································
• The following may increase the blood glucose-lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide
antibiotics. (7)
• The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral
contraceptives), atypical antipsychotics. (7)
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or
weaken the blood-glucose-lowering effect of insulin. (7)
• Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia. (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine, and
reserpine. (7)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: [3/2008]
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of diabetes mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion by External Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Mixing of Insulins
5.9 Subcutaneous Continuous Insulin Infusion by External Pump
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal toxicology and/or pharmacology
14
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous subcutaneous insulin infusion (CSII) by external
pump
14.3 Intravenous Administration of NovoLog
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How supplied
16.2 Recommended Storage
17
PATIENT COUNSELING INFORMATION
17.1 Physician Instructions
17.2 Patients using pumps
17.3 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 1 of 23 Submitted 14Mar08
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of diabetes mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin. [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous subcutaneous insulin infusion (CSII) by external pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.9, 5.10), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 of 23 Submitted 14Mar08
NovoLog in the reservoir, the infusion sets and the infusion set insertion site at least every
48 hours.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5.9), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
10 mL vials
3 mL PenFill cartridges for the 3mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
3 mL NovoLog FlexPen Prefilled Syringe
4
CONTRAINDICATIONS
NovoLog is contraindicated
during episodes of hypoglycemia
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of Novolog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3 of 23 Submitted 14Mar08
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.3
Hypokalemia
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
5.4
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Clinical Pharmacology (12.3)].
5.5
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Clinical Pharmacology (12.3)].
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5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.7
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12-
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.8
Mixing of Insulins
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
Insulin mixtures should not be administered intravenously.
5.9
Subcutaneous continuous insulin infusion by external pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
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Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required. [see Dosage
and Administration (2.3), Warnings and Precautions (5.9, 5.10), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17)]
NovoLog is recommended for use in pump systems suitable for insulin infusion as listed
below.
Pumps:
MiniMed 500 series and other equivalent pumps.
Reservoirs and infusion sets:
NovoLog is recommended for use in reservoir and infusion sets that are compatible with
insulin and the specific pump. In-vitro studies have shown that pump malfunction, loss of
metacresol, and insulin degradation, may occur when NovoLog is maintained in a pump system
for longer than 48 hours. Reservoirs and infusion sets should be changed at least every 48 hours.
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent. [see
Dosage and Administration (2.3), Warnings and Precautions (5.9, 5.10) and How
Supplied/Storage and Handling (16.2), Patient Counseling Information (17)].
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog. [see Warnings and Precautions (5)]
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
Weight gain
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Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL,with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during postapproval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
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uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during postapproval use. [see Patient Counseling Information (17)]
7
DRUG INTERACTIONS
A number of substances affect glucose metabolism and may require insulin dose
adjustment and particularly close monitoring.
The following are examples of substances that may increase the blood-glucose-
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide),
sulfonamide antibiotics.
The following are examples of substances that may reduce the blood-glucose-
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
atypical antipsychotics.
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
the blood-glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
products such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
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Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. Please see Section 14 CLINICAL
STUDIES for summaries of clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90) .The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age, particularly in patients with type 2 diabetes.
Additional studies in larger populations of patients 65 years of age or over are needed to permit
conclusions regarding the safety of NovoLog in elderly compared to younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog
action have not been performed.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
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11
DESCRIPTION
NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8.
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys
Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly
Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, and sodium chloride 0.58
mg/mL. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium hydroxide 10%
may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset of action than regular human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 2). The
duration of action for NovoLog is 3 to 5 hours. The time course of action of insulin and insulin
analogs such as NovoLog may vary considerably in different individuals or within the same
individual. The parameters of NovoLog activity (time of onset, peak time and duration) as
designated in Figure 2 should be considered only as general guidelines. The rate of insulin
absorption and onset of activity is affected by the site of injection, exercise, and other variables
[see Warnings and Precautions (5.1)].
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Figure 2. Serial mean serum glucose collected up to 6 hours following a single
pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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Mean Blood Glucose (mg/dL)
0
18
36
54
72
90
108
126
144
162
180
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to
regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the
regular human insulin group.
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of
action, and a shorter duration of action than regular human insulin after subcutaneous injection
(see Figure 2 and Figure 4). The relative bioavailability of NovoLog compared to regular human
insulin indicates that the two insulins are absorbed to a similar extent.
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Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single pre-meal dose of NovoLog (solid curve) or regular human insulin
(hatched curve) injected immediately before a meal in 22 patients with type 1
diabetes.
In studies in healthy volunteers (total n=l07) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin
aspart have not been established in patients with type 2 diabetes.
The intra-individual variability in time to maximum serum insulin concentration for
healthy male volunteers was significantly less for NovoLog than for regular human insulin. The
clinical significance of this observation has not been established.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
Specific Populations
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
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Gender - In healthy volunteers, no difference in insulin aspart levels was seen between
men and women when body weight differences were taken into account. There was no
significant difference in efficacy noted (as assessed by HbAlc) between genders in a trial in
patients with type 1 diabetes.
Obesity - A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.
Renal Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal (N=6) creatinine clearance
(CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50
ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment.
In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax
of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog,
may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4)].
Hepatic Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter.
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5)].
The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
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cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2 Animal Toxicology and/or pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c ,Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
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**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 16 of 23 Submitted 14Mar08
Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous subcutaneous insulin infusion (CSII) by external pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 17 of 23 Submitted 14Mar08
Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.3 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 18 of 23 Submitted 14Mar08
Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8). [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 19 of 23 Submitted 14Mar08
Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (0.4, 0.3)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen Prefilled syringe
NDC 0169-6339-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or sunlight. Opened vials may be refrigerated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 20 of 23 Submitted 14Mar08
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen Prefilled Syringes:
Once a cartridge or a NovoLog FlexPen Prefilled syringe is punctured, it should be kept
at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to excessive
heat or sunlight. Cartridges or NovoLog FlexPen Prefilled syringes in use must NOT be stored
in the refrigerator. Keep all PenFill® cartridges and disposable NovoLog FlexPen Prefilled
syringes away from direct heat and sunlight. Unpunctured PenFill cartridges and NovoLog
FlexPen Prefilled syringes can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused PenFill cartridges and NovoLog FlexPen Prefilled syringes
in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen Prefilled Syringe without a needle attached. This
prevents contamination and/or infection, or leakage of insulin, and will ensure accurate
dosing. Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 48 hours of use or
after exposure to temperatures that exceed 37°C (98.6°F).
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges and NovoLog FlexPen Prefilled syringe
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30°C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexPen Prefilled
syringe
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
Storage of NovoLog in Infusion Fluids
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 21 of 23 Submitted 14Mar08
Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling (17.3)]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.2 Patients using pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
Pumps:
NovoLog is recommended for use in MiniMed 500 series and other equivalent pumps
Reservoirs and infusion sets:
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), reservoirs, infusion sets, and injection site should be changed at least every 48
hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 22 of 23 Submitted 14Mar08
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
infused buffered regular insulin or multiple injection therapy. Prompt identification and
correction of the cause of hyperglycemia or ketosis is necessary. Problems include pump
malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin.
Less commonly, hypoglycemia from pump malfunction may occur. If these problems cannot be
promptly corrected, patients should resume therapy with subcutaneous insulin injection and
contact their physician. [see Dosage and Administration (2), Warnings and Precautions (5) and
How Supplied/Storage and Handling (16.2)]
17.3 FDA Approved Patient Labeling
Rx only
Date of Issue: March 14, 2008
Version 14
NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, PenMate®, and NovoFine® are
trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and other patents
pending.
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and other patents
pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured By Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark
Manufactured For Novo Nordisk Inc., Princeton, New Jersey 08540
www.novonordisk-us.com
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 1 of 7 Submitted 14Mar08
Patient Information
NovoLog® (NO-voe-log)
(insulin aspart [rDNA origin] Injection)
Important:
Know your insulin. Do not change the type of insulin you use unless told to do
so by your health care provider. The amount of insulin you take as well as the
best time for you to take your insulin may need to change if you take a different
type of insulin.
Make sure you know the type and strength of insulin prescribed for you.
Read the Patient Information that comes with NovoLog before you start taking it
and each time you get a refill. There may be new information. This leaflet does
not take the place of talking with your health care provider about your diabetes or
your treatment. Make sure you know how to manage your diabetes. Ask your
healthcare provider if you have any questions about managing your diabetes.
What is NovoLog?
NovoLog is a man-made insulin that is used to control high blood sugar in adults
and children with diabetes mellitus.
Who should not use NovoLog?
Do not take NovoLog if:
•
Your blood sugar is too low (hypoglycemia)
•
You are allergic to anything in NovoLog. See the end of this leaflet
for a complete list of ingredients in NovoLog. Check with your
healthcare provider if you are not sure.
Tell your health care provider:
•
about all of your medical conditions. Medical conditions can affect
your insulin needs and your dose of NovoLog.
•
if you are pregnant or breastfeeding, You and your healthcare
provider should talk about the best way to manage your diabetes
while you are pregnant or breastfeeding. NovoLog has not been
studied in nursing women.
•
about all medicines you take, including prescriptions and non-
prescription medicines, vitamins and herbal supplements. Your
NovoLog dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show
your healthcare providers when you get a new medicine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 of 7 Submitted 14Mar08
How should I take NovoLog?
Only use NovoLog if it appears clear and colorless. There may be air bubbles.
This is normal. If it looks cloudy, thickened, or colored, or if it contains solid
particles do not use it and call Novo Nordisk at 1-800-727-6500.
NovoLog comes in:
•
10 mL vials (small bottles) for use with syringe
•
3 mL PenFill® cartridges for use with the Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices and NovoFine®
disposable needles. The cartridge delivery device can be used with a
NovoPen® 3 PenMate®
•
3 mL NovoLog FlexPen®
Read the instructions for use that come with your NovoLog product. Talk
to your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject NovoLog before you start taking it.
•
Take NovoLog exactly as prescribed. You should eat a meal within
5 to 10 minutes after using NovoLog to avoid low blood sugar.
•
NovoLog is a fast-acting insulin. The effects of NovoLog start
working 10 to 20 minutes after injection or bolus pump infusion.
•
Do not inject NovoLog if you do not plan to eat right after your
injection or bolus pump infusion.
•
The greatest blood sugar lowering effect is between 1 and 3 hours
after the injection or infusion. This blood sugar lowering lasts for 3 to
5 hours.
•
While using NovoLog you may have to change your total dose of
insulin, your dose of longer-acting insulin, or the number of injections
of longer-acting insulin you use. Pump users given NovoLog may
need to change the amount of total insulin given as a basal infusion.
•
Do not mix NovoLog:
o with any other insulins when used in a pump
o with any insulins other than NPH when used with injections
by syringe
If your doctor recommends diluting NovoLog, follow your doctor’s
instructions exactly so that you know:
• How to make NovoLog more dilute (that is, a smaller number of
units of NovoLog for a given amount of liquid) and
• How to use this more dilute form of NovoLog. Do not use dilute
insulin in a pump.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3 of 7 Submitted 14Mar08
•
Inject NovoLog into the skin of your stomach area, upper arms,
buttocks or upper legs. NovoLog may affect your blood sugar
levels sooner if you inject it into the skin of your stomach area. Never
inject NovoLog into a vein or into a muscle.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the exact same spot for each injection.
•
If you take too much NovoLog, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia)
by drinking or eating something sugary right away (fruit juice, sugar
candies, or glucose tablets). It is important to treat low blood sugar
(hypoglycemia) right away because it could get worse and you could
pass out (become unconscious). If you pass out you will need help
from another person or emergency medical services right away, and
will need treatment with a glucagon injection or treatment at a
hospital. See “What are the possible side effects of NovoLog?” for
more information on low blood sugar (hypoglycemia).
•
If you forget to take your dose of NovoLog, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death. Follow
your healthcare provider’s instructions for treating high blood sugar.
Know your symptoms of high blood sugar which may include:
•
increased thirst
•
frequent urination
•
drowsiness
•
loss of appetite
•
a hard time
breathing
• fruity smell on the breath
• high amounts of sugar and
ketones in your urine
• nausea, vomiting (throwing up)
or stomach pain
•
Check your blood sugar levels. Ask your healthcare provider what
your blood sugars should be and when you should check your blood
sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
stress
•
other medicines you
take
• change in diet
• change in physical activity or
exercise
What should I avoid while using NovoLog?
•
Alcohol. Alcohol, including beer and wine, may affect your blood
sugar when you take NovoLog®.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4 of 7 Submitted 14Mar08
•
Driving and operating machinery. You may have difficulty
concentrating or reacting if you have low blood sugar (hypoglycemia).
Be careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright to drive if you often have:
• low blood sugar
• decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog?
•
low blood sugar (hypoglycemia). Symptoms of low blood sugar
may include:
•
sweating
•
dizziness or
lightheadedness
•
shakiness
•
hunger
•
fast heart beat
•
tingling of lips and
tongue
•
trouble concentrating or
confusion
•
blurred vision
•
slurred speech
•
anxiety, irritability or
mood changes
•
headache
Severe low blood sugar can cause unconsciousness (passing out),
seizures, and death. Know your symptoms of low blood sugar.
Follow your healthcare provider’s instructions for treating low blood
sugar. Talk to your healthcare provider if low blood sugar is a
problem for you.
•
Serious allergic reaction (whole body reaction). Get medical
help right away, if you develop a rash over your whole body, have
trouble breathing, a fast heartbeat, or sweating.
•
Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions or they are serious talk to your healthcare
provider. You may need to stop using NovoLog and use a different
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
•
Skin thickens or pits at the injection site (lipodystrophy).
Change (rotate) where you inject your insulin to help to prevent these
skin changes from happening. Do not inject insulin into this type of
skin.
•
Swelling of your hands and feet.
•
Vision changes
•
Low potassium in your blood (hypokalemia)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5 of 7 Submitted 14Mar08
•
Weight gain
These are not all of the possible side effects from NovoLog. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store NovoLog?
All Unopened NovoLog:
•
Keep all unopened NovoLog in the refrigerator between 36° to
46°F (2° to 8°C).
•
Do not freeze. Do not use NovoLog if it has been frozen.
•
Keep unopened NovoLog in the carton to protect from light.
NovoLog in use:
•
Vials.
• Keep in the refrigerator or at room temperature below 86°F
(30°C) for up to 28 days.
• Keep vials away from direct heat or light.
• Throw away an opened vial after 28 days of use, even if there is
insulin left in the vial.
• Do not draw up NovoLog into a syringe and store for later use
• Unopened vials can be used until the expiration date on the
NovoLog label, if the medicine has been stored in a refrigerator.
•
PenFill Cartridges or NovoLog FlexPen Prefilled syringe.
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store a PenFill cartridge or NovoLog FlexPen Prefilled
syringe that you are using in the refrigerator.
• Keep PenFill cartridges and NovoLog FlexPen Prefilled syringe
away from direct heat or light.
• Throw away a used PenFill cartridge or NovoLog FlexPen
Prefilled syringes after 28 days, even if there is insulin left in the
cartridge or syringe.
•
NovoLog in the pump reservoir and the complete external pump
infusion set
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6 of 7 Submitted 14Mar08
• The reservoir, tubing, and catheter-needle should be changed
at least every 48 hours. Change more often than every 48
hours if you have high blood sugar (hyperglycemia), the pump
alarm sounds, or the insulin flow is blocked (occlusion).
General advice about NovoLog
Medicines are sometimes prescribed for conditions that are not mentioned in the
patient leaflet. Do not use NovoLog for a condition for which it was not
prescribed. Do not give NovoLog to other people, even if they have the same
symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog. If you
would like more information about NovoLog or diabetes, talk with your healthcare
provider. You can ask your healthcare provider or pharmacist for information
about NovoLog that is written for healthcare professionals. Call 1-800-727-6500
or visit www.novonordisk-us.com for more information.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1660 Duke Street, Alexandria, VA 22314 and on
www.diabetes.org.
NovoLog® ingredients include:
• insulin aspart
• glycerin
• phenol
• metacresol
• zinc
• disodium hydrogen phosphate
dihydrate
• sodium chloride
All NovoLog vials, PenFill cartridges and NovoLog FlexPen Prefilled syringes are
latex free.
Date of Issue: March 14, 2008
Version: 6
NovoLog®, PenFill®, FlexPen®, NovoPen®, NovoFine®, PenMate®, are
trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and
other patents pending.
© 2002-2008 Novo Nordisk Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7 of 7 Submitted 14Mar08
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 1 of 5 Submitted 13Mar08
Patient Instructions for Use
NovoLog® FlexPen® Prefilled syringe
How to use the NovoLog FlexPen Prefilled syringe
The NovoLog FlexPen Prefilled syringe is a disposable insulin delivery system.
NovoLog FlexPen Prefilled syringe should be used with NovoFine® single use needles.
The NovoLog FlexPen Prefilled syringe should not be used by people who are blind or
have severe vision problems without the help of a person who has good eyesight and
who is trained to use the Prefilled syringe the right way.
Please read these instructions completely before using this device.
Diagram A
FlexPen Prefilled Syringe
NovoFine® needle
Diagram B
NovoFine needle
1. PREPARING THE NOVOLOG FLEXPEN PREFILLED SYRINGE
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. NovoLog should look clear.
Pull off the pen cap.
Wipe the rubber stopper with an alcohol swab.
Remove the protective tab from the disposable needle and screw the needle
tightly onto the NovoLog FlexPen Prefilled syringe (see diagram A and B). Do
not place a disposable needle on your NovoLog FlexPen Prefilled syringe until
you are ready to take your injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 of 5 Submitted 13Mar08
Pull off the outer and inner needle caps (see diagram C and D). Do not throw
away the big outer needle cap.
Giving the airshot before each injection:
Small amounts of air may collect in the needle and insulin cartridge during normal
use. To avoid injecting air and to make sure you take the right dose of insulin, do
the following:
Dial 2 units by turning the dose selector so that the arrow lines up
with the “2” in the dosage indicator window (see diagram E below).
Hold the NovoLog FlexPen Prefilled syringe with the needle
pointing up. Tap the insulin cartridge gently with your finger a
few times (see diagram F). A small air bubble may remain but it
will not be injected. The NovoLog FlexPen Prefilled syringe
prevents the cartridge from being completely emptied.
Keep the needle pointing up and press the push button (on the end
of the FlexPen) all the way in. You should see a drop of insulin at
the needle tip. If you do not see a drop of insulin, repeat these
steps: dial 2 units, tap the insulin cartridge and press the push
button, until insulin appears. You may need to do this up to 6
times. If you don’t see a drop of insulin after 6 times, do not use
the NovoLog FlexPen Prefilled syringe and contact Novo Nordisk at
1-800-727-6500.
E
F
C
D
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Page 3 of 5 Submitted 13Mar08
2. SETTING THE DOSE
Check and make sure that the dose selector is set at zero (0) (see diagram G).
Dial the number of units you need to inject. The arrow should line up with
your dose.
The dose can be corrected by turning the dose selector in either direction. When
dialing back, be careful not to press the push button, this will cause the insulin to
come out. You can not set a dose larger than the number of units left in the
cartridge. You will hear a click for every single unit dialed. Do not set the dose
by counting the number of clicks you hear.
3. GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider.
If you clean your injection site with an alcohol swab, let the injection site dry
before you inject.
Insert the needle into the skin. Push the needle into the skin (see diagram H).
Give the dose of insulin by pressing the push button all the way in (see diagram
I). Be careful to only press the button when injecting.
Keep the needle in the skin for at least 6 seconds, and keep the push button
pressed all the way in until the needle has been pulled out from the skin. This
will make sure that the full dose has been given. You may see a drop of
NovoLog at the needle tip. This is normal and has no effect on the dose you just
received..If blood appears after you take the needle out of your skin, press the
injection site lightly with a finger. Do not rub the area.
After the injection
• Do not recap the needle. Recapping can lead to a needle stick injury. Remove
the needle from the NovoLog FlexPen Prefilled syringe after each injection. This
H
I
G
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Page 4 of 5 Submitted 13Mar08
helps to prevent infection, and leakage of insulin, and will help to make sure you
inject the right dose of insulin. Put the needle and any empty NovoLog FlexPen
Prefilled syringes or any used NovoLog FlexPen Prefilled syringe still containing
insulin in a sharps container, or some type of hard plastic or metal container with
a screw top such as a detergent bottle or coffee can. These containers should
be sealed and thrown away the right way. Check with you doctor about the right
way to throw away used syringes and needles. There may be local or state laws
about how to throw away used needles and syringes. Do not throw away used
needles and syringes in household trash or recycling bins.
• Put the pen cap on the NovoLog FlexPen Prefilled syringe and store the
NovoLog FlexPen Prefilled syringe without the needle attached.
Health care providers, relatives and other caregivers should follow general
precautions for removing and disposing of needles to lessen the chance of a
needle stick injury.
4. FUTURE INJECTIONS
It is important that you use a new needle for each injection. Follow the directions in
steps 1, 2, and 3 above.
The numbers on the insulin cartridge can be used to estimate the amount of insulin left
in the NovoLog FlexPen Prefilled syringe. Do not use these numbers to measure the
insulin dose. You cannot set a dose more than the number of units remaining in the
cartridge.
5. FUNCTION CHECK
If your NovoLog FlexPen Prefilled syringe is not working the right way, follow this
procedure:
Screw on a new NovoFine needle
Do an airshot as described in step 1.
Put the outer needle cap onto the needle. Do not put on the inner needle cap.
Turn the dose selector so the dose indicator window shows 20 units.
Hold the NovoLog FlexPen Prefilled syringe so the needle is pointing down
Press the push button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram J). If the
NovoLog FlexPen Prefilled syringe has released too much or too little insulin, do the
function check again. If the same problem happens again, do not use your NovoLog
FlexPen Prefilled syringe and contact Novo Nordisk at 1-800-727-6500.
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6. IMPORTANT NOTES
• If you need to perform more than 6 airshots before the first use of each NovoLog
FlexPen Prefilled syringe to get a drop of insulin at the needle tip, do not use the
NovoLog FlexPen Prefilled syringe and contact Novo Nordisk at 1-800-727-6500.
• Remember to perform an air shot before each injection. See diagrams E and F..
• Do not drop the NovoLog FlexPen Prefilled syringe.
• Keep the NovoLog FlexPen Prefilled syringe with you. Do not leave it in a car or
other place where it can get too hot or too cold.
• NovoLog FlexPen Prefilled syringe should be used with NovoFine disposable
needles.
• Novo Nordisk is not responsible for harm due to using this insulin delivery system
with products not recommended by Novo Nordisk.
• Do not put a disposable needle on the NovoLog FlexPen Prefilled syringe until you
are ready to use it. Remove the needle right after use. Do not recap the needle.
• Throw away the used NovoLog FlexPen Prefilled syringe without the needle
attached.
• Always carry an extra NovoLog FlexPen Prefilled syringe with you in case the
NovoLog FlexPen Prefilled syringe is damaged or lost.
• Keep your NovoLog FlexPen Prefilled syringe and needles out of the reach
of children. Use NovoLog FlexPen Prefilled syringe as directed to treat your
diabetes. Do not share it with anyone else even if they also have diabetes.
J
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Patient Instructions for Use
NovoLog® 3 mL PenFill® cartridge (100 Units/mL, U-100)
Before using the NovoLog cartridge
1. Talk with your healthcare provider for information about where to inject
NovoLog (injection sites) and how to give an injection with your insulin
delivery device.
2. Read the instruction manual that comes with your insulin delivery
device for complete instructions on how to use the PenFill cartridge
with the device.
How to use the NovoLog cartridge
1. Check your insulin. Just before using your NovoLog cartridge,
check to make sure that you have the right type of insulin. This is
especially important if you use different types of insulin.
2. Carefully look at the cartridge and the insulin inside it. The insulin
should be clear and colorless. The tamper-resistant foil should be in
place before the first use. If the foil has been broken or removed before
your first use of the cartridge, or if the insulin is cloudy or colored, do
not use it. Call Novo Nordisk at 1-800-727-6500.
3. Wash your hands well with soap and water. If you clean your injection
site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider for guidance on injection sites and
how to give an injection with your insulin delivery device.
4. Gather your supplies for injecting NovoLog.
5. Insert a 3 mL cartridge into your Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery device. Wipe the front rubber stopper of the
3 mL PenFill cartridge with an alcohol swab, then screw on a new
needle. For NovoFine needles, remove the big outer needle cap and
the inner needle cap. Always use a new needle for each injection to
prevent infection.
Giving the airshot before each injection:
To prevent the injection of air and to make sure insulin is delivered, you must do
an air shot before each injection. Hold the device with the needle pointing up
and gently tap the PenFill® cartridge holder with your finger a few times to raise
any air bubbles to the top of the cartridge. Do the air shot as described in the
device instruction manual.
Giving the injection
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6. Dial the number of units on the insulin delivery device that you need to
inject. Inject the right way as shown to you by your healthcare provider.
7. Insert the needle into the skin. Inject the dose by pressing the push
button all the way in. Keep the needle in the skin for at least 6
seconds, and keep the push button pressed all the way in until the
needle has been pulled out from the skin. This will make sure that the
full dose has been given. You may see a drop of NovoLog at the
needle tip. This is normal and has no effect on the dose you just
received If blood appears after you take the needle out of your skin,
press the injection site lightly with a finger. Do not rub the area.
After the injection
8. Do not recap the needle. Recapping can lead to a needle stick injury.
9. Remove the needle from the PenFill cartridge after each injection.
Keep the 3 mL PenFill cartridge in the insulin delivery device. The
needle should not be attached to the 3 mL PenFill cartridge during
storage. This will prevent infection or leakage of insulin and will help
ensure that you receive the right dose of NovoLog.
10. Put the used needle and cartridge in a sharps container, or some type
of hard plastic or metal container with a screw on top such as a
detergent bottle or coffee can. Check with your doctor about the right
way to throw away used needles and cartridges. There may be local or
state laws about how to throw away used needles and syringes. Do
not throw used needles and cartridges in household trash or recycling
bins.
11. Put the pen cap back on the Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery device.
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Patient Instructions for Use
NovoLog® 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing
and giving your insulin injection.
Never re-use syringes and needles.
How should I use the NovoLog vial?
1. Check to make sure that you have the correct type of insulin. This is
especially important if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be clear and colorless. The
tamper-resistant cap should be in place before the first use. If the cap had
been removed before your first use of the vial, or if the insulin is cloudy or
colored, do not use it and call Novo Nordisk at 1-800-727-6500
3. Wash your hands with soap and water. If you clean your injection site with an
alcohol swab, let the injection site dry before you inject. Talk with your
healthcare provider about how to rotate injection sites and how to give an
injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber
stopper with an alcohol wipe.
5. Do not roll or shake the vial. Shaking right before the dose is drawn into the
syringe may cause bubbles or froth. This can cause you to draw up the wrong
dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for
the number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger
all the way in to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a
few units beyond correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the
air bubbles to the top. Then slowly push the plunger to the marking for your
correct dose. This process should move any air bubbles present in the
syringe back into the vial.
10. Check to make sure you have the right dose of NovoLog in the syringe.
11. Pull the syringe out of the vial’s rubber stopper.
12. Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important
to ask your doctor if you did not receive instructions on pinching the skin.
Insert the needle into the pinched skin. Press the plunger of the syringe to
inject the insulin. When you are finished injecting the insulin, pull the needle
out of your skin. You may see a drop of NovoLog at the needle tip. This is
normal and has no effect on the dose you just received. If you see blood after
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you take the needle out of your skin, press the injection site lightly with a
piece of gauze or an alcohol wipe. Do not rub the area.
13. After your injection, do not recap the needle. Place used syringes, needles
and used insulin vials in a disposable puncture-resistant sharps container, or
some type of hard plastic or metal container with a screw on cap such as a
detergent bottle or coffee can.
14. Ask your healthcare provider about the right way to throw away used syringes
and needles. There may be state or local laws about the right way to throw
away used syringes and needles. Do not throw away used needles and
syringes in household trash or recycle.
How should I mix insulins?
NovoLog should be mixed only when injections with syringes are used. NovoLog
can be mixed with NPH human insulin right before use. The NovoLog should be
drawn into the syringe before you draw up the NPH insulin. NovoLog should
not be mixed with any other insulin except NPH.
1. Add together the doses (total number of units) of NPH and NovoLog that you
need to inject. The total dose will determine the final amount (volume) in the
syringe after drawing up both insulins into the syringe. For example, if you
need 5 units of NPH and 2 units of NovoLog, the total dose of insulin in the
syringe would be 7 units.
2. Roll the NPH vial between your hands until the liquid is equally cloudy
throughout.
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air
into the NPH vial and then remove the needle from the vial but do not
withdraw any of the NPH insulin. (Transferring NPH to the NovoLog vial will
contaminate the NovoLog vial and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the NovoLog dose. Inject this
air into the NovoLog vial. With the needle in place, turn the vial upside down
and withdraw the correct dose of NovoLog. The tip of the needle must be in
the NovoLog to get the full dose and not an air dose.
5. After withdrawing the needle from the NovoLog vial, insert the needle into the
NPH vial. Turn the NPH vial upside down with the syringe and needle still in
it. Withdraw the correct dose of NPH.
6. Inject right away to avoid changes in how quickly the insulin works.
How do I use NovoLog in a pump?
Checking your blood sugar is very important for patients using pumps.
Pump or infusion set problems can result in you not getting enough
insulin. This can quickly cause you to have high blood sugar and diabetic
ketoacidosis.
Use insulin from a new vial of NovoLog if unexplained high blood sugar or
pump alarms do not respond to all of the following:
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o a repeat dose (injection or bolus) of NovoLog
o a change in the infusion set, including the NovoLog in the reservoir
o a change in the infusion site
If these measures do not work, you may need to go back to injecting
NovoLog with syringes, or insulin pens. Continue to monitor your blood
sugars and ketones. If problems continue, you must contact your
healthcare provider.
When NovoLog is used in pumps, use only pumps that are
recommended by your healthcare provider. The reservoir, infusion set,
and injection site should be changed at least every 48 hours. The
reservoir, the infusion set, and infusion site should also be changed:
o with unexpected high blood sugar
o when the alarm sounds (see your pump manual)
o if the insulin or pump has been exposed to temperatures over
98.6°F (37°C), such as in a sauna, with long showers, or on an
unusually hot day.
o if the insulin or pump could have absorbed heat, for example from
sunlight, that would heat the insulin to over 98.6°F (37°C). Dark
colored pump cases or sport covers can increase this type of heat.
The location where the pump is worn may also affect the
temperature
Patients who develop “pump bumps” (skin reactions at the infusion site) may
need to change infusion sites more often than every 48 hours.
NovoLog is recommended for use with MiniMed 500 series, or other pumps
recommended by your doctor.
1. Check to make sure that you have the right type of insulin.
2. Look at the vial and insulin. The insulin should be clear and colorless. The
tamper-resistant cap should be in place before the first use. If the cap had
been removed before your first use, or if the insulin is cloudy or colored,
do not use it and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water.
4. Fill the reservoir-syringe with 2 days worth of NovoLog plus about 25 extra
units to prime the pump and the infusion tubing.
5. Remove air bubbles from the reservoir by following the pump
manufacturers’ instructions.
6. Attach the infusion set to the reservoir. Make sure the connection is tight.
Prime the infusion set until you see a drop of insulin coming out of the
infusion needle-catheter. Follow the pump manufacturers’ instructions for
priming and removing air bubbles.
7. Clean your insertion site with an alcohol swab and let the site dry before
you insert the needle-catheter. Talk with your healthcare provider about
how to rotate insertion sites and how to insert the needle-catheter into the
skin.
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8. Insert the needle-catheter into the skin, remove the needle and prime the
catheter according to the pump manufacturers’ instructions. Do not insert
the needle-catheter into skin that is reddened, itchy, bumpy, or thickened.
9. Program the pump for mealtime NovoLog boluses and NovoLog basal
insulin infusion according to instructions from your healthcare provider and
the manufacturer of your pump equipment.
10. Change the infusion site, the insulin reservoir, the tubing, the catheter-
needle, and the insulin every 48 hours or less, even if you have not used
all of the insulin. This will help ensure that NovoLog and the pump work
well.
11. Change the infusion site, the insulin reservoir, the tubing, the catheter-
needle, and the insulin if you experience a pump alarm, catheter blockage,
high blood sugars, or if your pump insulin has been exposed to heat
greater than 98.6oF (37oC).
12. If you have high blood sugar (hyperglycemia) when you check your blood
sugar, this may be the first sign of a problem with the pump, infusion set,
or NovoLog. If you have high blood sugar without a pump alarm, you must
still check the pump because alarms may not detect all the changes to
NovoLog that could result in high blood sugar. You may need to start
insulin injections with syringes if the cause of the problem cannot be found
quickly or fixed. Long lengths of infusion-set tubing increase the risk for
kinking and expose the insulin in the tubing to more changes in
temperature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:26.997037 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020986s047lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 47} |
3,949 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog®
safely and effectively. See full prescribing information for NovoLog.
NovoLog (insulin aspart [rDNA origin] injection) solution for subcutaneous
use
Initial U.S. Approval: 2000
·······································INDICATIONS AND USAGE········································
• NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
··································DOSAGE AND ADMINISTRATION································
• The dosage of NovoLog must be individualized.
• Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
• Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
• Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL to
1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags.
NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium
chloride (2.4).
·······························DOSAGE FORMS AND STRENGTHS································
Each presentation contains 100 Units of insulin aspart per mL (U-100)
• 10 mL vials (3)
• 3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
• 3 mL NovoLog FlexPen (3)
········································CONTRAINDICATIONS··············································
• Do not use during episodes of hypoglycemia (4).
• Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
··································WARNINGS AND PRECAUTIONS······························
• Hypoglycemia is the most common adverse effect of insulin therapy. Glucose
monitoring is recommended for all patients with diabetes. Any change of
insulin dose should be made cautiously and only under medical supervision
(5.1, 5.2).
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of diabetes mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Mixing of Insulins
5.9 Continuous Subcutaneous Insulin Infusion by External Pump
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
• Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.3).
• Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.4, 5.5).
• Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.6).
········································ADVERSE REACTIONS···········································
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
···········································DRUG INTERACTIONS·······································
• The following may increase the blood-glucose-lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide
antibiotics (7).
• The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral
contraceptives), atypical antipsychotics (7).
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or
weaken the blood-glucose-lowering effect of insulin (7).
• Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia (7).
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine, and
reserpine (7).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
•
Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: [3/2008]
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17
PATIENT COUNSELING INFORMATION
17.1 Physician Instructions
17.2 Patients Using Pumps
17.3 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
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NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
•
10 mL vials
•
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
•
3 mL NovoLog FlexPen
4
CONTRAINDICATIONS
NovoLog is contraindicated
•
during episodes of hypoglycemia
•
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
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Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.3
Hypokalemia
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
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5.4
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Clinical Pharmacology (12.3)].
5.5
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Clinical Pharmacology (12.3)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.7
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.8
Mixing of Insulins
•
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
•
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
•
Insulin mixtures should not be administered intravenously.
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5.9
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.2)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9) and How
Supplied/Storage and Handling (16.2), Patient Counseling Information (17)].
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
•
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral Edema
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Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL,with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during postapproval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during postapproval use [see Patient Counseling Information (17)].
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7
DRUG INTERACTIONS
A number of substances affect glucose metabolism and may require insulin dose
adjustment and particularly close monitoring.
•
The following are examples of substances that may increase the blood-glucose
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide),
sulfonamide antibiotics.
•
The following are examples of substances that may reduce the blood-glucose
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
atypical antipsychotics.
•
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
the blood-glucose-lowering effect of insulin.
•
Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
•
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
products such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
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insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age, particularly in patients with type 2 diabetes.
Additional studies in larger populations of patients 65 years of age or over are needed to permit
conclusions regarding the safety of NovoLog in elderly compared to younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog
action have not been performed.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
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NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8. structural formula
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset of action than regular human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 2). The
duration of action for NovoLog is 3 to 5 hours. The time course of action of insulin and insulin
analogs such as NovoLog may vary considerably in different individuals or within the same
individual. The parameters of NovoLog activity (time of onset, peak time and duration) as
designated in Figure 2 should be considered only as general guidelines. The rate of insulin
absorption and onset of activity is affected by the site of injection, exercise, and other variables
[see Warnings and Precautions (5.1)].
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Serial mean serum glucose collected up to 6 hours following a single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.
Figure 2. Serial mean serum glucose collected up to 6 hours following a single
pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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Mean Blood Glucose (mg/dL)
Me
an
blo
od
glu
cos
e pr
ofil
es f
ollo
wing intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction.
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to
regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the
regular human insulin group.
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of
action, and a shorter duration of action than regular human insulin after subcutaneous injection
(see Figure 2 and Figure 4). The relative bioavailability of NovoLog compared to regular human
insulin indicates that the two insulins are absorbed to a similar extent.
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Serial mean serum free insulin concentration collected up to 6 hours
following a single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single pre-meal dose of NovoLog (solid curve) or regular human insulin
(hatched curve) injected immediately before a meal in 22 patients with type 1
diabetes.
In studies in healthy volunteers (total n=l07) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin
aspart have not been established in patients with type 2 diabetes.
The intra-individual variability in time to maximum serum insulin concentration for
healthy male volunteers was significantly less for NovoLog than for regular human insulin. The
clinical significance of this observation has not been established.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
Specific Populations
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Gender - In healthy volunteers, no difference in insulin aspart levels was seen between
men and women when body weight differences were taken into account. There was no
significant difference in efficacy noted (as assessed by HbAlc) between genders in a trial in
patients with type 1 diabetes.
Obesity - A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.
Renal Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal (N=6) creatinine clearance
(CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50
ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment.
In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax
of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog,
may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4)].
Hepatic Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter.
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5)].
The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
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when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c ,Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
Reference ID: 3212914
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.3 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (0.4, 0.3)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or sunlight. Opened vials may be refrigerated.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen Prefilled Syringes:
Once a cartridge or a NovoLog FlexPen is punctured, it should be kept at temperatures
below 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight. A
NovoLog FlexPen or cartridge in use must NOT be stored in the refrigerator. Keep the NovoLog
FlexPen and all PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog
FlexPen and PenFill cartridges can be used until the expiration date printed on the label if they
are stored in a refrigerator. Keep unused NovoLog FlexPen and PenFill cartridges in the carton
so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen without a needle attached. This prevents
contamination and/or infection, or leakage of insulin, and will ensure accurate dosing.
Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges and NovoLog FlexPen Prefilled
syringe
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30°C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage of NovoLog in Infusion Fluids
Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling (17.3)]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.2
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.3 FDA Approved Patient Labeling
Rx only
Date of Issue:
Version
®
NovoLog , NovoPen® 3, PenFill®, Novolin®, FlexPen®, PenMate®, and NovoFine® are
trademarks of Novo Nordisk A/S.
®
NovoLog is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and other patents
pending.
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and other patents
pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured By Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark
Manufactured For Novo Nordisk Inc., Princeton, New Jersey 08540
www.novonordisk-us.com
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] Injection)
Important:
Know your insulin. Do not change the type of insulin you use unless told to do
so by your healthcare provider. The amount of insulin you take as well as the
best time for you to take your insulin may need to change if you take a different
type of insulin.
Make sure you know the type and strength of insulin prescribed for you.
Read the Patient Information that comes with NovoLog before you start taking it
and each time you get a refill. There may be new information. This leaflet does
not take the place of talking with your healthcare provider about your diabetes or
your treatment. Make sure you know how to manage your diabetes. Ask your
healthcare provider if you have any questions about managing your diabetes.
What is NovoLog?
NovoLog is a man-made insulin that is used to control high blood sugar in adults
and children with diabetes mellitus.
Who should not use NovoLog?
Do not take NovoLog if:
•
Your blood sugar is too low (hypoglycemia)
•
You are allergic to anything in NovoLog. See the end of this leaflet
for a complete list of ingredients in NovoLog. Check with your
healthcare provider if you are not sure.
Tell your healthcare provider:
•
about all of your medical conditions. Medical conditions can affect
your insulin needs and your dose of NovoLog.
•
if you are pregnant or breastfeeding. You and your healthcare
provider should talk about the best way to manage your diabetes
while you are pregnant or breastfeeding. NovoLog has not been
studied in nursing women.
•
about all medicines you take, including prescriptions and non
prescription medicines, vitamins and herbal supplements. Your
NovoLog dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show
your healthcare providers when you get a new medicine.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take NovoLog?
Only use NovoLog if it appears clear and colorless. There may be air bubbles.
This is normal. If it looks cloudy, thickened, or colored, or if it contains solid
particles do not use it and call Novo Nordisk at 1-800-727-6500.
NovoLog comes in:
•
10 mL vials (small bottles) for use with syringe
•
3 mL PenFill® cartridges for use with the Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices and NovoFine®
disposable needles. The cartridge delivery device can be used with a
NovoPen® 3 PenMate®
•
3 mL NovoLog FlexPen®
Read the instructions for use that come with your NovoLog product. Talk
to your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject NovoLog before you start taking it.
•
Take NovoLog exactly as prescribed. You should eat a meal within
5 to 10 minutes after using NovoLog to avoid low blood sugar.
•
NovoLog is a fast-acting insulin. The effects of NovoLog start
working 10 to 20 minutes after injection or bolus pump infusion.
•
Do not inject NovoLog if you do not plan to eat right after your
injection or bolus pump infusion.
•
The greatest blood sugar lowering effect is between 1 and 3 hours
after the injection or infusion. This blood sugar lowering lasts for 3 to
5 hours.
•
While using NovoLog you may have to change your total dose of
insulin, your dose of longer-acting insulin, or the number of injections
of longer-acting insulin you use. Pump users given NovoLog may
need to change the amount of total insulin given as a basal infusion.
•
Do not mix NovoLog:
o with any other insulins when used in a pump
o with any insulins other than NPH when used with injections
by syringe
If your doctor recommends diluting NovoLog, follow your doctor’s
instructions exactly so that you know:
• How to make NovoLog more dilute (that is, a smaller number of
units of NovoLog for a given amount of liquid) and
• How to use this more dilute form of NovoLog. Do not use dilute
insulin in a pump.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Inject NovoLog into the skin of your stomach area, upper arms,
buttocks or upper legs. NovoLog may affect your blood sugar
levels sooner if you inject it into the skin of your stomach area. Never
inject NovoLog into a vein or into a muscle.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the exact same spot for each injection.
•
If you take too much NovoLog, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia)
by drinking or eating something sugary right away (fruit juice, sugar
candies, or glucose tablets). It is important to treat low blood sugar
(hypoglycemia) right away because it could get worse and you could
pass out (become unconscious). If you pass out you will need help
from another person or emergency medical services right away, and
will need treatment with a glucagon injection or treatment at a
hospital. See “What are the possible side effects of NovoLog?” for
more information on low blood sugar (hypoglycemia).
•
If you forget to take your dose of NovoLog, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death. Follow
your healthcare provider’s instructions for treating high blood sugar.
Know your symptoms of high blood sugar which may include:
•
increased thirst
• fruity smell on the breath
•
frequent urination
• high amounts of sugar and
•
drowsiness
ketones in your urine
•
loss of appetite
• nausea, vomiting (throwing up)
•
a hard time
or stomach pain
breathing
•
Check you r blood su gar levels. Ask your healthcare provider what
your blood sugars should be and when you should check your blood
sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
diet
change in
•
stress
• change in physical activity or
•
icines you
other med
exercise
take
What should I avoid while using NovoLog ?
•
Alcohol. Alcohol, including beer and wine, may affect your blood
sugar when you take NovoLog.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Driving and operating machinery. You may have difficulty
concentrating or reacting if you have low blood sugar (hypoglycemi a).
Be careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright to drive if you often have:
• low blood sugar
• decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog?
•
low b lo d sugar (hypoglycemia). Symptoms of low blood sugar
o
may in lu
c de:
•
sweating
•
or
trouble concentrating
•
dizziness or
confusion
lightheadedness
•
blurred vision
•
shakiness
•
slurred speech
•
hunger
•
anxiety, irritability or
•
fast heart beat
ges
mood chan
•
tingling of lips and
•
headache
tongue
Severe low blood sugar can cause unconsciousness (passing out),
seizures, and death. Know your symptoms of low blood sugar.
Follow your healthcare prov ider’s instructions for treating low blood
sugar. Talk to your healthcare provider if low blood sugar is a
problem for you.
•
Serious allergic reaction (whole body reaction). Get medical
help right away, if you develop a rash over your whole body, h ave
trouble breathing, a fast heartbeat, or sweating.
•
Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions or they are serious talk to your healthcare
provider. You may need to stop using NovoLog and use a differen t
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
•
Skin thickens or pits at the injection site (lipod ystrophy).
Change (rotate) where you inject your insulin to help to prevent these
skin changes from happening. Do not inject insulin into this type of
skin.
•
Swelling of your hands and feet.
•
Vision changes
•
Low potassium in your blood (hypokalemia)
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Weight gain
These are not all of the possible side effects from NovoLog. Ask your
health are provider or pha
c
rmacist for more information.
Call your doctor for medical advice about side effects. Yo u may report side
effects to FDA at 1-80 0-FDA-1088.
How should I store NovoLog?
All Unopened NovoLog:
•
Keep all unopened NovoLog in the refrigerator between 36° to
46°F (2° to 8°C).
•
Do not freeze. Do not use NovoLog if it has been frozen.
•
Keep unopened NovoLog in the carton to protect from light.
NovoLog in use:
•
Vials.
• Keep in the refrigerator or at room temperature belo w 86°F
(30°C) for up to 28 days.
• Keep vials away from direct heat or light.
• Throw away an opened vial after 28 days of use, even if there is
insulin left in the vial.
• Do not draw up NovoLog into a syringe and store for later use
• Unopened vials can be used until the expiration date on the
NovoLog label, if the medicine has been stored in a refrigerator.
•
PenFill Cartridges or NovoLog FlexPen Prefilled syringe.
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store a PenFill cartridge or NovoLog FlexPen Prefilled
syringe that you are using in the refrigerator.
• Keep PenFill cartridges and NovoLog FlexPen Prefilled syringe
away from direct heat or light.
• Throw away a used PenFill cartridge or NovoLog FlexPen
Prefilled syringes after 28 days, even if there is insulin left in the
cartridge or syringe.
•
NovoLog in the pump reservoir and the complete external pump
infusion set
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• The infusion set and the infusion site should be changed at
least every 3 days. The insulin in the reservoir should be
changed at least every 6 days even if you have not used all of
the insulin. Change the infusion set and the infusion site more
often than every 3 days if you have high blood sugar
(hyperglycemia), the pump alarm sounds, or the insulin flow is
blocked (occlusion).
General advice about NovoLog
Medicines are sometimes prescribed for conditions that are not mentioned in the
patient leaflet. Do not use NovoLog for a condition for which it was not
prescribed. Do not give NovoLog to other people, even if they have the same
symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog. If you
would like more information about N ovoLog or diabetes, talk with your healthcare
provider. You can ask your healthcare provider or pharmacist for information
about NovoLog that is written for healthcare professionals. Call 1-800-727-6500
or visit www.novonordisk-us.com for more information.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1701 N Beauregard Street Alexandria, VA 22311 and on
www.diabetes.org.
NovoLog ingredients include:
• insulin aspart
• zinc
• glycerin
• disodium hydrogen phosphate dihydrate
• phenol
• sodium chloride
• metacresol
• water for injection
All NovoLog vials, PenFill cartridges and NovoLog FlexPen Prefilled syringes are
latex free.
Date of Issu e:
Version: 7
®
®
®
NovoLog , PenFill®, FlexPen®, NovoPen , NovoFine , PenMate®, are
trademarks of Novo Nordisk A/S.
®
NovoLog is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
Reference ID: 3212914
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and
other patents pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3212914
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
NovoLog® 10 mL vial (100 Units/mL, U-100)
Before starting, gather all of the supplies that you will need to use for preparing
and giving your insulin injection.
Never re-use syringes and needles.
How should I use the NovoLog vial?
1. Check to make sure that you have the correct type of insulin. This is
especially important if you use different types of insulin.
2. Look at the vial and the insulin. The insulin should be clear and colorless. The
tamper-resistant cap should be in place before the first use. If the cap had
been removed before your first use of the vial, or if the insulin is cloudy or
colored, do not use it and call Novo Nordisk at 1-800-727-6500
3. Wash your hands with soap and water. If you clean your injection site with an
alcohol swab, let the injection site dry before you inject. Talk with your
healthcare provider about how to rotate injection sites and how to give an
injection.
4. If you are using a new vial, pull off the tamper-resistant cap. Wipe the rubber
stopper with an alcohol wipe.
5. Do not roll or shake the vial. Shaking right before the dose is drawn into the
syringe may cause bubbles or froth. This can cause you to draw up the wrong
dose of insulin.
6. Pull back the plunger on the syringe until the black tip reaches the marking for
the number of units you will inject.
7. Push the needle through the rubber stopper of the vial, and push the plunger
all the way in to force air into the vial.
8. Turn the vial and syringe upside down and slowly pull the plunger back to a
few units beyond correct dose.
9. If there are any air bubbles, tap the syringe gently with your finger to raise the
air bubbles to the top. Then slowly push the plunger to the marking for your
correct dose. This process should move any air bubbles present in the
syringe back into the vial.
10.Check to make sure you have the right dose of NovoLog in the syringe.
11.Pull the syringe out of the vial’s rubber stopper.
12.Your doctor should tell you if you need to pinch the skin before inserting the
needle. This can vary from patient to patient so it is important
to ask your doctor if you did not receive instructions on pinching the skin.
Insert the needle into the pinched skin. Press the plunger of the syringe to
inject the insulin. When you are finished injecting the insulin, pull the needle
out of your skin. You may see a drop of NovoLog at the needle tip. This is
normal and has no effect on the dose you just received. If you see blood after
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you take the needle out of your skin, press the injection site lightly with a
piece of gauze or an alcohol wipe. Do not rub the area.
13.After your injection, do not recap the needle. Place used syringes, needles
and used insulin vials in a disposable puncture-resistant sharps container, or
some type of hard plastic or metal container with a screw on cap such as a
detergent bottle or coffee can.
14.Ask your healthcare provider about the right way to throw away used syringes
and needles. There may be state or local laws about the right way to throw
away used syringes and needles. Do not throw away used needles and
syringes in household trash or recycle.
How should I mix insulins?
NovoLog should be mixed only when injections with syringes are used. NovoLog
can be mixed with NPH human insulin right before use. The NovoLog should be
drawn into the syringe before you draw up the NPH insulin. NovoLog should
not be mixed with any other insulin except NPH.
1. Add together the doses (total number of units) of NPH and NovoLog that you
need to inject. The total dose will determine the final amount (volume) in the
syringe after drawing up both insulins into the syringe. For example, if you
need 5 units of NPH and 2 units of NovoLog, the total dose of insulin in the
syringe would be 7 units.
2. Roll the NPH vial between your hands until the liquid is equally cloudy
throughout.
3. Draw into the syringe the same amount of air as the NPH dose. Inject this air
into the NPH vial and then remove the needle from the vial but do not
withdraw any of the NPH insulin. (Transferring NPH to the NovoLog vial will
contaminate the NovoLog vial and may change how quickly it works.)
4. Draw into the syringe the same amount of air as the NovoLog dose. Inject this
air into the NovoLog vial. With the needle in place, turn the vial upside down
and withdraw the correct dose of NovoLog. The tip of the needle must be in
the NovoLog to get the full dose and not an air dose.
5. After withdrawing the needle from the NovoLog vial, insert the needle into the
NPH vial. Turn the NPH vial upside down with the syringe and needle still in
it. Withdraw the correct dose of NPH.
6. Inject right away to avoid changes in how quickly the insulin works.
How do I use NovoLog in a pump?
•
Checking your blood sugar is very important for patients using pumps.
Pump or infusion set problems can result in you not getting enough
insulin. This can quickly cause you to have high blood sugar and diabetic
ketoacidosis.
•
Use insulin from a new vial of NovoLog if unexplained high blood sugar or
pump alarms do not respond to all of the following:
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o a repeat dose (injection or bolus) of NovoLog
o a change in the infusion set, including the NovoLog in the reservoir
o a change in the infusion site
•
If these measures do not work, you may need to go back to injecting
NovoLog with syringes, or insulin pens. Continue to monitor your blood
sugars and ketones. If problems continue, you must contact your
healthcare provider.
•
When NovoLog is used in pumps, use only pumps that are
recommended by your healthcare provider. The infusion set and
infusion site should be changed at least every 3 days. The insulin in the
reservoir should be changed at least every 6 days even if you have not
used all of the insulin. The reservoir, the infusion set, and infusion site
should also be changed:
o with unexpected high blood sugar
o when the alarm sounds (see your pump manual)
o if the insulin or pump has been exposed to temperatures over
98.6°F (37°C), such as in a sauna, with long showers, or on an
unusually hot day.
o if the insulin or pump could have absorbed heat, for example from
sunlight, that would heat the insulin to over 98.6°F (37°C). Dark
colored pump cases or sport covers can increase this type of heat.
The location where the pump is worn may also affect the
temperature
Patients who develop local skin reactions may need to change infusion sites
more often than every 3 days.
Use only insulin pumps that have been specially tested with NovoLog. Follow
your healthcare provider or pharmacist instructions for which insulin pumps may
be used.
Check with your healthcare provider or pharmacist to see if your pump and
infusion set can be used with NovoLog.
1. Check to make sure that you have the right type of insulin.
2. Look at the vial and insulin. The insulin should be clear and colorless. The
tamper-resistant cap should be in place before the first use. If the cap had
been removed before your first use, or if the insulin is cloudy or colored,
do not use it and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water.
4. Fill the reservoir-syringe with 2 days worth of NovoLog plus about 25 extra
units to prime the pump and the infusion tubing.
5. Remove air bubbles from the reservoir by following the pump
manufacturers’ instructions.
6. Attach the infusion set to the reservoir. Make sure the connection is tight.
Prime the infusion set until you see a drop of insulin coming out of the
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infusion needle-catheter. Follow the pump manufacturers’ instructions for
priming and removing air bubbles.
7. Clean your insertion site with an alcohol swab and let the site dry before
you insert the needle-catheter. Talk with your healthcare provider about
how to rotate insertion sites and how to insert the needle-catheter into the
skin.
8. Insert the needle-catheter into the skin, remove the needle and prime the
catheter according to the pump manufacturers’ instructions. Do not insert
the needle-catheter into skin that is reddened, itchy, bumpy, or thickened.
9. Program the pump for mealtime NovoLog boluses and NovoLog basal
insulin infusion according to instructions from your healthcare provider and
the manufacturer of your pump equipment.
10.Change the infusion site and infusion set at least every 3 days, and
change the insulin in the reservoir at least every 6 days even if you have
not used all of the insulin. This will help ensure that NovoLog and the
pump work well.
11.Change the infusion site, the infusion set, the insulin reservoir and the
insulin if you experience a pump alarm, catheter blockage, high blood
sugars, or if your pump insulin has been exposed to heat greater than
98.6oF (37oC).
12.If you have high blood sugar (hyperglycemia) when you check your blood
sugar, this may be the first sign of a problem with the pump, infusion set,
or NovoLog. If you have high blood sugar without a pump alarm, you must
still check the pump because alarms may not detect all the changes to
NovoLog that could result in high blood sugar. You may need to start
insulin injections with syringes if the cause of the problem cannot be found
quickly or fixed. Long lengths of infusion-set tubing increase the risk for
kinking and expose the insulin in the tubing to more changes in
temperature.
Reference ID: 3212914
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Introduction
Please read the following instructions carefully before using your NovoLog® FlexPen®.
NovoLog FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1
to 60 units in increments of 1 unit. NovoLog FlexPen is designed to be used with
NovoFine® needles.
NovoLog FlexPen should not be used by people who are blind or have severe visual
problems without the help of a person who has good eyesight and who is trained to
use the NovoLog FlexPen the right way.
Getting ready
Make sure you have the following items:
•
NovoLog FlexPen
•
New NovoFine needle
•
Alcohol swab NovoLog FlexPen
Preparing Your NovoLog FlexPen
Wash your hands with soap and water. Before you start to prepare your
injection, check the label to make sure that you are taking the right type of
insulin. This is especially important if you take more than 1 type of insulin.
NovoLog should look clear.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. pen cap
Reference ID: 3212914
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tapping cartridge with finger
pressing push-button in
B. Attaching the needle
Remove the protective tab from a disposable needle. protective tab
Screw the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your NovoLog FlexPen until
you are ready to take your injection.
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and dispose of it (see diagram D). needle cap
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of unexpected needle sticks, never put the inner needle cap back
on the needle.
Giving the airshot before each injection
Before each injection small amounts of air may collect in the cartridge during normal
use. To avoid injecting air and to ensure proper dosing:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your NovoLog FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any air
bubbles collect at the top of the cartridge (see diagram F).
G. Keep the needle pointing upwards, press the push-button all
the way in (see diagram G). The dose selector returns to 0.
A drop of insulin should appear at the needle tip. If not, change
the needle and repeat the procedure no more than 6 times.
If you do not see a drop of insulin after 6 times, do not use the
Reference ID: 3212914 turning dose selector
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
A small air bubble may remain at the needle tip, but it will not be
injected.
Selecting your dose
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the dose
selector in either direction until the correct dose lines up with the
pointer (see diagram H). When turning the dose selector, be
careful not to press the push-button as insulin will come out.
You cannot select a dose larger than the number of units left in
the cartridge. turning dose selector
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
Giving the injection
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until the 0
lines up with the pointer (see diagram I). Be careful only to push
the button when injecting. injecting dose
Turning the dose selector will not inject insulin.
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has been
pulled out from the skin (see diagram J). This will make sure
that the full dose has been given.
You may see a drop of NovoLog at the needle tip. This is
normal and has no effect on the dose you just received. If blood
appears after you take the needle out of your skin, press the
injection site lightly with a finger. Do not rub the area.
Reference ID: 3212914 needle in the skin
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After the injection
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog FlexPen after each injection. This helps
to prevent infection, leakage of insulin, and will help to make sure you inject the
right dose of insulin.
Put the needle and any empty NovoLog FlexPen or any used NovoLog
FlexPen still containing insulin in a sharps container or some type of hard
plastic or metal container with a screw top such as a detergent bottle or
empty coffee can. These containers should be sealed and thrown away the
right way. Check with your healthcare provider about the right way to throw
away used syringes and needles. There may be local or state laws about
how to throw away used needles and syringes. Do not throw away used
needles and syringes in household trash or recycling bins.
The NovoLog FlexPen prevents the cartridge from being completely emptied. It is
designed to deliver 300 units.
K. Put the pen cap on the NovoLog FlexPen and store the
NovoLog FlexPen without the needle attached (see diagram K). closing needle cap
L. Function Check
If your NovoLog FlexPen is not working the right way, follow the steps below: NovoLog FlexPen
•
Screw on a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap.
•
Do an airshot as described in “Giving the airshot before
each injection”.
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the NovoLog FlexPen so the needle is pointing down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram
L). If the NovoLog FlexPen has released too much or too little insulin, do the
function check again. If the same problem happens again, do not use your
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled
with care. Avoid dropping your FlexPen as it may damage it. If you are
concerned that your FlexPen is damaged, use a new one. You can clean the
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outside of your FlexPen by wiping it with a damp cloth. Do not soak or wash
your FlexPen as it may damage it. Do not refill your FlexPen.
Remove the needle from the NovoLog FlexPen after each injection. This
helps to ensure sterility, prevent leakage of insulin, and will help to make
sure you inject the right dose of insulin for future injections.
Be careful when handling used needles to avoid needle sticks and transfer
of infectious diseases.
Keep your NovoLog FlexPen and needles out of the reach of children.
Use NovoLog FlexPen as directed to treat your diabetes.
Needles and NovoLog FlexPen must not be shared. Always use a new
needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device in
case your NovoLog FlexPen is lost or damaged.
Remember to keep the disposable NovoLog FlexPen with you. Do not
leave it in a car or other location where it can get too hot or too cold.
Reference ID: 3212914
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For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:27.326497 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020986s057lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 57} |
3,951 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog®
safely and effectively. See full prescribing information for NovoLog.
NovoLog (insulin aspart [rDNA origin] injection) solution for subcutaneous
use
Initial U.S. Approval: 2000
·······································INDICATIONS AND USAGE········································
• NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
··································DOSAGE AND ADMINISTRATION································
• The dosage of NovoLog must be individualized.
• Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
• Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
• Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL to
1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags.
NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium
chloride (2.4).
·······························DOSAGE FORMS AND STRENGTHS································
Each presentation contains 100 Units of insulin aspart per mL (U-100)
• 10 mL vials (3)
• 3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
• 3 mL NovoLog FlexPen (3)
········································CONTRAINDICATIONS··············································
• Do not use during episodes of hypoglycemia (4).
• Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
··································WARNINGS AND PRECAUTIONS······························
• Hypoglycemia is the most common adverse effect of insulin therapy. Glucose
monitoring is recommended for all patients with diabetes. Any change of
insulin dose should be made cautiously and only under medical supervision
(5.1, 5.2).
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of diabetes mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Mixing of Insulins
5.9 Continuous Subcutaneous Insulin Infusion by External Pump
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
• Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.3).
• Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.4, 5.5).
• Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.6).
········································ADVERSE REACTIONS···········································
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
···········································DRUG INTERACTIONS·······································
• The following may increase the blood-glucose-lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide
antibiotics (7).
• The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral
contraceptives), atypical antipsychotics (7).
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or
weaken the blood-glucose-lowering effect of insulin (7).
• Pentamidine may cause hypoglycemia, which may sometimes be followed
by hyperglycemia (7).
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine, and
reserpine (7).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
•
Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: [3/2008]
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17
PATIENT COUNSELING INFORMATION
17.1 Physician Instructions
17.2 Patients Using Pumps
17.3 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3230591
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
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NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
•
10 mL vials
•
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
•
3 mL NovoLog FlexPen
4
CONTRAINDICATIONS
NovoLog is contraindicated
•
during episodes of hypoglycemia
•
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
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Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.3
Hypokalemia
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
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5.4
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Clinical Pharmacology (12.3)].
5.5
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Clinical Pharmacology (12.3)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.7
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.8
Mixing of Insulins
•
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
•
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
•
Insulin mixtures should not be administered intravenously.
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5.9
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.2)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9) and How
Supplied/Storage and Handling (16.2), Patient Counseling Information (17)].
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
•
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral Edema
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Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL,with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during postapproval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during postapproval use [see Patient Counseling Information (17)].
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7
DRUG INTERACTIONS
A number of substances affect glucose metabolism and may require insulin dose
adjustment and particularly close monitoring.
•
The following are examples of substances that may increase the blood-glucose
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide),
sulfonamide antibiotics.
•
The following are examples of substances that may reduce the blood-glucose
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
atypical antipsychotics.
•
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
the blood-glucose-lowering effect of insulin.
•
Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
•
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
products such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
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insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age, particularly in patients with type 2 diabetes.
Additional studies in larger populations of patients 65 years of age or over are needed to permit
conclusions regarding the safety of NovoLog in elderly compared to younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog
action have not been performed.
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
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NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8. empirical formula and molecular weight
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset of action than regular human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (see Figure 2). The
duration of action for NovoLog is 3 to 5 hours. The time course of action of insulin and insulin
analogs such as NovoLog may vary considerably in different individuals or within the same
individual. The parameters of NovoLog activity (time of onset, peak time and duration) as
designated in Figure 2 should be considered only as general guidelines. The rate of insulin
absorption and onset of activity is affected by the site of injection, exercise, and other variables
[see Warnings and Precautions (5.1)].
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graph
Figure 2. Serial mean serum glucose collected up to 6 hours following a single
pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve)
injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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Mean Blood Glucose (mg/dL)
gr
aph
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
NovoLog reduces the molecule's tendency to form hexamers as observed with regular human
insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to
regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the
regular human insulin group.
Bioavailability and Absorption - NovoLog has a faster absorption, a faster onset of
action, and a shorter duration of action than regular human insulin after subcutaneous injection
(see Figure 2 and Figure 4). The relative bioavailability of NovoLog compared to regular human
insulin indicates that the two insulins are absorbed to a similar extent.
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graph
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single pre-meal dose of NovoLog (solid curve) or regular human insulin
(hatched curve) injected immediately before a meal in 22 patients with type 1
diabetes.
In studies in healthy volunteers (total n=l07) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin
aspart have not been established in patients with type 2 diabetes.
The intra-individual variability in time to maximum serum insulin concentration for
healthy male volunteers was significantly less for NovoLog than for regular human insulin. The
clinical significance of this observation has not been established.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
Specific Populations
Children and Adolescents - The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Gender - In healthy volunteers, no difference in insulin aspart levels was seen between
men and women when body weight differences were taken into account. There was no
significant difference in efficacy noted (as assessed by HbAlc) between genders in a trial in
patients with type 1 diabetes.
Obesity - A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.
Renal Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal (N=6) creatinine clearance
(CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50
ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment.
In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax
of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog,
may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4)].
Hepatic Impairment - Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter.
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5)].
The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
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when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
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Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c ,Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
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Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
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Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
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Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.3 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
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Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
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Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (0.4, 0.3)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or sunlight. Opened vials may be refrigerated.
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Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen Prefilled Syringes:
Once a cartridge or a NovoLog FlexPen is punctured, it should be kept at temperatures
below 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight. A
NovoLog FlexPen or cartridge in use must NOT be stored in the refrigerator. Keep the NovoLog
FlexPen and all PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog
FlexPen and PenFill cartridges can be used until the expiration date printed on the label if they
are stored in a refrigerator. Keep unused NovoLog FlexPen and PenFill cartridges in the carton
so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen without a needle attached. This prevents
contamination and/or infection, or leakage of insulin, and will ensure accurate dosing.
Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges and NovoLog FlexPen Prefilled
syringe
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30°C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
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Storage of NovoLog in Infusion Fluids
Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA-Approved Patient Labeling (17.3)]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.2
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
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NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.3 FDA Approved Patient Labeling
Rx only
Date of Issue:
Version
®
NovoLog , NovoPen® 3, PenFill®, Novolin®, FlexPen®, PenMate®, and NovoFine® are
trademarks of Novo Nordisk A/S.
®
NovoLog is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and other patents
pending.
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and other patents
pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured By Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark
Manufactured For Novo Nordisk Inc., Princeton, New Jersey 08540
www.novonordisk-us.com
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Patient Information
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] Injection)
Important:
Know your insulin. Do not change the type of insulin you use unless told to do
so by your healthcare provider. The amount of insulin you take as well as the
best time for you to take your insulin may need to change if you take a different
type of insulin.
Make sure you know the type and strength of insulin prescribed for you.
Read the Patient Information that comes with NovoLog before you start taking it
and each time you get a refill. There may be new information. This leaflet does
not take the place of talking with your healthcare provider about your diabetes or
your treatment. Make sure you know how to manage your diabetes. Ask your
healthcare provider if you have any questions about managing your diabetes.
What is NovoLog?
NovoLog is a man-made insulin that is used to control high blood sugar in adults
and children with diabetes mellitus.
Who should not use NovoLog?
Do not take NovoLog if:
•
Your blood sugar is too low (hypoglycemia)
•
You are allergic to anything in NovoLog. See the end of this leaflet
for a complete list of ingredients in NovoLog. Check with your
healthcare provider if you are not sure.
Tell your healthcare provider:
•
about all of your medical conditions. Medical conditions can affect
your insulin needs and your dose of NovoLog.
•
if you are pregnant or breastfeeding. You and your healthcare
provider should talk about the best way to manage your diabetes
while you are pregnant or breastfeeding. NovoLog has not been
studied in nursing women.
•
about all medicines you take, including prescriptions and non
prescription medicines, vitamins and herbal supplements. Your
NovoLog dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show
your healthcare providers when you get a new medicine.
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How should I take NovoLog?
Only use NovoLog if it appears clear and colorless. There may be air bubbles.
This is normal. If it looks cloudy, thickened, or colored, or if it contains solid
particles do not use it and call Novo Nordisk at 1-800-727-6500.
NovoLog comes in:
•
10 mL vials (small bottles) for use with syringe
•
3 mL PenFill® cartridges for use with the Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices and NovoFine®
disposable needles. The cartridge delivery device can be used with a
NovoPen® 3 PenMate®
•
3 mL NovoLog FlexPen®
Read the instructions for use that come with your NovoLog product. Talk
to your healthcare provider if you have any questions. Your healthcare provider
should show you how to inject NovoLog before you start taking it.
•
Take NovoLog exactly as prescribed. You should eat a meal within
5 to 10 minutes after using NovoLog to avoid low blood sugar.
•
NovoLog is a fast-acting insulin. The effects of NovoLog start
working 10 to 20 minutes after injection or bolus pump infusion.
•
Do not inject NovoLog if you do not plan to eat right after your
injection or bolus pump infusion.
•
The greatest blood sugar lowering effect is between 1 and 3 hours
after the injection or infusion. This blood sugar lowering lasts for 3 to
5 hours.
•
While using NovoLog you may have to change your total dose of
insulin, your dose of longer-acting insulin, or the number of injections
of longer-acting insulin you use. Pump users given NovoLog may
need to change the amount of total insulin given as a basal infusion.
•
Do not mix NovoLog:
o with any other insulins when used in a pump
o with any insulins other than NPH when used with injections
by syringe
If your doctor recommends diluting NovoLog, follow your doctor’s
instructions exactly so that you know:
• How to make NovoLog more dilute (that is, a smaller number of
units of NovoLog for a given amount of liquid) and
• How to use this more dilute form of NovoLog. Do not use dilute
insulin in a pump.
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•
illness
• change in diet
•
stress
• change in physical activity or
•
other med icines you
exercise
take
•
Inject NovoLog into the skin of your stomach area, upper arms,
buttocks or upper legs. NovoLog may affect your blood sugar
levels sooner if you inject it into the skin of your stomach area. Never
inject NovoLog into a vein or into a muscle.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the exact same spot for each injection.
•
If you take too much NovoLog, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar (hypoglycemia)
by drinking or eating something sugary right away (fruit juice, sugar
candies, or glucose tablets). It is important to treat low blood sugar
(hypoglycemia) right away because it could get worse and you could
pass out (become unconscious). If you pass out you will need help
from another person or emergency medical services right away, and
will need treatment with a glucagon injection or treatment at a
hospital. See “What are the possible side effects of NovoLog?” for
more information on low blood sugar (hypoglycemia).
•
If you forget to take your dose of NovoLog, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death. Follow
your healthcare provider’s instructions for treating high blood sugar.
Know your symptoms of high blood sugar which may include:
•
increased thirst
• fruity smell on the breath
•
frequent urination
• high amounts of sugar and
•
drowsiness
ketones in your urine
•
loss of appetite
• nausea, vomiting (throwing up)
•
a hard time
or stomach pain
breathing
•
Check you r blood su gar levels. Ask your healthcare provider what
your blood sugars should be and when you should check your blood
sugar levels.
Your insulin dosage may need to change because of:
What should I avoid while using NovoLog ?
•
Alcohol. Alcohol, including beer and wine, may affect your blood
sugar when you take NovoLog.
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•
Driving and operating machinery. You may have difficulty
concentrating or reacting if you have low blood sugar (hypoglycemi a).
Be careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright to drive if you often have:
• low blood sugar
• decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog?
•
low b lo d sugar (hypoglycemia). Symptoms of low blood sugar
o
may in lu
c de:
•
sweating
•
or
trouble concentrating
•
dizziness or
confusion
lightheadedness
•
blurred vision
•
shakiness
•
slurred speech
•
hunger
•
anxiety, irritability or
•
fast heart beat
ges
mood chan
•
tingling of lips and
•
headache
tongue
Severe low blood sugar can cause unconsciousness (passing out),
seizures, and death. Know your symptoms of low blood sugar.
Follow your healthcare prov ider’s instructions for treating low blood
sugar. Talk to your healthcare provider if low blood sugar is a
problem for you.
•
Serious allergic reaction (whole body reaction). Get medical
help right away, if you develop a rash over your whole body, h ave
trouble breathing, a fast heartbeat, or sweating.
•
Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions or they are serious talk to your healthcare
provider. You may need to stop using NovoLog and use a differen t
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
•
Skin thickens or pits at the injection site (lipod ystrophy).
Change (rotate) where you inject your insulin to help to prevent these
skin changes from happening. Do not inject insulin into this type of
skin.
•
Swelling of your hands and feet.
•
Vision changes
•
Low potassium in your blood (hypokalemia)
Reference ID: 3230591
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For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Weight gain
These are not all of the possible side effects from NovoLog. Ask your
health are provider or pha
c
rmacist for more information.
Call your doctor for medical advice about side effects. Yo u may report side
effects to FDA at 1-80 0-FDA-1088.
How should I store NovoLog?
All Unopened NovoLog:
•
Keep all unopened NovoLog in the refrigerator between 36° to
46°F (2° to 8°C).
•
Do not freeze. Do not use NovoLog if it has been frozen.
•
Keep unopened NovoLog in the carton to protect from light.
NovoLog in use:
•
Vials.
• Keep in the refrigerator or at room temperature belo w 86°F
(30°C) for up to 28 days.
• Keep vials away from direct heat or light.
• Throw away an opened vial after 28 days of use, even if there is
insulin left in the vial.
• Do not draw up NovoLog into a syringe and store for later use
• Unopened vials can be used until the expiration date on the
NovoLog label, if the medicine has been stored in a refrigerator.
•
PenFill Cartridges or NovoLog FlexPen Prefilled syringe.
• Keep at room temperature below 86°F (30°C) for up to 28 days.
• Do not store a PenFill cartridge or NovoLog FlexPen Prefilled
syringe that you are using in the refrigerator.
• Keep PenFill cartridges and NovoLog FlexPen Prefilled syringe
away from direct heat or light.
• Throw away a used PenFill cartridge or NovoLog FlexPen
Prefilled syringes after 28 days, even if there is insulin left in the
cartridge or syringe.
•
NovoLog in the pump reservoir and the complete external pump
infusion set
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• The infusion set and the infusion site should be changed at
least every 3 days. The insulin in the reservoir should be
changed at least every 6 days even if you have not used all of
the insulin. Change the infusion set and the infusion site more
often than every 3 days if you have high blood sugar
(hyperglycemia), the pump alarm sounds, or the insulin flow is
blocked (occlusion).
General advice about NovoLog
Medicines are sometimes prescribed for conditions that are not mentioned in the
patient leaflet. Do not use NovoLog for a condition for which it was not
prescribed. Do not give NovoLog to other people, even if they have the same
symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog. If you
would like more information about N ovoLog or diabetes, talk with your healthcare
provider. You can ask your healthcare provider or pharmacist for information
about NovoLog that is written for healthcare professionals. Call 1-800-727-6500
or visit www.novonordisk-us.com for more information.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1701 N Beauregard Street Alexandria, VA 22311 and on
www.diabetes.org.
NovoLog ingredients include:
• insulin aspart
• zinc
• glycerin
• disodium hydrogen phosphate dihydrate
• phenol
• sodium chloride
• metacresol
• water for injection
All NovoLog vials, PenFill cartridges and NovoLog FlexPen Prefilled syringes are
latex free.
Date of Issu e:
Version: 7
®
®
®
NovoLog , PenFill®, FlexPen®, NovoPen , NovoFine , PenMate®, are
trademarks of Novo Nordisk A/S.
®
NovoLog is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
Reference ID: 3230591
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PenFill® is covered by US Patent Nos. 6,126,646, 5,693,027, DES 347894, and
other patents pending.
© 2002-2008 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3230591
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] injection)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® and each time you
get a refill. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your
treatment.
Supplies you will need to give your NovoLog® injection:
10 mL NovoLog® vial
insulin syringe and needle
alcohol swab usage illustration
Preparing your NovoLog® dose:
Wash your hands with soap and water.
Before you start to prepare your injection, check the NovoLog® label to make
sure that you are taking the right type of insulin. This is especially important
if you use more than 1 type of insulin.
NovoLog® should look clear and colorless. Do not use NovoLog® if it is thick,
cloudy, or is colored.
Do not use NovoLog® past the expiration date printed on the label. usage illustration
Reference ID: 3230591
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Step 1: Pull off the tamper resistant cap (See
Figure A).
Step 2: Wipe the rubber stopper with an alcohol
swab (See Figure B).
(Figure A Figure B)
Step 3: Hold the syringe with the needle pointing
up. Pull down on the plunger until the black tip
reaches the line for the number of units for your
prescribed dose (See Figure C).
(Figure C)
Step 4: Push the needle through the rubber
stopper of the NovoLog® vial (See Figure D).
.
(Figure D)
Step 5: Push the plunger all the way in. This puts
air into the NovoLog® vial (See Figure E).
(Figure E)
Step 6: Turn the NovoLog® vial and syringe upside
down and slowly pull the plunger down until the
black tip is a few units past the line for your dose
(See Figure F).
(Figure F)
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If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top
(See Figure G).
(Figure G)
Step 7: Slowly push the plunger up until the black
tip reaches the line for your NovoLog® dose (See
Figure H).
(Figure H)
Step 8: Check the syringe to make sure you have
the right dose of NovoLog® .
Step 9: Pull the syringe out of the vial’s rubber
stopper (See Figure I).
(Figure I)
Giving your Injection:
Inject your NovoLog® exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
NovoLog® can be injected under the skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper arms, infused in an insulin pump, or given
through a needle in your arm (intravenously) by your healthcare provider.
If you inject NovoLog®, change (rotate) your injection sites within the area you
choose for each dose. Do not use the same injection site for each injection.
If you use NovoLog® in an insulin pump, you should change your insertion site
every 3 days. The insulin in the reservoir should be changed at least every 6
days even if you have not used all of the insulin.
Reference ID: 3230591
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If you use NovoLog® in an insulin pump, see your insulin pump manual for
instructions or talk to your healthcare provider.
NPH insulin is the only type of insulin that can be mixed with NovoLog®. Do not
mix NovoLog® with any other type of insulin.
NovoLog® should only be mixed with NPH insulin if it is going to be injected
right away under your skin (subcutaneously).
NovoLog® should be drawn up into the syringe before you draw up your NPH
insulin.
Talk to your healthcare provider if you are not sure about the right way to mix
NovoLog® and NPH insulin.
Step 10: Choose your injection site and wipe the skin
an alcohol swab. Let the injection site dry before you
your dose (See Figure J).
(Figure J)
Step 11: Insert the needle into your skin. Push
down on the plunger to inject your dose (See Figure
K). Needle should remain in the skin for at
least 6 seconds to make sure you have
injected all the insulin.
(Figure K)
Step 12: Pull the needle out of your skin. After that,
you may see a drop of NovoLog® at the needle tip.
This is normal and does not affect the dose you
just received (See Figure L).
If you see blood after you take the needle out of
your skin, press the injection site lightly with a
piece of gauze or an alcohol swab. Do not rub
the area.
(Figure L)
Reference ID: 3230591
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For current labeling information, please visit https://www.fda.gov/drugsatfda
After your injection:
Do not recap the needle. Recapping the needle can lead to a needle stick
injury.
Throw away empty insulin vials, used syringes, and needles in a sharps
container or some type of hard plastic or metal container with a screw on cap
such as a detergent bottle or empty coffee can. Check with your healthcare
provider about the right way to throw away the container. There may be local
or state laws about how to throw away used syringes and needles. Do not
throw away used syringes and needles in household trash or recycling bins.
How should I store NovoLog®?
Do not freeze NovoLog® . Do not use NovoLog® if it has been frozen.
Keep NovoLog® away from heat or light.
Store opened and unopened NovoLog® vials in the refrigerator at 36OF to 46OF
(2OC to 8OC). Opened NovoLog® vials can also be stored out of the refrigerator
below 86OF (30OC).
Unopened vials may be used until the expiration date printed on the label, if
they are kept in the refrigerator.
Opened NovoLog® vials should be thrown away after 28 days, even if they still
have insulin left in them.
General information about the safe and effective use of NovoLog®
Always use a new syringe and needle for each injection.
Do not share syringes or needles.
Keep NovoLog® vials, syringes, and needles out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
NovoLog® is a registered trademark of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
© 2002-2012 Novo Nordisk Inc.
For information about NovoLog® contact:
Reference ID: 3230591
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Revised: December 2012
Reference ID: 3230591
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Introduction
Please read the following instructions carefully before using your NovoLog® FlexPen®.
NovoLog FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1
to 60 units in increments of 1 unit. NovoLog FlexPen is designed to be used with
NovoFine® needles.
NovoLog FlexPen should not be used by people who are blind or have severe visual
problems without the help of a person who has good eyesight and who is trained to
use the NovoLog FlexPen the right way.
Getting ready
Make sure you have the following items:
•
NovoLog FlexPen
•
New NovoFine needle
•
Alcohol swab usage illustration
Preparing Your NovoLog FlexPen
Wash your hands with soap and water. Before you start to prepare your
injection, check the label to make sure that you are taking the right type of
insulin. This is especially important if you take more than 1 type of insulin.
NovoLog should look clear.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustration
Reference ID: 3212914
Reference ID: 3230591
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For current labeling information, please visit https://www.fda.gov/drugsatfda
B. Attaching the needle
Remove the protective tab from a disposable needle. usage illustration
Screw the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your NovoLog FlexPen until
you are ready to take your injection.
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and dispose of it (see diagram D). usage illustration
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of unexpected needle sticks, never put the inner needle cap back
on the needle.
Giving the airshot before each injection
Before each injection small amounts of air may collect in the cartridge during normal
use. To avoid injecting air and to ensure proper dosing:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your NovoLog FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any air
bubbles collect at the top of the cartridge (see diagram F).
G. Keep the needle pointing upwards, press the push-button all
the way in (see diagram G). The dose selector returns to 0.
A drop of insulin should appear at the needle tip. If not, change
the needle and repeat the procedure no more than 6 times.
If you do not see a drop of insulin after 6 times, do not use the
Reference ID: 3212914
Reference ID: 3230591 usage illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
A small air bubble may remain at the needle tip, but it will not be
injected.
Selecting your dose
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the dose
selector in either direction until the correct dose lines up with the
pointer (see diagram H). When turning the dose selector, be
careful not to press the push-button as insulin will come out.
You cannot select a dose larger than the number of units left in
the cartridge. usage illustration
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
Giving the injection
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until the 0
lines up with the pointer (see diagram I). Be careful only to push
the button when injecting. usage illustration
Turning the dose selector will not inject insulin.
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has been
pulled out from the skin (see diagram J). This will make sure
that the full dose has been given.
You may see a drop of NovoLog at the needle tip. This is
normal and has no effect on the dose you just received. If blood
appears after you take the needle out of your skin, press the
injection site lightly with a finger. Do not rub the area.
Reference ID: 3212914
Reference ID: 3230591 usage illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After the injection
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog FlexPen after each injection. This helps
to prevent infection, leakage of insulin, and will help to make sure you inject the
right dose of insulin.
Put the needle and any empty NovoLog FlexPen or any used NovoLog
FlexPen still containing insulin in a sharps container or some type of hard
plastic or metal container with a screw top such as a detergent bottle or
empty coffee can. These containers should be sealed and thrown away the
right way. Check with your healthcare provider about the right way to throw
away used syringes and needles. There may be local or state laws about
how to throw away used needles and syringes. Do not throw away used
needles and syringes in household trash or recycling bins.
The NovoLog FlexPen prevents the cartridge from being completely emptied. It is
designed to deliver 300 units.
K. Put the pen cap on the NovoLog FlexPen and store the
NovoLog FlexPen without the needle attached (see diagram K). usage illustration
L. Function Check
If your NovoLog FlexPen is not working the right way, follow the steps below: usage illustration
•
Screw on a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap.
•
Do an airshot as described in “Giving the airshot before
each injection”.
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the NovoLog FlexPen so the needle is pointing down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram
L). If the NovoLog FlexPen has released too much or too little insulin, do the
function check again. If the same problem happens again, do not use your
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled
with care. Avoid dropping your FlexPen as it may damage it. If you are
concerned that your FlexPen is damaged, use a new one. You can clean the
Reference ID: 3212914
Reference ID: 3230591
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For current labeling information, please visit https://www.fda.gov/drugsatfda
outside of your FlexPen by wiping it with a damp cloth. Do not soak or wash
your FlexPen as it may damage it. Do not refill your FlexPen.
Remove the needle from the NovoLog FlexPen after each injection. This
helps to ensure sterility, prevent leakage of insulin, and will help to make
sure you inject the right dose of insulin for future injections.
Be careful when handling used needles to avoid needle sticks and transfer
of infectious diseases.
Keep your NovoLog FlexPen and needles out of the reach of children.
Use NovoLog FlexPen as directed to treat your diabetes.
Needles and NovoLog FlexPen must not be shared. Always use a new
needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device in
case your NovoLog FlexPen is lost or damaged.
Remember to keep the disposable NovoLog FlexPen with you. Do not
leave it in a car or other location where it can get too hot or too cold.
Reference ID: 3212914
Reference ID: 3230591
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:27.426236 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020986s064lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 64} |
3,952 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog
safely and effectively. See full prescribing information for NovoLog.
NovoLog® (insulin aspart [rDNA origin] injection)
solution for subcutaneous use
Initial U.S. Approval: 2000
·······································INDICATIONS AND USAGE········································
NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
··································DOSAGE AND ADMINISTRATION································
The dosage of NovoLog must be individualized.
Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL
to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion
bags. NovoLog has been shown to be stable in infusion fluids such as 0.9%
sodium chloride (2.4).
·······························DOSAGE FORMS AND STRENGTHS································
Each presentation contains 100 Units of insulin aspart per mL (U-100)
10 mL vials (3)
3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
3 mL NovoLog FlexPen® (3)
3 mL NovoLog FlexTouch® (3)
········································CONTRAINDICATIONS··············································
Do not use during episodes of hypoglycemia (4).
Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Mixing of Insulins
5.9 Continuous Subcutaneous Insulin Infusion by External Pump
5.10 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of
NovoLog
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering
Effect of NovoLog
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
··································WARNINGS AND PRECAUTIONS······························
Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under medical
supervision (5.1, 5.2).
Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.3).
Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.4, 5.5).
Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.6).
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin,
including NovoLog (5.10).
········································ADVERSE REACTIONS··········································
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
···········································DRUG INTERACTIONS·······································
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may
be needed. (7.1, 7.2, 7.3)
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (7.3, 7.4)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 01/2015
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17
PATIENT COUNSELING INFORMATION
17.1 Physician Instructions
17.2 Patients Using Pumps
17.3 FDA Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3687161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
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NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
•
10 mL vials
•
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
•
3 mL NovoLog FlexPen
•
3 mL NovoLog FlexTouch
4
CONTRAINDICATIONS
NovoLog is contraindicated
•
during episodes of hypoglycemia
•
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
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Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.3
Hypokalemia
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
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5.4
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Use in Specific Populations (8.7)].
5.5
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Use in Specific Populations (8.8)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.7
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.8
Mixing of Insulins
•
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
•
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
•
Insulin mixtures should not be administered intravenously.
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5.9
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.2)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage
and Handling (16.2), and Patient Counseling Information (17.2)].
5.10
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor
(PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated
with insulin, including NovoLog, and a PPAR-gamma agonist should be observed for signs and
symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be
considered.
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
•
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
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(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
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Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during post-approval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during post-approval use [see Patient Counseling Information (17)].
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with NovoLog use may be increased with antidiabetic
agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine,
monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin
analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of NovoLog
The glucose lowering effect of NovoLog may be decreased when co-administered with
atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens,
glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral
contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol,
epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose
monitoring may be required when NovoLog is co-administered with these drugs.
7.3
Drugs That May Increase or Dec
rease the Blood Glucose Low ering Effect of
NovoLog
The glucose lowering effect of NovoLog may be increased or decreased when co-administered
with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia,
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which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.4
Drugs That May Affect Hypoglycemia Signs and Symptoms
The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine,
guanethidine, and reserpine are co-administered with NovoLog.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
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8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age.
8.6 Gender
There was no significant difference in efficacy noted (as assessed by HbAlc) between genders in
a trial in patients with type 1 diabetes.
8.7 Renal Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with renal impairment [see Warnings and Precautions (5.4)].
8.8 Hepatic Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic impairment [see Warnings and Precautions (5.5)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8.
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structural formula
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset and a shorter duration of action than regular
human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (0.15 U/kg) (see
Figure 2). The duration of action for NovoLog is 3 to 5 hours. The time course of action of
insulin and insulin analogs such as NovoLog may vary considerably in different individuals or
within the same individual. The parameters of NovoLog activity (time of onset, peak time and
duration) as designated in Figure 2 should be considered only as general guidelines. The rate of
insulin absorption and onset of activity is affected by the site of injection, exercise, and other
variables [see Warnings and Precautions (5.1)].
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graph
Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15
U/kg pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched
curve) injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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Mean Blood Glucose (mg/dL)
gr
aph
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
Absorption -The single substitution of the amino acid proline with aspartic acid at
position B28 in NovoLog reduces the molecule's tendency to form hexamers as observed with
regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous
injection compared to regular human insulin (see Figure 4) .
The relative bioavailability of NovoLog (0.15 U/kg) compared to regular human insulin
(0.15 U/kg) indicates that the two insulins are absorbed to a similar extent.
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graph
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single 0.15 U/kg pre-meal dose of NovoLog (solid curve) or regular
human insulin (hatched curve) injected immediately before a meal in 22 patients
with type 1 diabetes.
In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 L/h/kg for the NovoLog group and 1.2 L/h/kg for the
regular human insulin group.
Specific Populations
Age: Pediatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Age: Geriatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were investigated in a single dose study in 18 subjects with
type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and
pharmacodynamics in geriatric patients with type 2 diabetes between NovoLog and regular
human insulin were similar to those in younger adults.
Gender: In healthy volunteers given single subcutaneous dose of Novolog 0.06 U/kg, no
difference in insulin aspart levels was seen between men and women based on comparison of
AUC(0-10h) or Cmax.
Obesity: A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2 .
Renal Impairment: Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal renal function (N=6)
creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3;
CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min)
renal impairment. In this small study, there was no apparent effect of creatinine clearance values
on AUC and Cmax of NovoLog.
Hepatic Impairment:- Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic impairment and any NovoLog pharmacokinetic
parameter.
The effect of ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
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test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
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Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
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Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (97.5% confidence interval)
-0.2 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
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Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
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Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human
insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.2 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
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Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
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Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.3, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
3 mL NovoLog FlexTouch
NDC 0169-6338-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles. FlexPen and FlexTouch can be used with
NovoFine or NovoTwist disposable needles.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or light. Opened vials may be refrigerated.
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Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen and NovoLog FlexTouch:
Once a cartridge or NovoLog FlexPen or NovoLog FlexTouch is punctured, it should be
kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to
excessive heat or sunlight. A NovoLog FlexPen or NovoLog FlexTouch or cartridge in use must
NOT be stored in the refrigerator. Keep the NovoLog FlexPen or NovoLog FlexTouch and all
PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog FlexPen or
NovoLog FlexTouch and PenFill cartridges can be used until the expiration date printed on the
label if they are stored in a refrigerator. Keep unused NovoLog FlexPen or NovoLog FlexTouch
and PenFill cartridges in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen or NovoLog FlexTouch without a needle attached.
This prevents contamination and/or infection, or leakage of insulin, and will ensure
accurate dosing. Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges, NovoLog FlexPen, and NovoLog
FlexTouch
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexTouch
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
Storage of NovoLog in Infusion Fluids
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Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA Approved Patient Labeling (17.3)]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
Patients should receive proper training on how to use NovoLog. Instruct patients that
when injecting NovoLog, they must press and hold down the dose button until the dose counter
shows 0 and then keep the needle in the skin and count slowly to 6. When the dose counter
returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is
removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose
will not be delivered (a possible under-dose may occur by as much as 20%), and they should
increase the frequency of checking their blood glucose levels and possible additional insulin
administration may be necessary.
If 0 does not appear in the dose counter after continuously pressing the dose button, the
patient may have used a blocked needle. In this case they would not have received any
insulin – even though the dose counter has moved from the original dose that was set.
If the patient did have a blocked needle, instruct them to change the needle as described
in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with
Section 1: Prepare your pen with a new needle. Make sure the patient selects the full
dose needed.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
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prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.2
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
Medtronic Paradigm® 512 and 712
MiniMed 508
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.3 FDA Approved Patient Labeling
See separate leaflet.
Rx only
Date of issue: January 14, 2015
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Version: 23
Novo Nordisk®, NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, FlexTouch®, PenMate® ,
NovoFine®, and NovoTwist® are registered trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent No. 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. RE 41,956, 6,004,297, RE 43,834, and other patents
pending.
FlexTouch® pen is covered by US Patent Nos. 7,686,786, 6,899,699, and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
†The brands listed are the registered trademarks of their respective owners and are not
trademarks of Novo Nordisk A/S.
© 2002-2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3687161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:27.673213 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020986s078lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 78} |
3,953 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog
safely and effectively. See full prescribing information for NovoLog.
NovoLog® (insulin aspart [rDNA origin] injection)
solution for subcutaneous use
Initial U.S. Approval: 2000
·······································INDICATIONS AND USAGE········································
NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
··································DOSAGE AND ADMINISTRATION································
The dosage of NovoLog must be individualized.
Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL
to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion
bags. NovoLog has been shown to be stable in infusion fluids such as 0.9%
sodium chloride (2.4).
·······························DOSAGE FORMS AND STRENGTHS································
Each presentation contains 100 Units of insulin aspart per mL (U-100)
10 mL vials (3)
3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
3 mL NovoLog FlexPen® (3)
3 mL NovoLog FlexTouch® (3)
········································CONTRAINDICATIONS··············································
Do not use during episodes of hypoglycemia (4).
Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Mixing of Insulins
5.9 Continuous Subcutaneous Insulin Infusion by External Pump
5.10 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of
NovoLog
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering
Effect of NovoLog
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
··································WARNINGS AND PRECAUTIONS······························
Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under medical
supervision (5.1, 5.2).
Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.3).
Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.4, 5.5).
Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.6).
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin,
including NovoLog (5.10).
········································ADVERSE REACTIONS··········································
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
···········································DRUG INTERACTIONS·······································
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may
be needed. (7.1, 7.2, 7.3)
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (7.3, 7.4)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 01/2015
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17
PATIENT COUNSELING INFORMATION
17.1 Physician Instructions
17.2 Patients Using Pumps
17.3 FDA Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
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NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
•
10 mL vials
•
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
•
3 mL NovoLog FlexPen
•
3 mL NovoLog FlexTouch
4
CONTRAINDICATIONS
NovoLog is contraindicated
•
during episodes of hypoglycemia
•
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
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Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.3
Hypokalemia
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
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5.4
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Use in Specific Populations (8.7)].
5.5
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Use in Specific Populations (8.8)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.7
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.8
Mixing of Insulins
•
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
•
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
•
Insulin mixtures should not be administered intravenously.
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5.9
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.2)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage
and Handling (16.2), and Patient Counseling Information (17.2)].
5.10
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor
(PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated
with insulin, including NovoLog, and a PPAR-gamma agonist should be observed for signs and
symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be
considered.
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
•
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
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(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
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Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during post-approval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during post-approval use [see Patient Counseling Information (17)].
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with NovoLog use may be increased with antidiabetic
agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine,
monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin
analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of NovoLog
The glucose lowering effect of NovoLog may be decreased when co-administered with
atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens,
glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral
contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol,
epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose
monitoring may be required when NovoLog is co-administered with these drugs.
7.3
Drugs That May Increase or Dec
rease the Blood Glucose Low ering Effect of
NovoLog
The glucose lowering effect of NovoLog may be increased or decreased when co-administered
with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia,
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which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.4
Drugs That May Affect Hypoglycemia Signs and Symptoms
The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine,
guanethidine, and reserpine are co-administered with NovoLog.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
Reference ID: 3691464
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8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age.
8.6 Gender
There was no significant difference in efficacy noted (as assessed by HbAlc) between genders in
a trial in patients with type 1 diabetes.
8.7 Renal Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with renal impairment [see Warnings and Precautions (5.4)].
8.8 Hepatic Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic impairment [see Warnings and Precautions (5.5)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8.
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structural formula
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset and a shorter duration of action than regular
human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (0.15 U/kg) (see
Figure 2). The duration of action for NovoLog is 3 to 5 hours. The time course of action of
insulin and insulin analogs such as NovoLog may vary considerably in different individuals or
within the same individual. The parameters of NovoLog activity (time of onset, peak time and
duration) as designated in Figure 2 should be considered only as general guidelines. The rate of
insulin absorption and onset of activity is affected by the site of injection, exercise, and other
variables [see Warnings and Precautions (5.1)].
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graph
Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15
U/kg pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched
curve) injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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Mean Blood Glucose (mg/dL)
gr
aph
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
Absorption -The single substitution of the amino acid proline with aspartic acid at
position B28 in NovoLog reduces the molecule's tendency to form hexamers as observed with
regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous
injection compared to regular human insulin (see Figure 4) .
The relative bioavailability of NovoLog (0.15 U/kg) compared to regular human insulin
(0.15 U/kg) indicates that the two insulins are absorbed to a similar extent.
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graph
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single 0.15 U/kg pre-meal dose of NovoLog (solid curve) or regular
human insulin (hatched curve) injected immediately before a meal in 22 patients
with type 1 diabetes.
In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 L/h/kg for the NovoLog group and 1.2 L/h/kg for the
regular human insulin group.
Specific Populations
Age: Pediatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Age: Geriatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were investigated in a single dose study in 18 subjects with
type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and
pharmacodynamics in geriatric patients with type 2 diabetes between NovoLog and regular
human insulin were similar to those in younger adults.
Gender: In healthy volunteers given single subcutaneous dose of Novolog 0.06 U/kg, no
difference in insulin aspart levels was seen between men and women based on comparison of
AUC(0-10h) or Cmax.
Obesity: A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2 .
Renal Impairment: Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal renal function (N=6)
creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3;
CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min)
renal impairment. In this small study, there was no apparent effect of creatinine clearance values
on AUC and Cmax of NovoLog.
Hepatic Impairment:- Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic impairment and any NovoLog pharmacokinetic
parameter.
The effect of ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
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test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
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Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
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Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (97.5% confidence interval)
-0.2 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
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Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
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Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human
insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.2 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
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Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
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Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.3, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
3 mL NovoLog FlexTouch
NDC 0169-6338-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles. FlexPen and FlexTouch can be used with
NovoFine or NovoTwist disposable needles.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or light. Opened vials may be refrigerated.
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Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen and NovoLog FlexTouch:
Once a cartridge or NovoLog FlexPen or NovoLog FlexTouch is punctured, it should be
kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to
excessive heat or sunlight. A NovoLog FlexPen or NovoLog FlexTouch or cartridge in use must
NOT be stored in the refrigerator. Keep the NovoLog FlexPen or NovoLog FlexTouch and all
PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog FlexPen or
NovoLog FlexTouch and PenFill cartridges can be used until the expiration date printed on the
label if they are stored in a refrigerator. Keep unused NovoLog FlexPen or NovoLog FlexTouch
and PenFill cartridges in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen or NovoLog FlexTouch without a needle attached.
This prevents contamination and/or infection, or leakage of insulin, and will ensure
accurate dosing. Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges, NovoLog FlexPen, and NovoLog
FlexTouch
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexTouch
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
Storage of NovoLog in Infusion Fluids
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Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA Approved Patient Labeling (17.3)]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
Patients should receive proper training on how to use NovoLog. Instruct patients that
when injecting NovoLog, they must press and hold down the dose button until the dose counter
shows 0 and then keep the needle in the skin and count slowly to 6. When the dose counter
returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is
removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose
will not be delivered (a possible under-dose may occur by as much as 20%), and they should
increase the frequency of checking their blood glucose levels and possible additional insulin
administration may be necessary.
If 0 does not appear in the dose counter after continuously pressing the dose button, the
patient may have used a blocked needle. In this case they would not have received any
insulin – even though the dose counter has moved from the original dose that was set.
If the patient did have a blocked needle, instruct them to change the needle as described
in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with
Section 1: Prepare your pen with a new needle. Make sure the patient selects the full
dose needed.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
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prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.2
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.3 FDA Approved Patient Labeling
See separate leaflet.
Rx only
Date of issue: January 14, 2015
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Version: 23
Novo Nordisk®, NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, FlexTouch®, PenMate® ,
NovoFine®, and NovoTwist® are registered trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent No. 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. RE 41,956, 6,004,297, RE 43,834, and other patents
pending.
FlexTouch® pen is covered by US Patent Nos. 7,686,786, 6,899,699, and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
†The brands listed are the registered trademarks of their respective owners and are not
trademarks of Novo Nordisk A/S.
© 2002-2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3691464
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Patient Information
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] injection)
What is NovoLog?
• NovoLog is a man-made insulin that is used to control high blood sugar in adults and children with
diabetes mellitus.
Who should not take NovoLog?
Do not take NovoLog if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to NovoLog or any of the ingredients in NovoLog.
Before taking NovoLog, tell your healthcare provider about all your medical conditions including,
if you are:
•
pregnant, planning to become pregnant, or are breastfeeding.
•
taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.
Before you start taking NovoLog, talk to your healthcare provider about low blood sugar and how
to manage it.
How should I take NovoLog?
•
Read the Instructions for Use that come with your NovoLog.
•
Take NovoLog exactly as your healthcare provider tells you to.
•
NovoLog starts acting fast. You should eat a meal within 5 to 10 minutes after you take your dose of
NovoLog.
•
Know the type and strength of insulin you take. Do not change the type of insulin you take unless your
healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may
need to change if you take different types of insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and
when you should check your blood sugar levels.
•
Do not share your NovoLog FlexPen, FlexTouch or needles with another person. You may give
another person an infection or get an infection from them.
What should I avoid while taking NovoLog?
While taking NovoLog do not:
•
Drive or operate heavy machinery, until you know how NovoLog affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of NovoLog?
NovoLog may cause serious side effects that can lead to death, including:
Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
•
dizziness or light-headedness
●
blurred vision
●
anxiety, irritability, or mood changes
•
sweating
●
slurred speech
●
hunger
•
confusion
●
shakiness
●
headache
●
fast heart beat
Your insulin dose may need to change because of:
•
change in level of physical activity or exercise
●
increased stress
●
change in diet
•
weight gain or loss
●
illness
Other common side effects of NovoLog may include:
•
low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic
reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain,
and swelling of your hands and feet.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating,
extreme drowsiness, dizziness, confusion.
These are not all the possible side effects of NovoLog. Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of NovoLog.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You
can ask your pharmacist or healthcare provider for information about NovoLog that is written for health
professionals. Do not use NovoLog for a condition for which it was not prescribed. Do not give NovoLog to
other people, even if they have the same symptoms that you have. It may harm them.
What are the ingredients in NovoLog?
Active Ingredient: insulin aspart (rDNA origin)
Inactive Ingredients: glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride and water for
injection
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
Reference ID: 3691464
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For more information, go to www.novonordisk-us.com or call 1-800-727-6500.
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 10/2013 company logo
For more information go to
www.novologflextouch.com
© 2002-2013 Novo Nordisk company logo
Reference ID: 3691464
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® (NŌ-vō-log) FlexTouch® Pen
(insulin aspart [rDNA origin] injection)
• NovoLog FlexTouch Pen (“Pen”) is a prefilled disposable pen
containing 300 units of U-100 NovoLog (insulin aspart [rDNA origin]
injection) insulin. You can inject from 1 to 80 units in a single injection.
• Do not share your NovoLog FlexTouch Pen with another person. You
may give an infection to them or get an infection from them.
• This Pen is not recommended for use by the blind or visually impaired
without the assistance of a person trained in the proper use of the
product.
Supplies you will need to give your NovoLog injection:
• NovoLog FlexTouch Pen
• a new NovoFine, NovoFine Plus or NovoTwist needle
• alcohol swab
• 1 sharps container for throwing away used Pens and needles. See
“Disposing of used NovoLog FlexTouch Pens and needles” at the
end of these instructions.
Preparing your NovoLog FlexTouch Pen:
• Wash your hands with soap and water.
• Before you start to prepare your injection, check the NovoLog
FlexTouch Pen label to make sure you are taking the right type of
insulin. This is especially important if you take more than 1 type of
insulin.
• NovoLog should look clear and colorless. Do not use NovoLog if it is thick,
cloudy, or is colored.
• Do not use NovoLog past the expiration date printed on the label or 28
days after you start using the Pen.
• Always use a new needle for each injection to help ensure sterility
and prevent blocked needles.
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usage illustration
usage
illustratio
n
usage
illustratio
n
Reference ID: 3691464
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For current labeling information, please visit https://www.fda.gov/drugsatfda
usage
illustr
ation
(Figure A)
Step 1:
•
Pull Pen cap straight off (See Figure
B).
(Figure B)
Step 2:
•
Check the liquid in the Pen (See
Figure C). NovoLog should look clear
and colorless. Do not use it if it looks
cloudy or colored.
(Figure C)
Step 3:
•
Select a new needle.
•
Pull off the paper tab from the outer
needle cap (See Figure D).
NovoFine®
NovoFine® Plus
NovoTwist®
(Figure D)
Step 4:
•
Push the capped needle straight onto
the Pen and twist the needle on until
it is tight (See Figure E).
NovoFine®
NovoFine® Plus
NovoTwist®
(Figure E)
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Step 5:
•
Pull off the outer needle cap. Do not
throw it away (See Figure F).
Step 6:
•
Pull off the inner needle cap and
throw it away (See Figure G).
Priming your NovoLog FlexTouch Pen:
Step 7:
•
Turn the dose selector to select 2
units (See Figure H).
Step 8:
•
Hold the Pen with the needle pointing
up. Tap the top of the Pen gently a
few times to let any air bubbles rise to
the top (See Figure I).
u
s
a
g
e
i
l
lustration
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Step 9:
•
Hold the Pen with the needle
pointing up. Press and hold in the
dose button until the dose counter
shows “0”. The “0” must line up wit
the dose pointer.
•
A drop of insulin should be seen at
needle tip (See Figure J).
o If you do not see a drop of insu
repeat steps 7 to 9, no more th
6 times.
o If you still do not see a drop of
insulin, change the needle and
repeat steps 7 to 9.
Selecting your dose:
Step 10:
•
Turn the dose selector to select
the number of units you need t
inject. The dose pointer should lin
up with your dose (See Figure K).
o If you select the wrong dose,
you can turn the dose selector
forwards or backwards to the
correct dose.
o The even numbers are printed
on the dial.
o The odd numbers are shown as
lines.
•
The NovoLog FlexTouch Pen insulin
scale will show you how much
insulin is left in your Pen (See
Figure L).
h
the
lin,
an
(Figure J)
s
5 units
selected
24 units
selected
gure K)
ple|
rox.
nits
left
gure L)
o
e
Example
(Fi
Exam
App
200 u
(Fi
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u
s
a
g
e
illustration
Step 11:
•
Choose your injection site and wipe
the skin with an alcohol swab. Let
the injection site dry before you
inject your dose (See Figure M).
Step 12:
•
Insert the needle into your skin
(See Figure N).
o
Make sure you can see the
dose counter. Do not cover it
with your fingers, this can stop
your injection.
• To see how much insulin is left
in your NovoLog FlexTouch Pen:
o Turn the dose selector until it
stops. The dose counter will line
up with the number of units of
insulin that is left in your Pen. If
the dose counter shows 80,
there are at least 80 units left
in your Pen.
o If the dose counter shows less
than 80, the number shown in
the dose counter is the number
of units left in your Pen.
Giving your injection:
• Inject your NovoLog exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
• NovoLog can be injected under the skin (subcutaneously) of your stomach
area (abdomen), buttocks, upper legs (thighs) or upper arms.
• For each injection, change (rotate) your injection site within the area of
skin that you use. Do not use the same injection site for each injection.
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Step 13:
•
Press and hold down the dose
button until the dose counter
shows “0” (See Figure O).
o The “0” must line up with the
dose pointer. You may then hear
or feel a click.
(Figure O)
•
Keep the needle in your skin
after the dose counter has
returned to “0” and slowly count
to 6 (See Figure P).
o When the dose counter
returns to “0”, you will not
get your full dose until 6
seconds later.
o If the needle is removed
before you count to 6, you
may see a stream of insulin
coming from the needle tip.
o If you see a stream of insulin
coming from the needle tip
you will not get your full
dose. If this happens you
should check your blood
sugar levels more often
because you may need more
insulin.
Count slowly:
(Figure P)
Step 14:
•
Pull the needle out of your skin
(See Figure Q).
o If you see blood after you take
the needle out of your skin,
press the injection site lightly
with a piece of gauze or an
alcohol swab. Do not rub the
area.
(Figure Q)
Step 15:
•
Carefully remove the needle
from the Pen and throw it away
(See Figure R).
o Do not recap the needle.
Recapping the needle can lead
to needle stick injury.
NovoFine®
NovoFine® Plus
NovoTwist®
(Figure R)
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u
s
a
ge illustration
•
If you do not have a sharps
container, carefully slip the needle
into the outer needle cap (See
Figure S). Safely remove the needle
and throw it away as soon as you
can.
o
Do not store the Pen with the
needle attached. Storing without
the needle attached helps
prevent leaking, blocking of the
needle, and air from entering
the Pen.
Step 16:
•
Replace the Pen cap by pushing it
straight on (See Figure T).
After your injection:
• You can put your used NovoLog FlexTouch Pen and needles in a FDA-
cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and Pens in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of your sharps
disposal container. There may be state or local laws about how you should
throw away used needles and syringes. For more information about safe
sharps disposal, and for specific information about sharps disposal in the
state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your
used sharps disposal container.
How should I store my NovoLog FlexTouch Pen?
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• Store unused NovoLog FlexTouch Pens in the refrigerator at 36OF to 46OF
(2OC to 8OC).
• Store the Pen you are currently using out of the refrigerator below 86OF.
• Do not freeze NovoLog. Do not use NovoLog if it has been frozen.
• Keep NovoLog away from heat or light.
• Unused Pens may be used until the expiration date printed on the label, if
kept in the refrigerator.
• The NovoLog FlexTouch Pen you are using should be thrown away after 28
days, even if it still has insulin left in it.
General Information about the safe and effective use of NovoLog.
• Keep NovoLog FlexTouch Pens and needles out of the reach of
children.
• Always use a new needle for each injection.
• Do not share Pens or needles.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
Revised: 01/2015
Reference ID: 3691464
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Instructions for Use
NovoLog® (Nŭ-vŮ-log)
(insulin aspart [rDNA origin] injection)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® and each time you
get a refill. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your
treatment.
Supplies you will need to give your NovoLog® injection:
x
10 mL NovoLog® vial
x
insulin syringe and needle
x
alcohol swab usage illustration
Preparing your NovoLog® dose:
x Wash your hands with soap and water.
x Before you start to prepare your injection, check the NovoLog® label to make
sure that you are taking the right type of insulin. This is especially important
if you use more than 1 type of insulin.
x NovoLog® should look clear and colorless. Do not use NovoLog® if it is thick,
cloudy, or is colored.
x Do not use NovoLog® past the expiration date printed on the label. usage illustration
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(Figure A Figure B)
(Figure C)
(Figure D)
(Figure E)
(Figure F)
e
Step 1: Pull off the tamper resistant cap (See
Figure A).
Step 2: Wipe the rubber stopper with an alcohol
swab (See Figure B).
Step 3: Hold the syringe with the needle pointing
up. Pull down on the plunger until the black tip
reaches the line for the number of units for your
prescribed dose (See Figure C).
Step 4: Push the needle through the rubber
stopper of the NovoLog® vial (See Figure D).
.
Step 5: Push the plunger all the way in. This puts
air into the NovoLog® vial (See Figure E).
Step 6: Turn the NovoLog® vial and syringe upsid
down and slowly pull the plunger down until the
black tip is a few units past the line for your dose
(See Figure F).
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u
sage illust
ration
x
If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top
(See Figure G).
Step 7: Slowly push the plunger up until the black
tip reaches the line for your NovoLog® dose (See
Figure H).
Step 8: Check the syringe to make sure you have
the right dose of NovoLog® .
Step 9: Pull the syringe out of the vial’s rubber
stopper (See Figure I).
Giving your Injection:
x Inject your NovoLog® exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
x
NovoLog® can be injected under the skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper arms, infused in an insulin pump, or given
through a needle in your arm (intravenously) by your healthcare provider.
x
If you inject NovoLog®, change (rotate) your injection sites within the area you
choose for each dose. Do not use the same injection site for each injection.
x
If you use NovoLog® in an insulin pump, you should change your insertion site
every 3 days. The insulin in the reservoir should be changed at least every 6
days even if you have not used all of the insulin.
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usage illus
tration
x
If you use NovoLog® in an insulin pump, see your insulin pump manual for
instructions or talk to your healthcare provider.
x
NPH insulin is the only type of insulin that can be mixed with NovoLog® . Do not
mix NovoLog® with any other type of insulin.
x
NovoLog® should only be mixed with NPH insulin if it is going to be injected
right away under your skin (subcutaneously).
x
NovoLog® should be drawn up into the syringe before you draw up your NPH
insulin.
x Talk to your healthcare provider if you are not sure about the right way to mix
NovoLog® and NPH insulin.
Step 10: Choose your injection site and wipe the skin
an alcohol swab. Let the injection site dry before you
your dose (See Figure J).
Step 11: Insert the needle into your skin. Push
down on the plunger to inject your dose (See Figure
K). Needle should remain in the skin for at
least 6 seconds to make sure you have
injected all the insulin.
Step 12: Pull the needle out of your skin. After that,
you may see a drop of NovoLog® at the needle tip.
This is normal and does not affect the dose you
just received (See Figure L).
x
If you see blood after you take the needle out of
your skin, press the injection site lightly with a
piece of gauze or an alcohol swab. Do not rub
the area.
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After your injection:
x
Do not recap the needle. Recapping the needle can lead to a needle stick
injury.
x
Throw away empty insulin vials, used syringes, and needles in a sharps
container or some type of hard plastic or metal container with a screw on cap
such as a detergent bottle or empty coffee can. Check with your healthcare
provider about the right way to throw away the container. There may be local
or state laws about how to throw away used syringes and needles. Do not
throw away used syringes and needles in household trash or recycling bins.
How should I store NovoLog®?
Do not freeze NovoLog® . Do not use NovoLog® if it has been frozen.
x
Keep NovoLog® away from heat or light.
x
Store opened and unopened NovoLog® vials in the refrigerator at 36OF to 46OF
(2OC to 8OC). Opened NovoLog® vials can also be stored out of the refrigerator
below 86OF (30OC).
x Unopened vials may be used until the expiration date printed on the label, if
they are kept in the refrigerator.
x Opened NovoLog® vials should be thrown away after 28 days, even if they still
have insulin left in them.
General information about the safe and effective use of NovoLog®
x
Always use a new syringe and needle for each injection.
x
Do not share syringes or needles.
x
Keep NovoLog® vials, syringes, and needles out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
NovoLog® is a registered trademark of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
© 2002-2012 Novo Nordisk Inc.
For information about NovoLog® contact:
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Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Revised: December 2012
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Introduction
Please read the following instructions carefully before using your NovoLog® FlexPen® .
NovoLog FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1
to 60 units in increments of 1 unit. NovoLog FlexPen is designed to be used with
NovoFine® needles.
NovoLog FlexPen should not be used by people who are blind or have severe visual
problems without the help of a person who has good eyesight and who is trained to
use the NovoLog FlexPen the right way.
Getting ready
Make sure you have the following items:
•
usage illustration
Preparing Your NovoLog FlexPen
Wash your hands with soap and water. Before you start to prepare your
injection, check the label to make sure that you are taking the right type of
insulin. This is especially important if you take more than 1 type of insulin.
NovoLog should look clear.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustration
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B. Attaching the needle
Remove the protective tab from a disposable needle. usage illustration
Screw the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your NovoLog FlexPen until
you are ready to take your injection.
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and dispose of it (see diagram D). usage illustration
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of unexpected needle sticks, never put the inner needle cap back
on the needle.
Giving the airshot before each injection
Before each injection small amounts of air may collect in the cartridge during normal
use. To avoid injecting air and to ensure proper dosing:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your NovoLog FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any air
bubbles collect at the top of the cartridge (see diagram F).
G. Keep the needle pointing upwards, press the push-button all
the way in (see diagram G). The dose selector returns to 0.
A drop of insulin should appear at the needle tip. If not, change
the needle and repeat the procedure no more than 6 times.
If you do not see a drop of insulin after 6 times, do not use the usage illustration
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NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
A small air bubble may remain at the needle tip, but it will not be
injected.
Selecting your dose
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the dose
selector in either direction until the correct dose lines up with the
pointer (see diagram H). When turning the dose selector, be
careful not to press the push-button as insulin will come out.
You cannot select a dose larger than the number of units left in
the cartridge. usage illustration
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
Giving the injection
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until the 0
lines up with the pointer (see diagram I). Be careful only to push
the button when injecting. usage illustration
Turning the dose selector will not inject insulin.
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has been
pulled out from the skin (see diagram J). This will make sure
that the full dose has been given.
You may see a drop of NovoLog at the needle tip. This is
normal and has no effect on the dose you just received. If blood
appears after you take the needle out of your skin, press the
injection site lightly with a finger. Do not rub the area. usage illustration
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After the injection
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog FlexPen after each injection. This helps
to prevent infection, leakage of insulin, and will help to make sure you inject the
right dose of insulin.
Put the needle and any empty NovoLog FlexPen or any used NovoLog
FlexPen still containing insulin in a sharps container or some type of hard
plastic or metal container with a screw top such as a detergent bottle or
empty coffee can. These containers should be sealed and thrown away the
right way. Check with your healthcare provider about the right way to throw
away used syringes and needles. There may be local or state laws about
how to throw away used needles and syringes. Do not throw away used
needles and syringes in household trash or recycling bins.
The NovoLog FlexPen prevents the cartridge from being completely emptied. It is
designed to deliver 300 units.
K. Put the pen cap on the NovoLog FlexPen and store the
NovoLog FlexPen without the needle attached (see diagram K). usage illustration
L. Function Check
If your NovoLog FlexPen is not working the right way, follow the steps below: usage illustration
•
Screw on a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap.
•
Do an airshot as described in “Giving the airshot before
each injection”.
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the NovoLog FlexPen so the needle is pointing down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram
L). If the NovoLog FlexPen has released too much or too little insulin, do the
function check again. If the same problem happens again, do not use your
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled
with care. Avoid dropping your FlexPen as it may damage it. If you are
concerned that your FlexPen is damaged, use a new one. You can clean the
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outside of your FlexPen by wiping it with a damp cloth. Do not soak or wash
your FlexPen as it may damage it. Do not refill your FlexPen.
Remove the needle from the NovoLog FlexPen after each injection. This
helps to ensure sterility, prevent leakage of insulin, and will help to make
sure you inject the right dose of insulin for future injections.
Be careful when handling used needles to avoid needle sticks and transfer
of infectious diseases.
Keep your NovoLog FlexPen and needles out of the reach of children.
Use NovoLog FlexPen as directed to treat your diabetes.
Needles and NovoLog FlexPen must not be shared. Always use a new
needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device in
case your NovoLog FlexPen is lost or damaged.
Remember to keep the disposable NovoLog FlexPen with you. Do not
leave it in a car or other location where it can get too hot or too cold.
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Page 1 of 2 Submitted 13Mar08
Patient Instructions for Use
NovoLog® 3 mL PenFill® cartridge (100 Units/mL, U-100)
Before using the NovoLog cartridge
1. Talk with your healthcare provider for information about where to inject
NovoLog (injection sites) and how to give an injection with your insulin
delivery device.
2. Read the instruction manual that comes with your insulin delivery
device for complete instructions on how to use the PenFill cartridge
with the device.
How to use the NovoLog cartridge
1. Check your insulin. Just before using your NovoLog cartridge,
check to make sure that you have the right type of insulin. This is
especially important if you use different types of insulin.
2. Carefully look at the cartridge and the insulin inside it. The insulin
should be clear and colorless. The tamper-resistant foil should be in
place before the first use. If the foil has been broken or removed before
your first use of the cartridge, or if the insulin is cloudy or colored, do
not use it. Call Novo Nordisk at 1-800-727-6500.
3. Wash your hands well with soap and water. If you clean your injection
site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider for guidance on injection sites and
how to give an injection with your insulin delivery device.
4. Gather your supplies for injecting NovoLog.
5. Insert a 3 mL cartridge into your Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery device. Wipe the front rubber stopper of the
3 mL PenFill cartridge with an alcohol swab, then screw on a new
needle. For NovoFine needles, remove the big outer needle cap and
the inner needle cap. Always use a new needle for each injection to
prevent infection.
Giving the airshot before each injection:
To prevent the injection of air and to make sure insulin is delivered, you must do
an air shot before each injection. Hold the device with the needle pointing up
and gently tap the PenFill® cartridge holder with your finger a few times to raise
any air bubbles to the top of the cartridge. Do the air shot as described in the
device instruction manual.
Giving the injection
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Page 2 of 2 Submitted 13Mar08
6. Dial the number of units on the insulin delivery device that you need to
inject. Inject the right way as shown to you by your healthcare provider.
7. Insert the needle into the skin. Inject the dose by pressing the push
button all the way in. Keep the needle in the skin for at least 6
seconds, and keep the push button pressed all the way in until the
needle has been pulled out from the skin. This will make sure that the
full dose has been given. You may see a drop of NovoLog at the
needle tip. This is normal and has no effect on the dose you just
received If blood appears after you take the needle out of your skin,
press the injection site lightly with a finger. Do not rub the area.
After the injection
8. Do not recap the needle. Recapping can lead to a needle stick injury.
9. Remove the needle from the PenFill cartridge after each injection.
Keep the 3 mL PenFill cartridge in the insulin delivery device. The
needle should not be attached to the 3 mL PenFill cartridge during
storage. This will prevent infection or leakage of insulin and will help
ensure that you receive the right dose of NovoLog.
10.Put the used needle and cartridge in a sharps container, or some type
of hard plastic or metal container with a screw on top such as a
detergent bottle or coffee can. Check with your doctor about the right
way to throw away used needles and cartridges. There may be local or
state laws about how to throw away used needles and syringes. Do
not throw used needles and cartridges in household trash or recycling
bins.
11.Put the pen cap back on the Novo Nordisk 3 mL PenFill cartridge
compatible insulin delivery device.
Reference ID: 3691464
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:28.872945 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020986s080lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 80} |
4,071 |
1
1
2
HUMALOG® Mix50/50TM
3
50% INSULIN LISPRO PROTAMINE SUSPENSION AND
4
50% INSULIN LISPRO INJECTION
5
(rDNA ORIGIN)
6
100 UNITS PER ML (U-100)
7
DESCRIPTION
8
Humalog® Mix50/50™ [50% insulin lispro protamine suspension and 50% insulin lispro
9
injection, (rDNA origin)] is a mixture of insulin lispro solution, a rapid-acting blood glucose
10
lowering agent and insulin lispro protamine suspension, an intermediate-acting blood glucose
11
lowering agent. Chemically, insulin lispro is Lys(B28), Pro(B29) human insulin analog, created
12
when the amino acids at positions 28 and 29 on the insulin B-chain are reversed. Insulin lispro is
13
synthesized in a special non-pathogenic laboratory strain of Escherichia coli bacteria that has
14
been genetically altered to produce insulin lispro. Insulin lispro protamine suspension (NPL
15
component) is a suspension of crystals produced from combining insulin lispro and protamine
16
sulfate under appropriate conditions for crystal formation.
17
Insulin lispro has the following primary structure: primary structure
18
19
Insulin lispro has the empirical formula C257H383N65O77S6 and a molecular weight of 5808,
20
both identical to that of human insulin.
21
Humalog Mix50/50 vials and Pens contain a sterile suspension of insulin lispro protamine
22
suspension mixed with soluble insulin lispro for use as an injection.
23
Each milliliter of Humalog Mix50/50 injection contains insulin lispro 100 units, 0.19 mg
24
protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 2.20 mg Metacresol, zinc
25
oxide content adjusted to provide 0.0305 mg zinc ion, 0.89 mg phenol, and Water for Injection.
26
Humalog Mix50/50 has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10%
27
may have been added to adjust pH.
28
CLINICAL PHARMACOLOGY
29
Antidiabetic Activity
30
The primary activity of insulin, including Humalog Mix50/50, is the regulation of glucose
31
metabolism. In addition, all insulins have several anabolic and anti-catabolic actions on many
32
tissues in the body. In muscle and other tissues (except the brain), insulin causes rapid transport
33
of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism.
34
In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits
35
gluconeogenesis, and promotes the conversion of excess glucose into fat.
36
Insulin lispro, the rapid-acting component of Humalog Mix50/50, has been shown to be
37
equipotent to Regular human insulin on a molar basis. One unit of Humalog® has the same
Reference ID: 3252235
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
38
glucose-lowering effect as one unit of Regular human insulin, but its effect is more rapid and of
39
shorter duration.
40
Pharmacokinetics
41
Absorption — Studies in nondiabetic subjects and patients with type 1 (insulin-dependent)
42
diabetes demonstrated that Humalog, the rapid-acting component of Humalog Mix50/50, is
43
absorbed faster than Regular human insulin (U-100). In nondiabetic subjects given subcutaneous
44
doses of Humalog ranging from 0.1 to 0.4 U/kg, peak serum concentrations were observed 30 to
45
90 minutes after dosing. When nondiabetic subjects received equivalent doses of Regular human
46
insulin, peak insulin concentrations occurred between 50 to 120 minutes after dosing. Similar
47
results were seen in patients with type 1 diabetes. graph
48
Figure 1: Serum Immunoreactive Insulin (IRI) Concentrations, After Subcutaneous
49
Injection of Humalog Mix50/50 or Humulin 50/50 in Healthy Nondiabetic Subjects.
50
Humalog Mix50/50 has two phases of absorption. The early phase represents insulin lispro and
51
its distinct characteristics of rapid onset. The late phase represents the prolonged action of insulin
52
lispro protamine suspension. In 30 healthy nondiabetic subjects given subcutaneous doses
53
(0.3 U/kg) of Humalog Mix50/50, peak serum concentrations were observed 45 minutes to 13.5
54
hours (median, 60 minutes) after dosing (see Figure 1). In patients with type 1 diabetes, peak
55
serum concentrations were observed 45 minutes to 120 minutes (median, 60 minutes) after
56
dosing. The rapid absorption characteristics of Humalog are maintained with Humalog Mix50/50
57
(see Figure 1).
58
Direct comparison of Humalog Mix50/50 and Humulin 50/50 was not performed. However, a
59
cross-study comparison shown in Figure 1 suggests that Humalog Mix50/50 has a more rapid
60
absorption than Humulin 50/50.
61
Distribution — Radiolabeled distribution studies of Humalog Mix50/50 have not been
62
conducted. However, the volume of distribution following injection of Humalog is identical to
63
that of Regular human insulin, with a range of 0.26 to 0.36 L/kg.
64
Metabolism — Human metabolism studies of Humalog Mix50/50 have not been conducted.
65
Studies in animals indicate that the metabolism of Humalog, the rapid-acting component of
66
Humalog Mix50/50, is identical to that of Regular human insulin.
67
Elimination — Humalog Mix50/50 has two absorption phases, a rapid and a prolonged phase,
68
representative of the insulin lispro and insulin lispro protamine suspension components of the
69
mixture. As with other intermediate-acting insulins, a meaningful terminal phase half-life cannot
70
be calculated after administration of Humalog Mix50/50 because of the prolonged insulin lispro
71
protamine suspension absorption.
Reference ID: 3252235
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
72
Pharmacodynamics
73
Studies in nondiabetic subjects and patients with diabetes demonstrated that Humalog has a
74
more rapid onset of glucose-lowering activity, an earlier peak for glucose-lowering, and a shorter
75
duration of glucose-lowering activity than Regular human insulin. The early onset of activity of
76
Humalog Mix50/50 is directly related to the rapid absorption of Humalog. The time course of
77
action of insulin and insulin analogs, such as Humalog (and hence Humalog Mix50/50), may
78
vary considerably in different individuals or within the same individual. The parameters of
79
Humalog Mix50/50 activity (time of onset, peak time, and duration) as presented in Figures 2
80
and 3 should be considered only as general guidelines. The rate of insulin absorption and
81
consequently the onset of activity is known to be affected by the site of injection, exercise, and
82
other variables (see General under PRECAUTIONS).
83
In a glucose clamp study performed in 30 nondiabetic subjects, the onset of action and glucose
84
lowering activity of Humalog, Humalog Mix50/50, Humalog® Mix75/25™, and insulin lispro
85
protamine suspension (NPL component) were compared (see Figure 2). Graphs of mean glucose
86
infusion rate versus time showed a distinct insulin activity profile for each formulation. The
87
rapid onset of glucose-lowering activity characteristic of Humalog was maintained in Humalog
88
Mix50/50.
89
Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed.
90
However, a cross-study comparison shown on Figure 3 suggests that Humalog Mix50/50 has a
91
duration of activity that is similar to Humulin 50/50. graph
92
Figure 2: Glucose Infusion Rates (A Measure of Insulin Activity) After Injection of
93
Humalog, Humalog Mix50/50, Humalog Mix75/25, or Insulin Lispro Protamine Suspension
94
(NPL Component) in 30 Nondiabetic Subjects.
95
96
97
Reference ID: 3252235
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4
98
99 graph
100
Figure 3: Insulin Activity After Subcutaneous Injection of Humalog Mix50/50 and
101
Humulin 50/50 in Nondiabetic Subjects.
102
Figures 2 and 3 represent insulin activity profiles as measured by glucose clamp studies in
103
healthy nondiabetic subjects.
104
Figure 2 shows the time activity profiles of Humalog, Humalog Mix75/25, Humalog
105
Mix50/50, and insulin lispro protamine suspension (NPL component).
106
Figure 3 is a comparison of the time activity profiles of Humalog Mix50/50 (see Figure 3a) and
107
of Humulin 50/50 (see Figure 3b) from two different studies.
108
Special Populations
109
Age and Gender — Information on the effect of age on the pharmacokinetics of Humalog
110
Mix50/50 is unavailable. Pharmacokinetic and pharmacodynamic comparisons between men and
111
women administered Humalog Mix50/50 showed no gender differences. In large Humalog
112
clinical trials, sub-group analysis based on age and gender demonstrated that differences between
113
Humalog and Regular human insulin in postprandial glucose parameters are maintained across
114
sub-groups.
115
Smoking — The effect of smoking on the pharmacokinetics and pharmacodynamics of
116
Humalog Mix50/50 has not been studied.
117
Pregnancy — The effect of pregnancy on the pharmacokinetics and pharmacodynamics of
118
Humalog Mix50/50 has not been studied.
119
Obesity — The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics
120
and pharmacodynamics of Humalog Mix50/50 has not been studied. In large clinical trials,
121
which included patients with Body Mass Index up to and including 35 kg/m2, no consistent
122
differences were observed between Humalog and Humulin® R with respect to postprandial
123
glucose parameters.
124
Renal Impairment — The effect of renal impairment on the pharmacokinetics and
125
pharmacodynamics of Humalog Mix50/50 has not been studied. In a study of 25 patients with
126
type 2 diabetes and a wide range of renal function, the pharmacokinetic differences between
127
Humalog and Regular human insulin were generally maintained. However, the sensitivity of the
128
patients to insulin did change, with an increased response to insulin as the renal function
129
declined. Careful glucose monitoring and dose reductions of insulin, including Humalog
130
Mix50/50, may be necessary in patients with renal dysfunction.
Reference ID: 3252235
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
131
Hepatic Impairment — Some studies with human insulin have shown increased circulating
132
levels of insulin in patients with hepatic failure. The effect of hepatic impairment on the
133
pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. However,
134
in a study of 22 patients with type 2 diabetes, impaired hepatic function did not affect the
135
subcutaneous absorption or general disposition of Humalog when compared with patients with
136
no history of hepatic dysfunction. In that study, Humalog maintained its more rapid absorption
137
and elimination when compared with Regular human insulin. Careful glucose monitoring and
138
dose adjustments of insulin, including Humalog Mix50/50, may be necessary in patients with
139
hepatic dysfunction.
140
INDICATIONS AND USAGE
141
Humalog Mix50/50, a mixture of 50% insulin lispro protamine suspension and 50% insulin
142
lispro injection, (rDNA origin), is indicated in the treatment of patients with diabetes mellitus for
143
the control of hyperglycemia. Based on cross-study comparisons of the pharmacodynamics of
144
Humalog Mix50/50 and Humulin 50/50, it is likely that Humalog Mix50/50 has a more rapid
145
onset of glucose-lowering activity compared with Humulin 50/50 while having a similar duration
146
of action. This profile is achieved by combining the rapid onset of Humalog with the
147
intermediate action of insulin lispro protamine suspension.
148
CONTRAINDICATIONS
149
Humalog Mix50/50 is contraindicated during episodes of hypoglycemia and in patients
150
sensitive to insulin lispro or any of the excipients contained in the formulation.
151
WARNINGS
152
Humalog differs from Regular human insulin by its rapid onset of action as well as a
153
shorter duration of activity. Therefore, the dose of Humalog Mix50/50 should be given
154
within 15 minutes before a meal.
155
Hypoglycemia is the most common adverse effect associated with the use of insulins,
156
including Humalog Mix50/50. As with all insulins, the timing of hypoglycemia may differ
157
among various insulin formulations. Glucose monitoring is recommended for all patients
158
with diabetes.
159
Any change of insulin should be made cautiously and only under medical supervision.
160
Changes in insulin strength, manufacturer, type (e.g., Regular, NPH, analog), species, or
161
method of manufacture may result in the need for a change in dosage.
162
PRECAUTIONS
163
General
164
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated
165
with the use of all insulins. Because of differences in the action of Humalog Mix50/50 and other
166
insulins, care should be taken in patients in whom such potential side effects might be clinically
167
relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using
168
potassium-lowering drugs or patients taking drugs sensitive to serum potassium level).
169
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated
170
with the use of all insulins.
171
As with all insulin preparations, the time course of Humalog Mix50/50 action may vary in
172
different individuals or at different times in the same individual and is dependent on site of
173
injection, blood supply, temperature, and physical activity.
174
Adjustment of dosage of any insulin may be necessary if patients change their physical activity
175
or their usual meal plan. Insulin requirements may be altered during illness, emotional
176
disturbances, or other stress.
177
Hypoglycemia — As with all insulin preparations, hypoglycemic reactions may be associated
178
with the administration of Humalog Mix50/50. Rapid changes in serum glucose concentrations
Reference ID: 3252235
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6
179
may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value.
180
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
181
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
182
beta-blockers, or intensified diabetes control.
183
Renal Impairment — As with other insulins, the requirements for Humalog Mix50/50 may be
184
reduced in patients with renal impairment.
185
Hepatic Impairment — Although impaired hepatic function does not affect the absorption or
186
disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including
187
Humalog Mix50/50, may be necessary.
188
Allergy — Local Allergy — As with any insulin therapy, patients may experience redness,
189
swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to
190
a few weeks. In some instances, these reactions may be related to factors other than insulin, such
191
as irritants in the skin cleansing agent or poor injection technique.
192
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to
193
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
194
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
195
allergy, including anaphylactic reaction, may be life threatening. Localized reactions and
196
generalized myalgias have been reported with the use of cresol as an injectable excipient.
197
Antibody Production — In clinical trials, antibodies that cross-react with human insulin and
198
insulin lispro were observed in both human insulin mixtures and insulin lispro mixtures
199
treatment groups.
200
Information for Patients
201
Patients should be informed of the potential risks and advantages of Humalog Mix50/50 and
202
alternative therapies. Patients should not mix Humalog Mix50/50 with any other insulin. They
203
should also be informed about the importance of proper insulin storage, injection technique,
204
timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose
205
monitoring, periodic hemoglobin A1c testing, recognition and management of hypo- and
206
hyperglycemia, and periodic assessment for diabetes complications.
207
Patients should be advised to inform their physician if they are pregnant or intend to become
208
pregnant.
209
Refer patients to the Patient Information leaflet for information on normal appearance, timing
210
of dosing (within 15 minutes before a meal), storing, and common adverse effects.
211
For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read
212
the Patient Information leaflet that accompanies the drug product and the User Manual that
213
accompanies the delivery device and re-read them each time the prescription is renewed. Patients
214
should be instructed on how to properly use the delivery device, prime the Pen to a stream of
215
insulin, and properly dispose of needles. Patients should be advised not to share their Pens with
216
others.
217
Laboratory Tests
218
As with all insulins, the therapeutic response to Humalog Mix50/50 should be monitored by
219
periodic blood glucose tests. Periodic measurement of hemoglobin A1c is recommended for the
220
monitoring of long-term glycemic control.
221
Drug Interactions
222
Insulin requirements may be increased by medications with hyperglycemic activity such as
223
corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral
224
contraceptives, phenothiazines, and thyroid replacement therapy.
225
Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity
226
or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics,
Reference ID: 3252235
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7
227
certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme
228
inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of
229
pancreatic function (e.g., octreotide), and alcohol. Beta-adrenergic blockers may mask the
230
symptoms of hypoglycemia in some patients.
231
Carcinogenesis, Mutagenesis, Impairment of Fertility
232
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of
233
Humalog, Humalog Mix75/25, or Humalog Mix50/50. Insulin lispro was not mutagenic in a
234
battery of in vitro and in vivo genetic toxicity assays (bacterial mutation tests, unscheduled DNA
235
synthesis, mouse lymphoma assay, chromosomal aberration tests, and a micronucleus test).
236
There is no evidence from animal studies of impairment of fertility induced by insulin lispro.
237
Pregnancy
238
Teratogenic Effects — Pregnancy Category B — Reproduction studies with insulin lispro have
239
been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times,
240
respectively, the average human dose (40 units/day) based on body surface area. The results have
241
revealed no evidence of impaired fertility or harm to the fetus due to insulin lispro. There are,
242
however, no adequate and well-controlled studies with Humalog, Humalog Mix75/25, or
243
Humalog Mix50/50 in pregnant women. Because animal reproduction studies are not always
244
predictive of human response, this drug should be used during pregnancy only if clearly needed.
245
Nursing Mothers
246
It is unknown whether insulin lispro is excreted in significant amounts in human milk. Many
247
drugs, including human insulin, are excreted in human milk. For this reason, caution should be
248
exercised when Humalog Mix50/50 is administered to a nursing woman. Patients with diabetes
249
who are lactating may require adjustments in Humalog Mix50/50 dose, meal plan, or both.
250
Pediatric Use
251
Safety and effectiveness of Humalog Mix50/50 in patients less than 18 years of age have not
252
been established.
253
Geriatric Use
254
Clinical studies of Humalog Mix50/50 did not include sufficient numbers of patients aged 65
255
and over to determine whether they respond differently than younger patients. In general, dose
256
selection for an elderly patient should take into consideration the greater frequency of decreased
257
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this
258
population.
259
ADVERSE REACTIONS
260
Clinical studies comparing Humalog Mix50/50 with human insulin mixtures did not
261
demonstrate a difference in frequency of adverse events between the two treatments.
262
Adverse events commonly associated with human insulin therapy include the following:
263
Body as a Whole — allergic reactions (see PRECAUTIONS).
264
Skin and Appendages — injection site reaction, lipodystrophy, pruritus, rash.
265
Other — hypoglycemia (see WARNINGS and PRECAUTIONS).
266
OVERDOSAGE
267
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
268
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose.
269
Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes
270
with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
271
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation
272
may be necessary because hypoglycemia may recur after apparent clinical recovery.
Reference ID: 3252235
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8
273
DOSAGE AND ADMINISTRATION
274
275
276
Table 1*: Summary of Pharmacodynamic Properties of Insulin Products (Pooled Cross-
Study Comparison)
Insulin Products
Dose, U/kg
Time of Peak Activity,
Hours After Dosing
Percent of Total
Activity Occurring in
the First 4 Hours
Humalog
0.3
2.4
(0.8 - 4.3)
70%
(49 - 89%)
Humulin R
0.32
(0.26 - 0.37)
4.4
(4.0 - 5.5)
54%
(38 - 65%)
Humalog Mix75/25
0.3
2.6
(1.0 - 6.5)
35%
(21 - 56%)
Humulin 70/30
0.3
4.4
(1.5 - 16)
32%
(14 - 60%)
Humalog Mix50/50
0.3
2.3
(0.8 - 4.8)
45%
(27 - 69%)
Humulin 50/50
0.3
3.3
(2.0 - 5.5)
44%
(21 - 60%)
NPH
0.32
(0.27 - 0.40)
5.5
(3.5 - 9.5)
14%
(3.0 - 48%)
NPL component
0.3
5.8
(1.3 - 18.3)
22%
(6.3 - 40%)
277
* The information supplied in Table 1 indicates when peak insulin activity can be expected and the percent of the
278
total insulin activity occurring during the first 4 hours. The information was derived from 3 separate glucose clamp
279
studies in nondiabetic subjects. Values represent means, with ranges provided in parentheses.
280
281
Humalog Mix50/50 is intended only for subcutaneous administration. Humalog Mix50/50
282
should not be administered intravenously. Dosage regimens of Humalog Mix50/50 will vary
283
among patients and should be determined by the healthcare provider familiar with the patient’s
284
metabolic needs, eating habits, and other lifestyle variables. Humalog has been shown to be
285
equipotent to Regular human insulin on a molar basis. One unit of Humalog has the same
286
glucose-lowering effect as one unit of Regular human insulin, but its effect is more rapid and of
287
shorter duration. The quicker glucose-lowering effect of Humalog is related to the more rapid
288
absorption rate of insulin lispro from subcutaneous tissue.
289
Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed.
290
However, a cross-study comparison shown in Figure 3 suggests that Humalog Mix50/50 has a
291
duration of activity that is similar to Humulin 50/50.
292
The rate of insulin absorption and consequently the onset of activity are known to be affected
293
by the site of injection, exercise, and other variables. As with all insulin preparations, the time
294
course of action of Humalog Mix50/50 may vary considerably in different individuals or within
295
the same individual. Patients must be educated to use proper injection techniques.
296
Humalog Mix50/50 should be inspected visually before use. Humalog Mix50/50 should be
297
used only if it appears uniformly cloudy after mixing. Humalog Mix50/50 should not be used
298
after its expiration date.
299
HOW SUPPLIED
300
Humalog Mix50/50 [50% insulin lispro protamine suspension and 50% insulin lispro injection,
301
(rDNA origin)] is available in the following package sizes: each presentation containing 100
302
units insulin lispro per mL (U-100).
Reference ID: 3252235
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9
303
10 mL vials
NDC 0002-7512-01 (VL-7512)
5 x 3 mL prefilled insulin delivery devices (Pen)
NDC 0002-8793-59 (HP-8793)
5 x 3 mL prefilled insulin delivery devices (KwikPen™)
NDC 0002-8798-59 (HP-8798)
304
305
Storage — Humalog Mix50/50 should be stored in a refrigerator [2° to 8°C (36° to 46°F)], but
306
not in the freezer. Do not use Humalog Mix50/50 if it has been frozen. Unrefrigerated [below
307
30°C (86°F)] vials must be used within 28 days or be discarded, even if they still contain
308
Humalog Mix50/50. Unrefrigerated [below 30°C (86°F)] Pens, and KwikPens must be used
309
within 10 days or be discarded, even if they still contain Humalog Mix50/50. Protect from direct
310
heat and light. See table below:
311
Not In-Use (Unopened)
Room Temperature
[Below 30°C (86°F)]
Not In-Use (Unopened)
Refrigerated
In-Use (Opened) Room
Temperature [Below
30°C (86°F)]
10 mL Vial
28 days
Until expiration date
28 days,
refrigerated/room
temperature.
3 mL Pen and
KwikPen
(prefilled)
10 days
Until expiration date
10 days. Do not
refrigerate.
312
Literature revised Month dd, yyyy
313
KwikPens manufactured by
314
Eli Lilly and Company, Indianapolis, IN 46285, USA
315
Pens manufactured by
316
Eli Lilly and Company, Indianapolis, IN 46285, USA
317
Vials manufactured by
318
Eli Lilly and Company, Indianapolis, IN 46285, USA or
319
Lilly France, F-67640 Fegersheim, France
320
321
for Eli Lilly and Company, Indianapolis, IN 46285, USA
322
www.humalog.com
323
Copyright © 2007, yyyy Eli Lilly and Company. All rights reserved.
324
325
PRINTED IN USA
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
1
2
Patient Information
AAD_0018 NL 5573 AMP
3
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Humalog® (HU-ma-log) Mix50/50TM
50% insulin lispro protamine suspension and
50% insulin lispro injection (rDNA origin)
6
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by your
healthcare provider. Your insulin dose and the time you take your dose can change with different
types of insulin.
Make sure you have the right type and strength of insulin prescribed for you.
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8
Read the Patient Information that comes with Humalog Mix50/50 before you start using it and
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each time you get a refill. There may be new information. This leaflet does not take the place of
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talking with your healthcare provider about your diabetes or treatment. Make sure that you know
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how to manage your diabetes. Ask your healthcare provider if you have questions about
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managing your diabetes.
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What is Humalog Mix50/50?
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Humalog Mix50/50 is a mixture of fast-acting and longer-acting man-made insulins. Humalog
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Mix50/50 is used to control high blood sugar (glucose) in people with diabetes.
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Humalog Mix50/50 comes in:
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• 10 mL vials (bottles) for use with a syringe
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• Prefilled pens
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Who should not take Humalog Mix50/50?
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Do not take Humalog Mix50/50 if:
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• your blood sugar is too low (hypoglycemia). After treating your low blood sugar, follow
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your healthcare provider's instructions on the use of Humalog Mix50/50.
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• you are allergic to anything in Humalog Mix50/50. See the end of this leaflet for a
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complete list of ingredients in Humalog Mix50/50.
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Tell your healthcare provider:
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• about all your medical conditions. Medical conditions can affect your insulin needs and
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your dose of Humalog Mix50/50.
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• if you are pregnant or breastfeeding. You and your healthcare provider should talk about
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the best way to manage your diabetes while you are pregnant or breastfeeding. Humalog
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Mix50/50 has not been studied in pregnant or nursing women.
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• about all the medicines you take, including prescription and non-prescription
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medicines, vitamins and herbal supplements. Many medicines can affect your blood
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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sugar levels and insulin needs. Your Humalog Mix50/50 dose may need to change if you
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take other medicines.
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Know the medicines you take. Keep a list of your medicines with you to show to all of your
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healthcare providers.
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How should I use Humalog Mix50/50?
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Talk to your healthcare provider if you have any questions. Your healthcare provider will tell
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you the right syringes to use with Humalog Mix50/50 vials. Your healthcare provider should
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show you how to inject Humalog Mix50/50 before you start using it. Read the User Manual
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that comes with your Humalog Mix50/50 prefilled pen.
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• Use Humalog Mix50/50 exactly as prescribed by your healthcare provider.
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• Humalog Mix50/50 starts working faster than other insulins that contain regular
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human insulin. Inject Humalog Mix50/50 fifteen minutes or less before a meal. If you do
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not plan to eat within 15 minutes, delay the injection until the correct time (15 minutes
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before eating).
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• Check your blood sugar levels as told by your healthcare provider.
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• Mix Humalog Mix50/50 well before each use. For Humalog Mix50/50 in a vial, carefully
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shake or rotate the vial until completely mixed. For prefilled pens, carefully follow the
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User Manual for instructions on mixing the pen. Humalog Mix50/50 should be cloudy or
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milky after mixing well.
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• Look at your Humalog Mix50/50 before each injection. If it is not evenly mixed or has
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solid particles or clumps in it, do not use. Return it to your pharmacy for new Humalog
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Mix50/50.
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• Inject your dose of Humalog Mix50/50 under the skin of your stomach area, upper
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arm, upper leg, or buttocks. Never inject Humalog Mix50/50 into a muscle or vein.
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• Change (rotate) your injection site with each dose.
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• Your insulin needs may change because of:
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• illness
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• stress
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• other medicines you take
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• changes in eating
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• physical activity changes
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Follow your healthcare provider's instructions to make changes in your insulin dose.
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• Never mix Humalog Mix50/50 in the same syringe with other insulin products.
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• Never use Humalog Mix50/50 in an insulin pump.
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• Always carry a quick source of sugar to treat low blood sugar, such as glucose tablets,
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hard candy, or juice.
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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What are the possible side effects of Humalog Mix50/50?
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Low Blood Sugar (Hypoglycemia). Symptoms of low blood sugar include:
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• hunger
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• dizziness
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• feeling shaky or shakiness
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• lightheadedness
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• sweating
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• irritability
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• headache
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• fast heartbeat
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• confusion
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Low blood sugar symptoms can happen suddenly. Symptoms of low blood sugar may be
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different for each person and may change from time to time. Severe low blood sugar can cause
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seizures and death. Low blood sugar may affect your ability to drive a car or use mechanical
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equipment, risking injury to yourself or others. Know your symptoms of low blood sugar. Low
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blood sugar can be treated by drinking juice or regular soda or eating glucose tablets, sugar, or
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hard candy. Follow your healthcare provider's instructions for treating low blood sugar. Talk to
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your healthcare provider if low blood sugar is a problem for you.
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• Serious allergic reactions (whole body allergic reaction). Severe, life-threatening allergic
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reactions can happen with insulin. Get medical help right away if you develop a rash over
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your whole body, have trouble breathing, wheezing, a fast heartbeat, or sweating.
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• Reactions at the injection site (local allergic reaction). You may get redness, swelling,
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and itching at the injection site. If you keep having injection site reactions or they are
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serious, you need to call your healthcare provider. Do not inject insulin into a skin area that
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is red, swollen, or itchy.
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• Skin thickens or pits at the injection site (lipodystrophy). This can happen if you don't
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change (rotate) your injection sites enough.
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These are not all the side effects from Humalog Mix50/50. Ask your healthcare provider or
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pharmacist for more information.
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How should I store Humalog Mix50/50?
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• Store all unopened (unused) Humalog Mix50/50 in the original carton in a
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refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze.
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• Do not use Humalog Mix50/50 that has been frozen.
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• Do not use after the expiration date printed on the carton and label.
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• Protect Humalog Mix50/50 from extreme heat, cold or light.
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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After starting use (open):
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• Vials: Keep in the refrigerator or at room temperature below 86°F (30°C) for up to 28
111
days. Keep open vials away from direct heat or light. Throw away an opened vial 28 days
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after first use, even if there is insulin left in the vial.
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• Prefilled Pens: Do not store a prefilled pen that you are using in the refrigerator. Keep at
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room temperature below 86°F (30°C) for up to 10 days. Throw away a prefilled pen 10
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days after first use, even if there is insulin left in the pen.
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General information about Humalog Mix50/50
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Use Humalog Mix50/50 only to treat your diabetes. Do not share it with anyone else, even if
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they also have diabetes. It may harm them.
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This leaflet summarized the most important information about Humalog Mix50/50. If you would
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like more information about Humalog Mix50/50 or diabetes, talk with your healthcare provider.
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You can ask your healthcare provider or pharmacist for information about Humalog Mix50/50
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that is written for health professionals.
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For questions you may call 1-800-LillyRx (1-800-545-5979) or visit www.humalog.com.
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What are the ingredients in Humalog Mix50/50?
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Active ingredients: insulin lispro protamine suspension and insulin lispro.
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Inactive ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol, zinc
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oxide (zinc ion), phenol and water for injection.
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Patient Information issued/revised Month DD, YYYY
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KwikPens manufactured by
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Eli Lilly and Company, Indianapolis, IN 46285, USA
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Pens manufactured by
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Eli Lilly and Company, Indianapolis, IN 46285, USA
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Vials manufactured by
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Eli Lilly and Company, Indianapolis, IN 46285, USA or
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Lilly France, F-67640 Fegersheim, France
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for Eli Lilly and Company, Indianapolis, IN 46285, USA
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www.humalog.com
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Copyright © 200X, Eli Lilly and Company. All rights reserved.
AAD_0018 NL 5573 AMP
PRINTED IN USA
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Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A2.0 NL 8971 AMP
Instructions for Use
HUMALOG® Mix50/50™ KwikPen™
50% insulin lispro protamine suspension and
50% insulin lispro injection (rDNA origin) usage illustration
Read the Instructions for Use before you start taking HUMALOG Mix50/50 and each
time you get a refill. There may be new information. This information does not take
the place of talking to your healthcare provider about your medical condition or your
treatment.
HUMALOG® Mix50/50™ KwikPen™ (“Pen”) is a disposable pen containing 3 mL
(300 units) of U-100 HUMALOG® Mix50/50™ [50% insulin lispro protamine
suspension and 50% insulin lispro injection (rDNA origin)] insulin. You can inject from
1 to 60 units in a single injection.
Do not share your HUMALOG Mix50/50 KwikPen or needles with anyone
else. You may give an infection to them or get an infection from them.
This Pen is not recommended for use by the blind or visually impaired
without the assistance of a person trained in the proper use of the product. usage illustration
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Supplies you will need to give your HUMALOG Mix50/50 injection:
HUMALOG Mix50/50 KwikPen
HUMALOG Mix50/50 KwikPen compatible needle (Becton, Dickinson and
Company Pen Needles recommended)
Alcohol swab
Preparing HUMALOG Mix50/50 KwikPen:
Wash your hands with soap and water.
Check the HUMALOG Mix50/50 KwikPen Label to make sure you are taking the
right type of insulin. This is especially important if you use more than 1 type of
insulin.
Do not use HUMALOG Mix50/50 past the expiration date printed on the Label.
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Step 1:
Pull the Pen Cap straight off.
Wipe the Rubber Seal with an alcohol
swab.
Do not twist the cap.
Do not remove the KwikPen Label. usage illustration
Step2:
Gently roll the Pen ten times.
Invert the Pen ten times.
HUMALOG Mix50/50 should look white
and cloudy after mixing. Do not use if it
looks clear or contains any lumps or
particles. usage illustration
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 3:
Pull off the Paper Tab from Outer Needle
Shield. usage illustration
Step 4:
Push the capped Needle straight onto the
Pen and turn the Needle forward until it is
tight. usage illustration
Step 5:
Pull off the Outer Needle Shield. Do not
throw it away.
Pull off the Inner Needle Shield and throw
it away. usage illustration
Priming your HUMALOG Mix50/50 KwikPen:
Prime before each injection. Priming ensures the Pen is ready to dose and
removes air that may collect in the cartridge during normal use. If you do not prime
before each injection, you may get too much or too little insulin.
usage il
lustration
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 7:
Hold your Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top. usage illustration
Step 8:
Hold your Pen with Needle pointing up.
Push the Dose Knob in until it stops, and
“0” is seen in the Dose Window. Hold the
Dose Knob in and count to 5 slowly.
A stream of insulin should be seen
from the needle.
-
If you do not see a stream of
insulin, repeat steps 6 to 8, no
more than 4 times.
-
If you still do not see a stream
of insulin, change the needle
and repeat steps 6 to 8. usage illustration
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Selecting your dose:
Step 9:
Turn the Dose Knob to select the number
of units you need to inject. The Dose
Indicator should line up with your dose.
The dose can be corrected by
turning the Dose Knob in either
direction until the correct dose
lines up with the Dose Indicator.
The even numbers are printed on
the dial. The odd numbers, after
the number 1, are shown as full
lines.
(10 units shown)
(15 units shown)
The HUMALOG Mix50/50 KwikPen will not let you dial more than the number of
units left in the Pen.
If your dose is more than the number of units left in the Pen, you may either:
-
inject the amount left in your Pen and then use a new Pen to give the rest
of your dose, or
-
get a new Pen and inject the full dose.
The Pen is designed to deliver a total of 300 units of insulin. The cartridge
contains an additional small amount of insulin that can’t be delivered.
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Giving your HUMALOG Mix50/50 injection:
Inject your HUMALOG Mix50/50 as your healthcare provider has shown you.
Change (rotate) your injection site for each injection.
Do not try to change your dose while injecting HUMALOG Mix50/50.
Step 10:
Choose your injection site.
HUMALOG Mix50/50 is injected under the
skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper arms.
Wipe the skin with an alcohol swab, and
let the injection site dry before you inject
your dose. usage illustration
Step 11:
Insert the Needle into your skin. usage illustration
Step 12:
Put your thumb on the Dose Knob and
push the Dose Knob in until it stops. Hold
the Dose Knob in and slowly count to 5. usage illustration
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 13:
Pull the Needle out of your skin.
You should see “0” in the Dose Window.
If you do not see “0” in the Dose Window,
you did not receive your full dose.
If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of gauze
or an alcohol swab. Do not rub the area.
A drop of insulin at the needle tip is
normal. It will not affect your dose.
If you do not think you received your
full dose, do not take another dose.
Call Lilly or your healthcare provider for
assistance. usage illustration
Step 14:
Carefully replace the Outer Needle Shield. usage illustration
Step 15:
Unscrew the capped Needle and throw it
away.
Do not store the Pen with the Needle
attached to prevent leaking, blocking of
the Needle, and air from entering the
Pen. usage illustration
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 16:
Replace the Pen Cap by lining up the Cap
Clip with the Dose Indicator and pushing
straight on. usage illustration
After your injection:
Put your used needles and pens in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and pens in
your household trash.
If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
- made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
- upright and stable during use,
- leak-resistant, and
- properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and pens. For more information about safe sharps disposal, and
for specific information about sharps disposal in the state that you live in, go to
the FDA’s website at: http://www.fda.gov/safesharpsdisposal
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store my HUMALOG Mix50/50 KwikPen?
Store unused HUMALOG Mix50/50 Pens in the refrigerator at 36°F to 46°F (2°C
to 8°C). The Pen you are currently using can be stored out of the refrigerator
below 86°F (30°C).
Do not freeze HUMALOG Mix50/50. Do not use HUMALOG Mix50/50 if it has
been frozen.
Unused HUMALOG Mix50/50 Pens may be used until the expiration date
printed on the Label, if kept in the refrigerator.
The HUMALOG Mix50/50 Pen you are using should be thrown away after 10
days, even if it still has insulin left in it.
Keep HUMALOG Mix50/50 away from heat and out of the light.
General information about the safe and effective use of HUMALOG Mix50/50
KwikPen
Keep HUMALOG Mix50/50 KwikPen and needles out of the reach of
children.
Do not use your Pen if any part looks broken or damaged.
Always carry an extra Pen in case yours is lost or damaged.
If you can not remove the Pen Cap, gently twist the Pen Cap back and forth,
and then pull the Pen Cap straight off.
If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and
get a new one.
-
It may help to push the Dose Knob more slowly during your injection.
Use the space below to keep track of how long you should use each HUMALOG
Mix50/50 KwikPen.
-
Write down the date you start using your HUMALOG Mix50/50 KwikPen.
Count forward 10 days.
-
Write down the date you should throw it away.
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Humalog Mix50/50 KwikPen meets the current dose accuracy and functional
requirements of ISO 11608-1:2000.
A2.0 NL 8971 AMP
Example:
Pen 1 - First used on _______ +
10 days = Throw out on ______
Date
Date
Pen 1 - First used on _______ Throw out on _______
Date
Date
Pen 2 - First used on _______ Throw out on _______
Date
Date
Pen 3 - First used on _______ Throw out on _______
Date
Date
Pen 4 - First used on _______ Throw out on _______
Date
Date
Pen 5 - First used on _______ Throw out on _______
Date
Date
If you have any questions or problems with your HUMALOG Mix50/50 KwikPen,
contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for
help. For more information on HUMALOG Mix50/50 KwikPen and insulin, go to
www.humalog.com.
These Instructions for Use have been approved by the U.S. Food and Drug
Administration.
Humalog® Mix50/50™ and Humalog® Mix50/50™ KwikPen™ are trademarks of Eli
Lilly and Company.
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2007, 2012, Eli Lilly and Company. All rights reserved.
Revised: Month Day, Year
Reference ID: 3252235
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:29.014532 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021018s077lbl.pdf', 'application_number': 21018, 'submission_type': 'SUPPL ', 'submission_number': 77} |
3,955 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog
safely and effectively. See full prescribing information for NovoLog.
NovoLog® (insulin aspart [rDNA origin] injection)
solution for subcutaneous use
Initial U.S. Approval: 2000
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Warnings and Precautions (5.1)
02/2015
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• The dosage of NovoLog must be individualized.
• Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
• Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
• Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL
to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion
bags. NovoLog has been shown to be stable in infusion fluids such as 0.9%
sodium chloride (2.4).
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
Each presentation contains 100 Units of insulin aspart per mL (U-100)
• 10 mL vials (3)
• 3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
• 3 mL NovoLog FlexPen® (3)
• 3 mL NovoLog FlexTouch® (3)
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Do not use during episodes of hypoglycemia (4).
• Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Never share a NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge,
or Penfill cartridge compatible insulin delivery device between patients,
even if the needle is changed (5.1).
• Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under medical
supervision (5.2, 5.3).
• Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.4).
• Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.5, 5.6).
• Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.7).
• Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin,
including NovoLog (5.11).
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DRUG INTERACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may
be needed. (7.1, 7.2, 7.3)
• Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (7.3, 7.4)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 02/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
8
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
10
5
WARNINGS AND PRECAUTIONS
11
5.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill
12
Cartridge, or Penfill Cartridge Compatible Insulin Delivery Device
Between Patients
5.2 Administration
5.3 Hypoglycemia
13
5.4 Hypokalemia
5.5 Renal Impairment
5.6 Hepatic Impairment
14
5.7 Hypersensitivity and Allergic Reactions
5.8 Antibody Production
5.9 Mixing of Insulins
5.10 Continuous Subcutaneous Insulin Infusion by External Pump
5.11 Fluid retention and heart failure with concomitant use of PPAR-
16
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
17
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of
NovoLog
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering
Effect of NovoLog
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Gender
8.7 Renal Impairment
8.8 Hepatic Impairment
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
PATIENT COUNSELING INFORMATION
17.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch,
PenFill Cartridge, or Penfill Cartridge Device Between
Patients
17.2 Physician Instructions
17.3 Patients Using Pumps
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
17.4 FDA Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.9, 5.10), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
•
10 mL vials
•
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
•
3 mL NovoLog FlexPen
•
3 mL NovoLog FlexTouch
4
CONTRAINDICATIONS
NovoLog is contraindicated
•
during episodes of hypoglycemia
•
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill Cartridge, or
PenFill Cartridge Compatible Insulin Delivery Device Between Patients
NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge, and PenFill cartridge
compatible insulin delivery devices must never be shared between patients, even if the needle is
changed. Sharing poses a risk for transmission of blood-borne pathogens.
5.2
Administration
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.3
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.4
Hypokalemia
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
5.5
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Use in Specific Populations (8.7)].
5.6
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Use in Specific Populations (8.8)].
5.7
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.8
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.9
Mixing of Insulins
•
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
•
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
•
Insulin mixtures should not be administered intravenously.
5.10
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.9, 5.10), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.3)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.9, 5.10), How Supplied/Storage
and Handling (16.2), and Patient Counseling Information (17.3)].
5.11
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor
(PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated
with insulin, including NovoLog, and a PPAR-gamma agonist should be observed for signs and
symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be
considered.
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
•
Insulin initiation and glucose control intensification
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during post-approval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during post-approval use [see Patient Counseling Information (17)].
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with NovoLog use may be increased with antidiabetic
agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine,
monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin
analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of NovoLog
The glucose lowering effect of NovoLog may be decreased when co-administered with
atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens,
glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral
contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol,
epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose
monitoring may be required when NovoLog is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
NovoLog
The glucose lowering effect of NovoLog may be increased or decreased when co-administered
with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia,
Reference ID: 3733966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.4
Drugs That May Affect Hypoglycemia Signs and Symptoms
The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine,
guanethidine, and reserpine are co-administered with NovoLog.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age.
8.6
Gender
There was no significant difference in efficacy noted (as assessed by HbA1c) between
genders in a trial in patients with type 1 diabetes.
8.7
Renal Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with renal impairment [see Warnings and Precautions (5.5)].
8.8
Hepatic Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic impairment [see Warnings and Precautions (5.6)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8.
Reference ID: 3733966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset and a shorter duration of action than regular
human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (0.15 U/kg) (see
Figure 2). The duration of action for NovoLog is 3 to 5 hours. The time course of action of
insulin and insulin analogs such as NovoLog may vary considerably in different individuals or
within the same individual. The parameters of NovoLog activity (time of onset, peak time and
duration) as designated in Figure 2 should be considered only as general guidelines. The rate of
insulin absorption and onset of activity is affected by the site of injection, exercise, and other
variables [see Warnings and Precautions (5.2)].
Reference ID: 3733966
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graph
Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15
U/kg pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched
curve) injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
Reference ID: 3733966
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graph
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
Absorption -The single substitution of the amino acid proline with aspartic acid at
position B28 in NovoLog reduces the molecule's tendency to form hexamers as observed with
regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous
injection compared to regular human insulin (see Figure 4).
The relative bioavailability of NovoLog (0.15 U/kg) compared to regular human insulin
(0.15 U/kg) indicates that the two insulins are absorbed to a similar extent.
Reference ID: 3733966
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graph
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single 0.15 U/kg pre-meal dose of NovoLog (solid curve) or regular
human insulin (hatched curve) injected immediately before a meal in 22 patients
with type 1 diabetes.
In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 L/h/kg for the NovoLog group and 1.2 L/h/kg for the
regular human insulin group.
Specific Populations
Age: Pediatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade ≥ 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
Reference ID: 3733966
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Age: Geriatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were investigated in a single dose study in 18 subjects with
type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and
pharmacodynamics in geriatric patients with type 2 diabetes between NovoLog and regular
human insulin were similar to those in younger adults.
Gender: In healthy volunteers given single subcutaneous dose of Novolog 0.06 U/kg, no
difference in insulin aspart levels was seen between men and women based on comparison of
AUC(0-10h) or Cmax.
Obesity: A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2 .
Renal Impairment: Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal renal function (N=6)
creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3;
CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min)
renal impairment. In this small study, there was no apparent effect of creatinine clearance values
on AUC and Cmax of NovoLog.
Hepatic Impairment:- Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic impairment and any NovoLog pharmacokinetic
parameter.
The effect of ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
Reference ID: 3733966
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test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
Reference ID: 3733966
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Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
Reference ID: 3733966
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Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (97.5% confidence interval)
-0.2 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbA1c and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
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Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
Reference ID: 3733966
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Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human
insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.2 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
Reference ID: 3733966
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Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
Reference ID: 3733966
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Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.3, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
3 mL NovoLog FlexTouch
NDC 0169-6338-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles. FlexPen and FlexTouch can be used with
NovoFine or NovoTwist disposable needles. NovoLog FlexPen, NovoLog FlexTouch, PenFill
cartridge, and PenFill cartridge compatible insulin delivery devices must never be shared
between patients, even if the needle is changed.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
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Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or light. Opened vials may be refrigerated.
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen and NovoLog FlexTouch:
Once a cartridge or NovoLog FlexPen or NovoLog FlexTouch is punctured, it should be
kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to
excessive heat or sunlight. A NovoLog FlexPen or NovoLog FlexTouch or cartridge in use must
NOT be stored in the refrigerator. Keep the NovoLog FlexPen or NovoLog FlexTouch and all
PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog FlexPen or
NovoLog FlexTouch and PenFill cartridges can be used until the expiration date printed on the
label if they are stored in a refrigerator. Keep unused NovoLog FlexPen or NovoLog FlexTouch
and PenFill cartridges in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen or NovoLog FlexTouch without a needle attached.
This prevents contamination and/or infection, or leakage of insulin, and will ensure
accurate dosing. Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges, NovoLog FlexPen, and NovoLog
FlexTouch
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30°C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexTouch
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
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NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
Storage of NovoLog in Infusion Fluids
Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA Approved Patient Labeling (17.4)]
17.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill Cartridge, or PenFill
Cartridge Device Between Patients
Advise patients that they must never share a NovoLog FlexPen, NovoLog FlexTouch,
PenFill cartridge or PenFill cartridge compatible insulin delivery device with another person,
even if the needle is changed, because doing so carries a risk for transmission of blood-borne
pathogens.
17.2 Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
Patients should receive proper training on how to use NovoLog. Instruct patients that
when injecting NovoLog, they must press and hold down the dose button until the dose counter
shows 0 and then keep the needle in the skin and count slowly to 6. When the dose counter
returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is
removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose
will not be delivered (a possible under-dose may occur by as much as 20%), and they should
increase the frequency of checking their blood glucose levels and possible additional insulin
administration may be necessary.
• If 0 does not appear in the dose counter after continuously pressing the dose button, the
patient may have used a blocked needle. In this case they would not have received any
insulin – even though the dose counter has moved from the original dose that was set.
Reference ID: 3733966
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• If the patient did have a blocked needle, instruct them to change the needle as described
in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with
Section 1: Prepare your pen with a new needle. Make sure the patient selects the full
dose needed.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.3
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
Medtronic Paradigm® 512 a nd 712
MiniMed 508
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
Reference ID: 3733966
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disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.4
FDA Approved Patient Labeling
See separate leaflet.
Rx only
Date of Issue: February 2015
Version: XX
Novo Nordisk®, NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, FlexTouch®, PenMate® ,
NovoFine®, and NovoTwist® are registered trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent No. 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. RE 41,956, 6,004,297, RE 43,834, and other patents
pending.
FlexTouch® pen is covered by US Patent Nos. 7,686,786, 6,899,699, and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
†The brands listed are the registered trademarks of their respective owners and are not
trademarks of Novo Nordisk A/S.
© 2002-2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] injection)
Do not share your NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge or PenFill cartridge compatible insulin
delivery device with other people, even if the needle has been changed. You may give other people a serious
infection, or get a serious infection from them.
What is NovoLog?
• NovoLog is a man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.
Who should not take NovoLog?
Do not take NovoLog if you:
•
are having an episode of low blood sugar (hypoglycemia).
•
have an allergy to NovoLog or any of the ingredients in NovoLog.
Before taking NovoLog, tell your healthcare provider about all your medical conditions including, if you are:
•
pregnant, planning to become pregnant, or are breastfeeding.
•
taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.
Before you start taking NovoLog, talk to your healthcare provider about low blood sugar and how to manage it.
How should I take NovoLog?
•
Read the Instructions for Use that come with your NovoLog.
•
Take NovoLog exactly as your healthcare provider tells you to.
•
NovoLog starts acting fast. You should eat a meal within 5 to 10 minutes after you take your dose of NovoLog.
•
Know the type and strength of insulin you take. Do not change the type of insulin you take unless your healthcare
provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take
different types of insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should
check your blood sugar levels.
•
Do not reuse or share your needles with other people. You may give other people a serious infection or get a serious
infection from them.
What should I avoid while taking NovoLog?
While taking NovoLog do not:
•
Drive or operate heavy machinery, until you know how NovoLog affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of NovoLog?
NovoLog may cause serious side effects that can lead to death, including:
Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
•
dizziness or light-headedness
●
blurred vision
●
anxiety, irritability, or mood changes
•
sweating
●
slurred speech
●
hunger
•
confusion
●
shakiness
●
headache
●
fast heart beat
Your insulin dose may need to change because of:
•
change in level of physical activity or exercise
●
increased stress
●
change in diet
•
weight gain or loss
●
illness
Other common side effects of NovoLog may include:
•
low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole
body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and
feet.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme
drowsiness, dizziness, confusion.
These are not all the possible side effects of NovoLog. Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of NovoLog.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your
pharmacist or healthcare provider for information about NovoLog that is written for health professionals. Do not use NovoLog
for a condition for which it was not prescribed. Do not give NovoLog to other people, even if they have the same symptoms
that you have. It may harm them.
What are the ingredients in NovoLog?
Active Ingredient: insulin aspart (rDNA origin)
Inactive Ingredients: glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride and
water for injection
Manufactured by: Novo Nordisk A/S; DK-2880 Bagsvaerd, Denmark
For more information, go to www.novonordisk-us.com or call 1-800-727-6500.
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 04/2015
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
NovoLog® FlexPen®
Introduction
Please read the following instructions carefully before using your NovoLog® FlexPen® .
Do not share your NovoLog FlexPen with other people, even if the needle has been changed. You
may give other people a serious infection, or get a serious infection from them.
NovoLog FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to 60 units in
increments of 1 unit. NovoLog FlexPen is designed to be used with NovoFine®, NovoFine® Plus or
NovoTwist® needles.
NovoLog FlexPen should not be used by people who are blind or have severe visual problems
without the help of a person who has good eyesight and who is trained to use the NovoLog FlexPen
the right way.
Getting ready
Make sure you have the following items:
•
NovoLog FlexPen
•
New NovoFine, NovoFine Plus or NovoTwist needle
•
Alcohol swab usage illustration
Reference ID: 3733966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparing your NovoLog FlexPen
Wash your hands with soap and water. Before you start to prepare your injection, check the
label to make sure that you are taking the right type of insulin. This is especially important if
you take more than 1 type of insulin. NovoLog should look clear.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustration
B. Attaching the needle
Remove the protective tab from a disposable needle.
Screw the needle tightly onto your FlexPen. It is important that the needle is
put on straight (see diagram B).
Never place a disposable needle on your NovoLog FlexPen until you are
ready to take your injection.
C. Pull off the big outer needle cap (see diagram C).
usage illu
stration
D. Pull off the inner needle cap and dispose of it (see diagram D).
usage illu
stration
Always use a new needle for each injection to help ensure sterility and prevent blocked needles. Do
not reuse or share your needles with other people. You may give other people a serious infection, or
get a serious infection from them.
Be careful not to bend or damage the needle before use.
To reduce the risk of unexpected needle sticks, never put the inner needle cap back on the
needle.
Giving the airshot before each injection
Before each injection small amounts of air may collect in the cartridge during normal use. To avoid
injecting air and to ensure proper dosing:
Reference ID: 3733966
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E. Turn the dose selector to select 2 units (see diagram E). usage illustration
F. Hold your NovoLog FlexPen with the needle pointing up. Tap the cartridge
gently with your finger a few times to make any air bubbles collect at the top of
the cartridge (see diagram F).
G. Keep the needle pointing upwards, press the push-button all the way in
(see diagram G). The dose selector returns to 0.
A drop of insulin should appear at the needle tip. If not, change the needle
and repeat the procedure no more than 6 times.
If you do not see a drop of insulin after 6 times, do not use the NovoLog
FlexPen and contact Novo Nordisk at 1-800-727-6500.
A small air bubble may remain at the needle tip, but it will not be injected.
Selecting your dose
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to inject. The
pointer should line up with your dose.
The dose can be corrected either up or down by turning the dose selector in
either direction until the correct dose lines up with the pointer (see diagram H).
When turning the dose selector, be careful not to press the push-button as
insulin will come out.
You cannot select a dose larger than the number of units left in the cartridge.
You will hear a click for every single unit dialed. Do not set the dose by
counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to measure your
dose of insulin.
Giving the injection
Do the injection exactly as shown to you by your healthcare provider. Your healthcare provider
should tell you if you need to pinch the skin before injecting.
Novolog can be injected under the skin (subcutaneously) or your stomach area, buttocks, upper
legs (thighs), or upper arms.
For each injection, change (rotate) your injection site within the area of skin that you use. Do
not use the same injection site for each injection.
Reference ID: 3733966 usage illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until the 0 lines up with
the pointer (see diagram I). Be careful only to push the button when injecting.
Turning the dose selector will not inject insulin.
J. Keep the needle in the skin for at least 6 seconds, and keep the push-
button pressed all the way in until the needle has been pulled out from the
skin (see diagram J). This will make sure that the full dose has been given.
You may see a drop of insulin at the needle tip. This is normal and has no
effect on the dose you just received. If blood appears after you take the
needle out of your skin, press the injection site lightly with a finger. Do not usage illustration
rub the area.
After the injection
Do not recap the needle. Recapping can lead to a needle stick injury. Remove the needle
from the NovoLog FlexPen after each injection and dispose of it. This helps to prevent
infection, leakage of insulin, and will help to make sure you inject the right dose of insulin. If
you do not have a sharps container, carefully slip the needle into the outer needle cap. Safely
remove the needle and throw it away as soon as you can.
•
Put your used NovoLog FlexPen and needles in a FDA-cleared sharps disposal container
right away after use. Do not throw away (dispose of) loose needles and Pens in your
household trash.
•
If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to
come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be
state or local laws about how you should throw away used needles and syringes. For more
information about the safe sharps disposal, and for specific information about sharps
disposal in the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
The NovoLog FlexPen prevents the cartridge from being completely emptied. It is designed to deliver
300 units.
K. Put the pen cap on the NovoLog FlexPen and store the NovoLog FlexPen
without the needle attached (see diagram K). Storing without the needle
attached helps prevent leaking, blocking of the needle, and air from entering
the Pen. usage illustration
Reference ID: 3733966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store NovoLog FlexPen?
• Store unused NovoLog FlexPen in the refrigerator at 36°F to 46°F (2°C to 8°C).
• Store the FlexPen you are currently using out of the refrigerator below 86°F (30°C) for up to
28 days.
• Do not freeze NovoLog. Do not use NovoLog if it has been frozen.
• Keep NovoLog away from heat or light.
• Unused FlexPen may be used until the expiration date printed on the label, if kept in the
refrigerator.
• The NovoLog FlexPen you are using should be thrown away after 28 days, even if it still has
insulin left in it.
Maintenance
For the safe and proper use of your FlexPen be sure to handle it with care. .
Avoid dropping
your FlexPen as it may damage it. If you are concerned that your FlexPen is damaged, use a
new one. You can clean the outside of your FlexPen by wiping it with a damp cloth. Do not
soak or wash your FlexPen as it may damage it. Do not refill your FlexPen.
Remove the needle from the NovoLog FlexPen after each injection. This helps to ensure
sterility, prevent leakage of insulin, and will help to make sure you inject the right dose of
insulin for future injections.
Be careful when handling used needles to avoid needle sticks and transfer of infectious
diseases.
Keep your NovoLog FlexPen and needles out of the reach of children.
Use NovoLog FlexPen as directed to treat your diabetes.
Do not share your Novolog FlexPen or needles with other people. You may give other people a
serious infection, or get a serious infection from them.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with products not
recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device in case your
NovoLog FlexPen is lost or damaged.
Remember to keep the disposable NovoLog FlexPen with you. Do not leave it in a car or
other location where it can get too hot or too cold.
This Instructions for Use has been approved by the U.S. Food and Drug Administration
Revised: 04/2015
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® (NŌ-vō-log) FlexTouch® Pen
(insulin aspart [rDNA origin] injection)
• Do not share your NovoLog FlexTouch Pen with other people, even
if the needle has been is changed. You may give other people a
serious infection, or get a serious infection from them.
• NovoLog FlexTouch Pen (“Pen”) is a prefilled disposable pen
containing 300 units of U-100 NovoLog (insulin aspart [rDNA origin]
injection) insulin. You can inject from 1 to 80 units in a single injection.
• This Pen is not recommended for use by the blind or visually
impaired without the assistance of a person trained in the proper
use of the product.
Supplies you will need to give your NovoLog injection:
• NovoLog FlexTouch Pen
• a new NovoFine, NovoFine Plus or NovoTwist needle
• alcohol swab
• 1 sharps container for throwing away used Pens and needles. See
“Disposing of used NovoLog FlexTouch Pens and needles” at the
end of these instructions.
Preparing your NovoLog FlexTouch Pen:
• Wash your hands with soap and water.
• Before you start to prepare your injection, check the NovoLog
FlexTouch Pen label to make sure you are taking the right type of
insulin. This is especially important if you take more than 1 type of
insulin.
• NovoLog should look clear and colorless. Do not use NovoLog if it is thick,
cloudy, or is colored.
• Do not use NovoLog past the expiration date printed on the label or 28
days after you start using the Pen.
• Always use a new needle for each injection to help ensure sterility and
prevent blocked needles. Do not reuse or share your needles with
other people. You may give other people a serious infection, or get
a serious infection from them.
Reference ID: 3733966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
age illustration
usage
illustratio
n
(Figure A)
Step 1:
•
Pull Pen cap straight off (See Figure
B).
Reference ID: 3733966
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u
s
age illustration
Step 2:
•
Check the liquid in the Pen (See
Figure C). NovoLog should look clear
and colorless. Do not use it if it looks
cloudy or colored.
Step 3:
•
Select a new needle.
•
Pull off the paper tab from the outer
needle cap (See Figure D).
Step 4:
•
Push the capped needle straight onto
the Pen and twist the needle on until
it is tight (See Figure E).
Step 5:
•
Pull off the outer needle cap. Do not
throw it away (See Figure F).
Step 6:
•
Pull off the inner needle cap and
throw it away (See Figure G).
Priming your NovoLog FlexTouch Pen:
Step 7:
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u
s
a
g
e illustration
•
Turn the dose selector to select 2
units (See Figure H).
Step 8:
•
Hold the Pen with the needle pointing
up. Tap the top of the Pen gently a
few times to let any air bubbles rise to
the top (See Figure I).
Step 9:
•
Hold the Pen with the needle
pointing up. Press and hold in the
dose button until the dose counter
shows “0”. The “0” must line up with
the dose pointer.
•
A drop of insulin should be seen at the
needle tip (See Figure J).
o If you do not see a drop of insulin,
repeat steps 7 to 9, no more than
6 times.
o If you still do not see a drop of
insulin, change the needle and
repeat steps 7 to 9.
Selecting your dose:
Reference ID: 3733966
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Step 10:
•
Turn the dose selector to select
the number of units you need to
inject. The dose pointer should line
up with your dose (See Figure K).
o If you select the wrong dose,
you can turn the dose selector
forwards or backwards to the
correct dose.
o The even numbers are printed
on the dial.
o The odd numbers are shown as
lines.
5 units
selected
24 units
selected
Examples
(Figure K)
•
The NovoLog FlexTouch Pen insulin
scale will show you how much
insulin is left in your Pen (See
Figure L).
Example|
Approx.
200 units
left
(Figure L)
•
To see how much insulin is left
in your NovoLog FlexTouch Pen:
o Turn the dose selector until it
stops. The dose counter will line
up with the number of units of
insulin that is left in your Pen. If
the dose counter shows 80,
there are at least 80 units left
in your Pen.
o If the dose counter shows less
than 80, the number shown in
the dose counter is the number
of units left in your Pen.
Giving your injection:
• Inject your NovoLog exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Reference ID: 3733966
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• NovoLog can be injected under the skin (subcutaneously) of your stomach
area (abdomen), buttocks, upper legs (thighs) or upper arms.
• For each injection, change (rotate) your injection site within the area of
skin that you use. Do not use the same injection site for each injection.
Step 11:
•
Choose your injection site and wipe
the skin with an alcohol swab. Let
the injection site dry before you
inject your dose (See Figure M).
(Figure M)
Step 12:
•
Insert the needle into your skin
(See Figure N).
o Make sure you can see the
dose counter. Do not cover it
with your fingers, this can stop
your injection.
(Figure N)
Step 13:
•
Press and hold down the dose
button until the dose counter
shows “0” (See Figure O).
o The “0” must line up with the
dose pointer. You may then hear
or feel a click.
(Figure O)
•
Keep the needle in your skin
after the dose counter has
returned to “0” and slowly count
to 6 (See Figure P).
o When the dose counter
returns to “0”, you will not
get your full dose until 6
seconds later.
o If the needle is removed
before you count to 6, you
may see a stream of insulin
coming from the needle tip.
o If you see a stream of insulin
coming from the needle tip
you will not get your full
dose. If this happens you
Count slowly:
(Figure P)
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should check your blood
sugar levels more often
because you may need more
insulin.
Step 14:
•
Pull the needle out of your skin
(See Figure Q).
o If you see blood after you take
the needle out of your skin,
press the injection site lightly
with a piece of gauze or an
alcohol swab. Do not rub the
area.
(Figure Q)
Step 15:
•
Carefully remove the needle
from the Pen and throw it away
(See Figure R).
o Do not recap the needle.
Recapping the needle can lead
to needle stick injury.
•
If you do not have a sharps
container, carefully slip the needle
into the outer needle cap (See
Figure S). Safely remove the needle
and throw it away as soon as you
can.
o Do not store the Pen with the
needle attached. Storing without
the needle attached helps
prevent leaking, blocking of the
needle, and air from entering
the Pen.
NovoFine®
NovoFine® Plus
NovoTwist®
(Figure R)
(Figure S)
Step 16:
•
Replace the Pen cap by pushing it
straight on (See Figure T).
(Figure T)
After your injection:
• You can put your used NovoLog FlexTouch Pen and needles in a FDA-
cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and Pens in your household trash.
Reference ID: 3733966
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of your sharps
disposal container. There may be state or local laws about how you should
throw away used needles and syringes. Do not reuse or share your
needles or syringes with other people. For more information about safe
sharps disposal, and for specific information about sharps disposal in the
state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your
used sharps disposal container.
How should I store my NovoLog FlexTouch Pen?
• Store unused NovoLog FlexTouch Pens in the refrigerator at 36OF to 46OF
(2OC to 8OC).
• Store the Pen you are currently using out of the refrigerator below 86OF.
• Do not freeze NovoLog. Do not use NovoLog if it has been frozen.
• Keep NovoLog away from heat or light.
• Unused Pens may be used until the expiration date printed on the label, if
kept in the refrigerator.
• The NovoLog FlexTouch Pen you are using should be thrown away after 28
days, even if it still has insulin left in it.
General Information about the safe and effective use of NovoLog.
• Keep NovoLog FlexTouch Pens and needles out of the reach of
children.
• Always use a new needle for each injection.
• Do not share your Novolog FlexTouch Pens or needles with other people.
You may give other people a serious infection, or get a serious infection
from them.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DK-2880 Bagsvaerd, Denmark
Revised: 02/2015 company logo
For more information go to
www.novotraining.com/novologflextouch/us02
© 2002-2015 Novo Nordisk
NovoLog®
FlexTouch®
Read before first use
Reference ID: 3733966
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Instructions for Use
NovoLog® 3 mL PenFill® cartridge (100 Units/mL, U-100)
Do not share your Penfill cartridge or Penfill cartridge compatible insulin
delivery device with other people, even if the needle has been changed.
You may give other people a serious infection, or get a serious infection
from them.
Before using the NovoLog® cartridge
1. Talk with your healthcare provider for information about where to inject
NovoLog® (injection sites) and how to give an injection with your insulin
delivery device.
2. Read the instruction manual that comes with your insulin delivery
device for complete instructions on how to use the PenFill® cartridge
with the device.
How to use the NovoLog® cartridge
1. Check your insulin. Just before using your NovoLog® cartridge,
check to make sure that you have the right type of insulin. This is
especially important if you use different types of insulin.
2. Carefully look at the cartridge and the insulin inside it. The insulin
should be clear and colorless. The tamper-resistant foil should be in
place before the first use. If the foil has been broken or removed before
your first use of the cartridge, or if the insulin is cloudy or colored, do
not use it. Call Novo Nordisk at 1-800-727-6500.
3. Wash your hands well with soap and water. If you clean your injection
site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider for guidance on injection sites and
how to give an injection with your insulin delivery device.
4. Gather your supplies for injecting NovoLog® .
5. Insert a 3 mL cartridge into your Novo Nordisk 3 mL PenFill® cartridge
compatible insulin delivery device. Wipe the front rubber stopper of the
3 mL PenFill® cartridge with an alcohol swab, then attach a new
needle. For NovoFine® needles, remove the big outer needle cap and
the inner needle cap. Always use a new needle for each injection to
prevent infection. Do not share your PenFill cartridge or Penfill
cartridge compatible insulin delivery device with other people, even if
the needle has been changed. You may give other people a serious
infection, or get a serious infection from them.
Giving the airshot before each injection:
To prevent the injection of air and to make sure insulin is delivered, you must do
an airshot before each injection. Hold the device with the needle pointing up and
gently tap the PenFill® cartridge holder with your finger a few times to raise any
air bubbles to the top of the cartridge. Do the airshot as described in the device
instruction manual.
Reference ID: 3733966
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Giving the injection
6. Dial the number of units on the insulin delivery device that you need to
inject. Inject the right way as shown to you by your healthcare provider.
7. Insert the needle into the skin. Inject the dose by pressing the push
button all the way in. Keep the needle in the skin for at least 6
seconds, and keep the push button pressed all the way in until the
needle has been pulled out from the skin. This will make sure that the
full dose has been given. You may see a drop of NovoLog® at the
needle tip. This is normal and has no effect on the dose you just
received. If blood appears after you take the needle out of your skin,
press the injection site lightly with a finger. Do not rub the area.
After the injection
8. Do not recap the needle. Recapping can lead to a needle stick injury.
9. Remove the needle from the PenFill® cartridge after each injection.
Keep the 3 mL PenFill® cartridge in the insulin delivery device. The
needle should not be attached to the 3 mL PenFill® cartridge during
storage. This will prevent infection or leakage of insulin and will help
ensure that you receive the right dose of NovoLog® .
10. Put your used NovoLog Penfill cartridge and needles in a FDA-cleared
sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and Penfill cartridges in your household
trash.
• If you do not have a FDA-cleared sharps disposal container, you
may use a household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without
sharps being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to
follow your community guidelines for the right way to dispose of
your sharps disposal container. There may be state or local laws
about how you should throw away used needles and syringes. For
more information about the safe sharps disposal, and for specific
information about sharps disposal in the state that you live in, go to
the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your
household trash unless your community guidelines permit this. Do
not recycle your used sharps disposal container.
11.Put the pen cap back on the Novo Nordisk 3 mL PenFill® cartridge
compatible insulin delivery device.
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Date of Issue: February 2015
Version: XX
Novo Nordisk®, NovoLog®, PenFill®, and NovoFine® are registered trademarks of
Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
PenFill® is covered by US Patent No. 5,693,027.
© 2002-2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] injection)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® and each time you
get a refill. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your
treatment.
Supplies you will need to give your NovoLog® injection:
10 mL NovoLog® vial
insulin syringe and needle
alcohol swab usage illustration
Preparing your NovoLog® dose:
Wash your hands with soap and water.
Before you start to prepare your injection, check the NovoLog® label to make
sure that you are taking the right type of insulin. This is especially important
if you use more than 1 type of insulin.
NovoLog® should look clear and colorless. Do not use NovoLog® if it is thick,
cloudy, or is colored.
Do not use NovoLog® past the expiration date printed on the label. usage illustration
Reference ID: 3230591
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 1: Pull off the tamper resistant cap (See
Figure A).
Step 2: Wipe the rubber stopper with an alcohol
swab (See Figu
re B).
Step 3: Hold the syringe with the needle pointing
up. Pull down on the plunger until the black tip
reaches the line for the number of units for your
prescribed dose (See Figure C).
Step 4: Push the needle through the rubber
stopper of the NovoLog® vial (See Figure D).
.
Step 5: Push the plunger all the way in. This puts
air into the NovoLog® vial (See Figure E).
Step 6: Turn the NovoLog® vial and syringe upside
down and slowly pull the plunger down until the
black tip is a few units past the line for your dose
(See Figure F).
(Figure A Figure B)
(Figure C)
(Figure D)
(Figure E)
(Figure F)
Reference ID: 3230591
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top
(See Figure G).
Step 7: Slowly push the plunger up until the black
tip reaches the line for your NovoLog® dose (See
Figure H).
Step 8: Check the syringe to make sure you have
the right dose of NovoLog® .
Step 9: Pull the syringe out of the vial’s rubber
stopper (See Figure I).
u
s
a
g
e
illustratio
n
Giving your Injection:
Inject your NovoLog® exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
NovoLog® can be injected under the skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper arms, infused in an insulin pump, or given
through a needle in your arm (intravenously) by your healthcare provider.
If you inject NovoLog®, change (rotate) your injection sites within the area you
choose for each dose. Do not use the same injection site for each injection.
If you use NovoLog® in an insulin pump, you should change your insertion site
every 3 days. The insulin in the reservoir should be changed at least every 6
days even if you have not used all of the insulin.
Reference ID: 3230591
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 10: Choose your injection site and wipe the skin
an alcohol swab. Let the injection site dry before you
your dose (See Figure J).
Step 11: Insert the needle into your skin. Push
down on the plunger to inject your dose (See Figure
K). Needle should remain in the skin for at
least 6 seconds to make sure you have
injected all the insulin.
Step 12: Pull the needle out of your skin. After that,
you may see a drop of NovoLog® at the needle tip.
This is normal and does not affect the dose you
just received (See Figure L).
If you see blood after you take the needle out of
your skin, press the injection site lightly with a
piece of gauze or an alcohol swab. Do not rub
the area.
u
s
a
ge illustra
tion
If you use NovoLog® in an insulin pump, see your insulin pump manual for
instructions or talk to your healthcare provider.
NPH insulin is the only type of insulin that can be mixed with NovoLog® . Do not
mix NovoLog® with any other type of insulin.
NovoLog® should only be mixed with NPH insulin if it is going to be injected
right away under your skin (subcutaneously).
NovoLog® should be drawn up into the syringe before you draw up your NPH
insulin.
Talk to your healthcare provider if you are not sure about the right way to mix
NovoLog® and NPH insulin.
Reference ID: 3230591
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After your injection:
Do not recap the needle. Recapping the needle can lead to a needle stick
injury.
Throw away empty insulin vials, used syringes, and needles in a sharps
container or some type of hard plastic or metal container with a screw on cap
such as a detergent bottle or empty coffee can. Check with your healthcare
provider about the right way to throw away the container. There may be local
or state laws about how to throw away used syringes and needles. Do not
throw away used syringes and needles in household trash or recycling bins.
How should I store NovoLog®?
Do not freeze NovoLog® . Do not use NovoLog® if it has been frozen.
Keep NovoLog® away from heat or light.
Store opened and unopened NovoLog® vials in the refrigerator at 36OF to 46OF
(2OC to 8OC). Opened NovoLog® vials can also be stored out of the refrigerator
below 86OF (30OC).
Unopened vials may be used until the expiration date printed on the label, if
they are kept in the refrigerator.
Opened NovoLog® vials should be thrown away after 28 days, even if they still
have insulin left in them.
General information about the safe and effective use of NovoLog®
Always use a new syringe and needle for each injection.
Do not share syringes or needles.
Keep NovoLog® vials, syringes, and needles out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
NovoLog® is a registered trademark of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
© 2002-2012 Novo Nordisk Inc.
For information about NovoLog® contact:
Reference ID: 3230591
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Revised: December 2012
Reference ID: 3230591
Reference ID: 3733966
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:29.022616 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020986s082lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 82} |
3,954 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NovoLog
safely and effectively. See full prescribing information for NovoLog.
NovoLog® (insulin aspart [rDNA origin] injection)
solution for subcutaneous use
Initial U.S. Approval: 2000
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Warnings and Precautions (5.1)
02/2015
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• NovoLog is an insulin analog indicated to improve glycemic control in adults
and children with diabetes mellitus (1.1).
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• The dosage of NovoLog must be individualized.
• Subcutaneous injection: NovoLog should generally be given immediately
(within 5-10 minutes) prior to the start of a meal (2.2).
• Use in pumps: Change the NovoLog in the reservoir at least every 6 days,
change the infusion set, and the infusion set insertion site at least every 3 days.
NovoLog should not be mixed with other insulins or with a diluent when it is
used in the pump (2.3).
• Intravenous use: NovoLog should be used at concentrations from 0.05 U/mL
to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion
bags. NovoLog has been shown to be stable in infusion fluids such as 0.9%
sodium chloride (2.4).
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
Each presentation contains 100 Units of insulin aspart per mL (U-100)
• 10 mL vials (3)
• 3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3)
• 3 mL NovoLog FlexPen® (3)
• 3 mL NovoLog FlexTouch® (3)
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Do not use during episodes of hypoglycemia (4).
• Do not use in patients with hypersensitivity to NovoLog or one of its
excipients.
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Never share a NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge,
or Penfill cartridge compatible insulin delivery device between patients,
even if the needle is changed (5.1).
• Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under medical
supervision (5.2, 5.3).
• Insulin, particularly when given intravenously or in settings of poor
glycemic control, can cause hypokalemia. Use caution in patients
predisposed to hypokalemia (5.4).
• Like all insulins, NovoLog requirements may be reduced in patients with
renal impairment or hepatic impairment (5.5, 5.6).
• Severe, life-threatening, generalized allergy, including anaphylaxis, may
occur with insulin products, including NovoLog (5.7).
• Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin,
including NovoLog (5.11).
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
Adverse reactions observed with NovoLog include hypoglycemia, allergic
reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DRUG INTERACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
• Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may
be needed. (7.1, 7.2, 7.3)
• Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or
absent. (7.3, 7.4)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• Pediatric: Has not been studied in children with type 2 diabetes. Has not
been studied in children with type 1 diabetes <2 years of age (8.4).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 02/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
8
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
2.4 Intravenous Use
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
10
5
WARNINGS AND PRECAUTIONS
11
5.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill
12
Cartridge, or Penfill Cartridge Compatible Insulin Delivery Device
Between Patients
5.2 Administration
5.3 Hypoglycemia
13
5.4 Hypokalemia
5.5 Renal Impairment
5.6 Hepatic Impairment
14
5.7 Hypersensitivity and Allergic Reactions
5.8 Antibody Production
5.9 Mixing of Insulins
5.10 Continuous Subcutaneous Insulin Infusion by External Pump
5.11 Fluid retention and heart failure with concomitant use of PPAR-
16
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
17
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of
NovoLog
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering
Effect of NovoLog
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Gender
8.7 Renal Impairment
8.8 Hepatic Impairment
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
CLINICAL STUDIES
14.1 Subcutaneous Daily Injections
14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External
Pump
14.3 Intravenous Administration of NovoLog
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
PATIENT COUNSELING INFORMATION
17.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch,
PenFill Cartridge, or Penfill Cartridge Device Between
Patients
17.2 Physician Instructions
17.3 Patients Using Pumps
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
17.4 FDA Approved Patient Labeling
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
NovoLog is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog is an insulin analog with an earlier onset of action than regular human insulin.
The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection
should generally be used in regimens with an intermediate or long-acting insulin [see Warnings
and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin
requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-
related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be
provided by NovoLog and the remainder provided by an intermediate-acting or long-acting
insulin. Because of NovoLog’s comparatively rapid onset and short duration of glucose
lowering activity, some patients may require more basal insulin and more total insulin to prevent
pre-meal hyperglycemia when using NovoLog than when using human regular insulin.
Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and
colorless. NovoLog should not be used after the printed expiration date.
2.2
Subcutaneous Injection
NovoLog should be administered by subcutaneous injection in the abdominal region,
buttocks, thigh, or upper arm. Because NovoLog has a more rapid onset and a shorter duration
of activity than human regular insulin, it should be injected immediately (within 5-10 minutes)
before a meal. Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the
dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous
injection. Diluting one part NovoLog to nine parts diluent will yield a concentration one-tenth
that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield a
concentration one-half that of NovoLog (equivalent to U-50).
2.3
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings
and Precautions (5.9, 5.10), How Supplied/Storage and Handling (16.2)]. Diluted insulin should
not be used in external insulin pumps. Because NovoLog has a more rapid onset and a shorter
duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused
immediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy. The initial programming of the external insulin
infusion pump should be based on the total daily insulin dose of the previous regimen. Although
there is significant interpatient variability, approximately 50% of the total dose is usually given
as meal-related boluses of NovoLog and the remainder is given as a basal infusion. Change the
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog in the reservoir at least every 6 days, change the infusion sets and the infusion set
insertion site at least every 3 days.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using a different insulin pump with NovoLog, read the pump label to make sure
the pump has been evaluated with NovoLog.
2.4
Intravenous Use
NovoLog can be administered intravenously under medical supervision for glycemic
control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].
For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL
insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown
to be stable in infusion fluids such as 0.9% sodium chloride.
Inspect NovoLog for particulate matter and discoloration prior to parenteral
administration.
3
DOSAGE FORMS AND STRENGTHS
NovoLog is available in the following package sizes: each presentation contains 100 units
of insulin aspart per mL (U-100).
•
10 mL vials
•
3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device
(with or without the addition of a NovoPen® 3 PenMate®) with NovoFine®
disposable needles
•
3 mL NovoLog FlexPen
•
3 mL NovoLog FlexTouch
4
CONTRAINDICATIONS
NovoLog is contraindicated
•
during episodes of hypoglycemia
•
in patients with hypersensitivity to NovoLog or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill Cartridge, or
PenFill Cartridge Compatible Insulin Delivery Device Between Patients
NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge, and PenFill cartridge
compatible insulin delivery devices must never be shared between patients, even if the needle is
changed. Sharing poses a risk for transmission of blood-borne pathogens.
5.2
Administration
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog has a more rapid onset of action and a shorter duration of activity than regular
human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10
minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be
used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes.
Glucose monitoring is recommended for all patients with diabetes and is particularly important
for patients using external pump infusion therapy.
Any change of insulin dose should be made cautiously and only under medical
supervision. Changing from one insulin product to another or changing the insulin strength may
result in the need for a change in dosage. As with all insulin preparations, the time course of
NovoLog action may vary in different individuals or at different times in the same individual and
is dependent on many conditions, including the site of injection, local blood supply, temperature,
and physical activity. Patients who change their level of physical activity or meal plan may
require adjustment of insulin dosages. Insulin requirements may be altered during illness,
emotional disturbances, or other stresses.
Patients using continuous subcutaneous insulin infusion pump therapy must be trained to
administer insulin by injection and have alternate insulin therapy available in case of pump
failure.
5.3
Hypoglycemia
Hypoglycemia is the most common adverse effect of all insulin therapies, including
NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may
result in temporary or permanent impairment of brain function or death. Severe hypoglycemia
requiring the assistance of another person and/or parenteral glucose infusion or glucagon
administration has been observed in clinical trials with insulin, including trials with NovoLog.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations [see Clinical Pharmacology (12)]. Other factors such as changes in food
intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant
medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all
insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The
patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may
present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as
longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of
hypoglycemia. Intravenously administered insulin has a more rapid onset of action than
subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.
5.4
Hypokalemia
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All insulin products, including NovoLog, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations, and patients receiving intravenously
administered insulin).
5.5
Renal Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with renal impairment [see Use in Specific Populations (8.7)].
5.6
Hepatic Impairment
As with other insulins, the dose requirements for NovoLog may be reduced in patients
with hepatic impairment [see Use in Specific Populations (8.8)].
5.7
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few
days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique. Localized reactions and generalized myalgias have
been reported with injected metacresol, which is an excipient in NovoLog.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog
have been reported post-approval. Generalized allergy to insulin may also cause whole body rash
(including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled
clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular
human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and
uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to
allergic reactions.
5.8
Antibody Production
Increases in anti-insulin antibody titers that react with both human insulin and insulin
aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies
are observed more frequently with NovoLog than with regular human insulin. Data from a 12
month controlled trial in patients with type 1 diabetes suggest that the increase in these
antibodies is transient, and the differences in antibody levels between the regular human insulin
and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12
months. The clinical significance of these antibodies is not known. These antibodies do not
appear to cause deterioration in glycemic control or necessitate increases in insulin dose.
5.9
Mixing of Insulins
•
Mixing NovoLog with NPH human insulin immediately before injection
attenuates the peak concentration of NovoLog, without significantly affecting the
time to peak concentration or total bioavailability of NovoLog. If NovoLog is
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mixed with NPH human insulin, NovoLog should be drawn into the syringe first,
and the mixture should be injected immediately after mixing.
•
The efficacy and safety of mixing NovoLog with insulin preparations produced
by other manufacturers have not been studied.
•
Insulin mixtures should not be administered intravenously.
5.10
Continuous Subcutaneous Insulin Infusion by External Pump
When used in an external subcutaneous insulin infusion pump, NovoLog should not
be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump,
the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing
infusion sets) because NovoLog-specific information may differ from general pump manual
instructions.
Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of
hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially
pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a
shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage
and Administration (2.3), Warnings and Precautions (5.9, 5.10), How Supplied/Storage and
Handling (16.2), and Patient Counseling Information (17.3)].
NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog
that will be used in a pump should not be mixed with other insulin or with a diluent [see
Dosage and Administration (2.3), Warnings and Precautions (5.9, 5.10), How Supplied/Storage
and Handling (16.2), and Patient Counseling Information (17.3)].
5.11
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor
(PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated
with insulin, including NovoLog, and a PPAR-gamma agonist should be observed for signs and
symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be
considered.
6
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using
insulin, including NovoLog [see Warnings and Precautions (5)].
•
Insulin initiation and glucose control intensification
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Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy
(thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may
affect insulin absorption. Rotate insulin injection or infusion sites within the same
region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog, and has
been attributed to the anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
•
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during NovoLog clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables
below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus
(Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog
compared to human regular insulin are listed)
NovoLog + NPH
N= 596
Human Regular Insulin + NPH
N= 286
Preferred Term
N
(%)
N
(%)
Hypoglycemia*
448
75%
205
72%
Headache
70
12%
28
10%
Injury accidental
65
11%
29
10%
Nausea
43
7%
13
5%
Diarrhea
28
5%
9
3%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
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Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus
(except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more
frequently with NovoLog compared to human regular insulin are listed)
NovoLog + NPH
N= 91
Human Regular Insulin + NPH
N= 91
N
(%)
N
(%)
Hypoglycemia*
25
27%
33
36%
Hyporeflexia
10
11%
6
7%
Onychomycosis
9
10%
5
5%
Sensory disturbance
8
9%
6
7%
Urinary tract infection
7
8%
6
7%
Chest pain
5
5%
3
3%
Headache
5
5%
3
3%
Skin disorder
5
5%
2
2%
Abdominal pain
5
5%
1
1%
Sinusitis
5
5%
1
1%
*Hypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See
Section 14 for the incidence of serious hypoglycemia in the individual clinical trials.
Postmarketing Data
The following additional adverse reactions have been identified during post-approval use
of NovoLog. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors
in which other insulins have been accidentally substituted for NovoLog have been identified
during post-approval use [see Patient Counseling Information (17)].
7
DRUG INTERACTIONS
7.1
Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with NovoLog use may be increased with antidiabetic
agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine,
monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin
analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.2
Drugs That May Decrease the Blood Glucose Lowering Effect of NovoLog
The glucose lowering effect of NovoLog may be decreased when co-administered with
atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens,
glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral
contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol,
epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose
monitoring may be required when NovoLog is co-administered with these drugs.
7.3
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
NovoLog
The glucose lowering effect of NovoLog may be increased or decreased when co-administered
with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia,
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which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of
glucose monitoring may be required when NovoLog is co-administered with these drugs.
7.4
Drugs That May Affect Hypoglycemia Signs and Symptoms
The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine,
guanethidine, and reserpine are co-administered with NovoLog.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or
other adverse outcome regardless of drug exposure. This background risk is increased in
pregnancies complicated by hyperglycemia and may be decreased with good metabolic control.
It is essential for patients with diabetes or history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physician if they intend to
become, or if they become pregnant while taking NovoLog.
An open-label, randomized study compared the safety and efficacy of NovoLog (n=157)
versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds
of the enrolled patients were already pregnant when they entered the study. Because only one-
third of the patients enrolled before conception, the study was not large enough to evaluate the
risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during
pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.
Subcutaneous reproduction and teratology studies have been performed with NovoLog
and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats
before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis.
The effects of NovoLog did not differ from those observed with subcutaneous regular human
insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and
visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a
dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at
high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at
a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits,
based on U/body surface area.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is
compatible with breastfeeding, but women with diabetes who are lactating may require
adjustments of their insulin doses.
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8.4
Pediatric Use
NovoLog is approved for use in children for subcutaneous daily injections and for
subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in
pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric
patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of
clinical studies.
8.5
Geriatric Use
Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical
studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes
(18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as
compared to human insulin, did not differ by age.
8.6
Gender
There was no significant difference in efficacy noted (as assessed by HbA1c) between
genders in a trial in patients with type 1 diabetes.
8.7
Renal Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with renal impairment [see Warnings and Precautions (5.5)].
8.8
Hepatic Impairment
Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be
necessary in patients with hepatic impairment [see Warnings and Precautions (5.6)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11
DESCRIPTION
NovoLog (insulin aspart [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. NovoLog is homologous with regular human insulin with the
exception of a single substitution of the amino acid proline by aspartic acid in position B28, and
is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast).
Insulin aspart has the empirical formula C256H381N65079S6 and a molecular weight of 5825.8.
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structural formula
Figure 1. Structural formula of insulin aspart.
NovoLog is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart
100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6
mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL
and water for injection. NovoLog has a pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium
hydroxide 10% may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog is the regulation of glucose metabolism. Insulins,
including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose
by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose
from the liver.
12.2
Pharmacodynamics
Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous
administration of NovoLog has a more rapid onset and a shorter duration of action than regular
human insulin.
In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect
of NovoLog occurred between 1 and 3 hours after subcutaneous injection (0.15 U/kg) (see
Figure 2). The duration of action for NovoLog is 3 to 5 hours. The time course of action of
insulin and insulin analogs such as NovoLog may vary considerably in different individuals or
within the same individual. The parameters of NovoLog activity (time of onset, peak time and
duration) as designated in Figure 2 should be considered only as general guidelines. The rate of
insulin absorption and onset of activity is affected by the site of injection, exercise, and other
variables [see Warnings and Precautions (5.2)].
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graph
Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15
U/kg pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched
curve) injected immediately before a meal in 22 patients with type 1 diabetes.
A double-blind, randomized, two-way cross-over study in 16 patients with type 1
diabetes demonstrated that intravenous infusion of NovoLog resulted in a blood glucose profile
that was similar to that after intravenous infusion with regular human insulin. NovoLog or
human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the
patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as
the time of autonomic reaction (R) (see Figure 3).
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graph
Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog
(hatched curve) and regular human insulin (solid curve) in 16 patients with type 1
diabetes. R represents the time of autonomic reaction.
12.3
Pharmacokinetics
Absorption -The single substitution of the amino acid proline with aspartic acid at
position B28 in NovoLog reduces the molecule's tendency to form hexamers as observed with
regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous
injection compared to regular human insulin (see Figure 4).
The relative bioavailability of NovoLog (0.15 U/kg) compared to regular human insulin
(0.15 U/kg) indicates that the two insulins are absorbed to a similar extent.
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graph
Figure 4. Serial mean serum free insulin concentration collected up to 6 hours
following a single 0.15 U/kg pre-meal dose of NovoLog (solid curve) or regular
human insulin (hatched curve) injected immediately before a meal in 22 patients
with type 1 diabetes.
In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total
n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as
regular human insulin. The median time to maximum concentration in these trials was 40 to 50
minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in
patients with type 1 diabetes, NovoLog and regular human insulin, both administered
subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of
82 and 36 mU/L, respectively.
In a clinical study in healthy non-obese subjects, the pharmacokinetic differences
between NovoLog and regular human insulin described above, were observed independent of the
site of injection (abdomen, thigh, or upper arm).
Distribution and Elimination - NovoLog has low binding to plasma proteins (<10%),
similar to that seen with regular human insulin. After subcutaneous administration in normal
male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with
an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects
between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular
human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for
the two groups with mean values of 1.2 L/h/kg for the NovoLog group and 1.2 L/h/kg for the
regular human insulin group.
Specific Populations
Age: Pediatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12
years, n=9) and adolescents (13-17 years [Tanner grade ≥ 2], n=9) with type 1 diabetes. The
relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with
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type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy
adult subjects and adults with type 1 diabetes.
Age: Geriatric Population: The pharmacokinetic and pharmacodynamic properties of
NovoLog and regular human insulin were investigated in a single dose study in 18 subjects with
type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and
pharmacodynamics in geriatric patients with type 2 diabetes between NovoLog and regular
human insulin were similar to those in younger adults.
Gender: In healthy volunteers given single subcutaneous dose of Novolog 0.06 U/kg, no
difference in insulin aspart levels was seen between men and women based on comparison of
AUC(0-10h) or Cmax.
Obesity: A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study
of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2).
The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI
in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2
(N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with
BMI >32 kg/m2 compared to patients with BMI <23 kg/m2 .
Renal Impairment: Some studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg
NovoLog was administered in a study to subjects with either normal renal function (N=6)
creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3;
CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min)
renal impairment. In this small study, there was no apparent effect of creatinine clearance values
on AUC and Cmax of NovoLog.
Hepatic Impairment:- Some studies with human insulin have shown increased circulating
levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog
was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different
degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging
from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no
correlation between the degree of hepatic impairment and any NovoLog pharmacokinetic
parameter.
The effect of ethnic origin, pregnancy and smoking on the pharmacokinetics and
pharmacodynamics of NovoLog has not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed
subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a
dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females
when compared to untreated controls. The incidence of mammary tumors for NovoLog was not
significantly different than for regular human insulin. The relevance of these findings to humans
is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma
cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration
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test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct
adverse effects on male and female fertility, or general reproductive performance of animals was
observed.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog
is more rapid in onset and of shorter duration, compared to regular human insulin, due to its
faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY
Figure 2 and Figure 4).
14
CLINICAL STUDIES
14.1
Subcutaneous Daily Injections
Two six-month, open-label, active-controlled studies were conducted to compare the
safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the
two study designs and results were similar, data are shown for only one study (see Table 3).
NovoLog was administered by subcutaneous injection immediately prior to meals and regular
human insulin was administered by subcutaneous injection 30 minutes before meals. NPH
insulin was administered as the basal insulin in either single or divided daily doses. Changes in
HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events
requiring intervention from a third party) were comparable for the two treatment regimens in this
study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic
ketoacidosis was not reported in any of the adult studies in either treatment group.
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Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
NovoLog + NPH
Novolin R + NPH
N
596
286
Baseline HbA1c (%)*
7.9 ±1.1
8.0 ± 1.2
Change from Baseline HbA1c (%)
-0.1 ± 0.8
0.0 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.2 (-0.3, -0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
104 (17%)
54 (19%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.3 ± 14.5
0.5 ± 3.3
75.9 ± 13.1
0.9 ± 2.9
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n =
283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog
(n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog
achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4)
and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous
administration of NovoLog and regular human insulin have also been compared in children with
type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.
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Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks;
n=283)
NovoLog + NPH
Novolin R + NPH
N
187
96
Baseline HbA1c (%)*
8.3 ± 1.2
8.3 ± 1.3
Change from Baseline HbA1c (%)
0.1± 1.0
0.1± 1.1
Treatment Difference in HbA1c, Mean (97.5% confidence interval)
-0.2 (-0.5, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.4 ± 0.2
0.7 ± 0.2
Patients with severe hypoglycemia (n, %)**
11 (6%)
9 (9%)
Diabetic ketoacidosis (n, %)
10 (5%)
2 (2%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
50.6 ± 19.6
2.7 ± 3.5
48.7 ± 15.8
2.4 ± 2.6
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
One six-month, open-label, active-controlled study was conducted to compare the safety
and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was
administered by subcutaneous injection immediately prior to meals and regular human insulin
was administered by subcutaneous injection 30 minutes before meals. NPH insulin was
administered as the basal insulin in either single or divided daily doses. Changes in HbA1c and
the rates of severe hypoglycemia (as determined from the number of events requiring
intervention from a third party) were comparable for the two treatment regimens.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
NovoLog + NPH
Novolin R + NPH
N
90
86
Baseline HbA1c (%)*
8.1 ± 1.2
7.8 ± 1.1
Change from Baseline HbA1c (%)
-0.3 ± 1.0
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
- 0.1 (-0.4, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.7 ± 0.3
Patients with severe hypoglycemia (n, %)**
9 (10%)
5 (8%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
88.4 ± 13.3
1.2 ± 3.0
85.8 ± 14.8
0.4 ± 3.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
14.2
Continuous Subcutaneous Insulin Infusion (CSII) by External Pump
Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118])
compared NovoLog to buffered regular human insulin (Velosulin) in adults with type 1 diabetes
receiving a subcutaneous infusion with an external insulin pump. The two treatment regimens
had comparable changes in HbA1c and rates of severe hypoglycemia.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; n=118)
NovoLog
Buffered human
insulin
N
59
59
Baseline HbA1c (%)*
7.3 ± 0.7
7.5 ± 0.8
Change from Baseline HbA1c (%)
0.0 ± 0.5
0.2 ± 0.6
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.2 (-0.1, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.8
0.6 ± 0.2
End-of-Study insulin dose (IU/kg/24 hours)*
0.7 ± 0.7
0.6 ± 0.2
Patients with severe hypoglycemia (n, %)**
1 (2%)
2 (3%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
77.4 ± 16.1
0.1 ± 3.5
74.8 ± 13.8
-0.0 ± 1.7
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
A randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens
administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These
two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of
hypoglycemia after 16 weeks of treatment (see Table 7).
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
NovoLog
Lispro
N
198
100
Baseline HbA1c (%)*
8.0 ± 0.9
8.2 ± 0.8
Change from Baseline HbA1c (%)
-0.1 ± 0.8
-0.1 ± 0.7
Treatment Difference in HbA1c, Mean (95% confidence interval)
-0.1 (-0.3, 0.1)
Baseline insulin dose (IU/kg/24 hours)*
0.9 ± 0.3
0.9 ± 0.3
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.2
0.9 ± 0.2
Patients with severe hypoglycemia (n, %)**
19 (10%)
8 (8%)
Diabetic ketoacidosis (n, %)
1 (0.5%)
0 (0)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
54.1 ± 19.7
1.8 ± 2.1
55.5 ± 19.0
1.6 ± 2.1
*Values are Mean ± SD
**Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the
intervention of another person or hospitalization.
An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in
conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion
in 127 adults with type 2 diabetes. The two treatment groups had similar reductions in HbA1c and
rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127)
NovoLog pump
NovoLog + NPH
N
66
61
Baseline HbA1c (%)*
8.2 ± 1.4
8.0 ± 1.1
Change from Baseline HbA1c (%)
-0.6 ± 1.1
-0.5 ± 0.9
Treatment Difference in HbA1c, Mean (95% confidence interval)
0.1 (-0.3, 0.4)
Baseline insulin dose (IU/kg/24 hours)*
0.7 ± 0.3
0.8 ± 0.5
End-of-Study insulin dose (IU/kg/24 hours)*
0.9 ± 0.4
0.9 ± 0.5
Baseline body weight (kg)*
Weight Change from baseline (kg)*
96.4 ± 17.0
1.7 ± 3.7
96.9 ± 17.9
0.7 ± 4.1
*Values are Mean ± SD
14.3
Intravenous Administration of NovoLog
See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog is available in the following package sizes: each presentation containing 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-7501-11
3 mL PenFill cartridges*
NDC 0169-3303-12
3 mL NovoLog FlexPen
NDC 0169-6339-10
3 mL NovoLog FlexTouch
NDC 0169-6338-10
*NovoLog PenFill cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices (with or without the addition of a NovoPen 3
PenMate) with NovoFine disposable needles. FlexPen and FlexTouch can be used with
NovoFine or NovoTwist disposable needles. NovoLog FlexPen, NovoLog FlexTouch, PenFill
cartridge, and PenFill cartridge compatible insulin delivery devices must never be shared
between patients, even if the needle is changed.
16.2
Recommended Storage
Unused NovoLog should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do
not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze
NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into a
syringe and stored for later use.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Vials: After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28
days, but should not be exposed to excessive heat or light. Opened vials may be refrigerated.
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
PenFill cartridges or NovoLog FlexPen and NovoLog FlexTouch:
Once a cartridge or NovoLog FlexPen or NovoLog FlexTouch is punctured, it should be
kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to
excessive heat or sunlight. A NovoLog FlexPen or NovoLog FlexTouch or cartridge in use must
NOT be stored in the refrigerator. Keep the NovoLog FlexPen or NovoLog FlexTouch and all
PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog FlexPen or
NovoLog FlexTouch and PenFill cartridges can be used until the expiration date printed on the
label if they are stored in a refrigerator. Keep unused NovoLog FlexPen or NovoLog FlexTouch
and PenFill cartridges in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill cartridge
delivery device or NovoLog FlexPen or NovoLog FlexTouch without a needle attached.
This prevents contamination and/or infection, or leakage of insulin, and will ensure
accurate dosing. Always use a new needle for each injection to prevent contamination.
Pump:
NovoLog in the pump reservoir should be discarded after at least every 6 days of use or
after exposure to temperatures that exceed 37°C (98.6°F). The infusion set and the infusion set
insertion site should be changed at least every 3 days.
Summary of Storage Conditions:
The storage conditions are summarized in the following table:
Table 9. Storage conditions for vial, PenFill cartridges, NovoLog FlexPen, and NovoLog
FlexTouch
NovoLog
presentation
Not in-use (unopened)
Room Temperature
(below 30°C)
Not in-use
(unopened)
Refrigerated
In-use (opened)
Room Temperature
(below 30°C)
10 mL vial
28 days
Until expiration date
28 days
(refrigerated/room
temperature)
3 mL PenFill
cartridges
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexPen
28 days
Until expiration date
28 days
(Do not refrigerate)
3 mL NovoLog
FlexTouch
28 days
Until expiration date
28 days
(Do not refrigerate)
Storage of Diluted NovoLog
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog diluted with Insulin Diluting Medium for NovoLog to a concentration
equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C
(86°F) for 28 days.
Storage of NovoLog in Infusion Fluids
Infusion bags prepared as indicated under Dosage and Administration (2) are stable at
room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the
infusion bag.
17
PATIENT COUNSELING INFORMATION
[See FDA Approved Patient Labeling (17.4)]
17.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill Cartridge, or PenFill
Cartridge Device Between Patients
Advise patients that they must never share a NovoLog FlexPen, NovoLog FlexTouch,
PenFill cartridge or PenFill cartridge compatible insulin delivery device with another person,
even if the needle is changed, because doing so carries a risk for transmission of blood-borne
pathogens.
17.2 Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and benefits of NovoLog therapy including the possible adverse
reactions. Patients should also be offered continued education and advice on insulin therapies,
injection technique, life-style management, regular glucose monitoring, periodic glycosylated
hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to
meal planning, complications of insulin therapy, timing of dose, instruction in the use of
injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be
informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
Patients should receive proper training on how to use NovoLog. Instruct patients that
when injecting NovoLog, they must press and hold down the dose button until the dose counter
shows 0 and then keep the needle in the skin and count slowly to 6. When the dose counter
returns to 0, the prescribed dose is not completely delivered until 6 seconds later. If the needle is
removed earlier, they may see a stream of insulin coming from the needle tip. If so, the full dose
will not be delivered (a possible under-dose may occur by as much as 20%), and they should
increase the frequency of checking their blood glucose levels and possible additional insulin
administration may be necessary.
• If 0 does not appear in the dose counter after continuously pressing the dose button, the
patient may have used a blocked needle. In this case they would not have received any
insulin – even though the dose counter has moved from the original dose that was set.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If the patient did have a blocked needle, instruct them to change the needle as described
in Section 5 of the Instructions for Use and repeat all steps in the IFU starting with
Section 1: Prepare your pen with a new needle. Make sure the patient selects the full
dose needed.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog and other insulin products have been reported.
Patients should be instructed to always carefully check that they are administering the appropriate
insulin to avoid medication errors between NovoLog and any other insulin. The written
prescription for NovoLog should be written clearly, to avoid confusion with other insulin
products, for example, NovoLog Mix 70/30.
17.3
Patients Using Pumps
Patients using external pump infusion therapy should be trained in intensive insulin
therapy with multiple injections and in the function of their pump and pump accessories.
The following insulin pumps† have been used in NovoLog clinical or in vitro studies
conducted by Novo Nordisk, the manufacturer of NovoLog:
•
Medtronic Paradigm® 512 and 712
•
MiniMed 508
•
Disetronic® D-TRON® and H-TRON®
Before using another insulin pump with NovoLog, read the pump label to make sure the
pump has been evaluated with NovoLog.
NovoLog is recommended for use in any reservoir and infusion sets that are compatible
with insulin and the specific pump. Please see recommended reservoir and infusion sets in the
pump manual.
To avoid insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets
and infusion set insertion sites should be changed at least every 3 days.
Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous,
pruritic, or thickened should be reported to medical personnel, and a new site selected because
continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump
or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in a
short time because of the small subcutaneous depot of insulin. This is especially pertinent for
rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter
duration of action. These differences are particularly relevant when patients are switched from
multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or
ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump
malfunction may occur. If these problems cannot be promptly corrected, patients should resume
therapy with subcutaneous insulin injection and contact their physician [see Dosage and
Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling
(16.2)].
17.4
FDA Approved Patient Labeling
See separate leaflet.
Rx only
Date of Issue: February 2015
Version: XX
Novo Nordisk®, NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, FlexTouch®, PenMate® ,
NovoFine®, and NovoTwist® are registered trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent No. 5,866,538, and other patents pending.
FlexPen® is covered by US Patent Nos. RE 41,956, 6,004,297, RE 43,834, and other patents
pending.
FlexTouch® pen is covered by US Patent Nos. 7,686,786, 6,899,699, and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
†The brands listed are the registered trademarks of their respective owners and are not
trademarks of Novo Nordisk A/S.
© 2002-2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] injection)
Do not share your NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge or P
enFill cartridge
compatible insulin delivery device with other people, even if the needle has been changed. You
may give other people a serious infection, or get a serious infection from them.
What is NovoLog?
• NovoLog is a man-made insulin that is used to control high blood sugar i n adults and children with
diabetes mellitus.
Who should not take NovoLog?
Do not take NovoLog if you:
•
are having an e
pisode of low blood sugar (hypoglycemia).
•
have an allergy to NovoLog or any of the ingredients i n NovoLog.
Before taking NovoLog, tell your healthcare provider about all your medical conditions including,
if y
ou are:
•
pregnant, planning to become pregnant, or are breastfeeding.
•
taking new prescription or over-the-counter medicines, vitamins, or her
bal supplements.
Before you start taking NovoLog, talk to your healthcare provider about low blood sugar and how
to manage it.
How s
hould I take NovoLog?
•
Read the Instructions for Use that come with your NovoLog.
•
Take NovoLog exactly as your healthcare provider tells you to.
•
NovoLog starts acting fast. You should eat a meal within 5
to 10 minutes after you ta
ke your dose of
NovoLog.
•
Know the type and strength of insulin you take. Do not change the type of insulin you take unless your
healthcare provider t ells you to. The amount of insulin and the best time for you to t ake your insulin may
need to change if you take different types of insulin.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and
when you should check your blood sugar levels.
•
. Do not reuse or share your needles with other people. You may give other people a serious
infection or get a serious infection from them.
What should I avoid while taking NovoLog?
While t aking NovoLog do not:
•
Drive or operate heavy machinery, until you know how NovoLog affects you.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
What are t he possible side effects of NovoLog?
NovoLog may cause serious side effects that can lead to death, including:
Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
•
dizziness or light-headedness
● blurred vision
● anxiety, irritability, or mood changes
•
sweating
● slurred speech
● hunger
•
confusion
● shakiness
● headache
● fast heart beat
Your insulin dose m
ay need to change because of:
•
change in level of physical activity or exercise
● increased stress ● change in diet
•
weight gain o
r loss
● illness
Other common side effects of NovoLog may include:
•
low potassium in y
our blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic
reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain,
and swelling of your h
ands and feet.
Get emergency m
edical help i f y
ou have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating,
extreme drowsiness, dizziness, confusion.
These are not all the possible side effects of NovoLog. Call your doctor for medical advice about side effects.
You m
ay report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of N
ovoLog.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You
can ask your pharmacist or healthcare provider for information about NovoLog that is written f or health
professionals. D
o not use NovoLog for a condition for which it was n
ot prescribed. Do not give NovoLog to
other people, even if they have the same symptoms that you have. It may harm them.
What are t he ingredients in NovoLog?
Active Ingredient: insulin aspart (rDNA origin)
Inactive Ingredients: glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride and water for
Reference ID: 3706655
injection
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For more information, go to www.novonordisk-us.com or call 1-800-727-6500.
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 02/2015
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
NovoLog® FlexPen®
Introduction
Please read the following instructions carefully before using your NovoLog® FlexPen® .
Do not share your NovoLog FlexPen with other people, even if the needle has
been changed. You may give other people a serious infection, or get a serious
infection from them.
NovoLog FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1
to 60 units in increments of 1 unit. NovoLog FlexPen is designed to be used with
NovoFine® needles.
NovoLog FlexPen should not be used by people who are blind or have severe visual
problems without the help of a person who has good eyesight and who is trained to
use the NovoLog FlexPen the right way.
Getting ready
Make sure you have the following items:
•
NovoLog FlexPen
•
New NovoFine needle
•
Alcohol swab usage illustration
Preparing Your NovoLog FlexPen
Wash your hands with soap and water. Before you start to prepare your
injection, check the label to make sure that you are taking the right type of
insulin. This is especially important if you take more than 1 type of insulin.
NovoLog should look clear.
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustrationusage illustration
B. Attaching the needle
Remove the protective tab from a disposable needle.
Screw the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your NovoLog FlexPen until
you are ready to take your injection.
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and dispose of it (see diagram D). usage illustration
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles. Do not reuse or share your needles with other people. You may
give other people a serious infection, or get a serious infection from them.
Be careful not to bend or damage the needle before use.
To reduce the risk of unexpected needle sticks, never put the inner needle cap back
on the needle.
Giving the airshot before each injection
Before each injection small amounts of air may collect in the cartridge during normal
use. To avoid injecting air and to ensure proper dosing:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your NovoLog FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any air
bubbles collect at the top of the cartridge (see diagram F). usage illustration
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
G. Keep the needle pointing upwards, press the push-button all
the way in (see diagram G). The dose selector returns to 0.
A drop of insulin should appear at the needle tip. If not, change
the needle and repeat the procedure no more than 6 times.
If you do not see a drop of insulin after 6 times, do not use the
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
A small air bubble may remain at the needle tip, but it will not be
injected.
Selecting your dose
Check and make sure that the dose selector is set at 0. usage illustration
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the dose
selector in either direction until the correct dose lines up with the
pointer (see diagram H). When turning the dose selector, be
careful not to press the push-button as insulin will come out.
You cannot select a dose larger than the number of units left in
the cartridge. usage illustration
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
Giving the injection
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before
injecting.
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until the
0 lines up with the pointer (see diagram I). Be careful only to push
the button when injecting. usage illustration
Turning the dose selector will not inject insulin.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has been
pulled out from the skin (see diagram J). This will make sure
that the full dose has been given.
You may see a drop of NovoLog at the needle tip. This is usage illustration
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin, press
the injection site lightly with a finger. Do not rub the area.
After the injection
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog FlexPen after each injection. This helps
to prevent infection, leakage of insulin, and will help to make sure you inject the
right dose of insulin.
• Put your used NovoLog FlexPen and needles in a FDA-cleared sharps
disposal container right away after use. Do not throw away (dispose of)
loose needles and Pens in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may
use a household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without
sharps being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to
follow your community guidelines for the right way to dispose of your
sharps disposal container. There may be state or local laws about how
you should throw away used needles and syringes. For more information
about the safe sharps disposal, and for specific information about sharps
disposal in the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your
used sharps disposal container.
The NovoLog FlexPen prevents the cartridge from being completely emptied. It is
designed to deliver 300 units.
K. Put the pen cap on the NovoLog FlexPen and store the
NovoLog FlexPen without the needle attached (see diagram K). usage illustration
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
L. Function Check
If your NovoLog FlexPen is not working the right way, follow the steps below: usage illustration
•
Screw on a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap.
•
Do an airshot as described in “Giving the airshot before
each injection”.
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window
shows 20 units.
•
Hold the NovoLog FlexPen so the needle is pointing down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram
L). If the NovoLog FlexPen has released too much or too little insulin, do the
function check again. If the same problem happens again, do not use your
NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled
with care. Avoid dropping your FlexPen as it may damage it. If you are
concerned that your FlexPen is damaged, use a new one. You can clean the
outside of your FlexPen by wiping it with a damp cloth. Do not soak or wash
your FlexPen as it may damage it. Do not refill your FlexPen.
Remove the needle from the NovoLog FlexPen after each injection. This
helps to ensure sterility, prevent leakage of insulin, and will help to make
sure you inject the right dose of insulin for future injections.
Be careful when handling used needles to avoid needle sticks and transfer
of infectious diseases.
Keep your NovoLog FlexPen and needles out of the reach of children.
Use NovoLog FlexPen as directed to treat your diabetes.
Do not share your Novolog FlexPen or needles with other people. You may give
other people a serious infection, or get a serious infection from them.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device in
case your NovoLog FlexPen is lost or damaged.
Remember to keep the disposable NovoLog FlexPen with you. Do not
leave it in a car or other location where it can get too hot or too cold.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® (NŌ-vō-log) FlexTouch® Pen
(insulin aspart [rDNA origin] injection)
• Do not share your NovoLog FlexTouch Pen with other people, even
if the needle has been is changed. You may give other people a
serious infection, or get a serious infection from them.
• NovoLog FlexTouch Pen (“Pen”) is a prefilled disposable pen
containing 300 units of U-100 NovoLog (insulin aspart [rDNA origin]
injection) insulin. You can inject from 1 to 80 units in a single injection.
• This Pen is not recommended for use by the blind or visually
impaired without the assistance of a person trained in the proper
use of the product.
Supplies you will need to give your NovoLog injection:
• NovoLog FlexTouch Pen
• a new NovoFine, NovoFine Plus or NovoTwist needle
• alcohol swab
• 1 sharps container for throwing away used Pens and needles. See
“Disposing of used NovoLog FlexTouch Pens and needles” at the
end of these instructions.
Preparing your NovoLog FlexTouch Pen:
• Wash your hands with soap and water.
• Before you start to prepare your injection, check the NovoLog
FlexTouch Pen label to make sure you are taking the right type of
insulin. This is especially important if you take more than 1 type of
insulin.
• NovoLog should look clear and colorless. Do not use NovoLog if it is thick,
cloudy, or is colored.
• Do not use NovoLog past the expiration date printed on the label or 28
days after you start using the Pen.
• Always use a new needle for each injection to help ensure sterility and
prevent blocked needles. Do not reuse or share your needles with
other people. You may give other people a serious infection, or get
a serious infection from them.
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
ge illustration
Step 1:
•
Pull Pen cap straight off (See Figure
B).
usage
illustratio
n
(Figure A)
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a ge i
llus
t
r atio
n
Step 2:
•
Check the liquid in the Pen (See
Figure C). NovoLog should look clear
and colorless. Do not use it if it looks
cloudy or colored.
Step 3:
•
Select a new needle.
•
Pull off the paper tab from the outer
needle cap (See Figure D).
Step 4:
•
Push the capped needle straight onto
the Pen and twist the needle on until
it is tight (See Figure E).
Step 5:
•
Pull off the outer needle cap. Do not
throw it away (See Figure F).
Step 6:
•
Pull off the inner needle cap and
throw it away (See Figure G).
Priming your NovoLog FlexTouch Pen:
Step 7:
Reference ID: 3706655
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•
Turn the dose selector to select 2
units (See Figure H).
Step 8:
•
Hold the Pen with the needle pointing
up. Tap the top of the Pen gently a
few times to let any air bubbles rise tous
ag
e
i
l
l
u
s
t
ration
the top (See Figure I).
Step 9:
•
Hold the Pen with the needle
pointing up. Press and hold in the
dose button until the dose counter
shows “0”. The “0” must line up with
the dose pointer.
•
A drop of insulin should be seen at the
needle tip (See Figure J).
o If you do not see a drop of insulin,
repeat steps 7 to 9, no more than
6 times.
o If you still do not see a drop of
insulin, change the needle and
repeat steps 7 to 9.
Selecting your dose:
Reference ID: 3706655
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u
s
a
g
e
i
l
lustration
Step 10:
•
Turn the dose selector to select
the number of units you need to
inject. The dose pointer should line
up with your dose (See Figure K).
o If you select the wrong dose,
you can turn the dose selector
forwards or backwards to the
correct dose.
o The even numbers are printed
on the dial.
o The odd numbers are shown as
lines.
•
The NovoLog FlexTouch Pen insulin
scale will show you how much
insulin is left in your Pen (See
Figure L).
•
To see how much insulin is left
in your NovoLog FlexTouch Pen:
o
Turn the dose selector until it
stops. The dose counter will line
up with the number of units of
insulin that is left in your Pen. If
the dose counter shows 80,
there are at least 80 units left
in your Pen.
o
If the dose counter shows less
than 80, the number shown in
the dose counter is the number
of units left in your Pen.
Giving your injection:
• Inject your NovoLog exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Reference ID: 3706655
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u
sa
g
e
i
l
l
u
s
t
ration
Step 11:
•
Choose your injection site and wipe
the skin with an alcohol swab. Let
the injection site dry before you
inject your dose (See Figure M).
Step 12:
•
Insert the needle into your skin
(See Figure N).
o
Make sure you can see the
dose counter. Do not cover it
with your fingers, this can stop
your injection.
Step 13:
•
Press and hold down the dose
button until the dose counter
shows “0” (See Figure O).
o
The “0” must line up with the
dose pointer. You may then hear
or feel a click.
•
Keep the needle in your skin
after the dose counter has
returned to “0” and slowly count
to 6 (See Figure P).
o
When the dose counter
returns to “0”, you will not
get your full dose until 6
seconds later.
o
If the needle is removed
before you count to 6, you
may see a stream of insulin
coming from the needle tip.
o
If you see a stream of insulin
coming from the needle tip
you will not get your full
dose. If this happens you
• NovoLog can be injected under the skin (subcutaneously) of your stomach
area (abdomen), buttocks, upper legs (thighs) or upper arms.
• For each injection, change (rotate) your injection site within the area of
skin that you use. Do not use the same injection site for each injection.
Reference ID: 3706655
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should check your blood
sugar levels more often
because you may need more
insulin.
u
s
a
g
e
i
llustration
Step 14:
•
Pull the needle out of your skin
(See Figure Q).
o
If you see blood after you take
the needle out of your skin,
press the injection site lightly
with a piece of gauze or an
alcohol swab. Do not rub the
area.
Step 15:
•
Carefully remove the needle
from the Pen and throw it away
(See Figure R).
o
Do not recap the needle.
Recapping the needle can lead
to needle stick injury.
•
If you do not have a sharps
container, carefully slip the needle
into the outer needle cap (See
Figure S). Safely remove the needle
and throw it away as soon as you
can.
o
Do not store the Pen with the
needle attached. Storing without
the needle attached helps
prevent leaking, blocking of the
needle, and air from entering
the Pen.
Step 16:
•
Replace the Pen cap by pushing it
straight on (See Figure T).
After your injection:
• You can put your used NovoLog FlexTouch Pen and needles in a FDA-
cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and Pens in your household trash.
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of your sharps
disposal container. There may be state or local laws about how you should
throw away used needles and syringes. Do not reuse or share your
needles or syringes with other people. For more information about safe
sharps disposal, and for specific information about sharps disposal in the
state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your
used sharps disposal container.
How should I store my NovoLog FlexTouch Pen?
• Store unused NovoLog FlexTouch Pens in the refrigerator at 36OF to 46OF
(2OC to 8OC).
• Store the Pen you are currently using out of the refrigerator below 86OF.
• Do not freeze NovoLog. Do not use NovoLog if it has been frozen.
• Keep NovoLog away from heat or light.
• Unused Pens may be used until the expiration date printed on the label, if
kept in the refrigerator.
• The NovoLog FlexTouch Pen you are using should be thrown away after 28
days, even if it still has insulin left in it.
General Information about the safe and effective use of NovoLog.
• Keep NovoLog FlexTouch Pens and needles out of the reach of
children.
• Always use a new needle for each injection.
• Do not share your Novolog FlexTouch Pens or needles with other people.
You may give other people a serious infection, or get a serious infection
from them.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
Reference ID: 3706655
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DK-2880 Bagsvaerd, Denmark
Revised: 02/2015 company logo
For more information go to
www.novotraining.com/novologflextouch/us02
© 2002-2015 Novo Nordisk
NovoLog®
FlexTouch®
Read before first use
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Instructions for Use
NovoLog® 3 mL PenFill® cartridge (100 Units/mL, U-100)
Do not share your Penfill cartridge or Penfill cartridge compatible insulin
delivery device with other people, even if the needle has been changed.
You may give other people a serious infection, or get a serious infection
from them.
Before using the NovoLog® cartridge
1. Talk with your healthcare provider for information about where to inject
NovoLog® (injection sites) and how to give an injection with your insulin
delivery device.
2. Read the instruction manual that comes with your insulin delivery
device for complete instructions on how to use the PenFill® cartridge
with the device.
How to use the NovoLog® cartridge
1. Check your insulin. Just before using your NovoLog® cartridge,
check to make sure that you have the right type of insulin. This is
especially important if you use different types of insulin.
2. Carefully look at the cartridge and the insulin inside it. The insulin
should be clear and colorless. The tamper-resistant foil should be in
place before the first use. If the foil has been broken or removed before
your first use of the cartridge, or if the insulin is cloudy or colored, do
not use it. Call Novo Nordisk at 1-800-727-6500.
3. Wash your hands well with soap and water. If you clean your injection
site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider for guidance on injection sites and
how to give an injection with your insulin delivery device.
4. Gather your supplies for injecting NovoLog® .
5. Insert a 3 mL cartridge into your Novo Nordisk 3 mL PenFill® cartridge
compatible insulin delivery device. Wipe the front rubber stopper of the
3 mL PenFill® cartridge with an alcohol swab, then attach a new
needle. For NovoFine® needles, remove the big outer needle cap and
the inner needle cap. Always use a new needle for each injection to
prevent infection. Do not share your PenFill cartridge or Penfill
cartridge compatible insulin delivery device with other people, even if
the needle has been changed. You may give other people a serious
infection, or get a serious infection from them.
Giving the airshot before each injection:
To prevent the injection of air and to make sure insulin is delivered, you must do
an airshot before each injection. Hold the device with the needle pointing up and
gently tap the PenFill® cartridge holder with your finger a few times to raise any
air bubbles to the top of the cartridge. Do the airshot as described in the device
instruction manual.
Reference ID: 3706655
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Giving the injection
6. Dial the number of units on the insulin delivery device that you need to
inject. Inject the right way as shown to you by your healthcare provider.
7. Insert the needle into the skin. Inject the dose by pressing the push
button all the way in. Keep the needle in the skin for at least 6
seconds, and keep the push button pressed all the way in until the
needle has been pulled out from the skin. This will make sure that the
full dose has been given. You may see a drop of NovoLog® at the
needle tip. This is normal and has no effect on the dose you just
received. If blood appears after you take the needle out of your skin,
press the injection site lightly with a finger. Do not rub the area.
After the injection
8. Do not recap the needle. Recapping can lead to a needle stick injury.
9. Remove the needle from the PenFill® cartridge after each injection.
Keep the 3 mL PenFill® cartridge in the insulin delivery device. The
needle should not be attached to the 3 mL PenFill® cartridge during
storage. This will prevent infection or leakage of insulin and will help
ensure that you receive the right dose of NovoLog® .
10. Put your used NovoLog Penfill cartridge and needles in a FDA-cleared
sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and Penfill cartridges in your household
trash.
• If you do not have a FDA-cleared sharps disposal container, you
may use a household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without
sharps being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to
follow your community guidelines for the right way to dispose of
your sharps disposal container. There may be state or local laws
about how you should throw away used needles and syringes. For
more information about the safe sharps disposal, and for specific
information about sharps disposal in the state that you live in, go to
the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your
household trash unless your community guidelines permit this. Do
not recycle your used sharps disposal container.
11.Put the pen cap back on the Novo Nordisk 3 mL PenFill® cartridge
compatible insulin delivery device.
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Date of Issue: February 2015
Version: XX
Novo Nordisk®, NovoLog®, PenFill®, and NovoFine® are registered trademarks of
Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
PenFill® is covered by US Patent No. 5,693,027.
© 2002-2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® (NŌ-vō-log)
(insulin aspart [rDNA origin] injection)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® and each time you
get a refill. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your
treatment.
Supplies you will need to give your NovoLog® injection:
10 mL NovoLog® vial
insulin syringe and needle
alcohol swab
Preparing your NovoLog® dose:
Wash your hands with soap and water.
Before you start to prepare your injection, check the NovoLog® label to make
sure that you are taking the right type of insulin. This is especially important
if you use more than 1 type of insulin.
NovoLog® should look clear and colorless. Do not use NovoLog® if it is thick,
cloudy, or is colored.
Do not use NovoLog® past the expiration date printed on the label. usage illustration
Reference ID: 3230591
Reference ID: 3706655
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Step 1: Pull off the tamper resistant cap (See
Figure A).
Step 2: Wipe the rubber stopper with an alcohol
swab (See Figu
re B).
Step 3: Hold the syringe with the needle pointing
up. Pull down on the plunger until the black tip
reaches the line for the number of units for your
prescribed dose (See Figure C).
Step 4: Push the needle through the rubber
stopper of the NovoLog® vial (See Figure D).
.
Step 5: Push the plunger all the way in. This puts
air into the NovoLog® vial (See Figure E).
Step 6: Turn the NovoLog® vial and syringe upside
down and slowly pull the plunger down until the
black tip is a few units past the line for your dose
(See Figure F).
(Figure A Figure B)
(Figure C)
(Figure D)
(Figure E)
(Figure F)
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If there are air bubbles, tap the syringe gently a
few times to let any air bubbles rise to the top
(See Figure G).
Step 7: Slowly push the plunger up until the black
tip reaches the line for your NovoLog® dose (See
Figure H).
Step 8: Check the syringe to make sure you have
the right dose of NovoLog® .
Step 9: Pull the syringe out of the vial’s rubber
stopper (See Figure I).
u
s
a
g
e
illustratio
n
Giving your Injection:
Inject your NovoLog® exactly as your healthcare provider has shown you. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
NovoLog® can be injected under the skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper arms, infused in an insulin pump, or given
through a needle in your arm (intravenously) by your healthcare provider.
If you inject NovoLog®, change (rotate) your injection sites within the area you
choose for each dose. Do not use the same injection site for each injection.
If you use NovoLog® in an insulin pump, you should change your insertion site
every 3 days. The insulin in the reservoir should be changed at least every 6
days even if you have not used all of the insulin.
Reference ID: 3230591
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
ag
e
i
l
l
u
stration
Step 10: Choose your injection site and wipe the skin
an alcohol swab. Let the injection site dry before you
your dose (See Figure J).
Step 11: Insert the needle into your skin. Push
down on the plunger to inject your dose (See Figure
K). Needle should remain in the skin for at
least 6 seconds to make sure you have
injected all the insulin.
Step 12: Pull the needle out of your skin. After that,
you may see a drop of NovoLog® at the needle tip.
This is normal and does not affect the dose you
just received (See Figure L).
If you see blood after you take the needle out of
your skin, press the injection site lightly with a
piece of gauze or an alcohol swab. Do not rub
the area.
If you use NovoLog® in an insulin pump, see your insulin pump manual for
instructions or talk to your healthcare provider.
NPH insulin is the only type of insulin that can be mixed with NovoLog® . Do not
mix NovoLog® with any other type of insulin.
NovoLog® should only be mixed with NPH insulin if it is going to be injected
right away under your skin (subcutaneously).
NovoLog® should be drawn up into the syringe before you draw up your NPH
insulin.
Talk to your healthcare provider if you are not sure about the right way to mix
NovoLog® and NPH insulin.
Reference ID: 3230591
Reference ID: 3706655
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For current labeling information, please visit https://www.fda.gov/drugsatfda
After your injection:
Do not recap the needle. Recapping the needle can lead to a needle stick
injury.
Throw away empty insulin vials, used syringes, and needles in a sharps
container or some type of hard plastic or metal container with a screw on cap
such as a detergent bottle or empty coffee can. Check with your healthcare
provider about the right way to throw away the container. There may be local
or state laws about how to throw away used syringes and needles. Do not
throw away used syringes and needles in household trash or recycling bins.
How should I store NovoLog®?
Do not freeze NovoLog® . Do not use NovoLog® if it has been frozen.
Keep NovoLog® away from heat or light.
Store opened and unopened NovoLog® vials in the refrigerator at 36OF to 46OF
(2OC to 8OC). Opened NovoLog® vials can also be stored out of the refrigerator
below 86OF (30OC).
Unopened vials may be used until the expiration date printed on the label, if
they are kept in the refrigerator.
Opened NovoLog® vials should be thrown away after 28 days, even if they still
have insulin left in them.
General information about the safe and effective use of NovoLog®
Always use a new syringe and needle for each injection.
Do not share syringes or needles.
Keep NovoLog® vials, syringes, and needles out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
NovoLog® is a registered trademark of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents
pending.
© 2002-2012 Novo Nordisk Inc.
For information about NovoLog® contact:
Reference ID: 3230591
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Revised: December 2012
Reference ID: 3230591
Reference ID: 3706655
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:29.315742 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020986s059s081lbl.pdf', 'application_number': 20986, 'submission_type': 'SUPPL ', 'submission_number': 81} |
4,072 |
HUMALOG® Mix50/50TM
50% INSULIN LISPRO PROTAMINE SUSPENSION AND
50% INSULIN LISPRO INJECTION
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
DESCRIPTION
Humalog® Mix50/50™ [50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA
origin)] is a mixture of insulin lispro solution, a rapid-acting blood glucose-lowering agent and insulin lispro
protamine suspension, an intermediate-acting blood glucose-lowering agent. Chemically, insulin lispro is
Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the
insulin B-chain are reversed. Insulin lispro is synthesized in a special non-pathogenic laboratory strain of
Escherichia coli bacteria that has been genetically altered to produce insulin lispro. Insulin lispro
protamine suspension (NPL component) is a suspension of crystals produced from combining insulin
lispro and protamine sulfate under appropriate conditions for crystal formation.
Insulin lispro has the following primary structure: structural formula
Insulin lispro has the empirical formula C257H383N65O77S6 and a molecular weight of 5808, both identical
to that of human insulin.
Humalog Mix50/50 vials and Pens contain a sterile suspension of insulin lispro protamine suspension
mixed with soluble insulin lispro for use as an injection.
Each milliliter of Humalog Mix50/50 injection contains insulin lispro 100 units, 0.19 mg protamine
sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 2.20 mg Metacresol, zinc oxide content
adjusted to provide 0.0305 mg zinc ion, 0.89 mg phenol, and Water for Injection. Humalog Mix50/50 has
a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may have been added to adjust
pH.
CLINICAL PHARMACOLOGY
Antidiabetic Activity
The primary activity of insulin, including Humalog Mix50/50, is the regulation of glucose metabolism. In
addition, all insulins have several anabolic and anti-catabolic actions on many tissues in the body. In
muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids
intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the
uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the
conversion of excess glucose into fat.
Insulin lispro, the rapid-acting component of Humalog Mix50/50, has been shown to be equipotent to
Regular human insulin on a molar basis. One unit of Humalog® has the same glucose-lowering effect as
one unit of Regular human insulin, but its effect is more rapid and of shorter duration.
Pharmacokinetics
Absorption — Studies in nondiabetic subjects and patients with type 1 (insulin-dependent) diabetes
demonstrated that Humalog, the rapid-acting component of Humalog Mix50/50, is absorbed faster than
Regular human insulin (U-100). In nondiabetic subjects given subcutaneous doses of Humalog ranging
Reference ID: 3706731
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For current labeling information, please visit https://www.fda.gov/drugsatfda
from 0.1 to 0.4 U/kg, peak serum concentrations were observed 30 to 90 minutes after dosing. When
nondiabetic subjects received equivalent doses of Regular human insulin, peak insulin concentrations
occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1
diabetes. graph
Figure 1: Serum Immunoreactive Insulin (IRI) Concentrations, After Subcutaneous Injection of
Humalog Mix50/50 or Humulin 50/50 in Healthy Nondiabetic Subjects.
Humalog Mix50/50 has two phases of absorption. The early phase represents insulin lispro and its
distinct characteristics of rapid onset. The late phase represents the prolonged action of insulin lispro
protamine suspension. In 30 healthy nondiabetic subjects given subcutaneous doses (0.3 U/kg) of
Humalog Mix50/50, peak serum concentrations were observed 45 minutes to 13.5 hours (median, 60
minutes) after dosing (see Figure 1). In patients with type 1 diabetes, peak serum concentrations were
observed 45 minutes to 120 minutes (median, 60 minutes) after dosing. The rapid absorption
characteristics of Humalog are maintained with Humalog Mix50/50 (see Figure 1).
Direct comparison of Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross-
study comparison shown in Figure 1 suggests that Humalog Mix50/50 has a more rapid absorption than
Humulin 50/50.
Distribution — Radiolabeled distribution studies of Humalog Mix50/50 have not been conducted.
However, the volume of distribution following injection of Humalog is identical to that of Regular human
insulin, with a range of 0.26 to 0.36 L/kg.
Metabolism — Human metabolism studies of Humalog Mix50/50 have not been conducted. Studies in
animals indicate that the metabolism of Humalog, the rapid-acting component of Humalog Mix50/50, is
identical to that of Regular human insulin.
Elimination — Humalog Mix50/50 has two absorption phases, a rapid and a prolonged phase,
representative of the insulin lispro and insulin lispro protamine suspension components of the mixture. As
with other intermediate-acting insulins, a meaningful terminal phase half-life cannot be calculated after
administration of Humalog Mix50/50 because of the prolonged insulin lispro protamine suspension
absorption.
Pharmacodynamics
Studies in nondiabetic subjects and patients with diabetes demonstrated that Humalog has a more
rapid onset of glucose-lowering activity, an earlier peak for glucose-lowering, and a shorter duration of
glucose-lowering activity than Regular human insulin. The early onset of activity of Humalog Mix50/50 is
directly related to the rapid absorption of Humalog. The time course of action of insulin and insulin
analogs, such as Humalog (and hence Humalog Mix50/50), may vary considerably in different individuals
or within the same individual. The parameters of Humalog Mix50/50 activity (time of onset, peak time, and
duration) as presented in Figures 2 and 3 should be considered only as general guidelines. The rate of
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insulin absorption and consequently the onset of activity is known to be affected by the site of injection,
exercise, and other variables (see General under PRECAUTIONS).
In a glucose clamp study performed in 30 nondiabetic subjects, the onset of action and glucose-
lowering activity of Humalog, Humalog Mix50/50, Humalog® Mix75/25™, and insulin lispro protamine
suspension (NPL component) were compared (see Figure 2). Graphs of mean glucose infusion rate
versus time showed a distinct insulin activity profile for each formulation. The rapid onset of glucose-
lowering activity characteristic of Humalog was maintained in Humalog Mix50/50.
Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a
cross-study comparison shown on Figure 3 suggests that Humalog Mix50/50 has a duration of activity
that is similar to Humulin 50/50. graph
Figure 2: Glucose Infusion Rates (A Measure of Insulin Activity) After Injection of Humalog,
Humalog Mix50/50, Humalog Mix75/25, or Insulin Lispro Protamine Suspension (NPL Component)
in 30 Nondiabetic Subjects.
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graph
Figure 3: Insulin Activity After Subcutaneous Injection of Humalog Mix50/50 and Humulin 50/50 in
Nondiabetic Subjects.
Figures 2 and 3 represent insulin activity profiles as measured by glucose clamp studies in healthy
nondiabetic subjects.
Figure 2 shows the time activity profiles of Humalog, Humalog Mix75/25, Humalog Mix50/50, and
insulin lispro protamine suspension (NPL component).
Figure 3 is a comparison of the time activity profiles of Humalog Mix50/50 (see Figure 3a) and of
Humulin 50/50 (see Figure 3b) from two different studies.
Special Populations
Age and Gender — Information on the effect of age on the pharmacokinetics of Humalog Mix50/50 is
unavailable. Pharmacokinetic and pharmacodynamic comparisons between men and women
administered Humalog Mix50/50 showed no gender differences. In large Humalog clinical trials, sub
group analysis based on age and gender demonstrated that differences between Humalog and Regular
human insulin in postprandial glucose parameters are maintained across sub-groups.
Smoking — The effect of smoking on the pharmacokinetics and pharmacodynamics of Humalog
Mix50/50 has not been studied.
Pregnancy — The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Humalog
Mix50/50 has not been studied.
Obesity — The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and
pharmacodynamics of Humalog Mix50/50 has not been studied. In large clinical trials, which included
patients with Body Mass Index up to and including 35 kg/m2, no consistent differences were observed
between Humalog and Humulin® R with respect to postprandial glucose parameters.
Renal Impairment — The effect of renal impairment on the pharmacokinetics and pharmacodynamics of
Humalog Mix50/50 has not been studied. In a study of 25 patients with type 2 diabetes and a wide range
of renal function, the pharmacokinetic differences between Humalog and Regular human insulin were
generally maintained. However, the sensitivity of the patients to insulin did change, with an increased
response to insulin as the renal function declined. Careful glucose monitoring and dose reductions of
insulin, including Humalog Mix50/50, may be necessary in patients with renal dysfunction.
Hepatic Impairment — Some studies with human insulin have shown increased circulating levels of
insulin in patients with hepatic failure. The effect of hepatic impairment on the pharmacokinetics and
pharmacodynamics of Humalog Mix50/50 has not been studied. However, in a study of 22 patients with
type 2 diabetes, impaired hepatic function did not affect the subcutaneous absorption or general
disposition of Humalog when compared with patients with no history of hepatic dysfunction. In that study,
Humalog maintained its more rapid absorption and elimination when compared with Regular human
insulin. Careful glucose monitoring and dose adjustments of insulin, including Humalog Mix50/50, may be
necessary in patients with hepatic dysfunction.
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INDICATIONS AND USAGE
Humalog Mix50/50, a mixture of 50% insulin lispro protamine suspension and 50% insulin lispro
injection, (rDNA origin), is indicated in the treatment of patients with diabetes mellitus for the control of
hyperglycemia. Based on cross-study comparisons of the pharmacodynamics of Humalog Mix50/50 and
Humulin 50/50, it is likely that Humalog Mix50/50 has a more rapid onset of glucose-lowering activity
compared with Humulin 50/50 while having a similar duration of action. This profile is achieved by
combining the rapid onset of Humalog with the intermediate action of insulin lispro protamine suspension.
CONTRAINDICATIONS
Humalog Mix50/50 is contraindicated during episodes of hypoglycemia and in patients sensitive to
insulin lispro or any of the excipients contained in the formulation.
WARNINGS
Humalog® Mix50/50™ KwikPens® must never be shared between patients, even if the needle is
changed. Patients using Humalog Mix50/50 vials must never share needles or syringes with
another person. Sharing poses a risk for transmission of blood-borne pathogens.
Humalog differs from Regular human insulin by its rapid onset of action as well as a shorter
duration of activity. Therefore, the dose of Humalog Mix50/50 should be given within 15 minutes
before a meal.
Hypoglycemia is the most common adverse effect associated with the use of insulins, including
Humalog Mix50/50. As with all insulins, the timing of hypoglycemia may differ among various
insulin formulations. Glucose monitoring is recommended for all patients with diabetes.
Any change of insulin should be made cautiously and only under medical supervision. Changes
in insulin strength, manufacturer, type (e.g., Regular, NPH, analog), species, or method of
manufacture may result in the need for a change in dosage.
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists:
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma
agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid
retention may lead to or exacerbate heart failure. Patients treated with insulin, including Humalog
Mix50/50, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If
heart failure develops, it should be managed according to current standards of care, and discontinuation
or dose reduction of the PPAR-gamma agonist must be considered.
PRECAUTIONS
General
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the
use of all insulins. Because of differences in the action of Humalog Mix50/50 and other insulins, care
should be taken in patients in whom such potential side effects might be clinically relevant (e.g., patients
who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking
drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential
clinical adverse effects associated with the use of all insulins.
As with all insulin preparations, the time course of Humalog Mix50/50 action may vary in different
individuals or at different times in the same individual and is dependent on site of injection, blood supply,
temperature, and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their
usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other
stress.
Hypoglycemia — As with all insulin preparations, hypoglycemic reactions may be associated with the
administration of Humalog Mix50/50. Rapid changes in serum glucose concentrations may induce
symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning
symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long
duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified
diabetes control.
Renal Impairment — As with other insulins, the requirements for Humalog Mix50/50 may be reduced
in patients with renal impairment.
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Hepatic Impairment — Although impaired hepatic function does not affect the absorption or disposition
of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog Mix50/50,
may be necessary.
Allergy — Local Allergy — As with any insulin therapy, patients may experience redness, swelling, or
itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In
some instances, these reactions may be related to factors other than insulin, such as irritants in the skin
cleansing agent or poor injection technique.
Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which
may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in
blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic
reaction, may be life threatening. Localized reactions and generalized myalgias have been reported with
the use of cresol as an injectable excipient.
Antibody Production — In clinical trials, antibodies that cross-react with human insulin and insulin lispro
were observed in both human insulin mixtures and insulin lispro mixtures treatment groups.
Information for Patients
Patients should be informed of the potential risks and advantages of Humalog Mix50/50 and alternative
therapies. Patients should not mix Humalog Mix50/50 with any other insulin. They should also be
informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence
to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1c
testing, recognition and management of hypo- and hyperglycemia, and periodic assessment for diabetes
complications.
Patients should be advised to inform their physician if they are pregnant or intend to become pregnant.
Refer patients to the Patient Information leaflet for information on normal appearance, timing of dosing
(within 15 minutes before a meal), storing, and common adverse effects.
For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the
Patient Information leaflet that accompanies the drug product and the User Manual that accompanies the
delivery device and re-read them each time the prescription is renewed. Patients should be instructed on
how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of
needles. Patients should be advised not to share their Pens with others.
Laboratory Tests
As with all insulins, the therapeutic response to Humalog Mix50/50 should be monitored by periodic
blood glucose tests. Periodic measurement of hemoglobin A1c is recommended for the monitoring of long-
term glycemic control.
Drug Interactions
Insulin requirements may be increased by medications with hyperglycemic activity such as
corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives,
phenothiazines, and thyroid replacement therapy.
Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have
hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain
antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II
receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and
alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of
Humalog, Humalog Mix75/25, or Humalog Mix50/50. Insulin lispro was not mutagenic in a battery of in
vitro and in vivo genetic toxicity assays (bacterial mutation tests, unscheduled DNA synthesis, mouse
lymphoma assay, chromosomal aberration tests, and a micronucleus test). There is no evidence from
animal studies of impairment of fertility induced by insulin lispro.
Pregnancy
Teratogenic Effects — Pregnancy Category B — Reproduction studies with insulin lispro have been
performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the
average human dose (40 units/day) based on body surface area. The results have revealed no evidence
of impaired fertility or harm to the fetus due to insulin lispro. There are, however, no adequate and well-
controlled studies with Humalog, Humalog Mix75/25, or Humalog Mix50/50 in pregnant women. Because
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animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
It is unknown whether insulin lispro is excreted in significant amounts in human milk. Many drugs,
including human insulin, are excreted in human milk. For this reason, caution should be exercised when
Humalog Mix50/50 is administered to a nursing woman. Patients with diabetes who are lactating may
require adjustments in Humalog Mix50/50 dose, meal plan, or both.
Pediatric Use
Safety and effectiveness of Humalog Mix50/50 in patients less than 18 years of age have not been
established.
Geriatric Use
Clinical studies of Humalog Mix50/50 did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently than younger patients. In general, dose selection for an
elderly patient should take into consideration the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy in this population.
ADVERSE REACTIONS
Clinical studies comparing Humalog Mix50/50 with human insulin mixtures did not demonstrate a
difference in frequency of adverse events between the two treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as a Whole — allergic reactions (see PRECAUTIONS).
Skin and Appendages — injection site reaction, lipodystrophy, pruritus, rash.
Other — hypoglycemia (see W ARNINGS and PRECAUTIONS).
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure,
or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug
dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or
neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
hypoglycemia may recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION
Table 1*: Summary of Pharmacodynamic Properties of Insulin Products (Pooled Cross-Study
Comparison)
Insulin Products
Dose, U/kg
Time of Peak Activity,
Hours After Dosing
Percent of Total Activity
Occurring in the First
4 Hours
Humalog
0.3
2.4
(0.8 - 4.3)
70%
(49 - 89%)
Humulin R
0.32
(0.26 - 0.37)
4.4
(4.0 - 5.5)
54%
(38 - 65%)
Humalog Mix75/25
0.3
2.6
(1.0 - 6.5)
35%
(21 - 56%)
Humulin 70/30
0.3
4.4
(1.5 - 16)
32%
(14 - 60%)
Humalog Mix50/50
0.3
2.3
(0.8 - 4.8)
45%
(27 - 69%)
Humulin 50/50
0.3
3.3
(2.0 - 5.5)
44%
(21 - 60%)
NPH
0.32
(0.27 - 0.40)
5.5
(3.5 - 9.5)
14%
(3.0 - 48%)
NPL component
0.3
5.8
(1.3 - 18.3)
22%
(6.3 - 40%)
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A1.01-LOG5050-0001-USPI-YYYYMMDD
* The information supplied in Table 1 indicates when peak insulin activity can be expected and the percent of
the total insulin activity occurring during the first 4 hours. The information was derived from 3 separate
glucose clamp studies in nondiabetic subjects. Values represent means, with ranges provided in
parentheses.
Humalog Mix50/50 is intended only for subcutaneous administration. Humalog Mix50/50 should not be
administered intravenously. Dosage regimens of Humalog Mix50/50 will vary among patients and should
be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and
other lifestyle variables. Humalog has been shown to be equipotent to Regular human insulin on a molar
basis. One unit of Humalog has the same glucose-lowering effect as one unit of Regular human insulin,
but its effect is more rapid and of shorter duration. The quicker glucose-lowering effect of Humalog is
related to the more rapid absorption rate of insulin lispro from subcutaneous tissue.
Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a
cross-study comparison shown in Figure 3 suggests that Humalog Mix50/50 has a duration of activity that
is similar to Humulin 50/50.
The rate of insulin absorption and consequently the onset of activity are known to be affected by the
site of injection, exercise, and other variables. As with all insulin preparations, the time course of action of
Humalog Mix50/50 may vary considerably in different individuals or within the same individual. Patients
must be educated to use proper injection techniques.
Humalog Mix50/50 should be inspected visually before use. Humalog Mix50/50 should be used only if it
appears uniformly cloudy after mixing. Humalog Mix50/50 should not be used after its expiration date.
HOW SUPPLIED
Humalog Mix50/50 [50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA
origin)] is available in the following package sizes: each presentation containing 100 units insulin lispro
per mL (U-100).
10 mL vials
NDC 0002-7512-01 (VL-7512)
5 x 3 mL prefilled insulin delivery devices (KwikPen®)
NDC 0002-8798-59 (HP-8798)
Each prefilled Humalog Mix50/50 KwikPen is for use by a single patient. Humalog Mix50/50 KwikPens
must never be shared between patients, even if the needle is changed. Patients using Humalog Mix50/50
vials must never share needles or syringes with another person.
Storage — Humalog Mix50/50 should be stored in a refrigerator [2° to 8°C (36° to 46°F)], but not in the
freezer. Do not use Humalog Mix50/50 if it has been frozen. Unrefrigerated [below 30°C (86°F)] vials
must be used within 28 days or be discarded, even if they still contain Humalog Mix50/50. Unrefrigerated
[below 30°C (86°F)] KwikPens must be used within 10 days or be discarded, even if they still contain
Humalog Mix50/50. Protect from direct heat and light. See table below:
Not In-Use (Unopened)
Room Temperature
[Below 30°C (86°F)]
Not In-Use (Unopened)
Refrigerated
In-Use (Opened) Room
Temperature [Below
30°C (86°F)]
10 mL Vial
28 days
Until expiration date
28 days,
refrigerated/room
temperature.
3 mL KwikPen
(prefilled)
10 days
Until expiration date
10 days. Do not
refrigerate.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
www.humalog.com
Copyright © 2007, YYYY, Eli Lilly and Company. All rights reserved.
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Patient Information
Humalog® (HU-ma-log) Mix50/50TM
50% insulin lispro protamine suspension and
50% insulin lispro injection (rDNA origin)
Important:
Know your insulin. Do not change the type of insulin you use unless told to do so by
your healthcare provider. Your insulin dose and the time you take your dose can change
with different types of insulin.
Make sure you have the right type and strength of insulin prescribed for you.
Read the Patient Information that comes with Humalog Mix50/50 before you start using
it and each time you get a refill. There may be new information. This leaflet does not
take the place of talking with your healthcare provider about your diabetes or treatment.
Make sure that you know how to manage your diabetes. Ask your healthcare provider if
you have questions about managing your diabetes.
Do not share your Humalog Mix50/50 KwikPen or syringes with other people,
even if the needle has been changed. You may give other people a serious
infection or get a serious infection from them.
What is Humalog Mix50/50?
Humalog Mix50/50 is a mixture of fast-acting and longer-acting man-made insulins.
Humalog Mix50/50 is used to control high blood sugar (glucose) in people with diabetes.
Humalog Mix50/50 comes in:
• 10 mL vials (bottles) for use with a syringe
• Prefilled pens
Who should not take Humalog Mix50/50?
Do not take Humalog Mix50/50 if:
• your blood sugar is too low (hypoglycemia). After treating your low blood sugar,
follow your healthcare provider’s instructions on the use of Humalog Mix50/50.
• you are allergic to anything in Humalog Mix50/50. See the end of this leaflet for a
complete list of ingredients in Humalog Mix50/50.
What should I tell my healthcare provider before taking Humalog Mix50/50?
Before you use Humalog Mix50/50, tell your healthcare provider if you:
• have liver or kidney problems or any other medical conditions. Medical
conditions can affect your insulin needs and your dose of Humalog Mix50/50.
• take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
• have heart failure or other heart problems. If you have heart failure, it may get
worse while you take TZDs with Humalog Mix50/50.
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• are pregnant or breastfeeding. You and your healthcare provider should talk
about the best way to manage your diabetes while you are pregnant or
breastfeeding. Humalog Mix50/50 has not been studied in pregnant or nursing
women.
• take other medicines, including prescription and non-prescription
medicines, vitamins and herbal supplements. Many medicines can affect your
blood sugar levels and insulin needs. Your Humalog Mix50/50 dose may need to
change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to show to all of
your healthcare providers.
How should I use Humalog Mix50/50?
Talk to your healthcare provider if you have any questions. Your healthcare provider will
tell you the right syringes to use with Humalog Mix50/50 vials. Your healthcare provider
should show you how to inject Humalog Mix50/50 before you start using it. Read the
User Manual that comes with your Humalog Mix50/50 prefilled pen.
• Do not share your Humalog Mix50/50 KwikPen or syringes with other
people, even if the needle has been changed. You may give other people a
serious infection or get a serious infection from them.
• Use Humalog Mix50/50 exactly as prescribed by your healthcare provider.
• Humalog Mix50/50 starts working faster than other insulins that contain
regular human insulin. Inject Humalog Mix50/50 fifteen minutes or less before a
meal. If you do not plan to eat within 15 minutes, delay the injection until the
correct time (15 minutes before eating).
• Check your blood sugar levels as told by your healthcare provider.
• Mix Humalog Mix50/50 well before each use. For Humalog Mix50/50 in a vial,
carefully shake or rotate the vial until completely mixed. For prefilled pens,
carefully follow the User Manual for instructions on mixing the pen. Humalog
Mix50/50 should be cloudy or milky after mixing well.
• Look at your Humalog Mix50/50 before each injection. If it is not evenly mixed or
has solid particles or clumps in it, do not use. Return it to your pharmacy for new
Humalog Mix50/50.
• Inject your dose of Humalog Mix50/50 under the skin of your stomach area,
upper arm, upper leg, or buttocks. Never inject Humalog Mix50/50 into a
muscle or vein.
• Change (rotate) your injection site with each dose.
• Your insulin needs may change because of:
• illness
• stress
• other medicines you take
• changes in eating
• physical activity changes
Follow your healthcare provider’s instructions to make changes in your insulin
dose.
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• Never mix Humalog Mix50/50 in the same syringe with other insulin
products.
• Never use Humalog Mix50/50 in an insulin pump.
• Always carry a quick source of sugar to treat low blood sugar, such as
glucose tablets, hard candy, or juice.
What are the possible side effects of Humalog Mix50/50?
Low Blood Sugar (Hypoglycemia). Symptoms of low blood sugar include:
• hunger
• dizziness
• feeling shaky or shakiness
• lightheadedness
• sweating
• irritability
• headache
• fast heartbeat
• confusion
Low blood sugar symptoms can happen suddenly. Symptoms of low blood sugar may
be different for each person and may change from time to time. Severe low blood sugar
can cause seizures and death. Low blood sugar may affect your ability to drive a car or
use mechanical equipment, risking injury to yourself or others. Know your symptoms of
low blood sugar. Low blood sugar can be treated by drinking juice or regular soda or
eating glucose tablets, sugar, or hard candy. Follow your healthcare provider’s
instructions for treating low blood sugar. Talk to your healthcare provider if low blood
sugar is a problem for you.
• Serious allergic reactions (whole body allergic reaction). Severe, life-
threatening allergic reactions can happen with insulin. Get medical help right
away if you develop a rash over your whole body, have trouble breathing,
wheezing, a fast heartbeat, or sweating.
• Reactions at the injection site (local allergic reaction). You may get redness,
swelling, and itching at the injection site. If you keep having injection site
reactions or they are serious, you need to call your healthcare provider. Do not
inject insulin into a skin area that is red, swollen, or itchy.
• Skin thickens or pits at the injection site (lipodystrophy). This can happen if
you don’t change (rotate) your injection sites enough.
Humalog Mix50/50 may cause serious side effects, including:
• swelling of your hands and feet
• heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs”
with Humalog Mix50/50 may cause heart failure in some people. This can
happen even if you have never had heart failure or heart problems before. If you
already have heart failure it may get worse while you take TZDs with Humalog
Mix50/50. Your healthcare provider should monitor you closely while you are
taking TZDs with Humalog Mix50/50. Tell your healthcare provider if you have
any new or worse symptoms of heart failure including:
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A1.01-LOG5050-5572-PPI-YYYYMMDD
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and Humalog Mix50/50 may need to be adjusted or stopped by
your healthcare provider if you have new or worse heart failure.
These are not all the side effects from Humalog Mix50/50. Ask your healthcare provider
or pharmacist for more information.
How should I store Humalog Mix50/50?
• Store all unopened (unused) Humalog Mix50/50 in the original carton in a
refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze.
• Do not use Humalog Mix50/50 that has been frozen.
• Do not use after the expiration date printed on the carton and label.
• Protect Humalog Mix50/50 from extreme heat, cold or light.
After starting use (open):
• Vials: Keep in the refrigerator or at room temperature below 86°F (30°C) for up
to 28 days. Keep open vials away from direct heat or light. Throw away an
opened vial 28 days after first use, even if there is insulin left in the vial.
• Prefilled Pens: Do not store a prefilled pen that you are using in the refrigerator.
Keep at room temperature below 86°F (30°C) for up to 10 days. Throw away a
prefilled pen 10 days after first use, even if there is insulin left in the pen.
General information about Humalog Mix50/50
Use Humalog Mix50/50 only to treat your diabetes. Do not share it with other people,
even if they also have diabetes. It may harm them.
This leaflet summarized the most important information about Humalog Mix50/50. If you
would like more information about Humalog Mix50/50 or diabetes, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for information
about Humalog Mix50/50 that is written for healthcare providers.
For questions you may call 1-800-LillyRx (1-800-545-5979) or visit www.humalog.com.
What are the ingredients in Humalog Mix50/50?
Active ingredients: insulin lispro protamine suspension and insulin lispro.
Inactive ingredients: protamine sulfate, glycerin, dibasic sodium phosphate,
metacresol, zinc oxide (zinc ion), phenol and water for injection.
Patient Information revised: February 2015
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
www.humalog.com
Copyright © 2007, yyyy, Eli Lilly and Company. All rights reserved.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
HUMALOG® Mix50/50™ KwikPen®
50% insulin lispro protamine suspension and
50% insulin lispro injection (rDNA origin) usage illustration
Read the Instructions for Use before you start taking HUMALOG Mix50/50 and each
time you get a refill. There may be new information. This information does not take
the place of talking to your healthcare provider about your medical condition or your
treatment.
Do not share your HUMALOG Mix50/50 KwikPen with other people, even if
the needle has been changed. You may give other people a serious infection
or get a serious infection from them.
HUMALOG® Mix50/50™ KwikPen® (“Pen”) is a disposable pen containing 3 mL
(300 units) of U-100 HUMALOG® Mix50/50™ [50% insulin lispro protamine
suspension and 50% insulin lispro injection (rDNA origin)] insulin. You can inject
from 1 to 60 units in a single injection.
This Pen is not recommended for use by the blind or visually impaired
without the assistance of a person trained in the proper use of the product. usage illustration
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 1:
Pull the Pen Cap straight off.
Wipe the Rubber Seal with an alcohol
swab.
• Do not twist the cap.
• Do not remove the KwikPen Label.
Step 2:
Gently roll the Pen ten times.
Invert the Pen ten times.
HUMALOG Mix50/50 should look white
and cloudy after mixing. Do not use if it
looks clear or contains any lumps or
particles.
u
s
age illustration
Supplies you will need to give your HUMALOG Mix50/50 injection:
• HUMALOG Mix50/50 KwikPen
• HUMALOG Mix50/50 KwikPen compatible needle (Becton, Dickinson and
Company Pen Needles recommended)
• Alcohol swab
Preparing HUMALOG Mix50/50 KwikPen:
• Wash your hands with soap and water.
• Check the HUMALOG Mix50/50 KwikPen Label to make sure you are taking the
right type of insulin. This is especially important if you use more than 1 type of
insulin.
• Do not use HUMALOG Mix50/50 past the expiration date printed on the Label.
• Always use a new needle for each injection to help ensure sterility and
prevent blocked needles. Do not reuse or share your needles with
other people. You may give other people a serious infection or get a
serious infection from them.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
age illustration
Step 6:
Turn the Dose Knob to select 2 units.
Step 7:
Hold your Pen with the Needle pointing
up. Tap the Cartridge Holder gently to
collect air bubbles at the top.
u
sage illustration
Step 3:
Pull off the Paper Tab from Outer Needle
Shield.
Step 4:
Push the capped Needle straight onto the
Pen and turn the Needle forward until it is
tight.
Step 5:
Pull off the Outer Needle Shield. Do not
throw it away.
Pull off the Inner Needle Shield and throw
it away.
Priming your HUMALOG Mix50/50 KwikPen:
Prime before each injection. Priming ensures the Pen is ready to dose and
removes air that may collect in the cartridge during normal use. If you do not prime
before each injection, you may get too much or too little insulin.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
sage illustration
Step 9:
Turn the Dose Knob to select the number
of units you need to inject. The Dose
Indicator should line up with your dose.
• The dose can be corrected by
turning the Dose Knob in either
direction until the correct dose
lines up with the Dose Indicator.
• The even numbers are printed on
the dial. The odd numbers, after
the number 1, are shown as full
lines.
u
s
a
g
e
illustration
Step 8:
Hold your Pen with Needle pointing up.
Push the Dose Knob in until it stops, and
“0” is seen in the Dose Window. Hold the
Dose Knob in and count to 5 slowly.
• A stream of insulin should be seen
from the needle.
-
If you do not see a stream of
insulin, repeat steps 6 to 8, no
more than 4 times.
-
If you still do not see a stream
of insulin, change the needle
and repeat steps 6 to 8.
Selecting your dose:
• The HUMALOG Mix50/50 KwikPen will not let you dial more than the number of
units left in the Pen.
• If your dose is more than the number of units left in the Pen, you may either:
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 10:
Choose your injection site.
HUMALOG Mix50/50 is injected under the
skin (subcutaneously) of your stomach
area, buttocks, upper legs or upper arms.
Wipe the skin with an alcohol swab, and
let the injection site dry before you inject
your dose.
Step 11:
Insert the Needle into your skin.
Step 12:
Put your thumb on the Dose Knob and
push the Dose Knob in until it stops. Hold
the Dose Knob in and slowly count to
5.
u
s
age illustration
-
inject the amount left in your Pen and then use a new Pen to give the rest
of your dose, or
-
get a new Pen and inject the full dose.
• The Pen is designed to deliver a total of 300 units of insulin. The cartridge
contains an additional small amount of insulin that can’t be delivered.
Giving your HUMALOG Mix50/50 injection:
• Inject your HUMALOG Mix50/50 as your healthcare provider has shown you.
• Change (rotate) your injection site for each injection.
• Do not try to change your dose while injecting HUMALOG Mix50/50.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
ge illustration
Step 13:
Pull the Needle out of your skin.
You should see “0” in the Dose Window.
If you do not see “0” in the Dose
Window, you did not receive your full
dose.
If you see blood after you take the
Needle out of your skin, press the
injection site lightly with a piece of gauze
or an alcohol swab. Do not rub the area.
A drop of insulin at the needle tip is
normal. It will not affect your dose.
If you do not think you received your
full dose, do not take another dose.
Call Lilly or your healthcare provider for
assistance.
Step 14:
Carefully replace the Outer Needle
Shield.
Step 15:
Unscrew the capped Needle and throw it
away.
Do not store the Pen with the Needle
attached to prevent leaking, blocking of
the Needle, and air from entering the
Pen.
Step 16:
Replace the Pen Cap by lining up the Cap
Clip with the Dose Indicator and pushing
straight on.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After your injection:
• Put your used needles in a FDA-cleared sharps disposal container right away
after use. Do not throw away (dispose of) loose needles in your household
trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a
household container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your
community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used needles and syringes. For more information about safe sharps disposal,
and for specific information about sharps disposal in the state that you live in,
go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal
• Do not dispose of your used sharps disposal container in your household trash
unless your community guidelines permit this. Do not recycle your used sharps
disposal container.
• The used Pen may be discarded in your household trash after you have
removed the needle.
How should I store my HUMALOG Mix50/50 KwikPen?
• Store unused HUMALOG Mix50/50 Pens in the refrigerator at 36°F to 46°F
(2°C to 8°C). The Pen you are currently using can be stored out of the
refrigerator below 86°F (30°C).
• Do not freeze HUMALOG Mix50/50. Do not use HUMALOG Mix50/50 if it has
been frozen.
• Unused HUMALOG Mix50/50 Pens may be used until the expiration date
printed on the Label, if kept in the refrigerator.
• The HUMALOG Mix50/50 Pen you are using should be thrown away after 10
days, even if it still has insulin left in it.
• Keep HUMALOG Mix50/50 away from heat and out of the light.
General information about the safe and effective use of HUMALOG Mix50/50
KwikPen
• Keep HUMALOG Mix50/50 KwikPen and needles out of the reach of
children.
• Always use a new needle for each injection.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not share your Pen or needles with other people. You may give other
people a serious infection or get a serious infection from them.
• Do not use your Pen if any part looks broken or damaged.
• Always carry an extra Pen in case yours is lost or damaged.
• If you can not remove the Pen Cap, gently twist the Pen Cap back and forth,
and then pull the Pen Cap straight off.
• If it is hard to push the Dose Knob or the Pen is not working the right way:
-
Your Needle may be blocked. Put on a new Needle and prime the Pen.
-
You may have dust, food, or liquid inside the Pen. Throw the Pen away and
get a new one.
-
It may help to push the Dose Knob more slowly during your injection.
• Use the space below to keep track of how long you should use each HUMALOG
Mix50/50 KwikPen.
-
Write down the date you start using your HUMALOG Mix50/50 KwikPen.
Count forward 10 days.
-
Write down the date you should throw it away.
Example:
Pen 1 - First used on _______ + 10 days = Throw out on ______
Date
Date
Pen 1 - First used on _______ Throw out on _______
Date
Date
Pen 2 - First used on _______ Throw out on _______
Date
Date
Pen 3 - First used on _______ Throw out on _______
Date
Date
Pen 4 - First used on _______ Throw out on _______
Date
Date
Pen 5 - First used on _______ Throw out on _______
Date
Date
If you have any questions or problems with your HUMALOG Mix50/50 KwikPen,
contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for
help. For more information on HUMALOG Mix50/50 KwikPen and insulin, go to
www.humalog.com.
These Instructions for Use have been approved by the U.S. Food and Drug
Administration.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A2.01-LOG5050KP-8972-IFU-YYYYMMDD
Humalog® Mix50/50™ and Humalog® Mix50/50™ KwikPen® are trademarks of Eli Lilly
and Company.
Revised: February 2015
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2007, YYYY, Eli Lilly and Company. All rights reserved.
Humalog Mix50/50 KwikPen meets the current dose accuracy and functional
requirements of ISO 11608-1:2000.
Reference ID: 3706731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:29.636565 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021018s100lbl.pdf', 'application_number': 21018, 'submission_type': 'SUPPL ', 'submission_number': 100} |
4,543 | NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 1
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
1
DESCRIPTION
2
NovoLog Mix 70/30 (70% insulin aspart [rDNA origin] protamine suspension and 30% insulin aspart
3
[rDNA origin] injection) is a human insulin analogue suspension containing 70% insulin aspart
4
protamine crystals and 30% soluble insulin aspart. NovoLog Mix 70/30 is a blood glucose-lowering
5
agent with a rapid onset and an intermediate duration of action. Insulin aspart is homologous with
6
regular human insulin with the exception of a single substitution of the amino acid proline by aspartic
7
acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces
8
cerevisiae (baker’s yeast) as the production organism. Insulin aspart (NovoLog) has the empirical
9
formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
10
11
Structural formula:
12
Gly Ile Val Glu Gin Cys
Thr Ser Ile Cys Ser Leu Tyr Gin Leu Glu Asn Tyr Cys Asn
Cys
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
A-chain
B-chain
Phe Val Asn Gin His Leu Cys Gly Ser His Leu Val Glu Als Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Asp Lys Thr
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
NH2
-COOH
S
S
S
S
S
S
Asp
Pro
13
14
Figure 1. Structural formula of insulin aspart
15
16
NovoLog Mix 70/30 is a uniform, white, sterile suspension that contains insulin aspart (B28 asp
17
regular human insulin analogue) 100 Units/mL, mannitol 36.4 mg/mL, phenol 1.50 mg/mL,
18
metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL,
19
sodium chloride 0.58 mg/mL, and protamine sulfate 0.33 mg/mL. NovoLog Mix 70/30 has a pH
20
of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
21
22
23
CLINICAL PHARMACOLOGY
24
Mechanism of action
25
The primary activity of NovoLog Mix 70/30 is the regulation of glucose metabolism. Insulins,
26
including NovoLog Mix 70/30, exert their specific action through binding to insulin receptors. Insulin
27
binding activates mechanisms to lower blood glucose by facilitating cellular uptake of glucose into
28
skeletal muscle and fat, simultaneously inhibiting the output of glucose from the liver.
29
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 2
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-lowering
31
effect as one unit of regular human insulin. However, the effect of NovoLog Mix 70/30 is more rapid in
32
onset compared to Novolin (human insulin) 70/30 due to its faster absorption after subcutaneous
33
injection.
34
35
Pharmacokinetics
36
Bioavailability and absorption
37
The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart
38
(NovoLog) reduces the molecule’s tendency to form hexamers as observed with regular human
39
insulin. The rapid absorption characteristics of NovoLog® are maintained by NovoLog Mix 70/30. The
40
insulin aspart in the soluble component of NovoLog Mix 70/30 is absorbed more rapidly from the
41
subcutaneous layer than regular human insulin. The remaining 70% is in crystalline form as insulin
42
aspart protamine which has a prolonged absorption profile after subcutaneous injection.
43
44
The relative bioavailability of NovoLog Mix 70/30 compared to NovoLog and Novolin 70/30
45
indicates that they are absorbed to similar degrees. In euglycemic clamp studies in healthy
46
volunteers (n=23) after dosing with 0.2 U/kg of NovoLog Mix 70/30, a mean maximum serum
47
concentration (Cmax) of 23.4 ± 5.3 mU/L was reached after 60 minutes. The mean half-life
48
(t1/2) of NovoLog Mix 70/30 was about 8 to 9 hours. Serum insulin levels returned to baseline
49
15 to 18 hours after a subcutaneous dose. Similar data were seen in a separate euglycemic clamp
50
study in healthy volunteers (n=24) after dosing with 0.3 U/kg of NovoLog Mix 70/30. A Cmax
51
of 61.3 ± 20.1 mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12
52
hours after a subcutaneous dose.
53
54
The Cmax and the area under the insulin concentration-time curve (AUC) after administration of
55
NovoLog Mix 70/30 differed by approximately 20% from those after administration of NovoLog
56
Mix 50/50 (investigational drug, not marketed.) and Novolin 70/30 (see Fig. 2 and 3 for
57
pharmacokinetic profiles).
58
59
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 3
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
NovoLog Mix 70/30
Novolin 70/30
M ean Serum Insuli
n (m U/L)
Time (hours)
30
15
12
15
24
21
18
0
5
10
20
25
3
6
9
0
Points represent mean ± 2 SEM
60
61
Figure 2. Pharmacokinetic Profiles of NovoLog Mix 70/30 and Novolin® 70/30
62
63
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 4
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
Time (hours)
0
2
4
6
8
10 12 14 16 18 20 22 24
NovoLog Mix 70/30
NovoLog Mix 50/50*
NovoLog Mix 30/70*
NovoLog
Mean Serum Insulin (mU/L
64
65
Figure 3 Pharmacokinetic profiles for NovoLog Mix 70/30 and other proportional mixes (*
66
investigational drugs, not marketed).
67
68
Pharmacokinetic measurements were generated in clamp studies employing insulin doses of 0.3
69
U/kg.. Insulin kinetics exhibit significant inter- and intra-patient variability. The rate of insulin
70
absorption and consequently the onset of activity is known to be affected by the site of injection,
71
exercise, and other variables (see PRECAUTIONS, General). Differences in pharmacokinetics
72
between NovoLog Mix 70/30 and products to which it has been compared are not associated
73
with differences in overall glycemic control. .
74
75
76
77
Distribution and elimination- NovoLoghas a low binding to plasma proteins, 0 to 9%, similar
78
to regular human insulin. After subcutaneous administration in normal male volunteers (n=24),
79
NovoLog was more rapidly eliminated than regular human insulin with an average apparent
80
half-life of 81 minutes compared to 141 minutes for regular human insulin.
81
82
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 5
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Pharmacodynamics
83
The two euglycemic clamp studies described above assessed glucose utilization after dosing of healthy
84
volunteers. NovoLog Mix 70/30 has a more rapid onset of action than regular human insulin in studies
85
of normal volunteers and patients with diabetes. The peak pharmacodynamic effect of NovoLog Mix
86
70/30 occurs between 1 and 4 hours after injection. The duration of action may be as long as 24 hours
87
(see Figures 4 and 5).
88
89
90
NovoLog Mix 70/30
Novolin 70/30
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
Glucose Infusion Rate (mg/kg
*min)
2
8
9
10
7
6
5
4
3
1
0
91
92
Fig 4: Pharmacodynamic Activity Profile of NovoLog Mix 70/30 and Novolin 70/30 in healthy
93
subjects.
94
95
96
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 6
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Glucose infusion rate (mg/kg
*min)
0
2
4
6
8
10
12
14
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
NovoLog Mix 70/30
NovoLog Mix 50/50*
NovoLog Mix 30/70*
NovoLog
97
Figure 5. Pharmacodynamic Activity Profiles for NovoLog Mix 70/30 and other
98
proportional mixes (* investigational drugs, not marketed)
99
100
101
Pharmacodynamic measurements were generated in clamp studies employing insulin doses of 0.3 U/kg..
102
Insulin pharmacodynamics exhibit significant inter- and intra-patient variability. The rate of insulin
103
absorption and consequently the onset of activity is known to be affected by the site of injection,
104
exercise, and other variables (see PRECAUTIONS, General). Differences in pharmacodynamics
105
between NovoLog Mix 70/30 and products to which it has been compared are not associated with
106
differences in overall glycemic control.
107
108
109
Special populations
110
Children and adolescents-The pharmacokinetic and pharmacodynamic properties of NovoLog Mix
111
70/30 have not been assessed in children and adolescents less than 18 years of age.
112
113
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 7
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Geriatrics-The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog Mix 70/30
114
has not been studied.
115
116
Gender- The effect of gender on the pharmacokinetics and pharmacodynamics of NovoLog Mix 70/30
117
has not been studied.
118
119
Obesity-The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and
120
pharmacodynamics of NovoLog Mix 70/30 has not been studied but data on the rapid acting component
121
(NovoLog®) show no significant effect.
122
123
Ethnic origin-The effect of ethnic origin on the pharmacokinetics and pharmacodynamics of NovoLog
124
Mix 70/ 30 has not been studied.
125
126
Renal impairment-The effect of renal function on the pharmacokinetics and pharmacodynamics of
127
NovoLog Mix 70/30 has not been studied but data on the rapid acting component (NovoLog®) show no
128
significant effect. Some studies with human insulin have shown increased circulating levels of insulin in
129
patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including
130
NovoLog Mix 70/30, may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal
131
Impairment).
132
133
Hepatic impairment- The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics
134
of NovoLog Mix 70/30 has not been studied but data on the rapid-acting component (NovoLog®) show
135
no significant effect. Some studies with human insulin have shown increased circulating levels of
136
insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin,
137
including NovoLog Mix 70/30, may be necessary in patients with hepatic dysfunction (see
138
PRECAUTIONS, Hepatic Impairment).
139
140
Pregnancy-The effect of pregnancy on the pharmacokinetics and pharmacodynamics of NovoLog Mix
141
70/30 has not been studied (see PRECAUTIONS, Pregnancy).
142
143
Smoking-The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoLog Mix 70/30
144
has not been studied.
145
146
147
CLINICAL STUDIES
148
In a three-month, open-label trial, patients with Type 1 (n=146) or Type 2 (n=178) diabetes were treated
149
BID (before breakfast and before supper) with NovoLog Mix 70/30 or Novolin 70/30. The small
150
changes in glycemic control (HbA1c) were comparable across the treatment groups. (see Table 1).
151
152
153
154
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 8
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
155
156
Table 1: Glycemic Parameters at the End of Treatment ([Mean (SD)]
157
158
NovoLog Mix 70/30
Novolin 70/30
Type 1, N=92
Fasting Blood Glucose (mg/dL)
173 (62.3)
141 (58.7)
1.5 Hour Post Breakfast
185 (80.1)
198 (80.1)
1.5 Hour Post Dinner
158 (76.5)
169 (65.9)
HbA1c (%)
8.4 (1.1)
8.3 (1.0)
Type 2, N=169
Fasting Blood Glucose (mg/dL)
151 (39.2)
151 (67.6)
1.5 Hour Post Breakfast
180 (64.1)
198 (80.1)
1.5 Hour Post Dinner
166 (49.8)
189 (49.8)
HbA1c (%)
7.9 (1.0)
8.1 (1.1)
159
160
The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in
161
postprandial hyperglycemia between treatment groups has not been established.
162
163
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored
164
in the 3-month, open-label comparator trial as well as in a long-term extension trial. (see
165
PRECAUTIONS, Allergy).
166
167
168
169
170
INDICATIONS AND USAGE
171
NovoLog Mix 70/30 is indicated for the treatment of patients with diabetes mellitus for the control of
172
hyperglycemia.
173
174
CONTRAINDICATIONS
175
NovoLog Mix 70/30 is contraindicated during episodes of hypoglycemia and in patients hypersensitive
176
to NovoLog Mix 70/30 or one of its excipients.
177
178
WARNINGS
179
Because NovoLog Mix 70/30 has peak pharmacodynamic activity one hour after injection, it should be
180
administered with meals.
181
182
NovoLog Mix 70/30 should not be administered intravenously.
183
184
NovoLog Mix 70/30 is not to be used in insulin infusion pumps.
185
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 9
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
186
NovoLog Mix 70/30 should not be mixed with any other insulin product.
187
188
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog Mix 70/30.
189
As with all insulins, the timing of hypoglycemia may differ among various insulin formulations.
190
191
Glucose monitoring is recommended for all patients with diabetes.
192
193
Any change of insulin dose should be made cautiously and only under medical supervision. Changes in
194
insulin strength, manufacturer, type (e.g., regular, NPH, analog), species (animal, human), or method of
195
manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage.
196
197
PRECAUTIONS
198
199
General
200
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use
201
of all insulins. Because of differences in the action of NovoLog Mix 70/30 and other insulins, care
202
should be taken in patients in whom such potential side effects might be clinically relevant (e.g., patients
203
who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking
204
drugs sensitive to serum potassium level)
205
206
Fixed ratio insulins are typically dosed on a twice daily basis, i.e. before breakfast and supper,
207
with each dose intended to cover two meals or a meal and snack (see DOSAGE AND
208
ADMINISTRATION). Because there is diurnal variation in insulin resistance and endogenous
209
insulin secretion, variability in the time and content of meals, and variability in the time and
210
extent of exercise, fixed ratio insulin mixtures may not provide optimal glycemic control for all
211
patients. The dose of insulin required to provide adequate glycemic control for one of the meals
212
may result in hyper- or hypoglycemia for the other meal. The pharmacodynamic profile may
213
also be inadequate for patients (e.g. pregnant women) who require more frequent meals.
214
215
Adjustments in insulin dose or insulin type may be needed during illness, emotional stress, and
216
other physiologic stress in addition to changes in meals and exercise.
217
218
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site
219
used for injection and the degree of vascularization of the site. Smoking, temperature, and
220
exercise contribute to variations in blood flow and insulin absorption. These and other factors
221
contribute to inter- and intra-patient variability.
222
223
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the
224
use of all insulins.
225
226
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NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 10
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Hypoglycemia-As with all insulin preparations, hypoglycemic reactions may be associated with the
227
administration of NovoLog Mix 70/30. Rapid changes in serum glucose concentrations may induce
228
symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning
229
symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long
230
duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified
231
diabetes control.
232
233
Renal Impairment- Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients
234
with various degrees of renal impairment have not been conducted. As with other insulins, the
235
requirements for NovoLog Mix 70/30 may be reduced in patients with renal impairment.
236
237
Hepatic Impairment-Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients
238
with various degrees of hepatic impairment have not been conducted. As with other insulins, the
239
requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic impairment.
240
241
Allergy-
242
Local Reactions- Erythema, swelling, and pruritus at the injection site have been observed with
243
NovoLog Mix 70/30 as with other insulin therapy. Reactions may be related to the insulin molecule,
244
other components in the insulin preparation including protamine and cresol, components in skin
245
cleansing agents, or injection techniques.
246
247
Systemic Reactions- Less common, but potentially more serious, is generalized allergy to insulin,
248
which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction
249
in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic
250
reaction, may be life threatening. Localized reactions and generalized myalgias have been reported with
251
the use of cresol as an injectable excipient.
252
253
254
Antibody production-Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies
255
were monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial.
256
Changes in cross-reactive antibodies were more common after NovoLog Mix 70/30 than with Novolin®
257
70/30 but these changes did not correlate with change in HbA1c or increase in insulin dose. The clinical
258
significance of these antibodies has not been established. Antibodies did not increase further after long-
259
term exposure (>6 months) to NovoLog Mix 70/30. ..
260
261
Information for patients-
262
Patients should be informed about potential risks and advantages of NovoLog Mix 70/30 therapy
263
including the possible side effects. Patients should also be offered continued education and advice on
264
insulin therapies, injection technique, life-style management, regular glucose monitoring, periodic
265
glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence
266
to meal planning, complications of insulin therapy, timing of dose, instruction for use of injection
267
devices, and proper storage of insulin.
268
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 11
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
269
Female patients should be advised to discuss with their physician if they intend to, or if they become,
270
pregnant because information is not available on the use of NovoLog Mix 70/30 during pregnancy or
271
lactation (see PRECAUTIONS, Pregnancy).
272
273
Laboratory Tests- The therapeutic response to NovoLog Mix 70/30 should be assessed by measurement
274
of serum or blood glucose and glycosylated hemoglobin.
275
276
Drug Interactions A number of substances affect glucose metabolism and may require insulin dose
277
adjustment and particularly close monitoring. The following are examples of substances that may
278
increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic
279
products, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors,
280
propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide antibiotics.
281
282
The following are examples of substances that may reduce the blood-glucose-lowering effect:
283
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol,
284
terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens,
285
progestogens (e.g., in oral contraceptives).
286
287
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-
288
lowering effect of insulin.
289
290
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
291
292
In addition, under the influence of sympatholytic medical products such as beta-blockers, clonidine,
293
guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent (see CLINICAL
294
PHARMACOLOGY).
295
296
297
Mixing of insulins
298
NovoLog Mix 70/30 should not be mixed with any other insulin product.
299
300
Carcinogenicity, Mutagenicity, Impairment of Fertility
301
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic
302
potential of NovoLog Mix 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously
303
with NovoLog, the rapid-acting component of NovoLog Mix 70/30, at 10, 50, and 200 U/kg/day
304
(approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body
305
surface area, respectively). At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary
306
gland tumors in females when compared to untreated controls. The incidence of mammary tumors for
307
NovoLog was not significantly different than for regular human insulin. The relevance of these
308
findings to humans is not known. NovoLog was not genotoxic in the following tests: Ames test,
309
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 12
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome
310
aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In
311
fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day
312
(approximately 32 times the human subcutaneous dose, based on U/body surface area) had no direct
313
adverse effects on male and female fertility, or on general reproductive performance of animals.
314
315
Pregnancy: Teratogenic Effects: Pregnancy Category C:
316
Animal reproduction studies have not been conducted with NovoLog Mix 70/30. However,
317
reproductive toxicology and teratology studies have been performed with NovoLog (the rapid-acting
318
component of NovoLog Mix 70/30) and regular human insulin in rats and rabbits. In these studies,
319
NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to
320
rabbits during organogenesis. The effects of NovoLog did not differ from those observed with
321
subcutaneous regular human insulin. NovoLog, like human insulin, caused pre- and post-implantation
322
losses and visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the
323
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of 10
324
U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body
325
surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No
326
significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day.
327
These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal
328
to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface area.
329
330
It is not known whether NovoLog Mix 70/30 can cause fetal harm when administered to a pregnant
331
woman or can affect reproductive capacity. There are no adequate and well-controlled studies of the use
332
of NovoLog Mix 70/30 or NovoLog in pregnant women. NovoLog Mix 70/30 should be used during
333
pregnancy only if the potential benefit justifies the potential risk to the fetus.
334
335
Nursing mothers-It is unknown whether NovoLog Mix 70/30 is excreted in human milk as is human
336
insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 or
337
NovoLog in lactating women.
338
339
Pediatric Use-Safety and effectiveness of NovoLog Mix 70/30 in children have not been established.
340
341
Geriatric Use- Clinical studies of NovoLog Mix 70/30 did not include sufficient numbers of patients
342
aged 65 and over to determine whether they respond differently than younger patients. In general, dose
343
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range
344
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
345
disease or other drug therapy in this population.
346
347
348
ADVERSE REACTIONS
349
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 13
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Clinical trials comparing NovoLog Mix 70/30 with Novolin 70/30 did not demonstrate a difference in
350
frequency of adverse events between the two treatments.
351
Adverse events commonly associated with human insulin therapy include the following:
352
353
Body as whole: allergic reactions (see PRECAUTIONS, Allergy).
354
Skin and Appendages: Local injection site reactions or rash or pruritus, as with other insulin
355
therapies, occurred in 7% of all patients on NovoLog Mix 70/30 and 5% on Novolin® 70/30. Rash led
356
to withdrawal of therapy in <1% of patients on either drug. (see PRECAUTIONS, Allergy).
357
Hypoglycemia: see WARNINGS and PRECAUTIONS.
358
Other: Small elevations in alkaline phosphatase were observed in patients treated in NovoLog®
359
controlled clinical trials. There have been no clinical consequences of these laboratory findings.
360
361
362
OVERDOSAGE
363
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure,
364
or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug
365
dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or
366
neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated
367
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
368
hypoglycemia may recur after apparent clinical recovery.
369
370
371
DOSAGE AND ADMINISTRATION
372
General:
373
Fixed ratio insulins are typically dosed on a twice daily basis, i.e. before breakfast and supper,
374
with each dose intended to cover two meals or a meal and snack. NovoLog Mix 70/30 is
375
intended only for subcutaneous injection (into the abdominal wall, thigh, or upper arm).
376
NovoLog Mix 70/30 should not be administered intravenously. The absorption rate of NovoLog
377
Mix 70/30 from the subcutaneous tissue allows dosing within 15 minutes of meal initiation.
378
. Dose regimens of NovoLog Mix 70/30 will vary among patients and should be determined by
379
the health care professional familiar with the patient’s metabolic needs, eating habits, and other
380
lifestyle variables. As with all insulins, the duration of action may vary according to the dose,
381
injection site, blood flow, temperature, and level of physical activity and conditioning.
382
383
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 14
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Table 2 Summary of pharmacodynamic properties of insulin products (pooled cross-study
384
comparison) and recommended interval between dosing and meal initiation
385
386
Insulin Products
Dose (U/kg)
Used in
Study
Recommended
interval between
dosing and meal
initiation
(minutes)*
Time of Peak Activity
(hours after dosing)
(mean± SD)
Percent of Total Activity
Occurring in the First 4
hours (mean, range)
NovoLog
0.3
10-20
2.2 ± 0.98
65% ± 11%
Novolin R
0.2
30
3.3
60% ± 16%
Novolin 50/50
0.5
30
4.0 ± 0.6
54% ± 12%
NovoLog Mix
70/30
0.3
10-20
2.4 ± 0.80
45% ± 22%
Novolin 70/30
0.3
30
4.2 ± 0.39
25% ± 5%
Novolin N
0.3
-n/a
8.0 +- ±5.3
21% +-±11%
*Applicable only to Novolin® R and NovoLog® alone or as components of insulin mixes.
387
388
389
Administration using pens and NovoLog Mix 70/30 prefilled syringes::
390
PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery devices*: NovoLog Mix 70/30
391
PenFill suspension should be visually inspected and resuspended immediately before use. The
392
resuspended liquid must appear uniformly white and cloudy. Before insertion into the insulin delivery
393
system, roll the cartridge between your palms 10 times. Thereafter, turn the cartridge upside down so
394
that the glass ball moves from one end of the cartridge to the other. Do this at least 10 times. The
395
rolling and turning procedure must be repeated until the liquid appears uniformly white and cloudy.
396
Inject immediately. Before each subsequent injection, turn the 3 mL PenFill® cartridge compatible
397
delivery devices* upside down so that the glass ball moves from one end of the cartridge to the other.
398
Repeat this 10 times until the liquid appears uniformly white and cloudy. Inject immediately. After
399
use, needles on the insulin pen delivery devices should not be recapped. *(see HOW SUPPLIED)
400
401
* NovoLog Mix 70/30 PenFill cartridges are for use with the following 3 mL PenFill® cartridge
402
compatible delivery devices: NovoPen® 3, Innovo®, and InDuo™.
403
404
405
Disposable NovoLog Mix 70/30 FlexPen™ Prefilled Syringes:
406
NovoLog Mix 70/30 suspension should be visually inspected and resuspended immediately before use.
407
The resuspended liquid must appear uniformly white and cloudy. Before use, roll the disposable
408
NovoLog Mix 70/30 FlexPen prefilled syringe between your palms 10 times. Thereafter, turn the
409
disposable NovoLog Mix 70/30 FlexPen prefilled syringe upside down so that the glass ball moves from
410
one end of the reservoir to the other. Do this at least 10 times. The rolling and turning procedure must
411
be repeated until the liquid appears uniformly white and cloudy. Inject immediately. Before each
412
subsequent injection, turn the disposable NovoLog Mix 70/30 FlexPen Prefilled syringe upside down
413
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 15
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
so that the glass ball moves from one end of the reservoir to the other at least 10 times and until the
414
liquid appears uniformly white and cloudy. Inject immediately. After use, needles on the disposable
415
NovoLog Mix 70/30 FlexPen prefilled syringes should not be recapped.
416
417
418
HOW SUPPLIED
419
NovoLog Mix 70/30 is available in the following package sizes: each presentation containing 100 Units
420
of insulin aspart per mL (U-100).
421
422
3 ml mL PenFill cartridges*
NDC xxxx-xxxx-xx
423
3 mL NovoLog® Mix 70/30 FlexPen® Prefilled Syringe
NDC xxxx-xxxx-xx
424
425
426
*
NovoLog Mix 70/30 PenFill cartridges are for use with the following 3 mL PenFill® cartridge
427
compatible delivery devices: NovoPen® 3, Innovo®, and InDuo™.
428
429
RECOMMENDED STORAGE
430
NovoLog Mix 70/30 should be stored between 2 and 8°C (36° to 46°F). Do not freeze. Do not
431
use NovoLog Mix 70/30 if it has been frozen.
432
433
PenFill® cartridges or NovoLog Mix 70/30 FlexPen™ Prefilled syringes:
434
435
Once a cartridge or a NovoLog Mix 70/30 FlexPen® prefilled syringe is punctured, it may be
436
used for up to 14 days if it is kept at room temperature below 30°C (86°F). Cartridges or
437
NovoLog Mix 70/30 FlexPen® prefilled syringes in use must NOT be stored in the refrigerator.
438
. Keep all PenFill® cartridges and disposable NovoLog® Mix 70/30 FlexPen® Prefilled
439
syringes away from direct heat and sunlight. Unpunctured PenFill® cartridges and NovoLog
440
Mix 70/30 FlexPen® Prefilled syringes can be used until the expiration date printed on the label
441
if they are stored in a refrigerator. Keep unused PenFill® cartridges and NovoLog® Mix 70/30
442
FlexPen® Prefilled syringes in the carton so they will stay clean and protected form light.
443
444
Rx Only.
445
446
447
Manufactured by:
448
Novo Nordisk A/S
449
2880 Bagsvaerd, Denmark
450
451
452
Manufactured for:
453
Novo Nordisk Pharmaceuticals, Inc.
454
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-003
FDA revision date (6/16/02)
Novo’s submission date: 6/13/02
Page 16
NovoLog Mix 70/30
(70% insulin aspart [rDNA origin] protamine suspension and 30%
insulin aspart [rDNA origin] injection)
Princeton, NJ 08540
455
456
www.novonordisk-us.com
457
458
459
Add circular number
460
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
6/26/02 04:08:26 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:29.798109 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21172s3lbl.pdf', 'application_number': 21172, 'submission_type': 'SUPPL ', 'submission_number': 3} |
4,544 | NDA 21-172/S-021
Final
Page 1
Submission date: November 21, 2005
NovoLog® Mix 70/30
70% insulin aspart protamine suspension and 30% insulinaspart injection, (rDNA origin)
DESCRIPTION
NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart
injection, [rDNA origin]) is a human insulin analog suspension containing 70% insulin aspart
protamine crystals and 30% soluble insulin aspart. NovoLog Mix 70/30 is a blood glucose-
lowering agent with a rapid onset and an intermediate duration of action. Insulin aspart is
homologous with regular human insulin with the exception of a single substitution of the amino
acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology
utilizing Saccharomyces cerevisiae (baker’s yeast) as the production organism. Insulin aspart
(NovoLog®) has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
Structural formula:
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
Figure 1. Structural formula of insulin aspart
NovoLog Mix 70/30 is a uniform, white, sterile suspension that contains insulin aspart (B28 asp
regular human insulin analog) 100 Units/mL, mannitol 36.4 mg/mL, phenol 1.50 mg/mL,
metacresol 1.72 mg/mL, zinc 19.6 µg/mL, disodium hydrogen phosphate dihydrate 1.25
mg/mL, sodium chloride 0.58 mg/mL, and protamine sulfate 0.33 mg/mL. NovoLog Mix 70/30
has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
CLINICAL PHARMACOLOGY
Mechanism of action
The primary activity of NovoLog Mix 70/30 is the regulation of glucose metabolism. Insulins,
including NovoLog Mix 70/30, exert their specific action through binding to insulin receptors.
Insulin binding activates mechanisms to lower blood glucose by facilitating cellular uptake of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-021
Final
Page 2
Submission date: November 21, 2005
glucose into skeletal muscle and fat, simultaneously inhibiting the output of glucose from the
liver.
In standard biological assays in mice and rabbits, one unit of NovoLog® has the same glucose-
lowering effect as one unit of regular human insulin. However, the effect of NovoLog Mix
70/30 is more rapid in onset compared to Novolin® (human insulin) 70/30 due to its faster
absorption after subcutaneous injection.
Pharmacokinetics
Bioavailability and Absorption-
The single substitution of the amino acid proline with aspartic acid at position B28 in insulin
aspart (NovoLog®) reduces the molecule’s tendency to form hexamers as observed with regular
human insulin. The rapid absorption characteristics of NovoLog® are maintained by NovoLog
Mix 70/30. The insulin aspart in the soluble component of NovoLog Mix 70/30 is absorbed
more rapidly from the subcutaneous layer than regular human insulin. The remaining 70% is in
crystalline form as insulin aspart protamine which has a prolonged absorption profile after
subcutaneous injection.
The relative bioavailability of NovoLog Mix 70/30 compared to NovoLog® and Novolin 70/30
indicates that they are absorbed to similar degrees. In euglycemic clamp studies in healthy
volunteers (n=23) after dosing with 0.2 U/kg of NovoLog Mix 70/30, a mean maximum serum
concentration (Cmax) of 23.4 ± 5.3 mU/L was reached after 60 minutes. The mean half-life
(t1/2) of NovoLog Mix 70/30 was about 8 to 9 hours. Serum insulin levels returned to baseline
15 to 18 hours after a subcutaneous dose. Similar data were seen in a separate euglycemic
clamp study in healthy volunteers (n=24) after dosing with 0.3 U/kg of NovoLog Mix 70/30. A
Cmax of 61.3 ± 20.1 mU/L was reached after 85 minutes. Serum insulin levels returned to
baseline 12 hours after a subcutaneous dose.
The Cmax and the area under the insulin concentration-time curve (AUC) after administration of
NovoLog Mix 70/30 differed by approximately 20% from those after administration of
NovoLog Mix 50/50 (investigational drug, not marketed.) and Novolin 70/30 (see Fig. 2 and 3
for pharmacokinetic profiles).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-021
Final
Page 3
Submission date: November 21, 2005
NovoLog Mix 70/30
Novolin 70/30
Mean Serum Insulin (mU/L)
Time (hours)
30
15
12
15
24
21
18
0
5
10
20
25
3
6
9
0
Points represent m ean ± 2 SEM
Figure 2. Pharmacokinetic Profiles of NovoLog Mix 70/30 and Novolin® 70/30
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
NovoLog Mix 70/30
NovoLog Mix 50/50*
NovoLog Mix 30/70*
NovoLog
Mean Serum Insulin (mU/L)
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-021
Final
Page 4
Submission date: November 21, 2005
Figure 3. Pharmacokinetic profiles for NovoLog Mix 70/30 and other proportional mixes
(* investigational drugs, not marketed).
Pharmacokinetic measurements were generated in clamp studies employing insulin doses of 0.3
U/kg. Insulin kinetics exhibit significant inter- and intra-patient variability. The rate of insulin
absorption and consequently the onset of activity is known to be affected by the site of
injection, exercise, and other variables (see PRECAUTIONS, General). Differences in
pharmacokinetics between NovoLog Mix 70/30 and products to which it has been compared are
not associated with differences in overall glycemic control.
Distribution and Elimination- NovoLog® has a low binding to plasma proteins, 0 to 9%, similar
to regular human insulin. After subcutaneous administration in normal male volunteers (n=24),
NovoLog® was more rapidly eliminated than regular human insulin with an average apparent
half-life of 81 minutes compared to 141 minutes for regular human insulin.
Pharmacodynamics
The two euglycemic clamp studies described above assessed glucose utilization after dosing of
healthy volunteers. NovoLog Mix 70/30 has a more rapid onset of action than regular human
insulin in studies of normal volunteers and patients with diabetes. The peak pharmacodynamic
effect of NovoLog Mix 70/30 occurs between 1 and 4 hours after injection. The duration of
action may be as long as 24 hours (see Figures 4 and 5).
NovoLog Mix 70/30
Novolin 70/30
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
Glucose Infusion Rate (mg/kg*min)
2
8
9
10
7
6
5
4
3
1
0
Figure 4. Pharmacodynamic Activity Profile of NovoLog Mix 70/30 and Novolin 70/30 in
healthy subjects.
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Final
Page 5
Submission date: November 21, 2005
Glucose infusion rate (mg/kg*min)
0
2
4
6
8
10
12
14
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
NovoLog Mix 70/30
NovoLog Mix 50/50*
NovoLog Mix 30/70*
NovoLog
Figure 5. Pharmacodynamic Activity Profiles for NovoLog Mix 70/30 and other
proportional mixes (* investigational drugs, not marketed)
Pharmacodynamic measurements were generated in clamp studies employing insulin doses of
0.3 U/kg. Insulin pharmacodynamics exhibit significant inter- and intra-patient variability. The
rate of insulin absorption and consequently the onset of activity is known to be affected by the
site of injection, exercise, and other variables (see PRECAUTIONS, General). Differences in
pharmacodynamics between NovoLog Mix 70/30 and products to which it has been compared
are not associated with differences in overall glycemic control.
Special populations
Children and adolescents-The pharmacokinetic and pharmacodynamic properties of NovoLog
Mix 70/30 have not been assessed in children and adolescents less than 18 years of age.
Geriatrics-The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog Mix
70/30 has not been studied.
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Final
Page 6
Submission date: November 21, 2005
Gender- The effect of gender on the pharmacokinetics and pharmacodynamics of NovoLog Mix
70/30 has not been studied.
Obesity-The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and
pharmacodynamics of NovoLog Mix 70/30 has not been studied but data on the rapid acting
component (NovoLog®) show no significant effect.
Ethnic origin-The effect of ethnic origin on the pharmacokinetics and pharmacodynamics of
NovoLog Mix 70/30 has not been studied.
Renal impairment-The effect of renal function on the pharmacokinetics and pharmacodynamics
of NovoLog Mix 70/30 has not been studied but data on the rapid acting component
(NovoLog®) show no significant effect. Some studies with human insulin have shown
increased circulating levels of insulin in patients with renal failure. Careful glucose
monitoring and dose adjustments of insulin, including NovoLog Mix 70/30, may be necessary
in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).
Hepatic impairment- The effect of hepatic impairment on the pharmacokinetics and
pharmacodynamics of NovoLog Mix 70/30 has not been studied but data on the rapid-acting
component (NovoLog®) show no significant effect. Some studies with human insulin have
shown increased circulating levels of insulin in patients with liver failure. Careful glucose
monitoring and dose adjustments of insulin, including NovoLog Mix 70/30, may be necessary
in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).
Pregnancy-The effect of pregnancy on the pharmacokinetics and pharmacodynamics of
NovoLog Mix 70/30 has not been studied (see PRECAUTIONS, Pregnancy).
Smoking-The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoLog
Mix 70/30 has not been studied.
CLINICAL STUDIES
In a three-month, open-label trial, patients with Type 1 (n=146) or Type 2 (n=178) diabetes
were treated BID (before breakfast and before supper) with NovoLog Mix 70/30 or Novolin®
70/30. The small changes in HbA1c were comparable across the treatment groups (see Table
1).
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Final
Page 7
Submission date: November 21, 2005
Table 1: Glycemic Parameters at the End of Treatment [Mean (SD)]
NovoLog Mix 70/30
Novolin 70/30
Type 1, N=92
Fasting Blood Glucose (mg/dL)
173 (62)
141 (59)
1.5 Hour Post Breakfast
185 (80)
198 (80)
1.5 Hour Post Dinner
158 (77)
169 (66)
HbA1c (%)
8.4 (1.1)
8.3 (1.0)
Type 2, N=169
Fasting Blood Glucose (mg/dL)
151 (39)
151 (68)
1.5 Hour Post Breakfast
180 (64)
198 (80)
1.5 Hour Post Dinner
166 (50)
189 (50)
HbA1c (%)
7.9 (1.0)
8.1 (1.1)
The significance, with respect to the long-term clinical sequelae of diabetes, of the differences
in postprandial hyperglycemia between treatment groups has not been established.
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored
in the 3-month, open-label comparator trial as well as in a long-term extension trial (see
PRECAUTIONS, Allergy).
In a 28-week, open-label trial, insulin-naïve patients with type 2 diabetes with fasting plasma
glucose above 140 mg/dl currently treated with metformin ± thiazolidinedione therapy were
randomized to receive either NovoLog Mix 70/30 twice daily [before breakfast and before
supper] or basal (long acting) insulin analog once daily1 (see Table 2). NovoLog® Mix 70/30
was started at an average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and
before supper), and bedtime basal (long acting) insulin analog was started at 10-12 IU (0.13 ±
0.03 IU/kg). Insulin doses were titrated weekly by decrements or increments of -2 to +6 units
per injection to a pre-meal glucose goal of 80-110 mg/dl. The metformin dose was adjusted to
2550 mg/day. Approximately one-third of the patients in each group were also treated with
pioglitazone (30 mg/day). Insulin secretagogues were discontinued in order to reduce the risk of
hypoglycemia. Most patients were Caucasian (53%), and the mean initial weight was 90 kg.
Table 2:
Combination Therapy with Oral Agents and Insulin In Patients with Type 2 Diabetes Mellitus
[Mean (SD)]
Treatment duration 28-weeks
NovoLog Mix 70/30
Basal (Long
Acting) Insulin
Analog
Number of patients
117
116
HbA1c
Baseline mean (%)
9.7 (1.5)
9.8 (1.4)
End-of-study mean (± SD)
6.9 (1.2)
7.4 (1.2)
Mean change from baseline
-2.8
-2.4
Percentage of subjects reaching HbA1c≤7.0%
66%
40%
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Final
Page 8
Submission date: November 21, 2005
Total Daily Insulin Dose at end of study (U)
79 (40)
51 (27)
Number of patients with severe hypoglycemia
0
0
Minor hypoglycemic event/month/patient
0.28
0.06
Weight gain at end of study
5.4 (4.8)
3.5 (4.5)
INDICATIONS AND USAGE
NovoLog Mix 70/30 is indicated for the treatment of patients with diabetes mellitus for the
control of hyperglycemia.
CONTRAINDICATIONS
NovoLog Mix 70/30 is contraindicated during episodes of hypoglycemia and in patients
hypersensitive to NovoLog Mix 70/30 or one of its excipients.
WARNINGS
Because NovoLog Mix 70/30 has peak pharmacodynamic activity one hour after injection, it
should be administered with meals.
NovoLog Mix 70/30 should not be administered intravenously.
NovoLog Mix 70/30 is not to be used in insulin infusion pumps.
NovoLog Mix 70/30 should not be mixed with any other insulin product.
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog Mix
70/30. As with all insulins, the timing of hypoglycemia may differ among various insulin
formulations.
Glucose monitoring is recommended for all patients with diabetes.
Any change of insulin dose should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog), species (animal,
human), or method of manufacture (rDNA versus animal-source insulin) may result in the need
for a change in dosage.
PRECAUTIONS
General
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with
the use of all insulins. Because of differences in the action of NovoLog Mix 70/30 and other
insulins, care should be taken in patients in whom such potential side effects might be clinically
relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using potassium-
lowering drugs or patients taking drugs sensitive to serum potassium level).
Fixed ratio insulins are typically dosed on a twice daily basis, i.e., before breakfast and supper,
with each dose intended to cover two meals or a meal and snack (see DOSAGE AND
ADMINISTRATION). The dose of insulin required to provide adequate glycemic control for
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NDA 21-172/S-021
Final
Page 9
Submission date: November 21, 2005
one of the meals may result in hyper- or hypoglycemia for the other meal. The
pharmacodynamic profile may also be inadequate for patients (e.g. pregnant women) who
require more frequent meals.
Adjustments in insulin dose or insulin type may be needed during illness, emotional stress, and
other physiologic stress in addition to changes in meals and exercise.
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site
used for injection and the degree of vascularization of the site. Smoking, temperature, and
exercise contribute to variations in blood flow and insulin absorption. These and other factors
contribute to inter- and intra-patient variability.
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated
with the use of all insulins.
Hypoglycemia-As with all insulin preparations, hypoglycemic reactions may be associated with
the administration of NovoLog Mix 70/30. Rapid changes in serum glucose concentrations may
induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as
beta-blockers, or intensified diabetes control.
Renal Impairment- Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic
patients with various degrees of renal impairment have not been conducted. As with other
insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients with renal
impairment.
Hepatic Impairment-Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic
patients with various degrees of hepatic impairment have not been conducted. As with other
insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic
impairment.
Allergy-
Local Reactions- Erythema, swelling, and pruritus at the injection site have been observed with
NovoLog Mix 70/30 as with other insulin therapy. Reactions may be related to the insulin
molecule, other components in the insulin preparation including protamine and cresol,
components in skin cleansing agents, or injection techniques.
Systemic Reactions- Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
allergy, including anaphylactic reaction, may be life threatening. Localized reactions and
generalized myalgias have been reported with the use of cresol as an injectable excipient.
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Final
Page 10
Submission date: November 21, 2005
Antibody production-Specific anti-insulin antibodies as well as cross-reacting anti-insulin
antibodies were monitored in the 3-month, open-label comparator trial as well as in a long-term
extension trial. Changes in cross-reactive antibodies were more common after NovoLog Mix
70/30 than with Novolin® 70/30 but these changes did not correlate with change in HbA1c or
increase in insulin dose. The clinical significance of these antibodies has not been established.
Antibodies did not increase further after long-term exposure (>6 months) to NovoLog Mix
70/30.
Information for patients-
Patients should be informed about potential risks and advantages of NovoLog Mix 70/30
therapy including the possible side effects. Patients should also be offered continued education
and advice on insulin therapies, injection technique, life-style management, regular glucose
monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo-
and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of
dose, instruction for use of injection devices, and proper storage of insulin.
Female patients should be advised to discuss with their physician if they intend to, or if they
become, pregnant because information is not available on the use of NovoLog Mix 70/30 during
pregnancy or lactation (see PRECAUTIONS, Pregnancy).
Laboratory Tests- The therapeutic response to NovoLog Mix 70/30 should be assessed by
measurement of serum or blood glucose and glycosylated hemoglobin.
Drug Interactions A number of substances affect glucose metabolism and may require insulin
dose adjustment and particularly close monitoring. The following are examples of substances
that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral
antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide
antibiotics.
The following are examples of substances that may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine,
salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones,
estrogens, progestogens (e.g., in oral contraceptives).
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-
glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
In addition, under the influence of sympatholytic medical products such as beta-blockers,
clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent (see
CLINICAL PHARMACOLOGY).
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NDA 21-172/S-021
Final
Page 11
Submission date: November 21, 2005
Mixing of insulins
NovoLog Mix 70/30 should not be mixed with any other insulin product.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
carcinogenic potential of NovoLog Mix 70/30. In 52-week studies, Sprague-Dawley rats were
dosed subcutaneously with NovoLog®, the rapid-acting component of NovoLog Mix 70/30, at
10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of
1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day,
NovoLog® increased the incidence of mammary gland tumors in females when compared to
untreated controls. The incidence of mammary tumors for NovoLog® was not significantly
different than for regular human insulin. The relevance of these findings to humans is not
known. NovoLog® was not genotoxic in the following tests: Ames test, mouse lymphoma cell
forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in
vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility
studies in male and female rats, NovoLog® at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area) had no
direct adverse effects on male and female fertility, or on general reproductive performance of
animals.
Pregnancy - Teratogenic Effects - Pregnancy Category C
Animal reproduction studies have not been conducted with NovoLog Mix 70/30. However,
reproductive toxicology and teratology studies have been performed with NovoLog® (the
rapid-acting component of NovoLog Mix 70/30) and regular human insulin in rats and rabbits.
In these studies, NovoLog® was given to female rats before mating, during mating, and
throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog® did not
differ from those observed with subcutaneous regular human insulin. NovoLog®, like human
insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a
dose of 200 U/kg/day (approximately 32-times the human subcutaneous dose of 1.0 U/kg/day,
based on U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three
times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The
effects are probably secondary to maternal hypoglycemia at high doses. No significant effects
were observed in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day. These doses
are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to
the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface area.
It is not known whether NovoLog Mix 70/30 can cause fetal harm when administered to a
pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled
studies of the use of NovoLog Mix 70/30 or NovoLog® in pregnant women. NovoLog Mix
70/30 should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
Nursing mothers-It is unknown whether NovoLog Mix 70/30 is excreted in human milk as is
human insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix
70/30 or NovoLog® in lactating women.
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Final
Page 12
Submission date: November 21, 2005
Pediatric Use-Safety and effectiveness of NovoLog Mix 70/30 in children have not been
established.
Geriatric Use- Clinical studies of NovoLog Mix 70/30 did not include sufficient numbers of
patients aged 65 and over to determine whether they respond differently than younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy in this population.
ADVERSE REACTIONS
Clinical trials comparing NovoLog Mix 70/30 with Novolin® 70/30 did not demonstrate a
difference in frequency of adverse events between the two treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as whole: Allergic reactions (see PRECAUTIONS, Allergy).
Skin and Appendages: Local injection site reactions or rash or pruritus, as with other insulin
therapies, occurred in 7% of all patients on NovoLog Mix 70/30 and 5% on Novolin® 70/30.
Rash led to withdrawal of therapy in <1% of patients on either drug (see PRECAUTIONS,
Allergy).
Hypoglycemia: see WARNINGS and PRECAUTIONS.
Other: Small elevations in alkaline phosphatase were observed in patients treated in NovoLog®
controlled clinical trials. There have been no clinical consequences of these laboratory findings.
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes
with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation
may be necessary because hypoglycemia may recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION
General
Fixed ratio insulins are typically dosed on a twice daily basis, i.e. before breakfast and supper,
with each dose intended to cover two meals or a meal and snack. NovoLog Mix 70/30 is
intended only for subcutaneous injection (into the abdominal wall, thigh, or upper arm).
NovoLog Mix 70/30 should not be administered intravenously. The absorption rate of
NovoLog Mix 70/30 from the subcutaneous tissue allows dosing within 15 minutes of meal
initiation.
Dose regimens of NovoLog Mix 70/30 will vary among patients and should be determined by
the health care professional familiar with the patient’s metabolic needs, eating habits, and other
lifestyle variables. As with all insulins, the duration of action may vary according to the dose,
injection site, blood flow, temperature, and level of physical activity and conditioning.
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NDA 21-172/S-021
Final
Page 13
Submission date: November 21, 2005
Table 3. Summary of pharmacodynamic properties of insulin products (pooled cross-study
comparison) and recommended interval between dosing and meal initiation
Insulin Products
Dose (U/kg)
Used in
Study
Recommended
interval between
dosing and meal
initiation
(minutes)*
Time of Peak Activity
(hours after dosing)
(mean± SD)
Percent of Total Activity
Occurring in the First 4
hours (mean, range)
NovoLog®
0.3
10-20
2.2 ± 0.98
65% ± 11%
Novolin® R
0.2
30
3.3
60% ± 16%
Novolin® 50/50
0.5
30
4.0 ± 0.6
54% ± 12%
NovoLog Mix
70/30
0.3
10-20
2.4 ± 0.80
45% ± 22%
Novolin® 70/30
0.3
30
4.2 ± 0.39
25% ± 5%
Novolin® N
0.3
n/a
8.0 ± 5.3
21% ±11%
*Applicable only to Novolin® R and NovoLog® alone or as components of insulin mixes.
Administration using PenFill® Cartridges for 3 mL PenFill® cartridge compatible
delivery devices, NovoLog® Mix 70/30 FlexPen Prefilled syringes, or vials:
PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery devices*: NovoLog
Mix 70/30 PenFill® suspension should be visually inspected and resuspended immediately
before use. The resuspended NovoLog Mix 70/30 must appear uniformly white and cloudy.
Before inserting the cartridge into the insulin delivery system, roll the cartridge between your
palms 10 times. Thereafter, turn the cartridge upside down so that the glass ball moves from
one end of the cartridge to the other. Do this at least 10 times. The rolling and turning
procedure must be repeated until the suspension appears uniformly white and cloudy. Inject
immediately. Before each subsequent injection, turn the 3 mL PenFill® cartridge compatible
delivery devices* upside down so that the glass ball moves from one end of the cartridge to the
other. Repeat this 10 times until the suspension appears uniformly white and cloudy. Inject
immediately. After use, needles on the insulin pen delivery devices should not be recapped.
Used syringes, needles, or lancets should be placed in sharps containers (such as red
biohazard containers), hard plastic containers (such as detergent bottles), or metal
containers (such as an empty coffee can). Such containers should be sealed and disposed
of properly.
* NovoLog® Mix 70/30 PenFill® cartridges are for use with the following 3 mL PenFill®
cartridge compatible delivery devices: NovoPen® 3, Innovo®, and InDuo™.
Disposable NovoLog Mix 70/30 FlexPen® Prefilled Syringes:
NovoLog Mix 70/30 suspension should be visually inspected and resuspended immediately
before use. The resuspended NovoLog Mix 70/30 must appear uniformly white and cloudy.
Before use, roll the disposable NovoLog Mix 70/30 FlexPen prefilled syringe between your
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NDA 21-172/S-021
Final
Page 14
Submission date: November 21, 2005
palms 10 times. Thereafter, turn the disposable NovoLog Mix 70/30 FlexPen prefilled syringe
upside down so that the glass ball moves from one end of the reservoir to the other. Do this at
least 10 times. The rolling and turning procedure must be repeated until the suspension appears
uniformly white and cloudy. Inject immediately. Before each subsequent injection, turn the
disposable NovoLog Mix 70/30 FlexPen Prefilled syringe upside down so that the glass ball
moves from one end of the reservoir to the other at least 10 times and until the suspension
appears uniformly white and cloudy. Inject immediately. After use, needles on the disposable
NovoLog Mix 70/30 FlexPen prefilled syringes should not be recapped. Used syringes,
needles, or lancets should be placed in sharps containers (such as red biohazard
containers), hard plastic containers (such as detergent bottles), or metal containers (such
as an empty coffee can). Such containers should be sealed and disposed of properly.
Vial: NovoLog Mix 70/30 vial must be resuspended immediately before use. Roll the vial
gently 10 times in your hand to mix it. The resuspended NovoLog Mix 70/30 must appear
uniformly white and cloudy.
HOW SUPPLIED
NovoLog Mix 70/30 is available in the following package sizes: each presentation contains 100
Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-3685-12
3 mL PenFill® cartridges*
NDC 0169-3682-13
3 mL NovoLog® Mix 70/30 FlexPen® Prefilled Syringe
NDC 0169-3696-19
*
NovoLog Mix 70/30 PenFill® cartridges are for use with the following 3 mL PenFill®
cartridge compatible delivery devices and the NovoPen® 3 PenMate®.
RECOMMENDED STORAGE
NovoLog Mix 70/30 should be stored between 2°C and 8°C (36° F to 46°F). Do not freeze. Do
not use NovoLog Mix 70/30 if it has been frozen.
Vials:
The vials should be stored in a refrigerator, not in a freezer. If refrigeration is not possible, the
bottle in use can be kept unrefrigerated at room temperature below 30°C (86°F) for up to 28
days, as long as it is kept as cool as possible and away from direct heat and light.
Unpunctured vials can be used until the expiration date printed on the label if they are stored in
a refrigerator. Keep unused vials in the carton so they will stay clean and protected from light.
PenFill® cartridges or NovoLog Mix 70/30 FlexPen® Prefilled syringes:
Once a cartridge or a NovoLog Mix 70/30 FlexPen® prefilled syringe is punctured, it may be
used for up to 14 days if it is kept at room temperature below 30°C (86°F). Cartridges or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 21-172/S-021
Final
Page 15
Submission date: November 21, 2005
NovoLog Mix 70/30 FlexPen® prefilled syringes in use must NOT be stored in the refrigerator.
Keep all PenFill® cartridges and disposable NovoLog® Mix 70/30 FlexPen® Prefilled syringes
away from direct heat and sunlight. Unpunctured PenFill® cartridges and NovoLog Mix 70/30
FlexPen® Prefilled syringes can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused PenFill® cartridges and NovoLog® Mix 70/30 FlexPen®
Prefilled syringes in the carton so they will stay clean and protected from light.
Rx Only.
Date of issue:
REFERENCES:
1. Raskin R, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a
comparison of biphasic and basal insulin analogs. Diabetes Care. 2005; 28:260-265.
Novo Nordisk®, NovoLog®, FlexPen®, Innovo®, Novolin®, NovoPen®, PenFill® and
NovoFine® are trademarks owned by Novo Nordisk® A/S. In Duo® is a trademark of
LifeScan, Inc., a Johnson and Johnson company.
© Novo Nordisk A/S
License under U.S. Patent No. 5,618,913 and Des. 347,894.
Manufactured by:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Manufactured for:
Novo Nordisk Inc.
Princeton, NJ 08540
www.novonordisk-us.com
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:29.811781 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021172s021lbl.pdf', 'application_number': 21172, 'submission_type': 'SUPPL ', 'submission_number': 21} |
4,545 |
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NovoLog Mix 70/30 safely and effectively. See full prescribing
information for NovoLog Mix 70/30.
NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30%
insulin aspart injection, [rDNA origin])
Suspension for subcutaneous injection
Initial U.S. Approval: 2001
---------------------------------RECENT MAJOR CHANGES-------------------------
• Indications and Usage (1) 4/2010
• Dosage and Administration (2.1) 4/2010
----------------------------INDICATIONS AND USAGE---------------------------
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control
in patients with diabetes mellitus.
Important Limitations of Use: In premix insulins, such as Novolog Mix 70/30,
the proportions of rapid acting and long acting insulins are fixed and do not
allow for basal versus prandial dose adjustments. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
• Only for subcutaneous injection (2.1)
Type 1 DM: dose within 15 minutes before meal initiation.
Type 2 DM: dose within 15 minutes before or after starting a meal.
• Do not administer intravenously (2.1)
• Do not use in insulin infusion pumps (2.1)
• Must be resuspended immediately before use (2.2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Each presentation contains 100 Units of insulin aspart per mL (U-100) (3)
• 10 mL vials
• 3 mL NovoLog Mix 70/30 FlexPen
-------------------------------CONTRAINDICATIONS------------------------------
• Do not use during episodes of hypoglycemia (4)
• Do not use in patients with hypersensitivity to NovoLog Mix 70/30 or
one of its excipients (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
• NovoLog Mix 70/30 should not be mixed with any other insulin product
(5.1)
• Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under
medical supervision. (5.1, 5.2).
• Insulin, particularly when given in settings of poor glycemic control,
can cause hypokalemia. Use caution in patients predisposed to
hypokalemia (5.3)
• Like all insulins, NovoLog Mix 70/30 requirements may be reduced
in patients with renal impairment or hepatic impairment (5.4, 5.5)
• Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with insulin products, including NovoLog Mix 70/30 (5.6)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions observed with insulin therapy include hypoglycemia,
allergic reactions, local injection site reactions, lipodystrophy, rash and
pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• The following may increase the blood glucose lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g.
octreotide), sulfonamide antibiotics (7)
• The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine
derivatives, somatropin, thyroid hormones, estrogens, progestogens
(e.g., in oral contraceptives), atypical antipsychotics (7)
• Beta-blockers, clonidine, lithium salts, and alcohol may either
potentiate or weaken the blood-glucose-lowering effect of insulin (7)
• Pentamidine may cause hypoglycemia, which may be followed by
hyperglycemia (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine,
and reserpine (7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 4/2010
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Resuspension
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 NovoLog Mix 70/30 versus Novolin 70/30
14.2
Combination Therapy: Insulin and Oral Agents in Patients with
Type 2 Diabetes
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Recommended Storage
17 PATIENT COUNSELING INFORMATION
17.1
Physician Instructions
*Sections or subsections omitted from the full prescribing information are not
listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
____________________________________________________________________________________________________________________
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control in
patients with diabetes mellitus.
Important Limitations of Use:
In premix insulins, such as Novolog Mix 70/30, the proportions of rapid acting and long
acting insulins are fixed and do not allow for basal versus prandial dose adjustments.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog Mix 70/30 is an insulin analog with an earlier onset and intermediate duration
of action in comparison to the basal human insulin premix. The addition of protamine to the
rapid-acting aspart insulin analog (NovoLog) results in insulin activity that is 30% short-acting
and 70% long-acting. NovoLog Mix 70/30 is typically dosed on a twice-daily basis (with each
dose intended to cover 2 meals or a meal and a snack). The dosage of NovoLog Mix 70/30 must
be individualized. The written prescription for NovoLog Mix 70/30 should include the full
name, to avoid confusion with NovoLog (insulin aspart) and Novolin 70/30 (human premix).
NovoLog Mix 70/30 should appear uniformly white and cloudy. Do not use it if it looks
clear or if it contains solid particles. NovoLog Mix 70/30 should not be used after the printed
expiration date.
NovoLog Mix 70/30 should be administered by subcutaneous injection in the abdominal
region, buttocks, thigh, or upper arm. NovoLog Mix 70/30 has a faster onset of action than
human insulin premix 70/30 and should be dosed within 15 minutes before meal initiation for
patients with type 1 diabetes. For patients with type 2 diabetes, dosing should occur within 15
minutes before or after meal initiation. Injection sites should be rotated within the same region
to reduce the risk of lipodystrophy. As with all insulins, the duration of action may vary
according to the dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog Mix 70/30 should not be administered intravenously or used in insulin
infusion pumps. Dose regimens of NovoLog Mix 70/30 will vary among patients and should be
determined by the health care professional familiar with the patient’s recommended glucose
treatment goals, metabolic needs, eating habits, and other lifestyle variables.
2.2
Resuspension
NovoLog Mix 70/30 is a suspension that must be visually inspected and resuspended
immediately before use.
The NovoLog Mix 70/30 vial should be rolled gently in your hands in a horizontal position 10
times to mix it. The rolling procedure must be repeated until the suspension appears uniformly
white and cloudy. Inject immediately. Resuspension is easier when the insulin has reached
room temperature.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
The NovoLog Mix 70/30 FlexPen should be rolled 10 times gently between your hands in a
47
horizontal position. Thereafter, turn the NovoLog Mix 70/30 FlexPen upside down so that the
48
glass ball moves from one end of the reservoir to the other. Do this at least 10 times. The
49
rolling and turning procedure must be repeated until the suspension appears uniformly white
50
and cloudy. Inject immediately. Before each subsequent injection, turn the disposable NovoLog
51
Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to
52
the other at least 10 times and until the suspension appears uniformly white and cloudy. Inject
53
immediately.
54
55
3
DOSAGE FORMS AND STRENGTHS
56
NovoLog Mix 70/30 is available in the following package sizes: each presentation
57
contains 100 units of insulin aspart per mL (U-100).
58
• 10 mL vials
59
• 3 mL NovoLog Mix 70/30 FlexPen
60
61
4
CONTRAINDICATIONS
62
NovoLog Mix 70/30 is contraindicated
63
• during episodes of hypoglycemia
64
• in patients with hypersensitivity to NovoLog Mix 70/30 or one of its excipients.
65
66
5
WARNINGS AND PRECAUTIONS
67
5.1
Administration
68
The short and long-acting components of insulin mixes, including NovoLog Mix 70/30,
69
cannot be titrated independently. Because NovoLog Mix 70/30 has peak pharmacodynamic
70
activity between 1-4 hours after injection, it should be administered within 15 minutes of meal
71
initiation [see Clinical Pharmacology (12)]. The dose of insulin required to provide adequate
72
glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal.
73
The pharmacodynamic profile may also be inadequate for patients who require more frequent
74
meals.
75
NovoLog Mix 70/30 should not be mixed with any other insulin product.
76
NovoLog Mix 70/30 should not be used intravenously.
77
NovoLog Mix 70/30 should not be used in insulin infusion pumps.
78
Glucose monitoring is recommended for all patients with diabetes. Any change of
79
insulin dose should be made cautiously and only under medical supervision. Changing from one
80
insulin product to another or changing the insulin strength may result in the need for a change in
81
dosage. Changes may also be necessary during illness, emotional stress, and other physiologic
82
stress in addition to changes in meals and exercise.
83
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by
84
the site used for injection and the degree of vascularization of the site. Smoking, temperature,
85
and exercise contribute to variations in blood flow and insulin absorption. These and other
86
factors contribute to inter- and intra-patient variability.
87
NovoLog Mix 70/30 FlexPen is for use by one person only.
88
89
5.2
Hypoglycemia
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
90
Hypoglycemia is the most common adverse effect of insulin therapy, including
91
NovoLog Mix 70/30. Severe hypoglycemia may lead to unconsciousness and/or convulsions
92
and may result in temporary or permanent impairment of brain function or even death. Severe
93
hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or
94
glucagon administration has been observed in clinical trials with insulin, including trials with
95
NovoLog Mix 70/30.
96
The timing of hypoglycemia may reflect the time-action profile of the insulin
97
formulation [see Clinical Pharmacology (12)]. Other factors, such as changes in dietary intake
98
(e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications
99
may also alter the risk of hypoglycemia [See Drug Interactions (7)]. As with all insulins, use
100
caution in patients with hypoglycemia unawareness and in patients who may be predisposed to
101
hypoglycemia (e.g. patients who are fasting or have erratic food intake). The patient’s ability to
102
concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in
103
situations where these abilities are especially important, such as driving or operating machinery.
104
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
105
persons with diabetes, regardless of the glucose value. Early warning symptoms of
106
hypoglycemia may be different or less pronounced under certain conditions, such as long
107
duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
108
intensified diabetes control [see Drug Interactions (7)].
109
5.3
Hypokalemia
110
All insulin products, including NovoLog Mix 70/30, cause a shift in potassium from the
111
extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may
112
cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may
113
be at risk for hypokalemia (e.g. patients using potassium-lowering medications or patients
114
taking medications sensitive to potassium concentrations).
115
116
5.4
Renal Impairment
117
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various
118
degrees of renal impairment have not been conducted. As with other insulins, the requirements
119
for NovoLog Mix 70/30 may be reduced in patients with renal impairment. [see Clinical
120
Pharmacology (12.3)]
121
122
5.5
Hepatic Impairment
123
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with
124
various degrees of hepatic impairment have not been conducted. As with other insulins, the
125
requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic impairment. [see
126
Clinical Pharmacology (12.3)]
127
128
5.6
Hypersensitivity and Allergic Reactions
129
Local Reactions- As with other insulin therapy, patients may experience reactions such
130
as erythema, edema or pruritus at the site of NovoLog Mix 70/30 injection. These reactions
131
usually resolve in a few days to a few weeks, but in some occasions, may require
132
discontinuation of NovoLog Mix 70/30. In some instances, these reactions may be related to the
133
insulin molecule, other components in the insulin preparation including protamine and cresol,
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
134
components in skin cleansing agents, or injection techniques. Localized reactions and
135
generalized myalgias have been reported with the use of cresol as an injectable excipient.
136
Systemic Reactions- Less common, but potentially more serious, is generalized allergy to
137
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
138
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
139
allergy, including anaphylactic reaction, may be life threatening.
140
141
5.7
Antibody Production
142
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were
143
monitored in a 3-month, open-label comparator trial as well as in a long-term extension trial.
144
Changes in cross-reactive antibodies were more common after NovoLog Mix 70/30 than with
145
Novolin® 70/30 but these changes did not correlate with change in HbA1c or increase in insulin
146
dose. The clinical significance of these antibodies has not been established. Antibodies did not
147
increase further after long-term exposure (>6 months) to NovoLog Mix 70/30.
148
149
6
ADVERSE REACTIONS
150
Clinical Trial Experience
151
Clinical trials are conducted under widely varying designs, therefore, the adverse reaction
152
rates reported in one clinical trial may not be easily compared to those rates reported in another
153
clinical trial, and may not reflect the rates actually observed in clinical practice.
154
• Hypoglycemia
155
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
156
including NovoLog Mix 70/30 [see Warnings and Precautions (5.2)]. NovoLog Mix
157
70/30 should not be used during episodes of hypoglycemia [see Contraindications (4)
158
and Warnings and Precautions (5)].
159
• Insulin initiation and glucose control intensification
160
Intensification or rapid improvement in glucose control has been associated with
161
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
162
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
163
control decreases the risk of diabetic retinopathy and neuropathy.
164
• Lipodystrophy
165
Long-term use of insulin, including NovoLog Mix 70/30, can cause lipodystrophy at the
166
site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of
167
adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin
168
absorption. Rotate insulin injection sites within the same region to reduce the risk of
169
lipodystrophy.
170
• Weight gain
171
Weight gain can occur with some insulin therapies, including NovoLog Mix 70/30, and
172
has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
173
• Peripheral Edema
174
Insulin may cause sodium retention and edema, particularly if previously poor metabolic
175
control is improved by intensified insulin therapy.
176
• Frequencies of adverse drug reactions
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
177
The frequencies of adverse drug reactions during a clinical trial with NovoLog Mix 70/30
178
in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the
179
tables below. The trial was a three-month, open-label trial in patients with Type 1 or
180
Type 2 diabetes who were treated twice daily (before breakfast and before supper) with
181
NovoLog Mix 70/30.
182
183
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 diabetes mellitus
184
(Adverse events with frequency ≥ 5% are included.)
NovoLog Mix 70/30
(N=55)
Novolin 70/30
(N=49)
Preferred Term
N
%
N
%
Hypoglycemia
38
69
37
76
Headache
19
35
6
12
Influenza-like symptoms
7
13
1
2
Dyspepsia
5
9
3
6
Back pain
4
7
2
4
Diarrhea
4
7
3
6
Pharyngitis
4
7
1
2
Rhinitis
3
5
6
12
Skeletal pain
3
5
2
4
Upper respiratory tract infection
3
5
1
2
185
186
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 diabetes mellitus
187
(Adverse events with frequency ≥ 5% are included.)
NovoLog Mix 70/30
(N=85)
Novolin 70/30
(N=102)
Preferred Term
N
%
N
%
Hypoglycemia
40
47
51
50
Upper respiratory tract infection
10
12
6
6
Headache
8
9
8
8
Diarrhea
7
8
2
2
Neuropathy
7
8
2
2
Pharyngitis
5
6
4
4
Abdominal pain
4
5
0
0
Rhinitis
4
5
2
2
188
189
Postmarketing Data
190
Additional adverse reactions have been identified during post-approval use of NovoLog
191
Mix 70/30. Because these adverse reactions are reported voluntarily from a population of
192
uncertain size, it is generally not possible to reliably estimate their frequency. They include
193
medication errors in which other insulins have been accidentally substituted for NovoLog Mix
194
70/30 [see Patient Counseling Information (17)].
195
196
7
DRUG INTERACTIONS
197
A number of substances affect glucose metabolism and may require insulin dose
198
adjustment and particularly close monitoring.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
199
• The following are examples of substances that may increase the blood-glucose
200
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
201
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
202
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide),
203
sulfonamide antibiotics.
204
• The following are examples of substances that may reduce the blood-glucose
205
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
206
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
207
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
208
atypical antipsychotics.
209
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
210
the blood-glucose-lowering effect of insulin.
211
• Pentamidine may cause hypoglycemia, which may sometimes be followed by
212
hyperglycemia.
213
• The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
214
products such as beta-blockers, clonidine, guanethidine, and reserpine.
215
216
8
USE IN SPECIFIC POPULATIONS
217
8.1
Pregnancy
218
Pregnancy Category B.
219
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
220
regardless of drug exposure. This background risk is increased in pregnancies complicated by
221
hyperglycemia and may be decreased with good metabolic control. It is essential for patients
222
with diabetes or history of gestational diabetes to maintain good metabolic control before
223
conception and throughout pregnancy. Insulin requirements may decrease during the first
224
trimester, generally increase during the second and third trimesters, and rapidly decline after
225
delivery. Careful monitoring of glucose control is essential in such patients.
226
An open-label, randomized study compared the safety and efficacy of NovoLog (the
227
rapid-acting component of NovoLog Mix 70/30) versus human insulin in the treatment of
228
pregnant women with Type 1 diabetes (322 exposed pregnancies (NovoLog: 157, human
229
insulin: 165)). Two-thirds of the enrolled patients were already pregnant when they entered the
230
study. Since only one-third of the patients enrolled before conception, the study was not large
231
enough to evaluate the risk of congenital malformations. Mean HbA1c of ~ 6% was observed in
232
both groups during pregnancy, and there was no significant difference in the incidence of
233
maternal hypoglycemia.
234
Animal reproduction studies have not been conducted with NovoLog Mix 70/30.
235
However, subcutaneous reproduction and teratology studies have been performed with
236
NovoLog (the rapid-acting component of NovoLog Mix 70/30) and regular human insulin in
237
rats and rabbits. In these studies, NovoLog was given to female rats before mating, during
238
mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of
239
NovoLog did not differ from those observed with subcutaneous regular human insulin.
240
NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal
241
abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the human
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
242
subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of
243
10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based
244
on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high
245
doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a
246
dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
247
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits
248
based on U/body surface area.
249
Female patients should be advised to discuss with their physician if they intend to, or if
250
they become pregnant. There are no adequate and well-controlled studies of the use of
251
NovoLog Mix 70/30 in pregnant women.
252
253
8.3
Nursing Mothers
254
It is unknown whether insulin aspart is excreted in human milk as occurs with human
255
insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 or
256
NovoLog in lactating women. Women with diabetes who are lactating may require adjustments
257
of their insulin doses.
258
259
8.4
Pediatric Use
260
Safety and effectiveness of NovoLog Mix 70/30 have not been established in pediatric
261
patients.
262
263
8.5
Geriatric Use
264
Clinical studies of NovoLog Mix 70/30 did not include sufficient numbers of patients
265
aged 65 and over to determine whether they respond differently than younger patients. In
266
general, dose selection for an elderly patient should be cautious, usually starting at the low end of
267
the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function,
268
and of concomitant disease or other drug therapy in this population.
269
270
10
OVERDOSAGE
271
Hypoglycemia may occur as a result of an excess of insulin relative to food intake,
272
energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral
273
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
274
episodes with coma, seizure, or neurologic impairment may be treated with
275
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
276
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
277
apparent clinical recovery.
278
279
11
DESCRIPTION
280
NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart
281
injection, [rDNA origin]) is a human insulin analog suspension containing 70% insulin aspart
282
protamine crystals and 30% soluble insulin aspart. NovoLog Mix 70/30 is a blood glucose
283
lowering agent with an earlier onset and an intermediate duration of action. Insulin aspart is
284
homologous with regular human insulin with the exception of a single substitution of the amino
285
acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology
286
utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin aspart (NovoLog) has the empirical
287
formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
288
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Structur
a
l
Form
ula
289
290
Figure 1. Structural formula of insulin aspart
291
292
NovoLog Mix 70/30 is a uniform, white, sterile suspension that contains insulin aspart
293
100 Units/mL.
294
Inactive ingredients for the 10 mL vial are mannitol 36.4 mg/mL, phenol 1.50 mg/mL,
295
metacresol 1.72 mg/mL, zinc 19.6 μg/mL, disodium hydrogen phosphate dihydrate 1.25
296
mg/mL, sodium chloride 0.58 mg/mL, and protamine sulfate 0.32 mg/mL.
297
Inactive ingredients for the NovoLog Mix 70/30 FlexPen are glycerol 16.0 mg/mL,
298
phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 μg/mL, disodium hydrogen phosphate
299
dihydrate 1.25 mg/mL, sodium chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL.
300
NovoLog Mix 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be
301
added to adjust pH.
302
303
12
CLINICAL PHARMACOLOGY
304
12.1
Mechanism of Action
305
The primary activity of NovoLog Mix 70/30 is the regulation of glucose metabolism.
306
Insulins, including NovoLog Mix 70/30, bind to the insulin receptors on muscle, liver and fat
307
cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously
308
inhibiting the output of glucose from the liver.
309
310
12.2
Pharmacodynamics
311
The two euglycemic clamp studies described below [see Clinical Pharmacology (12.3)]
312
assessed glucose utilization after dosing of healthy volunteers. NovoLog Mix 70/30 has an
313
earlier onset of action than human premix 70/30 in studies of normal volunteers and patients
314
with diabetes. The onset of action is between 10-20 minutes for NovoLog Mix 70/30 compared
315
to 30 minutes for Novolin 70/30. The mean ± SD time to peak activity for NovoLog Mix 70/30
316
is 2.4 hr ± 0.8hr compared to 4.2 hr ± 0.4 hr for Novolin 70/30. The duration of action may be
317
as long as 24 hours (see Figure 2).
318
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
G
r
a
p
h
319
320
Figure 2. Pharmacodynamic Activity Profile of NovoLog Mix 70/30 and Novolin 70/30 in
321
healthy subjects.
322
323
12.3
Pharmacokinetics
324
The single substitution of the amino acid proline with aspartic acid at position B28 in
325
insulin aspart (NovoLog) reduces the molecule’s tendency to form hexamers as observed with
326
regular human insulin. The rapid absorption characteristics of NovoLog are maintained by
327
NovoLog Mix 70/30. The insulin aspart in the soluble component of NovoLog Mix 70/30 is
328
absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining
329
70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile
330
after subcutaneous injection.
331
Bioavailability and Absorption- The relative bioavailability of NovoLog Mix 70/30
332
compared to NovoLog and Novolin 70/30 indicates that the insulins are absorbed to similar
333
extent. In euglycemic clamp studies in healthy volunteers (n=23) after dosing with NovoLog
334
Mix 70/30 (0.2 U/kg), a mean maximum serum concentration (Cmax) of 23.4 ± 5.3 mU/L was
335
reached after 60 minutes. The mean half-life (t1/2) of NovoLog Mix 70/30 was about 8 to 9
336
hours. Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose of
337
NovoLog Mix 70/30. Similar data were seen in a separate euglycemic clamp study in healthy
338
volunteers (n=24) after dosing with NovoLog Mix 70/30 (0.3 U/kg). A Cmax of 61.3 ± 20.1
339
mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12 hours after a
340
subcutaneous dose.
341
The Cmax and the area under the insulin concentration-time curve (AUC) after
342
administration of NovoLog Mix 70/30 was approximately 20% greater than those after
343
administration of Novolin 70/30, (see Fig. 3 for pharmacokinetic profiles).
344
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mean Serum Insulin (mU/L)
30
25
20
15
10
5
0
Graph
12
15
18
21
24
Time (hours)
Points represent m ean ± 2 SEM
345
346
347
Figure 3. Pharmacokinetic Profiles of NovoLog Mix 70/30 and Novolin 70/30
348
349
Distribution and Elimination- NovoLog has a low binding to plasma proteins, 0 to 9%,
350
similar to regular human insulin. After subcutaneous administration in normal male volunteers
351
(n=24), NovoLog was more rapidly eliminated than regular human insulin with an average
352
apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
353
354
The effect of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy,
355
or smoking, on the pharmacodynamics and pharmacokinetics of NovoLog Mix 70/30 has not
356
been studied.
357
358
359
13
NONCLINICAL TOXICOLOGY
360
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
361
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
362
the carcinogenic potential of NovoLog Mix 70/30. In 52-week studies, Sprague-Dawley rats
363
were dosed subcutaneously with NovoLog, the rapid-acting component of NovoLog Mix 70/30,
364
at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of
365
1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day,
366
NovoLog increased the incidence of mammary gland tumors in females when compared to
367
untreated controls. The incidence of mammary tumors found with NovoLog was not
368
significantly different from that found with regular human insulin. The relevance of these
369
findings to humans is not known.
370
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
371
NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward
372
gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo
373
micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.
374
375
In fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day
376
(approximately 32 times the human subcutaneous dose, based on U/body surface area) had no
377
direct adverse effects on male and female fertility, or on general reproductive performance of
378
animals.
379
380
13.2
Animal Toxicology and/or Pharmacology
381
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
382
glucose-lowering effect as one unit of regular human insulin. However, the effect of NovoLog
383
Mix 70/30 is more rapid in onset compared to Novolin (human insulin) 70/30 due to its faster
384
absorption after subcutaneous injection.
385
386
14
CLINICAL STUDIES
387
14.1
NovoLog Mix 70/30 versus Novolin 70/30
388
In a three-month, open-label trial, patients with Type 1 (n=104) or Type 2 (n=187)
389
diabetes were treated twice daily (before breakfast and before supper) with NovoLog Mix 70/30
390
or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral
391
hypoglycemic agents were not allowed within 1 month prior to the study or during the study.
392
The small changes in HbA1c were comparable across the treatment groups (see Table 3).
393
394
395
Table 3: Glycemic Parameters at the End of Treatment [Mean ± SD (N subjects)]
NovoLog Mix 70/30
Novolin 70/30
Type 1, N=104
Fasting Blood Glucose (mg/dL)
174 ± 64 (48)
142 ± 59 (44)
1.5 Hour Post Breakfast (mg/dL)
187 ± 82 (48)
200 ± 82 (42)
1.5 Hour Post Dinner (mg/dL)
162 ± 77 (47)
171 ± 66 (41)
HbA1c (%) Baseline
8.4 ± 1.2 (51)
8.5 ± 1.1 (46)
HbA1c (%) Week 12
8.4 ± 1.1 (51)
8.3 ± 1.0 (47)
Type 2, N=187
Fasting Blood Glucose (mg/dL)
153 ± 40 (76)
152 ± 69 (93)
1.5 Hour Post Breakfast (mg/dL)
182 ± 65 (75)
200 ± 80 (92)
1.5 Hour Post Dinner (mg/dL)
168 ± 51 (75)
191 ± 65 (93)
HbA1c (%) Baseline
8.1 ± 1.2 (82)
8.2 ± 1.3 (98)
HbA1c (%) Week 12
7.9 ± 1.0 (81)
8.1 ± 1.1 (96)
396
397
The significance, with respect to the long-term clinical sequelae of diabetes, of the
398
differences in postprandial hyperglycemia between treatment groups has not been established.
399
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were
400
monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial
401
402
14.2
Combination Therapy: Insulin and Oral Agents in Patients with Type 2 Diabetes
403
404
Trial 1:
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
405
In a 34-week, open-label trial, insulin-naïve patients with type 2 diabetes currently
406
treated with 2 oral antidiabetic agents were switched to treatment with metformin and
407
pioglitazone. During an 8-week optimization period metformin and pioglitazone were increased
408
to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period,
409
subjects were randomized to receive either NovoLog Mix 70/30 twice daily added on to the
410
metformin and pioglitazone regimen or continue the current optimized metformin and
411
pioglitazone therapy. NovoLog Mix 70/30 was started at a dose of 6 IU twice daily (before
412
breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110
413
mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 IU.
414
415
Table 4: Combination Therapy with Oral Agents and Insulin in Patients with Type 2
416
Diabetes Mellitus [Mean (SD)]
Treatment duration 24-weeks
NovoLog Mix
70/30 +
Metformin
+ Pioglitazone
Metformin +
Pioglitazone
HbA1c
Baseline mean ± SD (n)
8.1 ± 1.0 (102)
8.1 ± 1.0 (98)
End-of-study mean ± SD (n) - LOCF
6.6 ± 1.0 (93)
7.8 ± 1.2 (87)
Adjusted Mean change from baseline ± SE (n)*
-1.6 ± 0.1 (93)
-0.3 ± 0.1 (87)
Treatment difference mean ± SE*
95% CI*
-1.3 ± 0.1
(-1.6, -1.0)
Percentage of subjects reaching HbA1c<7.0%
76%
24%
Percentage of subjects reaching HbA1c≤6.5%
59%
12%
Fasting Blood Glucose (mg/dL)
Baseline Mean ± SD (n)
173 ± 39.8 (93)
163 ± 35.4 (88)
End of Study Mean ± SD (n) – LOCF
130 ± 50.0 (90)
162 ± 40.8 (84)
Adjusted Mean change from baseline ± SE (n)*
-43.0 ± 5.3 (90)
-3.9 ± 5.3 (84)
End-of-Study Blood Glucose (Plasma) (mg/dL)
2 Hour Post Breakfast
138 ± 42.8 (86)
188 ± 57.7 (74)
2 Hour Post Lunch
150 ± 41.5 (86)
176 ± 56.5 (74)
2 Hour Post Dinner
141 ± 57.8 (86)
195 ± 60.1 (74)
% of patients with severe hypoglycemia**
3
0
% of patients with minor hypoglycemia**
52
3
Weight gain at end of study (kg)**
4.6 ± 4.3 (92)
0.8 ± 3.2 (86)
417
*Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with
418
treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.
419
**If metabolic control is improved by intensified insulin therapy, an increased risk of hypoglycemia and weight
420
gain may occur.
421
422
423
Trial 2:
424
In a 28-week, open-label trial, insulin-naïve patients with type 2 diabetes with fasting
425
plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy
426
were randomized to receive either NovoLog Mix 70/30 twice daily [before breakfast and before
427
supper] or insulin glargine once daily1 (see Table 5). NovoLog Mix 70/30 was started at an
428
average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and before supper), and
429
bedtime insulin glargine was started at 10-12 IU (0.13 ± 0.03 IU/kg). Insulin doses were titrated
430
weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
431
80-110 mg/dL. The metformin dose was adjusted to 2550 mg/day. Approximately one-third of
432
the patients in each group were also treated with pioglitazone (30 mg/day). Insulin
433
secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients
434
were Caucasian (53%), and the mean initial weight was 90 kg.
435
436
Table 5: Combination Therapy with Oral Agents and Two Types of Insulin in Patients
437
with Type 2 Diabetes Mellitus [Mean (SD)]
Treatment duration 28-weeks
NovoLog Mix 70/30
+ Metformin ±
Pioglitazone
Insulin
Glargine+
Metformin ±
Pioglitazone
Number of patients
117
116
HbA1c
Baseline mean (%)
9.7 ± 1.5 (117)
9.8 ± 1.4 (114)
End-of-study mean (± SD)
6.9 ± 1.2 (108)
7.4 ± 1.2 (114)
Mean change from baseline
-2.7 ± 1.6 (108)
-2.4 ± 1.5 (114)
Percentage of subjects reaching HbA1c<7.0%
66%
40%
Total Daily Insulin Dose at end of study (U)
78 ± 40 (117)
51 ± 27 (116)
% of patients with severe hypoglycemia
0
0
% of minor hypoglycemia
43
16
Weight gain at end of study
5.4 ± 4.8 (117)
3.5 ± 4.5 (116)
438
439
15
REFERENCES
440
1.
Raskin R, Allen E, Hollander P, et al. Initiating insulin therapy in type 2
441
diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care.
442
2005; 28:260-265.
443
444
16
HOW SUPPLIED/STORAGE HANDLING
445
16.1
How Supplied
446
NovoLog Mix 70/30 is available in the following package sizes: each presentation
447
contains 100 Units of insulin aspart per mL (U-100).
448
449
10 mL vials
NDC 0169-3685-12
450
3 mL NovoLog Mix 70/30 FlexPen NDC 0169-3696-19
451
NovoLog Mix 70/30 vials and NovoLog Mix 70/30 FlexPen are latex free.
452
453
16.2
Recommended Storage
454
Unused NovoLog Mix 70/30 should be stored in a refrigerator between 2°C and 8°C
455
(36°F to 46°F). Do not store in the freezer or directly adjacent to the refrigerator cooling
456
element. Do not freeze NovoLog Mix 70/30 or use NovoLog Mix 70/30 if it has been frozen.
457
Vials: After initial use, a vial may be kept at temperatures below 30°C (86°F) for up to
458
28 days, but should not be exposed to excessive heat or sunlight. Open vials may be refrigerated.
459
Unpunctured vials can be used until the expiration date printed on the label if they are
460
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
461
from light.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
462
NovoLog Mix 70/30 FlexPen: Once a NovoLog Mix 70/30 FlexPen is punctured, it
463
should be kept at temperatures below 30°C (86°F) for up to 14 days, but should not be exposed
464
to excessive heat or sunlight. A NovoLog Mix 70/30 FlexPen in use must NOT be stored in the
465
refrigerator. Keep the disposable NovoLog Mix 70/30 FlexPen away from direct heat and
466
sunlight. An unpunctured NovoLog Mix 70/30 FlexPen can be used until the expiration date
467
printed on the label if they are stored in a refrigerator. Keep any unused NovoLog Mix 70/30
468
FlexPen in the carton so it will stay clean and protected from light.
469
These storage conditions are summarized in the following table:
Not in-use (unopened)
Room Temperature
(below 30°C[86°F])
Not in-use (unopened)
Refrigerated
(2°C - 8°C [36°F- 46°F])
In-use (opened)
Room Temperature
(below 30°C[86°F])
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3ml NovoLog Mix 70/30
FlexPen
14 days
Until expiration date
14 days (Do not refrigerate)
470
471
472
17
PATIENT COUNSELING INFORMATION
473
[see FDA-Approved Patient Labeling]
474
475
17.1
Physician Instructions
476
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
477
mellitus and has been associated with a reduction in diabetic complications. Patients should be
478
informed about potential risks and advantages of NovoLog Mix 70/30 therapy including the
479
possible adverse reactions. Patients should also be offered continued education and advice on
480
insulin therapies, injection technique, life-style management, regular glucose monitoring,
481
periodic glycosylated hemoglobin testing, recognition and management of hypo- and
482
hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose,
483
instruction for use of injection devices, and proper storage of insulin. See Patient Information
484
supplied with the product. Patients should be informed that frequent, patient-performed blood
485
glucose measurements are needed to achieve optimal glycemic control and avoid both hyper-
486
and hypoglycemia, and diabetic ketoacidosis.
487
The patient’s ability to concentrate and react may be impaired as a result of
488
hypoglycemia. This may present a risk in situations where these abilities are especially
489
important, such as driving or operating other machinery. Patients who have frequent
490
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
491
caution when driving or operating machinery.
492
Accidental substitutions between NovoLog Mix 70/30 and other insulin products have
493
been reported. Patients should be instructed to always carefully check that they are
494
administering the appropriate insulin to avoid medication errors between NovoLog Mix 70/30
495
and any other insulin. The prescription for NovoLog Mix 70/30 should be written clearly in
496
order to avoid confusion with other insulin products, for example, NovoLog or Novolin
497
70/30. In addition, the written prescription should clearly indicate the presentation, for example
498
FlexPen or vial.
499
500
501
Rx only
502
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
503
Date of Issue:
504
505
Version:
506
507
Novo Nordisk®, NovoLog®, FlexPen®, and Novolin®, are trademarks owned by Novo Nordisk®
508
A/S.
509
510
NovoLog® Mix 70/30 is covered by US Patent Nos 5,547,930, 5,618,913, 5,834,422, 5,840,680,
511
5,866,538 and other patents pending.
512
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004 and other patents
513
pending.
514
515
© 2002 – 2010 Novo Nordisk A/S
516
517
Manufactured by:
518
Novo Nordisk A/S
519
DK-2880 Bagsvaerd, Denmark
520
521
For information about NovoLog Mix 70/30 contact:
522
Novo Nordisk Inc.
523
Princeton, New Jersey 08540
524
1-800-727-6500
525
526
www.novonordisk-us.com
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NovoLog® Mix 70/30
(NŌ-vō-log-MIX-SEV-en-tee-THIR-tee)
(70% insulin aspart protamine suspension and 30% insulin aspart injection,
[rDNA origin])
Read the Patient Information leaflet that comes with NovoLog® Mix 70/30
before you start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure you
know how to manage your diabetes. Ask your healthcare provider if you
have any questions about managing your diabetes.
What is NovoLog® Mix 70/30?
NovoLog® Mix 70/30 is a man-made insulin that is used to control high blood
sugar in adults with diabetes mellitus.
It is not known if NovoLog® Mix 70/30 is safe or effective in children.
Who should not use NovoLog® Mix 70/30?
Do not take NovoLog® Mix 70/30 if:
•
Your blood sugar is too low (hypoglycemia)
•
You are allergic to any of the ingredients in NovoLog® Mix 70/30.
See the end of this leaflet for a complete list of ingredients in
NovoLog® Mix 70/30. Check with your healthcare provider if you
are not sure.
What should I tell my healthcare provider before taking NovoLog®
Mix 70/30?
Before you use NovoLog® Mix 70/30, tell your healthcare provider if
you:
•
have kidney or liver problems
•
have any other medical conditions. Medical conditions can
affect your insulin needs and your dose of NovoLog® Mix 70/30.
•
are pregnant or plan to become pregnant. It is not known if
NovoLog® Mix 70/30 will harm your unborn baby. Talk to your
healthcare provider if you are pregnant or plan to become
pregnant. You and your healthcare provider should decide about
the best way to manage your diabetes while you are pregnant.
•
are breastfeeding or plan to breastfeed. It is not known if
NovoLog® Mix 70/30 passes into your breast milk. You and your
healthcare provider should decide if you will take NovoLog® Mix
70/30 while you breastfeed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all medicines you take, including
prescriptions and non-prescription medicines, vitamins and herbal
supplements.
NovoLog® Mix 70/30 may affect the way other medicines work, and other
medicines may affect how NovoLog® Mix 70/30 works. Your NovoLog® Mix
70/30 dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to
show your healthcare providers and pharmacist when you get a new
medicine.
How should I take NovoLog® Mix 70/30?
•
Take NovoLog® Mix 70/30 exactly as your healthcare provider tells
you to take it.
•
Your healthcare provider will tell you how much NovoLog® Mix
70/30 to take and when to take it.
•
Do not make any changes to your dose or type of insulin unless
your healthcare provider tells you to.
•
NovoLog Mix 70/30 starts acting fast. If you have Type 1
diabetes, inject it up to 15 minutes before you eat a meal.
Do not inject NovoLog® Mix 70/30 if you are not planning to eat
within 15 minutes.
•
If you have Type 2 diabetes, you may inject NovoLog® Mix
70/30 up to 15 minutes before or after starting your meal.
•
Do Not mix NovoLog® Mix 70/30 with other insulin products.
•
Do Not use NovoLog® Mix 70/30 in an insulin pump.
•
Inject NovoLog® Mix 70/30 under the skin
(subcutaneously) of your stomach area, upper arms,
buttocks or upper legs. NovoLog® Mix 70/30 may affect your
blood sugar levels faster if you inject it under the skin of your
stomach area. Never inject NovoLog® Mix 70/30 into a vein or into
a muscle.
•
Change (rotate) injection sites within the area you choose with
each dose. Do not inject into the exact same spot for each
injection.
•
Read the instructions for use that come with your
NovoLog® Mix 70/30. Talk to your healthcare provider if you
have any questions. Your healthcare provider should show you
how to inject NovoLog® Mix 70/30 before you start using it.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
NovoLog® Mix 70/30 comes in:
o 10 mL vials for use with a syringe
o 3 mL NovoLog® Mix 70/30 FlexPen®
•
If you take too much NovoLog® Mix 70/30, your blood
sugar may fall too low (hypoglycemia). You can treat mild
low blood sugar (hypoglycemia) by drinking or eating something
sugary right away (fruit juice, sugar candies, or glucose tablets).
It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (loss of
consciousness).
•
If you forget to take your dose of NovoLog® Mix 70/30,
your blood sugar may go too high (hyperglycemia). If high
blood sugar (hyperglycemia) is not treated it can lead to serious
problems, like passing out (loss of consciousness), coma or even
death. Follow your healthcare provider’s instructions for treating
high blood sugar. Know your symptoms of high blood sugar which
may include:
•
increased thirst
• fruity smell on the breath
•
frequent urination
• high amounts of sugar and
•
drowsiness
ketones in your urine
•
loss of appetite
• nausea, vomiting (throwing
•
a hard time
up) or stomach pain
breathing
•
Do not share needles, insulin pens or syringes with others.
•
Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check
your blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
• change in diet
•
stress
• change in physical activity or
•
other medicines you
exercise
take
See the end of this patient information for instructions about preparing and
giving your injection.
What should I consider while using NovoLog® Mix 70/30?
•
Alcohol. Drinking alcohol may affect your blood sugar when you
take NovoLog® Mix 70/30.
•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for you to
drive if you often have:
•
low blood sugar
•
decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog® Mix 70/30?
NovoLog® Mix 70/30 may cause serious side effects, including:
•
low blood sugar (hypoglycemia). Symptoms of low blood
sugar may include:
•
sweating
•
trouble concentrating
•
dizziness or
or confusion
lightheadedness
•
blurred vision
•
shakiness
•
slurred speech
•
hunger
•
anxiety, irritability or
•
fast heart beat
mood changes
•
tingling of lips and
•
headache
tongue
Very low blood sugar can cause you to pass out (loss of
consciousness), seizures, and death. Talk to your healthcare
provider about how to tell if you have low blood sugar and what to
do if this happens while taking NovoLog® Mix 70/30. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of NovoLog® Mix 70/30 may need to be changed.
•
Low potassium in your blood (hypokalemia)
•
Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious talk to your
healthcare provider.
•
Serious allergic reaction (whole body reaction). Get
medical help right away, if you have any of these
symptoms of an allergic reaction:
o a rash over your whole body
o have trouble breathing
o a fast heartbeat
o sweating
o feel faint
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The most common side effects of NovoLog® Mix 70/30 include:
•
Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) where you inject your insulin to help to prevent
these skin changes from happening. Do not inject insulin into this
type of skin.
•
Weight gain
•
Swelling of your hands and feet
•
Vision changes
These are not all of the possible side effects from NovoLog® Mix 70/30. Ask
your healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store NovoLog® Mix 70/30?
All Unopened NovoLog® Mix 70/30:
•
Keep all unopened NovoLog® Mix 70/30 in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Do not freeze or store next to the refrigerator cooling
element. Do not use NovoLog® Mix 70/30 if it has been frozen.
•
Keep unopened NovoLog® Mix 70/30 in the carton to protect from
light.
•
Unopened vials can be used until the expiration date on the
NovoLog® Mix 70/30 label, if the medicine has been stored in a
refrigerator.
•
Unused NovoLog® Mix 70/30 FlexPen® can be used until the
expiration date on the NovoLog® Mix 70/30 FlexPen® label, if the
medicine has been stored in a refrigerator.
After NovoLog® Mix 70/30 has been opened:
•
Vials
• Keep in the refrigerator or at room temperature below 86°F
(30°C) for up to 28 days.
• Keep vials away from direct heat or light.
• Throw away an opened vial after 28 days of use, even if
there is insulin left in the vial.
•
NovoLog® Mix 70/30 FlexPen®
• Keep at room temperature below 86°F (30°C) for up to 14
days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not store a NovoLog® Mix 70/30 FlexPen® that you are
using in the refrigerator.
• Keep NovoLog® Mix 70/30 FlexPen® away from direct heat or
light.
• Throw away a used NovoLog® Mix 70/30 FlexPen® after 14
days, even if there is insulin left in the syringe.
Never use insulin after the expiration date that is printed on the label
and carton.
Keep NovoLog® Mix 70/30 and all medicines out of the reach of
children.
General advice about NovoLog® Mix 70/30
Medicines are sometimes prescribed for conditions that are not mentioned in
the patient leaflet. Do not use NovoLog® Mix 70/30 for a condition for which
it was not prescribed. Do not give NovoLog® Mix 70/30 to other people, even
if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog® Mix
70/30. If you would like more information about NovoLog® Mix 70/30 or
diabetes, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about NovoLog® Mix 70/30 that is
written for healthcare professionals. For more information call 1-800-727
6500 or go to www.novonordisk-us.com.
What are the ingredients in NovoLog® Mix 70/30?
• Active Ingredients NovoLog® Mix 70/30 FlexPen® and Vial: 70%
Insulin aspart protamine suspension and 30% insulin aspart injection
(rDNA origin).
• Inactive Ingredients NovoLog® Mix 70/30 FlexPen®: glycerol,
phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium
chloride, protamine sulfate, water for injection, hydrochloric acid or
sodium hydroxide.
• Inactive Ingredients NovoLog® Mix 70/30 Vial: mannitol, phenol,
metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium
chloride, protamine sulfate, water for injection, hydrochloric acid or
sodium hydroxide.
All NovoLog® Mix 70/30 vials and NovoLog® Mix 70/30 FlexPen® are latex
free.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Helpful information for people with diabetes is published by the American
Diabetes Association, 1701 N Beauregard Street, Alexandria, VA 2311 and is
available at www.diabetes.org.
Date of Issue:
Version:
NovoLog®, FlexPen®, NovoFine®, are trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422,
5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004 and
other patents pending.
© 2002-2010 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog Mix 70/30® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
NovoLog® Mix 70/30 FlexPen®
Read the following instructions carefully before you start using your NovoLog® Mix
70/30 FlexPen® and each time you get a refill. There may be new information. You
should read the instructions even if you have used Novolog® Mix 70/30 FlexPen®
before.
NovoLog® Mix 70/30 FlexPen® is a disposable dial-a-dose insulin pen. You can
select doses from 1 to 60 units in increments of 1 unit. NovoLog® Mix 70/30
FlexPen® is designed to be used with NovoFine® needles.
NovoLog Mix® 70/30 FlexPen® should not be used by people who are blind or have
severe visual problems without the help of a person who has good eyesight and
who is trained to use the NovoLog® Mix 70/30 FlexPen® the right way.
Getting ready
Make sure you have the following items:
NovoLog® Mix 70/30 FlexPen®
New NovoFine® needle
Alcohol swab Usage Illustration
PREPARING YOUR NOVOLOG® MIX 70/30 FLEXPEN®
• Wash your hands with soap and water.
• Before you start to prepare your injection, check the label to make
sure that you are taking the right type of insulin. This is especially
important if you take more than 1 type of insulin. NovoLog® Mix
70/30 should look cloudy after mixing.
Before your first injection with a new NovoLog® Mix 70/30 FlexPen® you
must mix the insulin:
A. Let the insulin reach room temperature before you use it.
This makes it easier to mix.
Pull off the pen cap (see diagram A). Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
B. Roll the pen between your palms 10 times – it is
important that the pen is kept horizontal (see diagram
B).
C. Then gently move the pen up and down ten times
between position 1 and 2 as shown, so the glass ball
moves from one end of the cartridge to the other (see
diagram C).
Repeat rolling and moving the pen until the liquid appears
white and cloudy. Usage Illustration
For every following injection move the pen up and down between
positions 1 and 2 at least ten times until the liquid appears white and
cloudy.
After mixing, complete all the following steps of the injection right away. If
there is a delay, the insulin will need to be mixed again.
Wipe the rubber stopper with an alcohol swab.
Before you inject, there must be at least 12 units of insulin left in the cartridge to
make sure the remaining insulin is evenly mixed. If there are less than 12 units
left, use a new NovoLog® Mix 70/30 FlexPen® .
Attaching the needle
D. Remove the protective tab from a disposable needle.
Screw the needle tightly onto your NovoLog® Mix 70/30
FlexPen® . It is important that the needle is put on straight
(see diagram D).
Never place a disposable needle on your NovoLog® Mix 70/30
FlexPen® until you are ready to take your injection. Usage Illustration
E. Pull off the big outer needle cap (see diagram E). Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
F. Pull off the inner needle cap and dispose of it (see diagram
F). Usage Illustration
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of a needle stick, never put the inner needle cap back on
the needle.
Giving the airshot before each injection:
Before each injection small amounts of air may collect in the cartridge during
normal use. To avoid injecting air and to make sure you take the right dose
of insulin:
G. Turn the dose selector to select 2 units (see diagram G).
H. Hold your NovoLog® Mix 70/30 FlexPen® with the needle
pointing up. Tap the cartridge gently with your finger a few
times to make any air bubbles collect at the top of the
cartridge (see diagram H).
I. Keep the needle pointing upwards, press the push-button
all the way in (see diagram I). The dose selector returns
to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use
the NovoLog Mix® 70/30 FlexPen® and contact Novo Nordisk
at 1-800-727-6500. Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
J. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram J). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set
the dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before
injecting. Wipe the skin with an alcohol swab and let the area dry. Usage Illustration
K. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram K). Be careful only
to push the button when injecting.
Turning the dose selector will not inject insulin.
L. Keep the needle in the skin for at least 6 seconds, and
keep the push-button pressed all the way in until the
needle has been pulled out from the skin (see diagram L).
This will make sure that the full dose has been given.
You may see a drop of NovoLog® Mix 70/30 at the needle tip.
This is normal and has no effect on the dose you just
received. If blood appears after you take the needle out of
your skin, press the injection site lightly with an alcohol
swab. Do not rub the area.
After the injection Usage Illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog® Mix 70/30 FlexPen® after each
injection. This helps to prevent infection, leakage of insulin, and will help to
make sure you inject the right dose of insulin.
Put the needle and any empty NovoLog® Mix 70/30 FlexPen® or any
used NovoLog® Mix 70/30 FlexPen® still containing insulin in a sharps
container or some type of hard plastic or metal container with a screw
top such as a detergent bottle or empty coffee can. These containers
should be sealed and thrown away the right way. Check with your
healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away
used needles and syringes. Do not throw away used needles and
syringes in household trash or recycling bins.
The NovoLog® Mix 70/30 FlexPen® prevents the cartridge from being completely
emptied. It is designed to deliver 300 units.
M. Put the pen cap on the NovoLog® Mix 70/30 FlexPen® and
store the NovoLog® Mix 70/30 FlexPen® without the
needle attached (see diagram M). Usage Illustration
FUNCTION CHECK
If your NovoLog® Mix 70/30 FlexPen® is not working the right way, follow
the steps below:
Screw on a new NovoFine® needle
Remove the big outer needle cap and the inner needle
cap
Do an airshot as described in “Giving the airshot before
each injection”.
Put the big outer needle cap onto the needle. Do not
put on the inner needle cap.
Turn the dose selector so the dose indicator window
shows 20 units.
Hold the NovoLog® Mix 70/30 FlexPen® so the needle is
pointing down
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see
diagram N). If NovoLog® Mix 70/30 FlexPen® has released too much or too
little insulin, do the function check again. If the same problem happens
again, do not use your NovoLog® Mix 70/30 FlexPen® and contact Novo
Nordisk at 1-800-727-6500. Usage Illustration
Maintenance
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Your NovoLog® Mix 70/30 FlexPen® is designed to work accurately and
safely. It must be handled with care. Avoid dropping your NovoLog® Mix
70/30 FlexPen® as it may damage it. If you are concerned that your
NovoLog® Mix 70/30 FlexPen® is damaged, use a new one. You can clean
the outside of your NovoLog® Mix 70/30 FlexPen® by wiping it with a damp
cloth. Do not soak or wash your NovoLog® Mix 70/30 FlexPen® as it may
damage it. Do not refill your NovoLog® Mix 70/30 FlexPen® . bullet
Remove the needle from the NovoLog® Mix 70/30 FlexPen® after each
injection. This helps to ensure sterility, prevent leakage of insulin, and
will help to make sure you inject the right dose of insulin for future
injections. bullet
Be careful when handling used needles to avoid needle sticks and
transfer of infectious diseases. bullet
Keep your NovoLog® Mix 70/30 FlexPen® and needles out of the reach of
children. bullet
Use NovoLog® Mix 70/30 FlexPen® as directed to treat your diabetes.
Do not share it with anyone else even if they also have diabetes. bullet
Always use a new needle for each injection. bullet
Novo Nordisk is not responsible for harm due to using this insulin pen
with products not recommended by Novo Nordisk. bullet
As a precautionary measure, always carry a spare insulin delivery device
in case your NovoLog® Mix 70/30 FlexPen® is lost or damaged. bullet
Remember to keep the disposable NovoLog® Mix 70/30 FlexPen® with
you. Do not leave it in a car or other location where it can get too hot or
too cold.
NovoLog®, FlexPen®, NovoFine®, are trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422,
5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004
and other patents pending.
© 2002-2010 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog Mix 70/30® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
NovoLog® Mix 70/30 10ml vial (100 Units/mL, U-100)
Read the following Patient Instructions for Use carefully before you start
using your NovoLog® Mix 70/30 10ml vial and each time you get a refill.
There may be new information. You should read the instructions even if you
have used NovoLog® Mix 70/30 10ml vials before.
Before starting, gather all of the supplies that you will need to use for
preparing and giving your insulin injection.
Never re-use syringes and needles.
How should I prepare and deliver the injection using the NovoLog®
Mix 70/30 10 ml vial?
1.
Check to make sure you have the correct type of insulin. This is
especially important if you use different types of insulin.
2.
Look at the vial and the insulin. The insulin should be white and cloudy
after mixing. The tamper-resistant cap should be on the vial before the
first use. If the cap has already been removed before your first use of
the vial, or if the insulin looks clear or contains any particles, do not use
it and return it to your pharmacy.
3.
Wash your hands with soap and water. Clean your injection site with an
alcohol swab and let the injection site dry before you inject. Talk with
your healthcare provider about how to rotate injection sites and how to
give an injection.
4.
If you are using a new vial, pull off the tamper-resistant cap. Wipe the
rubber stopper with an alcohol swab.
5.
Roll the vial gently 10 times in your hands to mix it. This should be
done with the vial in a horizontal (flat) position between your palms. Do
not shake the vial. Shaking right before the dose is drawn into the
syringe may cause bubbles or foam. This can cause you to draw up the
wrong dose of insulin. The insulin should be used only if it looks white
and cloudy.
6.
Pull back the plunger on the syringe until the black tip reaches the
marking for the number of units you will inject.
7.
Push the needle through the rubber stopper into the vial, and push the
plunger all the way in to force air into the vial.
8.
Turn the vial and syringe upside down and slowly pull the plunger back
to a few units beyond the correct dose needed.
9.
If there are air bubbles in the syringe, tap the syringe gently with your
finger to raise the air bubbles to the top. Slowly push the plunger to the
marking for your dose. This should move any air bubbles in the syringe
back into the vial.
10. Check to make sure you have the right dose of NovoLog® Mix 70/30 in
the syringe.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11. Pull the syringe out of the vial’s rubber stopper.
12. If there is a delay after you rolled the vial, you will have to roll it again
to remix the insulin and redraw your medicine. Your healthcare provider
should tell you if you need to pinch the skin before inserting the needle.
This can be different from person to person so it is important to ask your
doctor if you did not receive instructions on pinching the skin. Insert the
needle into the skin right away. Push the plunger to inject the insulin
under your skin. Keep the needle under your skin for at least 6 seconds
to make sure you have injected all the insulin. When you are finished
injecting the insulin, pull the needle out of your skin.
13. Your may see a drop of NovoLog® Mix 70/30 at the needle tip. This is
normal and has no effect on the dose you just received. If blood
appears after you pull the needle from your skin, press the injection site
lightly with an alcohol swab. Do not rub the area. Do not recap the
needle.
14. After the injection, dispose of the needle and syringe in a
puncture-resistant container. Place used syringes, needles, and
insulin vials in a disposable puncture-resistant sharps container, or some
type of hard plastic or metal container with a screw on cap such as a
detergent bottle or coffee can.
15. Ask your healthcare provider about the right way to throw away used
syringes and needles. There may be state or local laws about the right
way to throw away used syringes and needles. Do not throw away
used needles and syringes in household trash or recycling bins.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1660 Duke Street, Alexandria, VA 22314.
Date of Issue:
Version:
Novo Nordisk®, NovoLog®, FlexPen® and NovoFine® are trademarks owned by
Novo Nordisk A/S.
© 2002–2010 Novo Nordisk A/S
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913,
5,834,422, 5,840,680, 5,866,538 and other patents pending.
For information about NovoLog® Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by
Novo Nordisk A/S
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DK-2880 Bagsvaerd, Denmark
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:30.174612 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021172s045s049lbl.pdf', 'application_number': 21172, 'submission_type': 'SUPPL ', 'submission_number': 49} |
4,546 |
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NovoLog Mix 70/30 safely and effectively. See full prescribing
information for NovoLog Mix 70/30.
NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30%
insulin aspart injection, [rDNA origin])
Suspension for subcutaneous injection
Initial U.S. Approval: 2001
---------------------------------RECENT MAJOR CHANGES-------------------------
• Indications and Usage (1) 5/2010
• Dosage and Administration (2.1) 5/2010
----------------------------INDICATIONS AND USAGE---------------------------
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control
in patients with diabetes mellitus.
Important Limitations of Use: In premix insulins, such as NovoLog Mix 70/30,
the proportions of rapid acting and long acting insulins are fixed and do not
allow for basal versus prandial dose adjustments (1).
----------------------DOSAGE AND ADMINISTRATION-----------------------
• Only for subcutaneous injection (2.1).
Type 1 DM: dose within 15 minutes before meal initiation.
Type 2 DM: dose within 15 minutes before or after starting a meal.
• Do not administer intravenously (2.1).
• Do not use in insulin infusion pumps (2.1).
• Must be resuspended immediately before use (2.2).
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Each presentation contains 100 Units of insulin aspart per mL (U-100) (3)
• 10 mL vials
• 3 mL NovoLog Mix 70/30 FlexPen
-------------------------------CONTRAINDICATIONS------------------------------
• Do not use during episodes of hypoglycemia (4).
• Do not use in patients with hypersensitivity to NovoLog Mix 70/30 or
one of its excipients (4).
-----------------------WARNINGS AND PRECAUTIONS-----------------------
• NovoLog Mix 70/30 should not be mixed with any other insulin product
(5.1).
• Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under
medical supervision (5.1, 5.2).
• Insulin, particularly when given in settings of poor glycemic control,
can cause hypokalemia. Use caution in patients predisposed to
hypokalemia (5.3).
• Like all insulins, NovoLog Mix 70/30 requirements may be reduced
in patients with renal impairment or hepatic impairment (5.4, 5.5).
• Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with insulin products, including NovoLog Mix 70/30 (5.6).
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions observed with insulin therapy include hypoglycemia,
allergic reactions, local injection site reactions, lipodystrophy, rash and
pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• The following may increase the blood-glucose-lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g.
octreotide), sulfonamide antibiotics (7).
• The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine
derivatives, somatropin, thyroid hormones, estrogens, progestogens
(e.g., in oral contraceptives), atypical antipsychotics (7).
• Beta-blockers, clonidine, lithium salts, and alcohol may either
potentiate or weaken the blood-glucose-lowering effect of insulin (7).
• Pentamidine may cause hypoglycemia, which may be followed by
hyperglycemia (7).
• The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine,
and reserpine (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 9/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Resuspension
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 NovoLog Mix 70/30 versus Novolin 70/30
14.2
Combination Therapy: Insulin and Oral Agents in Patients with
Type 2 Diabetes
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Recommended Storage
17 PATIENT COUNSELING INFORMATION
17.1
Physician Instructions
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3103527
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
____________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control in
patients with diabetes mellitus.
Important Limitations of Use:
In premix insulins, such as NovoLog Mix 70/30, the proportions of rapid acting and long
acting insulins are fixed and do not allow for basal versus prandial dose adjustments.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog Mix 70/30 is an insulin analog with an earlier onset and intermediate duration
of action in comparison to the basal human insulin premix. The addition of protamine to the
rapid-acting aspart insulin analog (NovoLog) results in insulin activity that is 30% short-acting
and 70% long-acting. NovoLog Mix 70/30 is typically dosed on a twice-daily basis (with each
dose intended to cover 2 meals or a meal and a snack). The dosage of NovoLog Mix 70/30 must
be individualized. The written prescription for NovoLog Mix 70/30 should include the full
name, to avoid confusion with NovoLog (insulin aspart) and Novolin 70/30 (human premix).
NovoLog Mix 70/30 should appear uniformly white and cloudy. Do not use it if it looks
clear or if it contains solid particles. NovoLog Mix 70/30 should not be used after the printed
expiration date.
NovoLog Mix 70/30 should be administered by subcutaneous injection in the abdominal
region, buttocks, thigh, or upper arm. NovoLog Mix 70/30 has a faster onset of action than
human insulin premix 70/30 and should be dosed within 15 minutes before meal initiation for
patients with type 1 diabetes. For patients with type 2 diabetes, dosing should occur within 15
minutes before or after meal initiation. Injection sites should be rotated within the same region
to reduce the risk of lipodystrophy. As with all insulins, the duration of action may vary
according to the dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog Mix 70/30 should not be administered intravenously or used in insulin
infusion pumps. Dose regimens of NovoLog Mix 70/30 will vary among patients and should be
determined by the health care professional familiar with the patient’s recommended glucose
treatment goals, metabolic needs, eating habits, and other lifestyle variables.
2.2
Resuspension
NovoLog Mix 70/30 is a suspension that must be visually inspected and resuspended
immediately before use.
The NovoLog Mix 70/30 vial should be rolled gently in your hands in a horizontal position 10
times to mix it. The rolling procedure must be repeated until the suspension appears uniformly
white and cloudy. Inject immediately. Resuspension is easier when the insulin has reached
room temperature.
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The NovoLog Mix 70/30 FlexPen should be rolled 10 times gently between your hands in a
horizontal position. Thereafter, turn the NovoLog Mix 70/30 FlexPen upside down so that the
glass ball moves from one end of the reservoir to the other. Do this at least 10 times. The
rolling and turning procedure must be repeated until the suspension appears uniformly white
and cloudy. Inject immediately. Before each subsequent injection, turn the disposable NovoLog
Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to
the other at least 10 times and until the suspension appears uniformly white and cloudy. Inject
immediately.
3
DOSAGE FORMS AND STRENGTHS
NovoLog Mix 70/30 is available in the following package sizes: each presentation
contains 100 units of insulin aspart per mL (U-100).
• 10 mL vials
• 3 mL NovoLog Mix 70/30 FlexPen
4
CONTRAINDICATIONS
NovoLog Mix 70/30 is contraindicated
• during episodes of hypoglycemia
• in patients with hypersensitivity to NovoLog Mix 70/30 or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
The short and long-acting components of insulin mixes, including NovoLog Mix 70/30,
cannot be titrated independently. Because NovoLog Mix 70/30 has peak pharmacodynamic
activity between 1-4 hours after injection, it should be administered within 15 minutes of meal
initiation [see Clinical Pharmacology (12)]. The dose of insulin required to provide adequate
glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal.
The pharmacodynamic profile may also be inadequate for patients who require more frequent
meals.
NovoLog Mix 70/30 should not be mixed with any other insulin product.
NovoLog Mix 70/30 should not be used intravenously.
NovoLog Mix 70/30 should not be used in insulin infusion pumps.
Glucose monitoring is recommended for all patients with diabetes. Any change of
insulin dose should be made cautiously and only under medical supervision. Changing from one
insulin product to another or changing the insulin strength may result in the need for a change in
dosage. Changes may also be necessary during illness, emotional stress, and other physiologic
stress in addition to changes in meals and exercise.
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by
the site used for injection and the degree of vascularization of the site. Smoking, temperature,
and exercise contribute to variations in blood flow and insulin absorption. These and other
factors contribute to inter- and intra-patient variability.
Needles and NovoLog Mix 70/30 FlexPen must not be shared.
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5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of insulin therapy, including
NovoLog Mix 70/30. Severe hypoglycemia may lead to unconsciousness and/or convulsions
and may result in temporary or permanent impairment of brain function or even death. Severe
hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or
glucagon administration has been observed in clinical trials with insulin, including trials with
NovoLog Mix 70/30.
The timing of hypoglycemia may reflect the time-action profile of the insulin
formulation [see Clinical Pharmacology (12)]. Other factors, such as changes in dietary intake
(e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications
may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all insulins, use
caution in patients with hypoglycemia unawareness and in patients who may be predisposed to
hypoglycemia (e.g. patients who are fasting or have erratic food intake). The patient’s ability to
concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in
situations where these abilities are especially important, such as driving or operating machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as long
duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)].
5.3
Hypokalemia
All insulin products, including NovoLog Mix 70/30, cause a shift in potassium from the
extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may
cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may
be at risk for hypokalemia (e.g. patients using potassium-lowering medications or patients
taking medications sensitive to potassium concentrations).
5.4
Renal Impairment
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various
degrees of renal impairment have not been conducted. As with other insulins, the requirements
for NovoLog Mix 70/30 may be reduced in patients with renal impairment [see Clinical
Pharmacology (12.3)].
5.5
Hepatic Impairment
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with
various degrees of hepatic impairment have not been conducted. As with other insulins, the
requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic impairment [see
Clinical Pharmacology (12.3)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions- As with other insulin therapy, patients may experience reactions such
as erythema, edema or pruritus at the site of NovoLog Mix 70/30 injection. These reactions
usually resolve in a few days to a few weeks, but in some occasions, may require
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discontinuation of NovoLog Mix 70/30. In some instances, these reactions may be related to the
insulin molecule, other components in the insulin preparation including protamine and cresol,
components in skin cleansing agents, or injection techniques. Localized reactions and
generalized myalgias have been reported with the use of cresol as an injectable excipient.
Systemic Reactions- Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
allergy, including anaphylactic reaction, may be life threatening.
5.7
Antibody Production
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were
monitored in a 3-month, open-label comparator trial as well as in a long-term extension trial.
Changes in cross-reactive antibodies were more common after NovoLog Mix 70/30 than with
Novolin 70/30 but these changes did not correlate with change in HbA1c or increase in insulin
dose. The clinical significance of these antibodies has not been established. Antibodies did not
increase further after long-term exposure (>6 months) to NovoLog Mix 70/30.
6
ADVERSE REACTIONS
Clinical Trial Experience
Clinical trials are conducted under widely varying designs, therefore, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
• Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including NovoLog Mix 70/30 [see Warnings and Precautions (5.2)]. NovoLog Mix
70/30 should not be used during episodes of hypoglycemia [see Contraindications (4)
and Warnings and Precautions (5)].
• Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
• Lipodystrophy
Long-term use of insulin, including NovoLog Mix 70/30, can cause lipodystrophy at the
site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of
adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin
absorption. Rotate insulin injection sites within the same region to reduce the risk of
lipodystrophy.
• Weight gain
Weight gain can occur with some insulin therapies, including NovoLog Mix 70/30, and
has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
• Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
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• Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during a clinical trial with NovoLog Mix 70/30
in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the
tables below. The trial was a three-month, open-label trial in patients with Type 1 or
Type 2 diabetes who were treated twice daily (before breakfast and before supper) with
NovoLog Mix 70/30.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 diabetes mellitus
(Adverse events with frequency ≥ 5% are included.)
NovoLog Mix 70/30
(N=55)
Novolin 70/30
(N=49)
Preferred Term
N
%
N
%
Hypoglycemia
38
69
37
76
Headache
19
35
6
12
Influenza-like symptoms
7
13
1
2
Dyspepsia
5
9
3
6
Back pain
4
7
2
4
Diarrhea
4
7
3
6
Pharyngitis
4
7
1
2
Rhinitis
3
5
6
12
Skeletal pain
3
5
2
4
Upper respiratory tract infection
3
5
1
2
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 diabetes mellitus
(Adverse events with frequency ≥ 5% are included.)
NovoLog Mix 70/30
(N=85)
Novolin 70/30
(N=102)
Preferred Term
N
%
N
%
Hypoglycemia
40
47
51
50
Upper respiratory tract infection
10
12
6
6
Headache
8
9
8
8
Diarrhea
7
8
2
2
Neuropathy
7
8
2
2
Pharyngitis
5
6
4
4
Abdominal pain
4
5
0
0
Rhinitis
4
5
2
2
Postmarketing Data
Additional adverse reactions have been identified during post-approval use of NovoLog
Mix 70/30. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. They include
medication errors in which other insulins have been accidentally substituted for NovoLog Mix
70/30 [see Patient Counseling Information (17)].
7
DRUG INTERACTIONS
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A number of substances affect glucose metabolism and may require insulin dose
adjustment and particularly close monitoring.
• The following are examples of substances that may increase the blood-glucose
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide),
sulfonamide antibiotics.
• The following are examples of substances that may reduce the blood-glucose
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
atypical antipsychotics.
• Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
the blood-glucose-lowering effect of insulin.
• Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
• The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
products such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B.
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. This background risk is increased in pregnancies complicated by
hyperglycemia and may be decreased with good metabolic control. It is essential for patients
with diabetes or history of gestational diabetes to maintain good metabolic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first
trimester, generally increase during the second and third trimesters, and rapidly decline after
delivery. Careful monitoring of glucose control is essential in such patients.
An open-label, randomized study compared the safety and efficacy of NovoLog (the
rapid-acting component of NovoLog Mix 70/30) versus human insulin in the treatment of
pregnant women with Type 1 diabetes (322 exposed pregnancies (NovoLog: 157, human
insulin: 165)). Two-thirds of the enrolled patients were already pregnant when they entered the
study. Since only one-third of the patients enrolled before conception, the study was not large
enough to evaluate the risk of congenital malformations. Mean HbA1c of ~ 6% was observed in
both groups during pregnancy, and there was no significant difference in the incidence of
maternal hypoglycemia.
Animal reproduction studies have not been conducted with NovoLog Mix 70/30.
However, subcutaneous reproduction and teratology studies have been performed with
NovoLog (the rapid-acting component of NovoLog Mix 70/30) and regular human insulin in
rats and rabbits. In these studies, NovoLog was given to female rats before mating, during
mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of
NovoLog did not differ from those observed with subcutaneous regular human insulin.
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NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal
abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the human
subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of
10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based
on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high
doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a
dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits
based on U/body surface area.
Female patients should be advised to discuss with their physician if they intend to, or if
they become pregnant. There are no adequate and well-controlled studies of the use of
NovoLog Mix 70/30 in pregnant women.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk as occurs with human
insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 or
NovoLog in lactating women. Women with diabetes who are lactating may require adjustments
of their insulin doses.
8.4
Pediatric Use
Safety and effectiveness of NovoLog Mix 70/30 have not been established in pediatric
patients.
8.5
Geriatric Use
Clinical studies of NovoLog Mix 70/30 did not include sufficient numbers of patients
aged 65 and over to determine whether they respond differently than younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of
the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function,
and of concomitant disease or other drug therapy in this population.
10
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake,
energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery.
11
DESCRIPTION
NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart
injection, [rDNA origin]) is a human insulin analog suspension containing 70% insulin aspart
protamine crystals and 30% soluble insulin aspart. NovoLog Mix 70/30 is a blood-glucose
lowering agent with an earlier onset and an intermediate duration of action. Insulin aspart is
homologous with regular human insulin with the exception of a single substitution of the amino
acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology
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12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog Mix 70/30 is the regulation of glucose metabolism.
Insulins, including NovoLog Mix 70/30, bind to the insulin receptors on muscle, liver and fat
cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously
inhibiting the output of glucose from the liver.
utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin aspart (NovoLog) has the empirical
formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
empi
rica
l f
ormu la a
nd m olec
ular
we
ight
Figure 1. Structural formula of insulin aspart
NovoLog Mix 70/30 is a uniform, white, sterile suspension that contains insulin aspart
100 Units/mL.
Inactive ingredients are glycerol 16.0 mg/mL, phenol 1.50 mg/mL, metacresol 1.72
mg/mL, zinc 19.6 μg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium
chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL. NovoLog Mix 70/30 has a pH of
7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
12.2
Pharmacodynamics
The two euglycemic clamp studies described below [see Clinical Pharmacology (12.3)]
assessed glucose utilization after dosing of healthy volunteers. NovoLog Mix 70/30 has an
earlier onset of action than human premix 70/30 in studies of normal volunteers and patients
with diabetes. The onset of action is between 10-20 minutes for NovoLog Mix 70/30 compared
to 30 minutes for Novolin 70/30. The mean ± SD time to peak activity for NovoLog Mix 70/30
is 2.4 hr ± 0.8 hr compared to 4.2 hr ± 0.4 hr for Novolin 70/30. The duration of action may be
as long as 24 hours (see Figure 2).
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10
9
8
7
6
5
4
3
2
1
0
Time (hours)
Figure 2. Pharmacodynamic Activity Profile of NovoLog Mix 70/30 and Novolin 70/30 in
healthy subjects.
12.3
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
insulin aspart (NovoLog) reduces the molecule’s tendency to form hexamers as observed with
regular human insulin. The rapid absorption characteristics of NovoLog are maintained by
NovoLog Mix 70/30. The insulin aspart in the soluble component of NovoLog Mix 70/30 is
absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining
70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile
after subcutaneous injection.
Bioavailability and Absorption- The relative bioavailability of NovoLog Mix 70/30
compared to NovoLog and Novolin 70/30 indicates that the insulins are absorbed to similar
extent. In euglycemic clamp studies in healthy volunteers (n=23) after dosing with NovoLog
Mix 70/30 (0.2 U/kg), a mean maximum serum concentration (Cmax) of 23.4 ± 5.3 mU/L was
reached after 60 minutes. The mean half-life (t1/2) of NovoLog Mix 70/30 was about 8 to 9
hours. Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose of
NovoLog Mix 70/30. Similar data were seen in a separate euglycemic clamp study in healthy
volunteers (n=24) after dosing with NovoLog Mix 70/30 (0.3 U/kg). A Cmax of 61.3 ± 20.1
mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12 hours after a
subcutaneous dose.
The Cmax and the area under the insulin concentration-time curve (AUC) after
administration of NovoLog Mix 70/30 was approximately 20% greater than those after
administration of Novolin 70/30, (see Fig. 3 for pharmacokinetic profiles).
Glucose Infusion Rate (mg/kg*min)
graph
0
2
4
6
8
10
12
14
16
18
20
22
24
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g
r
a
p
h
Time (hours)
Points represent m ean ± 2 SEM
Figure 3. Pharmacokinetic Profiles of NovoLog Mix 70/30 and Novolin 70/30
Distribution and Elimination- NovoLog has a low binding to plasma proteins, 0 to 9%,
similar to regular human insulin. After subcutaneous administration in normal male volunteers
(n=24), NovoLog was more rapidly eliminated than regular human insulin with an average
apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
The effect of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy,
or smoking, on the pharmacodynamics and pharmacokinetics of NovoLog Mix 70/30 has not
been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog Mix 70/30. In 52-week studies, Sprague-Dawley rats
were dosed subcutaneously with NovoLog, the rapid-acting component of NovoLog Mix 70/30,
at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of
1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day,
NovoLog increased the incidence of mammary gland tumors in females when compared to
untreated controls. The incidence of mammary tumors found with NovoLog was not
significantly different from that found with regular human insulin. The relevance of these
findings to humans is not known.
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NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward
gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo
micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.
In fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area) had no
direct adverse effects on male and female fertility, or on general reproductive performance of
animals.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. However, the effect of NovoLog
Mix 70/30 is more rapid in onset compared to Novolin (human insulin) 70/30 due to its faster
absorption after subcutaneous injection.
14
CLINICAL STUDIES
14.1
NovoLog Mix 70/30 versus Novolin 70/30
In a three-month, open-label trial, patients with Type 1 (n=104) or Type 2 (n=187)
diabetes were treated twice daily (before breakfast and before supper) with NovoLog Mix 70/30
or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral
hypoglycemic agents were not allowed within 1 month prior to the study or during the study.
The small changes in HbA1c were comparable across the treatment groups (see Table 3).
Table 3: Glycemic Parameters at the End of Treatment [Mean ± SD (N subjects)]
NovoLog Mix 70/30
Novolin 70/30
Type 1, N=104
Fasting Blood Glucose (mg/dL)
174 ± 64 (48)
142 ± 59 (44)
1.5 Hour Post Breakfast (mg/dL)
187 ± 82 (48)
200 ± 82 (42)
1.5 Hour Post Dinner (mg/dL)
162 ± 77 (47)
171 ± 66 (41)
HbA1c (%) Baseline
8.4 ± 1.2 (51)
8.5 ± 1.1 (46)
HbA1c (%) Week 12
8.4 ± 1.1 (51)
8.3 ± 1.0 (47)
Type 2, N=187
Fasting Blood Glucose (mg/dL)
153 ± 40 (76)
152 ± 69 (93)
1.5 Hour Post Breakfast (mg/dL)
182 ± 65 (75)
200 ± 80 (92)
1.5 Hour Post Dinner (mg/dL)
168 ± 51 (75)
191 ± 65 (93)
HbA1c (%) Baseline
8.1 ± 1.2 (82)
8.2 ± 1.3 (98)
HbA1c (%) Week 12
7.9 ± 1.0 (81)
8.1 ± 1.1 (96)
The significance, with respect to the long-term clinical sequelae of diabetes, of the
differences in postprandial hyperglycemia between treatment groups has not been established.
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were
monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial.
14.2
Combination Therapy: Insulin and Oral Agents in Patients with Type 2 Diabetes
Trial 1:
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In a 34-week, open-label trial, insulin-naïve patients with type 2 diabetes currently
treated with 2 oral antidiabetic agents were switched to treatment with metformin and
pioglitazone. During an 8-week optimization period metformin and pioglitazone were increased
to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period,
subjects were randomized to receive either NovoLog Mix 70/30 twice daily added on to the
metformin and pioglitazone regimen or continue the current optimized metformin and
pioglitazone therapy. NovoLog Mix 70/30 was started at a dose of 6 IU twice daily (before
breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110
mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 IU.
Table 4: Combination Therapy with Oral Agents and Insulin in Patients with Type 2
Diabetes Mellitus [Mean (SD)]
Treatment duration 24-weeks
NovoLog Mix
70/30 +
Metformin
+ Pioglitazone
Metformin +
Pioglitazone
HbA1c
Baseline mean ± SD (n)
8.1 ± 1.0 (102)
8.1 ± 1.0 (98)
End-of-study mean ± SD (n) - LOCF
6.6 ± 1.0 (93)
7.8 ± 1.2 (87)
Adjusted Mean change from baseline ± SE (n)*
-1.6 ± 0.1 (93)
-0.3 ± 0.1 (87)
Treatment difference mean ± SE*
95% CI*
-1.3 ± 0.1
(-1.6, -1.0)
Percentage of subjects reaching HbA1c <7.0%
76%
24%
Percentage of subjects reaching HbA1c ≤6.5%
59%
12%
Fasting Blood Glucose (mg/dL)
Baseline Mean ± SD (n)
173 ± 39.8 (93)
163 ± 35.4 (88)
End of Study Mean ± SD (n) – LOCF
130 ± 50.0 (90)
162 ± 40.8 (84)
Adjusted Mean change from baseline ± SE (n)*
-43.0 ± 5.3 (90)
-3.9 ± 5.3 (84)
End-of-Study Blood Glucose (Plasma) (mg/dL)
2 Hour Post Breakfast
138 ± 42.8 (86)
188 ± 57.7 (74)
2 Hour Post Lunch
150 ± 41.5 (86)
176 ± 56.5 (74)
2 Hour Post Dinner
141 ± 57.8 (86)
195 ± 60.1 (74)
% of patients with severe hypoglycemia**
3
0
% of patients with minor hypoglycemia**
52
3
Weight gain at end of study (kg)**
4.6 ± 4.3 (92)
0.8 ± 3.2 (86)
*Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with
treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.
**If metabolic control is improved by intensified insulin therapy, an increased risk of hypoglycemia and weight
gain may occur.
Trial 2:
In a 28-week, open-label trial, insulin-naïve patients with type 2 diabetes with fasting
plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy
were randomized to receive either NovoLog Mix 70/30 twice daily [before breakfast and before
supper] or insulin glargine once daily1 (see Table 5). NovoLog Mix 70/30 was started at an
average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and before supper), and
bedtime insulin glargine was started at 10-12 IU (0.13 ± 0.03 IU/kg). Insulin doses were titrated
weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of
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80-110 mg/dL. The metformin dose was adjusted to 2550 mg/day. Approximately one-third of
the patients in each group were also treated with pioglitazone (30 mg/day). Insulin
secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients
were Caucasian (53%), and the mean initial weight was 90 kg.
Table 5: Combination Therapy with Oral Agents and Two Types of Insulin in Patients
with Type 2 Diabetes Mellitus [Mean (SD)]
Treatment duration 28-weeks
NovoLog Mix 70/30
+ Metformin ±
Pioglitazone
Insulin
Glargine +
Metformin ±
Pioglitazone
Number of patients
117
116
HbA1c
Baseline mean (%)
9.7 ± 1.5 (117)
9.8 ± 1.4 (114)
End-of-study mean (± SD)
6.9 ± 1.2 (108)
7.4 ± 1.2 (114)
Mean change from baseline
-2.7 ± 1.6 (108)
-2.4 ± 1.5 (114)
Percentage of subjects reaching HbA1c <7.0%
66%
40%
Total Daily Insulin Dose at end of study (U)
78 ± 40 (117)
51 ± 27 (116)
% of patients with severe hypoglycemia
0
0
% of minor hypoglycemia
43
16
Weight gain at end of study
5.4 ± 4.8 (117)
3.5 ± 4.5 (116)
15
REFERENCES
1.
Raskin R, Allen E, Hollander P, et al. Initiating insulin therapy in type 2
diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care.
2005; 28:260-265.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog Mix 70/30 is available in the following package sizes: each presentation
contains 100 Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-3685-12
3 mL NovoLog Mix 70/30 FlexPen NDC 0169-3696-19
NovoLog Mix 70/30 vials and NovoLog Mix 70/30 FlexPen are latex free.
16.2
Recommended Storage
Unused NovoLog Mix 70/30 should be stored in a refrigerator between 2°C and 8°C
(36°F to 46°F). Do not store in the freezer or directly adjacent to the refrigerator cooling
element. Do not freeze NovoLog Mix 70/30 or use NovoLog Mix 70/30 if it has been frozen.
Vials: After initial use, a vial may be kept at temperatures below 30°C (86°F) for up to
28 days, but should not be exposed to excessive heat or sunlight. Open vials may be refrigerated.
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
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NovoLog Mix 70/30 FlexPen: Once a NovoLog Mix 70/30 FlexPen is punctured, it
should be kept at temperatures below 30°C (86°F) for up to 14 days, but should not be exposed
to excessive heat or sunlight. A NovoLog Mix 70/30 FlexPen in use must NOT be stored in the
refrigerator. Keep the disposable NovoLog Mix 70/30 FlexPen away from direct heat and
sunlight. An unpunctured NovoLog Mix 70/30 FlexPen can be used until the expiration date
printed on the label if they are stored in a refrigerator. Keep any unused NovoLog Mix 70/30
FlexPen in the carton so it will stay clean and protected from light.
These storage conditions are summarized in the following table:
Not in-use (unopened)
Room Temperature
(below 30°C [86°F])
Not in-use (unopened)
Refrigerated
(2°C - 8°C [36°F- 46°F])
In-use (opened)
Room Temperature
(below 30°C [86°F])
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3 mL NovoLog Mix
70/30 FlexPen
14 days
Until expiration date
14 days (Do not refrigerate)
17
PATIENT COUNSELING INFORMATION
[see FDA-Approved Patient Labeling]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and advantages of NovoLog Mix 70/30 therapy including the
possible adverse reactions. Patients should also be offered continued education and advice on
insulin therapies, injection technique, life-style management, regular glucose monitoring,
periodic glycosylated hemoglobin testing, recognition and management of hypo- and
hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose,
instruction for use of injection devices, and proper storage of insulin. See Patient Information
supplied with the product. Patients should be informed that frequent, patient-performed blood
glucose measurements are needed to achieve optimal glycemic control and avoid both hyper-
and hypoglycemia, and diabetic ketoacidosis.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog Mix 70/30 and other insulin products have
been reported. Patients should be instructed to always carefully check that they are
administering the appropriate insulin to avoid medication errors between NovoLog Mix 70/30
and any other insulin. The prescription for NovoLog Mix 70/30 should be written clearly in
order to avoid confusion with other insulin products, for example, NovoLog or Novolin
70/30. In addition, the written prescription should clearly indicate the presentation, for example
FlexPen or vial.
Rx only
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Date of Issue: September 20, 2011
Version: 10
Novo Nordisk®, NovoLog®, FlexPen®, and Novolin® are registered trademarks of Novo
Nordisk® A/S.
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422,
5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004 and other patents
pending.
© 2002 – 2011 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
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Patient Information
NovoLog® Mix 70/30
(NŌ-vō-log-MIX-SEV-en-tee-THIR-tee)
(70% insulin aspart protamine suspension and 30% insulin aspart injection,
[rDNA origin])
Read the Patient Information leaflet that comes with NovoLog® Mix 70/30
before you start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure you
know how to manage your diabetes. Ask your healthcare provider if you
have any questions about managing your diabetes.
What is NovoLog® Mix 70/30?
NovoLog® Mix 70/30 is a man-made insulin that is used to control high blood
sugar in adults with diabetes mellitus.
It is not known if NovoLog® Mix 70/30 is safe or effective in children.
Who should not use NovoLog® Mix 70/30?
Do not take NovoLog® Mix 70/30 if:
•
Your blood sugar is too low (hypoglycemia)
•
You are allergic to any of the ingredients in NovoLog® Mix 70/30.
See the end of this leaflet for a complete list of ingredients in
NovoLog® Mix 70/30. Check with your healthcare provider if you
are not sure.
What should I tell my healthcare provider before taking NovoLog®
Mix 70/30?
Before you use NovoLog® Mix 70/30, tell your healthcare provider if
you:
•
have kidney or liver problems
•
have any other medical conditions. Medical conditions can
affect your insulin needs and your dose of NovoLog® Mix 70/30.
•
are pregnant or plan to become pregnant. It is not known if
NovoLog® Mix 70/30 will harm your unborn baby. Talk to your
healthcare provider if you are pregnant or plan to become
pregnant. You and your healthcare provider should decide about
the best way to manage your diabetes while you are pregnant.
•
are breastfeeding or plan to breastfeed. It is not known if
NovoLog® Mix 70/30 passes into your breast milk. You and your
healthcare provider should decide if you will take NovoLog® Mix
70/30 while you breastfeed.
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Tell your healthcare provider about all medicines you take, including
prescriptions and non-prescription medicines, vitamins and herbal
supplements.
NovoLog® Mix 70/30 may affect the way other medicines work, and other
medicines may affect how NovoLog® Mix 70/30 works. Your NovoLog® Mix
70/30 dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to
show your healthcare providers and pharmacist when you get a new
medicine.
How should I take NovoLog® Mix 70/30?
•
Take NovoLog® Mix 70/30 exactly as your healthcare provider tells
you to take it.
•
Your healthcare provider will tell you how much NovoLog® Mix
70/30 to take and when to take it.
•
Do not make any changes to your dose or type of insulin unless
your healthcare provider tells you to.
•
NovoLog® Mix 70/30 starts acting fast. If you have Type 1
diabetes, inject it up to 15 minutes before you eat a meal.
Do not inject NovoLog® Mix 70/30 if you are not planning to eat
within 15 minutes.
•
If you have Type 2 diabetes, you may inject NovoLog® Mix
70/30 up to 15 minutes before or after starting your meal.
•
Do Not mix NovoLog® Mix 70/30 with other insulin products.
•
Do Not use NovoLog® Mix 70/30 in an insulin pump.
•
Inject NovoLog® Mix 70/30 under the skin
(subcutaneously) of your stomach area, upper arms,
buttocks or upper legs. NovoLog® Mix 70/30 may affect your
blood sugar levels faster if you inject it under the skin of your
stomach area. Never inject NovoLog® Mix 70/30 into a vein or into
a muscle.
•
Change (rotate) injection sites within the area you choose with
each dose. Do not inject into the exact same spot for each
injection.
•
Read the instructions for use that come with your
NovoLog® Mix 70/30. Talk to your healthcare provider if you
have any questions. Your healthcare provider should show you
how to inject NovoLog® Mix 70/30 before you start using it.
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•
NovoLog® Mix 70/30 comes in:
o 10 mL vials for use with a syringe
o 3 mL NovoLog® Mix 70/30 FlexPen®
•
If you take too much NovoLog® Mix 70/30, your blood
sugar may fall too low (hypoglycemia). You can treat mild
low blood sugar (hypoglycemia) by drinking or eating something
sugary right away (fruit juice, sugar candies, or glucose tablets).
It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (loss of
consciousness).
•
If you forget to take your dose of NovoLog® Mix 70/30,
your blood sugar may go too high (hyperglycemia). If high
blood sugar (hyperglycemia) is not treated it can lead to serious
problems, like passing out (loss of consciousness), coma or even
death. Follow your healthcare provider’s instructions for treating
high blood sugar. Know your symptoms of high blood sugar which
may include:
•
increased thirst
• fruity smell on the breath
•
frequent urination
• high amounts of sugar and
•
drowsiness
ketones in your urine
•
loss of appetite
• nausea, vomiting (throwing
•
a hard time
up) or stomach pain
breathing
•
Do not share needles, insulin pens or syringes with others.
•
Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check
your blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
• change in diet
•
stress
• change in physical activity or
•
other medicines you
exercise
take
See the end of this patient information for instructions about preparing and
giving your injection.
What should I consider while using NovoLog® Mix 70/30?
•
Alcohol. Drinking alcohol may affect your blood sugar when you
take NovoLog® Mix 70/30.
•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
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(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for you to
drive if you often have:
•
low blood sugar
•
decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog® Mix 70/30?
NovoLog® Mix 70/30 may cause serious side effects, including:
•
low blood sugar (hypoglycemia). Symptoms of low blood
sugar may include:
•
sweating
•
trouble concentrating
•
dizziness or
or confusion
lightheadedness
•
blurred vision
•
shakiness
•
slurred speech
•
hunger
•
anxiety, irritability or
•
fast heart beat
mood changes
•
tingling of lips and
•
headache
tongue
Very low blood sugar can cause you to pass out (loss of
consciousness), seizures, and death. Talk to your healthcare
provider about how to tell if you have low blood sugar and what to
do if this happens while taking NovoLog® Mix 70/30. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of NovoLog® Mix 70/30 may need to be changed.
•
Low potassium in your blood (hypokalemia)
•
Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious talk to your
healthcare provider.
•
Serious allergic reaction (whole body reaction). Get
medical help right away, if you have any of these
symptoms of an allergic reaction:
o a rash over your whole body
o have trouble breathing
o a fast heartbeat
o sweating
o feel faint
Reference ID: 3103527
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The most common side effects of NovoLog® Mix 70/30 include:
•
Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) where you inject your insulin to help to prevent
these skin changes from happening. Do not inject insulin into this
type of skin.
•
Weight gain
•
Swelling of your hands and feet
•
Vision changes
These are not all of the possible side effects from NovoLog® Mix 70/30. Ask
your healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store NovoLog® Mix 70/30?
All Unopened NovoLog® Mix 70/30:
•
Keep all unopened NovoLog® Mix 70/30 in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Do not freeze or store next to the refrigerator cooling
element. Do not use NovoLog® Mix 70/30 if it has been frozen.
•
Keep unopened NovoLog® Mix 70/30 in the carton to protect from
light.
•
Unopened vials can be used until the expiration date on the
NovoLog® Mix 70/30 label, if the medicine has been stored in a
refrigerator.
•
Unused NovoLog® Mix 70/30 FlexPen® can be used until the
expiration date on the NovoLog® Mix 70/30 FlexPen® label, if the
medicine has been stored in a refrigerator.
After NovoLog® Mix 70/30 has been opened:
•
Vials
• Keep in the refrigerator or at room temperature below 86°F
(30°C) for up to 28 days.
• Keep vials away from direct heat or light.
• Throw away an opened vial after 28 days of use, even if
there is insulin left in the vial.
•
NovoLog® Mix 70/30 FlexPen®
• Keep at room temperature below 86°F (30°C) for up to 14
days.
Reference ID: 3103527
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• Do not store a NovoLog® Mix 70/30 FlexPen® that you are
using in the refrigerator.
• Keep NovoLog® Mix 70/30 FlexPen® away from direct heat or
light.
• Throw away a used NovoLog® Mix 70/30 FlexPen® after 14
days, even if there is insulin left in the syringe.
Never use insulin after the expiration date that is printed on the label
and carton.
Keep NovoLog® Mix 70/30 and all medicines out of the reach of
children.
General advice about NovoLog® Mix 70/30
Medicines are sometimes prescribed for conditions that are not mentioned in
the patient leaflet. Do not use NovoLog® Mix 70/30 for a condition for which
it was not prescribed. Do not give NovoLog® Mix 70/30 to other people, even
if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog® Mix
70/30. If you would like more information about NovoLog® Mix 70/30 or
diabetes, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about NovoLog® Mix 70/30 that is
written for healthcare professionals. For more information call 1-800-727
6500 or go to www.novonordisk-us.com.
What are the ingredients in NovoLog® Mix 70/30?
• Active Ingredients in NovoLog® Mix 70/30: 70% insulin aspart
protamine suspension and 30% insulin aspart injection (rDNA origin).
• Inactive Ingredients in NovoLog® Mix 70/30: glycerol, phenol,
metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium
chloride, protamine sulfate, water for injection, hydrochloric acid or
sodium hydroxide.
All NovoLog® Mix 70/30 vials and NovoLog® Mix 70/30 FlexPen® are latex
free.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1701 N Beauregard Street, Alexandria, VA 22311 and
is available at www.diabetes.org.
Date of Issue:September 20, 2011
Version: 8
Reference ID: 3103527
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, NovoLog®, and FlexPen® are registered trademarks of Novo
Nordisk A/S.
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913,
5,834,422, 5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004 and
other patents pending.
© 2002-2011 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3103527
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® Mix 70/30 (NŌvōLog-MIX-SEV-en-tee-THIR-tee)
(70% insulin aspart protamine suspension and 30% insulin aspart [rDNA
origin] injection)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® Mix 70/30 and each
time you get a refill. There may be new information. This information does not
take the place of talking to your healthcare provider about your medical condition
or your treatment.
Supplies you will need to give your NovoLog® Mix 70/30 injection:
10 mL NovoLog® Mix 70/30 vial
insulin syringe and needle
alcohol swab usage illustration
Preparing your NovoLog® Mix 70/30 dose:
Wash your hands with soap and water.
Before you start to prepare your injection, check the NovoLog® Mix 70/30
label to make sure that you are taking the right type of insulin. This is
especially important if you use more than 1 type of insulin.
NovoLog® Mix 70/30 should look white and cloudy after mixing. Do not use
NovoLog Mix 70/30 if it looks clear or contains any lumps or particles.
NovoLog® Mix 70/30 is easier to mix when it is at room temperature.
After mixing NovoLog® Mix 70/30, inject your dose right away. If you wait to
inject your dose, the insulin will need to be mixed again.
Do not use NovoLog® Mix 70/30 past the expiration date printed on the
label.
Reference ID: 3230601
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For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Step 1: If you are using a new vial, pull
off the tamper-resistant cap (See Figure
A).
Step 2: Wipe the rubber stopper with an
alcohol swab (See Figure B).
(Figure A Figure B)
Step 3: Roll the NovoLog Mix 70/30 vial
between your hands 10 times. Keep
the vial in a horizontal (flat) position
(See Figure C). Roll the vial between
your hands until the Novolog® Mix
70/30 looks white and cloudy. Do not
shake the vial.
(Figure C)
Step 4: Hold the syringe with the needle
pointing up. Pull down on the plunger
until the black tip reaches the line for
the number of units for your prescribed
dose (See Figure D).
(Figure D)
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usage illustration
Step 5: Push the needle through the
rubber stopper of the NovoLog® Mix
70/30 vial (See Figure E).
(Figure E)
Step 6: Push the plunger all the way in.
This puts air into the NovoLog® Mix
70/30 vial (See Figure F).
(Figure F)
Step 7: Turn the NovoLog® Mix 70/30
vial and syringe upside down and slowly
pull the plunger down until the black tip
is a few units past the line for your dose
(See Figure G). usage illustration
If there are air bubbles, tap the
syringe gently a few times to let any
air bubbles rise to the top (See
Figure H).
(Figure G)
(Figure H)
Step 8: Slowly push the plunger up until
the black tip reaches the line for your
NovoLog® Mix 70/30 dose
(See Figure I).
(Figure I)
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Step 9: Check the syringe to make sure
you have the right dose of NovoLog® Mix
70/30.
Step 10: Pull the syringe out of the
vial’s rubber stopper (See Figure J).
(Figure J)
Giving your injection:
Inject your NovoLog® Mix 70/30 exactly as your healthcare provider has shown
you. Your healthcare provider should tell you if you need to pinch the skin
before injecting.
NovoLog® Mix 70/30 is injected under the skin (subcutaneously) of your stomach
area, buttocks, upper legs, or upper arms.
Change (rotate) your injection sites within the area you choose for each dose.
Do not use the same injection site for each injection.
Step 11: Choose your injection site and
wipe the skin with an alcohol swab. Let
the injection site dry before you inject
your dose (See Figure K).
(Figure K)
Step 12: Insert the needle into your
skin. Push down on the plunger to inject
your dose (See Figure L). Needle should
remain in the skin for at least 6 seconds to
make sure you have injected all the
insulin.
(Figure L)
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Step 13: Pull the needle out of your
skin. After that, you may see a drop
of NovoLog® Mix 70/30 at the needle tip.
This is normal and does not affect the
dose you just received (See Figure M).
If you see blood after you take the
needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
(Figure M)
After your injection:
Do not recap the needle. Recapping the needle can lead to a needle stick
injury.
Throw away empty insulin vials, used syringes and needles in a sharps container
or some type of hard plastic or metal container with a screw on cap such as a
detergent bottle or coffee can. Check with your healthcare provider about the
right way to throw away the container. There may be local or state laws about
how to throw away used syringes and needles. Do not throw away used
syringes and needles in household trash or recycling bins.
How should I store NovoLog® Mix 70/30?
Do not freeze NovoLog® Mix 70/30. Do not use NovoLog® Mix 70/30 if it has
been frozen.
Keep NovoLog® Mix 70/30 away from heat or light.
Store opened and unopened NovoLog® Mix 70/30 vials in the refrigerator at
36OF to 46OF (2OC to 8OC). Opened NovoLog® Mix 70/30 vials can also be
stored out of the refrigerator below 86OF (30OC).
Unopened vials may be used until the expiration date printed on the label, if
they are kept in the refrigerator.
Opened NovoLog® Mix 70/30 vials should be thrown away after 28 days, even if
they still have insulin left in them.
General information about the safe and effective use of NovoLog® Mix
70/30
Always use a new syringe and needle for each injection.
Do not share syringes or needles.
Keep NovoLog® Mix 70/30 vials, syringes, and needles out of the reach of children.
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
Revised: December 2012
NovoLog® is a registered trademark of Novo Nordisk A/S.
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913,
5,834,422, 5,840,680, 5,866,538 and other patents pending.
© 2002-2012 Novo Nordisk A/S
For information about NovoLog® Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
NovoLog® Mix 70/30 FlexPen®
Read the following instructions carefully before you start using your NovoLog® Mix
70/30 FlexPen® and each time you get a refill. There may be new information. You
should read the instructions even if you have used Novolog® Mix 70/30 FlexPen®
before.
NovoLog® Mix 70/30 FlexPen® is a disposable dial-a-dose insulin pen. You can
select doses from 1 to 60 units in increments of 1 unit. NovoLog® Mix 70/30
FlexPen® is designed to be used with NovoFine® needles.
NovoLog Mix® 70/30 FlexPen® should not be used by people who are blind or have
severe visual problems without the help of a person who has good eyesight and
who is trained to use the NovoLog® Mix 70/30 FlexPen® the right way.
Getting ready
Make sure you have the following items:
•
NovoLog® Mix 70/30 FlexPen®
•
New NovoFine® needle
•
Alcohol swab usage illustration
PREPARING YOUR NOVOLOG® MIX 70/30 FLEXPEN®
• Wash your hands with soap and water.
• Before you start to prepare your injection, check the label to make
sure that you are taking the right type of insulin. This is especially
important if you take more than 1 type of insulin. NovoLog® Mix
70/30 should look cloudy after mixing.
Before your first injection with a new NovoLog® Mix 70/30 FlexPen® you
must mix the insulin:
A. Let the insulin reach room temperature before you use it.
This makes it easier to mix.
Pull off the pen cap (see diagram A). usage illustration
Reference ID: 3230601
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For current labeling information, please visit https://www.fda.gov/drugsatfda
B. Roll the pen between your palms 10 times – it is
important that the pen is kept horizontal (see diagram
B).
C. Then gently move the pen up and down ten times
between position 1 and 2 as shown, so the glass ball
moves from one end of the cartridge to the other (see
diagram C).
Repeat rolling and moving the pen until the liquid appears
white and cloudy. usage illustration
For every following injection move the pen up and down between
positions 1 and 2 at least ten times until the liquid appears white and
cloudy.
After mixing, complete all the following steps of the injection right away. If
there is a delay, the insulin will need to be mixed again.
Wipe the rubber stopper with an alcohol swab.
Before you inject, there must be at least 12 units of insulin left in the cartridge to
make sure the remaining insulin is evenly mixed. If there are less than 12 units
left, use a new NovoLog® Mix 70/30 FlexPen® .
Attaching the needle
D. Remove the protective tab from a disposable needle.
Screw the needle tightly onto your NovoLog® Mix 70/30
FlexPen® . It is important that the needle is put on straight
(see diagram D).
Never place a disposable needle on your NovoLog® Mix 70/30
FlexPen® until you are ready to take your injection. usage illustration
E. Pull off the big outer needle cap (see diagram E). usage illustration
Reference ID: 3230601
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For current labeling information, please visit https://www.fda.gov/drugsatfda
F. Pull off the inner needle cap and dispose of it (see diagram
F). usage illustration
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of a needle stick, never put the inner needle cap back on
the needle.
Giving the airshot before each injection:
Before each injection small amounts of air may collect in the cartridge during
normal use. To avoid injecting air and to make sure you take the right dose
of insulin:
G. Turn the dose selector to select 2 units (see diagram G).
H. Hold your NovoLog® Mix 70/30 FlexPen® with the needle
pointing up. Tap the cartridge gently with your finger a few
times to make any air bubbles collect at the top of the
cartridge (see diagram H).
I. Keep the needle pointing upwards, press the push-button
all the way in (see diagram I). The dose selector returns
to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use
the NovoLog Mix® 70/30 FlexPen® and contact Novo Nordisk
at 1-800-727-6500. usage illustration
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
J. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram J). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set
the dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before
injecting. Wipe the skin with an alcohol swab and let the area dry. usage illustration
K. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram K). Be careful only
to push the button when injecting.
Turning the dose selector will not inject insulin.
L. Keep the needle in the skin for at least 6 seconds, and
keep the push-button pressed all the way in until the
needle has been pulled out from the skin (see diagram L).
This will make sure that the full dose has been given.
You may see a drop of NovoLog® Mix 70/30 at the needle tip.
This is normal and has no effect on the dose you just
received. If blood appears after you take the needle out of
your skin, press the injection site lightly with an alcohol
swab. Do not rub the area.
After the injection usage illustration
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog® Mix 70/30 FlexPen® after each
injection. This helps to prevent infection, leakage of insulin, and will help to
make sure you inject the right dose of insulin.
Put the needle and any empty NovoLog® Mix 70/30 FlexPen® or any
used NovoLog® Mix 70/30 FlexPen® still containing insulin in a sharps
container or some type of hard plastic or metal container with a screw
top such as a detergent bottle or empty coffee can. These containers
should be sealed and thrown away the right way. Check with your
healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away
used needles and syringes. Do not throw away used needles and
syringes in household trash or recycling bins.
The NovoLog® Mix 70/30 FlexPen® prevents the cartridge from being completely
emptied. It is designed to deliver 300 units.
M. Put the pen cap on the NovoLog® Mix 70/30 FlexPen® and
store the NovoLog® Mix 70/30 FlexPen® without the
needle attached (see diagram M). usage illustration
FUNCTION CHECK
If your NovoLog® Mix 70/30 FlexPen® is not working the right way, follow
the steps below:
•
Screw on a new NovoFine® needle
•
Remove the big outer needle cap and the inner needle
cap
•
Do an airshot as described in “Giving the airshot before
each injection”.
•
Put the big outer needle cap onto the needle. Do not
put on the inner needle cap.
•
Turn the dose selector so the dose indicator window usage illustration
shows 20 units.
•
Hold the NovoLog® Mix 70/30 FlexPen® so the needle is
pointing down
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see
diagram N). If NovoLog® Mix 70/30 FlexPen® has released too much or too
little insulin, do the function check again. If the same problem happens
again, do not use your NovoLog® Mix 70/30 FlexPen® and contact Novo
Nordisk at 1-800-727-6500.
Maintenance
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Your NovoLog® Mix 70/30 FlexPen® is designed to work accurately and
safely. It must be handled with care. Avoid dropping your NovoLog® Mix
70/30 FlexPen® as it may damage it. If you are concerned that your
NovoLog® Mix 70/30 FlexPen® is damaged, use a new one. You can clean
the outside of your NovoLog® Mix 70/30 FlexPen® by wiping it with a damp
cloth. Do not soak or wash your NovoLog® Mix 70/30 FlexPen® as it may
damage it. Do not refill your NovoLog® Mix 70/30 FlexPen® .
Remove the needle from the NovoLog® Mix 70/30 FlexPen® after each
injection. This helps to ensure sterility, prevent leakage of insulin, and
will help to make sure you inject the right dose of insulin for future
injections.
Be careful when handling used needles to avoid needle sticks and
transfer of infectious diseases.
Keep your NovoLog® Mix 70/30 FlexPen® and needles out of the reach of
children.
Use NovoLog® Mix 70/30 FlexPen® as directed to treat your diabetes.
Do not share it with anyone else even if they also have diabetes.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen
with products not recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device
in case your NovoLog® Mix 70/30 FlexPen® is lost or damaged.
Remember to keep the disposable NovoLog® Mix 70/30 FlexPen® with
you. Do not leave it in a car or other location where it can get too hot or
too cold.
NovoLog®, FlexPen®, NovoFine®, are trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422,
5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004
and other patents pending.
© 2002-2010 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog Mix 70/30® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3230601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:30.864477 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021172s051lbl.pdf', 'application_number': 21172, 'submission_type': 'SUPPL ', 'submission_number': 51} |
5,671 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LEVEMIR® safely and effectively. See full prescribing information
for LEVEMIR.
LEVEMIR® (insulin detemir [rDNA origin] injection) solution for
subcutaneous injection
Initial U.S. Approval: 2005
----------------------------INDICATIONS AND USAGE----------------------
LEVEMIR is a long-acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
Important Limitations of Use:
• Not recommended for treating diabetic ketoacidosis. Use intravenous,
rapid acting or short-acting insulin instead.
----------------------DOSAGE AND ADMINISTRATION-------------------
• The starting dose should be individualized based on the type of
diabetes and whether the patient is insulin-naïve (2.1, 2.2, 2.3)
• Administer subcutaneously once daily or in divided doses twice daily.
Once daily administration should be given with the evening meal or at
bedtime (2.1)
• Rotate injection sites within an injection area (abdomen, thigh, or
deltoid) to reduce the risk of lipodystrophy (2.1)
• Converting from other insulin therapies may require adjustment of
timing and dose of LEVEMIR. Closely monitor glucoses especially
upon converting to LEVEMIR and during the initial weeks thereafter
(2.3)
---------------------DOSAGE FORMS AND STRENGTHS-----------------
Solution for injection 100 Units/mL (U-100) in
• 3 mL LEVEMIR FlexPen®
• 10 mL vial (3)
------------------------------CONTRAINDICATIONS-------------------------
• Do not use in patients with hypersensitivity to LEVEMIR or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Dose adjustment and monitoring: Monitor blood glucose in all patients
treated with insulin. Insulin regimens should be modified cautiously and
only under medical supervision (5.1)
• Administration: Do not dilute or mix with any other insulin or solution.
Do not administer subcutaneously via an insulin pump, intramuscularly,
or intravenously because severe hypoglycemia can occur (5.2)
• Hypoglycemia is the most common adverse reaction of insulin therapy
and may be life-threatening (5.3, 6.1)
• Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur (5.4)
• Renal or hepatic impairment: May require adjustment of the LEVEMIR
dose (5.5, 5.6)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions associated with LEVEMIR include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, rash and pruritus (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• Certain drugs may affect glucose metabolism requiring insulin dose
adjustment and close monitoring of blood glucose (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine) (7)
----------------------USE IN SPECIFIC POPULATIONS-------------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not been
studied in children with type 1 diabetes < 2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 5/2012
__________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Initiation of LEVEMIR Therapy
2.3 Converting to LEVEMIR from Other Insulin Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Dosage Adjustment and Monitoring
5.2 Administration
5.3 Hypoglycemia
5.4 Hypersensitivity and Allergic Reactions
5.5 Renal Impairment
5.6 Hepatic Impairment
5.7 Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Preparation and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Patients
17.2 Never Share a LEVEMIR FlexPen Between Patients
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus.
Important Limitations of Use:
• LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting
or short-acting insulin is the preferred treatment for this condition.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration.
Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at
bedtime.
Patients who require twice-daily dosing can administer the evening dose with the evening meal, at
bedtime, or 12 hours after the morning dose.
The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is
essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].
In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting
insulin.
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid)
from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all
insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by
exercise and other variables, such as stress, intercurrent illness, or changes in co-administered
medications or meal patterns.
When using LEVEMIR with a glucagon-like peptide (GLP)-1 receptor agonist, administer as separate
injections. Never mix. It is acceptable to inject LEVEMIR and a GLP-1 receptor agonist in the same
body region but the injections should not be adjacent to each other.
2.2 Initiation of LEVEMIR Therapy
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately
one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be
used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on oral antidiabetic medications is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or
divided into a twice daily regimen.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on a GLP-1 receptor agonist is 10 Units given once daily in the evening.
LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages
of LEVEMIR should be individualized under the supervision of a healthcare provider.
2.3 Converting to LEVEMIR from other insulin therapies
If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients
with type 2 diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see
Clinical Studies (14)].
As with all insulins, close glucose monitoring is recommended during the transition and in the initial
weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other
concomitant antidiabetic treatment may need to be adjusted.
3 DOSAGE FORMS AND STRENGTHS
LEVEMIR solution for injection 100 Unit per mL is available as:
•
3 mL LEVEMIR FlexPen®
•
10 mL vial
4 CONTRAINDICATIONS
LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients.
Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen
should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a
change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different
individuals or at different times in the same individual and is dependent on many conditions, including
the local blood supply, local temperature, and physical activity.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Administration
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of
LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular
administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and
Precautions (5.3)].
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the
pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR
and the mixed insulin may be altered in an unpredictable manner.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk
of hypoglycemia increases with intensive glycemic control.
When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need
to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see Adverse
Reactions (6.1)].
All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to
unconsciousness or convulsions and may result in temporary or permanent impairment of brain function
or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion,
or glucagon administration has been observed in clinical trials with insulin, including trials with
LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals),
exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions
(7)].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions,
such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products,
including LEVEMIR.
5.5 Renal Impairment
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals
with renal impairment and healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with renal impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
renal impairment [see Clinical Pharmacology (12.3)].
5.6 Hepatic Impairment
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin
detemir compared to healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with liver impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
hepatic impairment [see Clinical Pharmacology (12.3)].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia
or hyperglycemia [see Drug Interactions (7)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions (5.3)]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in
one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not
reflect the rates actually observed in clinical practice.
The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical
trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below.
See Tables 5 and 6 for the hypoglycemia findings.
In the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg +
metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled
total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of
gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
those patients who completed the run-in period with inadequate glycemic control were randomized to 26
weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg +
metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in
≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated
with liraglutide 1.8 mg and metformin alone (6.9%).
In two pooled trials, a total of 1155 adults with type 1 diabetes were exposed to individualized doses of
LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and
the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are
summarized in Table 1.
Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and
24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 767)
NPH, %
(n = 388)
Upper respiratory tract infection
26.1
21.4
Headache
22.6
22.7
Pharyngitis
9.5
8.0
Influenza-like illness
7.8
7.0
Abdominal Pain
6.0
2.6
A total of 320 adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=161)
or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total
exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summized in
Table 2.
Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart
+ LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions
with incidence ≥ 5%)
LEVEMIR, %
(n = 161)
Glargine, %
(n = 159)
Upper respiratory tract infection
26.7
32.1
Headache
14.3
19.5
Back pain
8.1
6.3
Influenza-like illness
6.2
8.2
Gastroenteritis
5.6
4.4
Bronchitis
5.0
1.9
In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of
Levemir (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and the
total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions are
summarized in Table 3.
Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and
24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 432)
NPH, %
(n = 437)
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Upper respiratory tract infection
12.5
11.2
Headache
6.5
5.3
A total of 347 children and adolescents (6-17 years) with type 1 diabetes were exposed to individualized
doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180
days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions
are summarized in Table 4.
Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and
adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 232)
NPH, %
(n = 115)
Upper respiratory tract infection
35.8
42.6
Headache
31.0
32.2
Pharyngitis
17.2
20.9
Gastroenteritis
16.8
11.3
Influenza-like illness
13.8
20.9
Abdominal pain
13.4
13.0
Pyrexia
10.3
6.1
Cough
8.2
4.3
Viral infection
7.3
7.8
Nausea
6.5
7.0
Rhinitis
6.5
3.5
Vomiting
6.5
10.4
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
• Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
LEVEMIR [see Warnings and Precautions (5.3)].
Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR
clinical trials.
For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an
event with symptoms consistent with hypoglycemia requiring assistance of another person and
associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or
prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other
pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness,
unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who
may have required glucagon or intravenous glucose.
For the adult trials and pediatric Study D, non-severe hypoglycemia was defined as an asymptomatic or
symptomatic plasma glucose < 56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A
and C) that was self-treated by the patient. For pediatric Study I, non-severe hypoglycemia included
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asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient
could self-treat or treat by taking oral therapy provided by the caregiver.
The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study
designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see
Tables 5 and 6).
Table 5: Hypoglycemia in Patients with Type 1 Diabetes
Severe Hypoglycemia
Non-Severe Hypoglycemia
Percent of
patients with at
least 1 event
(n/total N)
Event/patient/
year
Percent of patients
(n/total N)
Event/patient/
year
Twice-Daily
LEVEMIR
8.7
(24/276)
0.52
88.0
(243/276)
26.4
Study A
Type 1 Diabetes
Adults
16 weeks
In combination
with
insulin aspart
Twice-Daily
NPH
10.6
(14/132)
0.43
89.4
(118/132)
37.5
Twice-Daily
LEVEMIR
5.0
(8/161)
0.13
82.0
(132/161)
20.2
Study B
Type 1 Diabetes
Adults
26 weeks
In combination
with
insulin aspart
Once-Daily
Glargine
10.1
(16/159)
0.31
77.4
(123/159)
21.8
Once-Daily
LEVEMIR
7.5
(37/491)
0.35
88.4
(434/491)
31.1
Study C
Type 1 Diabetes
Adults
24 weeks
In combination
with
regular insulin
Once-Daily
NPH
10.2
(26/256)
0.32
87.9
(225/256)
33.4
Once- or
Twice Daily
LEVEMIR
15.9
(37/232)
0.91
93.1
(216/232)
31.6
Study D
Type 1 Diabetes
Pediatrics
26 weeks
In combination
with
insulin aspart
Once- or
Twice Daily
NPH
20.0
(23/115)
0.99
95.7
(110/115)
37.0
Once- or
Twice Daily
LEVEMIR
1.7
(3/177)
0.02
94.9
(168/177)
56.1
Study I
Type 1 Diabetes
Pediatrics
52 weeks
In combination
with insulin aspart
Once- or
Twice Daily
NPH
7.1
(12/170)
0.09
97.6
(166/170)
70.7
Table 6: Hypoglycemia in Patients with Type 2 Diabetes
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Study E
Type 2 Diabetes
Adults
24 weeks
In combination with
oral agents
Study F
Type 2 Diabetes
Adults
22 weeks
In combination with
insulin aspart
Study H
Type 2 Diabetes
Adults
26 weeks in combination
with Liraglutide and
Metformin
Twice-
Daily
LEVEMIR
Twice-
Daily
NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
Once Daily
LEVEMIR +
Liraglutide +
Metformin
Liraglutide
+
Metformin
Percent of patients
with at least 1 event
(n/total N)
0.4
(1/237)
2.5
(6/238)
1.5
(3/195)
4.0
(8/199)
0
0
Severe
hypoglycemia
Event/patient/year
0.01
0.08
0.04
0.13
0
0
Percent of patients
(n/total N)
40.5
(96/237)
64.3
(153/238)
32.3
(63/195)
32.2
(64/199)
9.2
(15/163)
1.3
(2/158*)
Non-severe
hypoglycemia
Event/patient/year
3.5
6.9
1.6
2.0
0.29
0.03
*One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a
history of frequent hypoglycemia prior to the study
• Insulin Initiation and Intensification of Glucose Control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible
ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral
neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and
neuropathy.
• Lipodystrophy
Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy
(thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection sites within the
same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].
• Weight Gain
Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)].
• Peripheral Edema
Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
• Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions,
including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in
adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one
patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in
discontinuation of therapy.
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Rotation of the injection site within a given area from one injection to the next may help to reduce or
prevent these reactions. In some instances, these reactions may be related to factors other than insulin,
such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin
usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR,
and may be life-threatening [see Warnings and Precautions (5.4)].
• Antibody Production
All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase
or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical
trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic
control.
6.2 Postmarketing experience
The following adverse reactions have been identified during post approval use of LEVEMIR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported during post-approval use of LEVEMIR in which other insulins,
particularly rapid-acting or short-acting insulins, have been accidentally administered instead of
LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR
and other insulins, patients should be instructed always to verify the insulin label before each injection.
7 DRUG INTERACTIONS
A number of medications affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
The following are examples of medications that may increase the blood-glucose-lowering effect of
insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral
antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline,
salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood-glucose-lowering effect of
insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid
hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical
antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose-
lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
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The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as
beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all
pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant while taking
LEVEMIR. A randomized controlled clinical trial of pregnant women with type I diabetes using
LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive
toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups
indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and
teratogenicity that were attributed to maternal hypoglycemia.
Clinical Considerations
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased
with good glucose control before conception and throughout pregnancy. Because insulin requirements
vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is
essential in pregnant women.
Human Data
In an, open-label, clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of
gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or
NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of
152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the
study (Total pregnant women = 310). Approximately one half of the study participants in each arm were
randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first
8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <
7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted
mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient
(n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically
significant.
Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 7. The two
most common adverse reactions were nasopharyngitis and headache. These are consistent with findings
from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the
LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia,
eight (8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization.
The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by
diabetes. Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the
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definition of pre-eclampsia was not standardized in the trial making it difficult to establish a link
between a given treatment and an increased risk of pre-eclampsia. All events were considered unlikely
related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants.
Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group
than in the NPH insulin group as a whole. There was no difference between the treatment groups in
mean blood pressure during pregnancy and there was no indication of a general increase in blood
pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following
placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of
placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the
LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6%
and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’,
‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.
Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR to
insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with
incidence ≥ 5%)
LEVEMIR, %
(n = 152)
NPH, %
(n = 158)
Anemia
13.2
10.8
Diarrhea
11.8
5.1
Pre-eclampsia
10.5
7.0
Urinary tract infection
9.9
5.7
Gastroenteritis
8.6
5.1
Abdominal pain upper
5.9
3.8
Vomiting
5.3
4.4
Abortion spontaneous
5.3
2.5
Abdominal pain
5.3
6.3
Oropharyngeal pain
5.3
6.3
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be
easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and
NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patient-
year in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe
episodes of hypoglycemia were similar in both treatment groups (Table 8).
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Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes
Study G Type 1
Diabetes
Pregnancy
In combination with
insulin aspart
LEVEMIR
NPH
Percent of patients
with at least 1
event (n/total N)
16.4
(25/152)
20.9
(33/158)
Severe
hypoglycemia*
Events/patient/year
1.1
1.2
Percent of patients
with at least 1
event (n/total N)
94.7
(144/152)
92.4
(146/158)
Non-severe
hypoglycemia*
Events/patient/year
114.2
108.4
* For definition regarding severe and non-severe hypoglycemia see section 6, Hypoglycemia.
In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower
level of quantification (<25 pmol/L).
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR
use.
Animal Data
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300
nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day
(approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits
during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder
abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of
900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human
insulin control groups indicated that insulin detemir and human insulin had similar effects regarding
embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia
resulting from insulin exposure in normal animals.
8.3
Nursing Mothers
It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human
insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman.
Women with diabetes who are lactating may require adjustments of their insulin doses.
8.4
Pediatric Use
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been
established in pediatric patients (age 2 to 17 years) with type 1 diabetes [see Clinical Pharmacology
(12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than 2
years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2
diabetes.
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The dose recommendation when converting to LEVEMIR is the same as that described for adults [see
Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood
glucose.
8.5
Geriatric Use
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients
(3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were
≥65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥75 years of age. No
overall differences in safety or effectiveness were observed between these patients and younger patients,
but small sample sizes, particularly for patients ≥65 years of age in the type 1 diabetes trials and for
patients ≥75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals
cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and
maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to
recognize in the elderly.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].
11 DESCRIPTION
LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a
subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant
human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae followed by chemical modification.
Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been
omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a
molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:
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Figure 1: Structural Formula of insulin detemir
(A1)
(A21)
(B1)
(B29)
Gly
Ile Val Glu Gln Cys Cys Thr Ser
Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
Cys
Leu
His
Gln
Asn
Val
Phe
Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr
Pro Lys
NH
C
O
S
S
S
S
S
S
LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains
100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg
phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection.
Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of
approximately 7.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including
insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin
lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue
and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits
proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of
action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir
molecules from the injection site due to self-association of the drug molecules. In addition, the
distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24
hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection
and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to > 24 hours (24 hours
was the end of the observation period).
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Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum
effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2
diabetes. The clamp study was terminated at 16 hours according to protocol.
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Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study
12.3 Pharmacokinetics
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin
detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the
maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more
slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and
AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and
abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in
vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin
detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous
administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours
depending on dose.
Specific Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children
(6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir
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plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as
compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose
of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir
AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin
preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed
between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there
were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and
pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2
diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR
were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate,
severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics
of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with
human insulin have shown increased circulating levels of insulin in patients with renal impairment.
Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in
patients with renal impairment [see Warnings and Precautions (5.5)].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate
and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic
impairment with a corresponding increase in apparent clearance. However, some studies with human
insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful
glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients
with hepatic impairment [see Warnings and Precautions (5.6)].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR
has not been studied [see Use in Specific Populations (8.1)].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not
been studied.
Liraglutide -No pharmacokinetic interaction was observed between liraglutide and LEVEMIR when
separate subcutaneous injections of LEVEMIR 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady
state) were administered in patients with type 2 diabetes.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested
negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral
blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
14 CLINICAL STUDIES
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and
at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of
once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with
type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2
diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily
insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The
evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood
glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials
that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin
(HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to
treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and
bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered
before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar
HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9).
Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose
(FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized
to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine
(administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated
patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, open-label clinical study (Study C, n=749), adults with type 1 diabetes were randomized
to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination
with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on
HbA1c.
Reference ID: 3212923
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Table 9: Type 1 Diabetes Mellitus – Adult
Study A
Study B
Study C
Treatment duration
16 weeks
26 weeks
24 weeks
Treatment in combination with
NovoLog®
(insulin aspart)
NovoLog®
(insulin aspart)
Human Soluble Insulin
(regular insulin)
Twice-daily
LEVEMIR
Twice-daily
NPH
Twice-daily
LEVEMIR
Once-
daily
insulin
glargine
Once-daily
LEVEMIR
Once-
daily
NPH
Number of patients treated
276
133
161
159
492
257
HbA1c (%)
Baseline HbA1c
8.6
8.5
8.9
8.8
8.4
8.3
Adj. mean change from baseline
-0.8*
-0.7*
-0.6**
-0.5**
-0.1*
0.0*
LEVEMIR – NPH
95% CI for Treatment difference
-0.2
(-0.3, -0.0)
-0.0
(-0.2, 0.2)
-0.1
(-0.3, 0.0)
Basal insulin dose (units/day)
Baseline mean
21
24
27
23
12
24
Mean change from baseline
16
10
10
4
9
2
Total insulin dose (units/day)
Baseline mean
48
54
56
51
46
57
Mean change from baseline
17
10
9
6
11
3
Fasting blood glucose (mg/dL)
Baseline mean
209
220
153
150
213
206
Adj. mean change from baseline
-44*
-9*
-38**
-41**
-30*
-9*
Body weight (kg)
Baseline mean
74.6
75.5
77.5
75.1
76.5
76.9
Adj.Mean change from baseline
0.2*
0.8*
0.5**
1.0**
-0.3*
0.3*
*From an ANCOVA model adjusted for baseline value and country.
**From an ANCOVA model adjusted for baseline value and study site.
Type 1 Diabetes – Pediatric
Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with
type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6-17 years of age. The other
study was 52 weeks in duration and enrolled patients 2-16 years of age. In both studies, LEVEMIR and
NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each
meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of
NPH insulin (Table 10). In the 52-week study, the randomization was stratified by age (2-5 years, n=82,
and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in
the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
Study D
Study I
Treatment duration
26 weeks
52 weeks
Treatment in combination with
NovoLog®
(insulin aspart)
NovoLog®
(insulin aspart)
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily NPH
Number of subjects treated
232
115
177
170
HbA1c (%)
Baseline HbA1c
8.8
8.8
8.4
8.4
Reference ID: 3212923
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Adj. mean change from baseline
-0.7*
-0.8*
0.3**
0.2**
LEVEMIR – NPH
95% CI for Treatment difference
0.1
-0.1;0.3
0.1
-0.1; 0.4
Basal insulin dose (units/day)
Baseline mean
24
26
17
17
Mean change from baseline
8
6
8
7
Total insulin dose (units/day)
Baseline mean
48
50
35
34
Mean change from baseline
9
7
10
8
Fasting blood glucose (mg/dL)
Baseline mean
181
181
135
141
Adj. mean change from baseline
-39
-21
-10**
0**
Body weight (kg)
Baseline mean
Adj.Mean change from baseline
46.3
1.6*
46.2
2.7*
37.4
2.7**
36.5
3.6**
*From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).
**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).
Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-
daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before
breakfast and evening) as part of a regimen of stable combination therapy with one or two of the
following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase
inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin
similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes,
LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with
insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
Study E
Study F
Treatment duration
24 weeks
22 weeks
Treatment in combination with
oral agents
insulin aspart
Twice-daily
LEVEMIR
Twice-
daily
NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
Number of subjects treated
237
239
195
200
HbA1c (%)
Baseline HbA1c
8.6
8.5
8.2
8.1
Adj. mean change from baseline
-2.0*
-2.1*
-0.6**
-0.6**
LEVEMIR – NPH
95% CI for Treatment difference
0.1
(-0.0, 0.3)
-0.1
(-0.2, 0.1)
Basal insulin dose (units/day)
Baseline mean
18
17
22
22
Mean change from baseline
48
28
26
15
Total insulin dose1 (units/day)
Baseline mean
-
-
22
22
Mean change from baseline
-
-
57
42
Fasting blood glucose2 (mg/dL)
Baseline mean
179
173
-
-
Reference ID: 3212923
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Adj. mean change from baseline
-69*
-74*
-
-
Body weight (kg)
Baseline mean
82.5
82.3
82.0
79.6
Adj.Mean change from baseline
1.2*
2.8*
0.5**
1.2**
1Study E – Conducted in insulin-naïve patients
2Study F - Fasting blood glucose data not collected
*From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.
**From an ANCOVA model adjusted for baseline value and country.
Combination Therapy with Metformin and Liraglutide
This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%)
on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin
(≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued
the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on
therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%)
achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-
randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in
period with approximately one-half of these patients doing so because of gastrointestinal adverse
reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those
who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in
the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and
metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of
the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the
percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized
to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-
on therapy with LEVEMIR.
Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically
significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide
1.8 mg + metformin alone (Table 12). From a mean baseline body weight of 96 kg after randomization,
there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared
to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8
mg + metformin alone.
Table 12: Results of a 26-week open-label trial of LEVEMIR as add on to liraglutide + metformin
compared to continued treatment with liraglutide + metformin alone in patients not achieving
HbA1c < 7% after 12 weeks of Metformin and Liraglutide
Study H
LEVEMIR +
Liraglutide
+Metformin
Liraglutide+
Metformin
Intent-to-Treat Population (N)ª
162
157
HbA1c (%) (Mean)
Baseline (week 0)
7.6
7.6
Adjusted mean change from baseline
-0.5*
0*
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Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence Interval
-0.5***
(-0.7, -0.4)
Percentage of patients achieving A1c <7%
43**
17**
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline (week 0)
166
159
Adjusted mean change from baseline
-38*
-7*
Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence Interval
-31***
(-39 , -23)
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
*From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.
**From a logistic regression model adjusted for baseline HbA1c.
***p-value <0.0001
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin
detemir per mL (U-100).
3 mL LEVEMIR FlexPen® NDC 0169-6439-10
10 mL vial
NDC 0169-3687-12
FlexPen is for use with NovoFine® disposable needles. Each FlexPen is for use by a single patient.
LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.
16.2 Storage:
Unused (unopened) LEVEMIR should be stored in the refrigerator between 2° and 8°C (36° to 46°F).
Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not
use LEVEMIR if it has been frozen.
Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in
a refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.
If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room
temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and
light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator,
even if the FlexPen or vial still contains insulin.
Vials:
After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not
possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it
Reference ID: 3212923
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is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be
discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after
they are first kept out of the refrigerator.
LEVEMIR FlexPen:
After initial use, the LEVEMIR FlexPen must NOT be stored in a refrigerator and must NOT be stored
with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at
room temperature, below 30°C (86°F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days
after they are first kept out of the refrigerator.
The storage conditions are summarized in Table 13:
Table 13: Storage Conditions for LEVEMIR FlexPen and vial
Not in-use
(unopened)
Refrigerated
Not in-use
(unopened)
Room Temperature
(below 30°C)
In-use
(opened)
3 mL
LEVEMIR
FlexPen
Until expiration date
42 days*
42 days*
Room Temperature
(below 30°C)
(Do not refrigerate)
10 mL vial
Until expiration date
42 days*
42 days*
Refrigerated or Room
Temperature (below 30°C)
*The total time allowed at room temperature (below 30°C) is 42 days regardless of whether the product is in-use or not in-use.
16.3 Preparation and handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to
administration and should only be used if the solution appears clear and colorless.
Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See
Warnings and Precautions (5.2)].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1 Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under
medical supervision. Patients should be informed about the potential side effects of insulin therapy,
including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the
same body region), and allergic reactions. Patients should be informed that the ability to concentrate and
react may be impaired as a result of hypoglycemia. This may present a risk in situations where these
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abilities are especially important, such as driving or operating other machinery. Patients who have
frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been
reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to
always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients
must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
Patients should be instructed on self-management procedures including glucose monitoring, proper
injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional
disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin
dose, inadequate food intake, and skipped meals.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or
are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional
information.
17.2 Never Share a LEVEMIR FlexPen Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen with another person, even if the
needle is changed. Sharing of the FlexPen between patients may pose a risk of transmission of
infection.
Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo
Nordisk A/S.
LEVEMIR is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents
pending.
FlexPen is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-800-727-6500
Reference ID: 3212923
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For current labeling information, please visit https://www.fda.gov/drugsatfda
www.novonordisk-us.com
Reference ID: 3212923
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
LEVEMIR® (LEV–uh-mere)
(insulin detemir [rDNA origin] injection)
solution for subcutaneous injection
Read the Patient Information that comes with LEVEMIR® before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure
that you know how to manage your diabetes. Ask your healthcare
provider, if you have any questions about managing your diabetes.
What is LEVEMIR?
LEVEMIR is a man-made long-acting insulin used to control high blood
sugar in adults and children with diabetes mellitus.
It is not recommended to use LEVEMIR to treat diabetic ketoacidosis.
Who should not use LEVEMIR?
Do not use LEVEMIR if:
• you are allergic to any of the ingredients in LEVEMIR. See the end
of this leaflet for a complete list of ingredients in LEVEMIR.
What should I tell my healthcare provider before using
LEVEMIR?
Before you use LEVEMIR, tell your healthcare provider if you:
• have liver or kidney problems
• have any other medical conditions. Some medical conditions can
affect your insulin needs and your dose of LEVEMIR.
• are pregnant or plan to become pregnant. It is not known, if
LEVEMIR would harm your unborn baby. Talk to your healthcare
provider, if you are pregnant or plan to become pregnant. You and
your healthcare provider should talk about the best way to manage
your diabetes while you are pregnant.
• are breastfeeding or plan to breast-feed. It is not known if
LEVEMIR passes into breast milk. You and your healthcare provider
should decide if you will take LEVEMIR while you breastfeed.
Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins and
herbal supplements. LEVEMIR may affect the way other medicines
work, and other medicines may affect how LEVEMIR works.
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Know the medicines you take. Keep a list of your medicines with
you to show your healthcare provider and pharmacist when you get a
new medicine.
How should I use LEVEMIR?
• Use LEVEMIR exactly as your healthcare provider told you to use it.
• Your healthcare provider will tell you how much LEVEMIR to use and
when to use it.
• Do not make any changes to your dose or type of insulin unless you
are told to do so by your healthcare provider.
Know your insulin. Make sure you know:
• the type and strength of insulin prescribed for you.
• the amount of insulin you take.
• the best time for you to take your insulin. This may change if
you take a different type of insulin.
• Do not dilute or mix LEVEMIR with any other insulin or injectable
diabetes medicine. Your LEVEMIR will not work the right way and
you may lose control of your blood sugar, which can be serious.
Give yourself separate injections. You may give the separate
injections in the same body area (for example, your stomach area),
but you should not give the injections right next to each other.
• Do not use LEVEMIR in an insulin pump.
• Inject LEVEMIR under your skin (subcutaneously) in your upper
arm, abdomen (stomach area), or thigh. Never inject LEVEMIR into
a vein or muscle.
• Change injection sites within the area you choose with each dose.
Do not inject into the exact same spot for each injection.
• Read the instructions for use that comes with your LEVEMIR.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject LEVEMIR before
you start taking it.
• Your healthcare provider will decide which type of LEVEMIR to
prescribe for you.
LEVEMIR comes in:
• 10 mL vials (small bottles) for use with a syringe
• 3 mL LEVEMIR FlexPen®
Ask your healthcare provider how you should use LEVEMIR.
Reference ID: 3212923
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• If you use too much LEVEMIR, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away
(fruit juice, sugar candies, or glucose tablets). It is important to
treat low blood sugar (hypoglycemia) right away because it could
get worse and you could pass out (lose consciousness).
If you pass out you will need help from another person or
emergency medical services right away. See “What are the
possible side effects of LEVEMIR?” for more information on
low blood sugar (hypoglycemia).
• If you forget to take your dose of LEVEMIR, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death.
Follow your healthcare provider’s instructions for treating high
blood sugar.
Know your symptoms of high blood sugar, which may include:
• increased thirst
• frequent urination
• drowsiness
• loss of appetite
• a hard time breathing
• fruity smell on the breath
• high amounts of sugar and
ketones in your urine
• nausea, vomiting (throwing
up) or stomach pain
• Do not share needles, insulin pens or syringes with others.
• Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check your
blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
stress
•
other medicines you
take
•
change in diet
•
change in physical activity
or exercise
What should I avoid while taking LEVEMIR?
•
Alcohol. Drinking alcohol may affect your blood sugar when
you use LEVEMIR.
Reference ID: 3212923
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•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for
you to drive if you often have:
• low blood sugar (hypoglycemia)
• decreased or no warning signs of low blood sugar
What are the possible side effects of LEVEMIR?
LEVEMIR can cause serious side effects, including:
• Low blood sugar (hypoglycemia). Signs and symptoms of low
blood sugar may include:
• dizziness or
lightheadedness
• shakiness
• hunger
• fast heart beat
• tingling in your hands,
feet, lips or tongue
• trouble concentrating or
confusion
• blurred vision
• slurred speech
• anxiety or mood changes
• headache
• sweating
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, and death. In some people their blood sugar
may get so low that they need another person to help them. Talk to
your healthcare provider about how to tell if you have low blood sugar
and what to do if this happens while taking LEVEMIR. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
If you are using LEVEMIR with another diabetes medicine, your
LEVEMIR dose may need to be changed to reduce your chance of
getting low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of LEVEMIR may need to be changed.
• Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) the area where you inject your insulin to help
prevent these skin changes from happening. Do not inject insulin
into areas of skin that have thickening or pits.
• Serious allergic reactions. LEVEMIR can cause life
threatening symptoms. Get medical help right away if you have
any of these symptoms of an allergic reaction:
Reference ID: 3212923
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• a rash all over your body
• itching
• shortness of breath
• trouble breathing
(wheezing)
• fast heartbeat
• sweating
• feel faint
Common side effects of LEVEMIR include:
• Low blood sugar (hypoglycemia). See “What are the possible
side effects of LEVEMIR?” for more information on low blood
sugar (hypoglycemia).
• Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious, talk to your
healthcare provider.
• Weight gain. This can occur with any insulin therapy. Talk to your
healthcare provider about how LEVEMIR can affect your weight.
Tell your healthcare provider if you have any side effect that bothers
you or does not go away.
These are not all of the possible side effects from LEVEMIR. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store LEVEMIR?
Unopened LEVEMIR:
•
Keep all unopened LEVEMIR in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Unopened LEVEMIR can be kept until the expiration date on
the label if the medicine has been stored in a refrigerator.
•
If refrigeration is not possible, you can keep the unopened
LEVEMIR at room temperature below 86°F (30°C).
•
Throw away LEVEMIR 42 days after it is first kept out of the
refrigerator.
•
Do not freeze. Do not use LEVEMIR if it has been frozen.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Keep unopened LEVEMIR in the carton to protect it from
light.
LEVEMIR in use:
•
Vials
• Keep opened vials of LEVEMIR in the refrigerator or at
room temperature below 86°F (30°C) away from direct
heat or light.
• Throw away a vial that has always been kept in the
refrigerator after 42 days of use, even if there is insulin
left in the vial.
• Throw away a vial that has been kept at room
temperature 42 days after it is first kept out of the
refrigerator, even if there is insulin left in the vial.
•
LEVEMIR FlexPen
• Keep at room temperature below 86°F (30°C) for up to
42 days.
• Do not store a LEVEMIR FlexPen that you are using in
the refrigerator.
• Do not store LEVEMIR with the needle attached.
• Keep LEVEMIR FlexPen away from direct heat or light.
• Throw away used LEVEMIR FlexPens after 42 days, even
if there is insulin left in them.
Keep LEVEMIR and all medicines out of the reach of children.
General information about LEVEMIR
Medicines are sometimes prescribed for conditions that are not
mentioned in the patient leaflet. Do not use LEVEMIR for a condition
for which it was not prescribed. Do not give LEVEMIR to other people,
even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about
LEVEMIR. If you would like more information about LEVEMIR or
diabetes, talk with your healthcare provider. You can ask your
healthcare provider for information about LEVEMIR that is written for
healthcare professionals.
For more information about LEVEMIR, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in LEVEMIR?
Active Ingredient: Insulin detemir
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium
phosphate dihydrate, sodium chloride and water for injection.
Hydrochloric acid or sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks of
Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538,
6,011,007, 6,869,930 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297,
6,235,004 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Revised: April 2012
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions For Use
LEVEMIR® 10 mL vial
Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial
and each time you get a refill. You should read the instructions in this manual even if you have
used an insulin 10 mL vial before.
How should I use the LEVEMIR 10 mL vial?
Using the 10 mL vial:
1. Check to make sure that you have the correct type of insulin.
This is especially important if you use different types of insulin.
2. Look at the vial and the insulin. The LEVEMIR insulin should
be clear and colorless. The tamper-resistant cap should be in
place before the first use. If the cap has been removed before
your first use of the vial, or if the insulin is cloudy or colored,
Do not use the insulin and return it to your pharmacy.
3. Wash your hands with soap and water.
4. If you are using a new vial, pull off the tamper-resistant cap.
Before each use, wipe the rubber stopper with an alcohol
wipe.
4A
4B
5. Do not roll or shake the vial. Shaking the vial right before the
dose is drawn into the syringe may cause bubbles or foam.
This can cause you to draw up the wrong dose of insulin. The
insulin should be used only if it is clear and colorless.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Pull back the plunger on your syringe until the black tip
reaches the marking for the number of units you will inject.
6
7. Push the needle through the rubber stopper into the vial.
7
8. Push the plunger all the way in. This inserts air into the vial.
8
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose that you
need.
9
10. If there are air bubbles, tap the syringe gently with your finger
to raise the air bubbles to the top of the needle. Then slowly
push the plunger to the correct unit marking for your dose.
10
11. Check to make sure you have the right dose of LEVEMIR in
the syringe.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12. Pull the syringe out of the vial.
13. Inject your LEVEMIR right away as instructed by your
healthcare provider.
How should I inject LEVEMIR with a syringe?
If you clean your injection site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider about how to rotate injection sites and how to give an
injection.
1. Pinch your skin between two fingers, push the needle into the
skinfold, using a dart-like motion and push the plunger to inject
the insulin under your skin. The needle will be straight in.
1
2. Keep the needle under your skin for at least 6 seconds to
make sure you have injected all the insulin. After you pull the
needle from your skin you may see a drop of Levemir at the
needle tip. This is normal and has no effect on the dose you
just received.
3. If blood appears after you pull the needle from your skin, press
the injection site lightly with an alcohol swab. Do not rub the
area.
4. After each injection, remove the needle without recapping
and dispose of it in a puncture-resistant container. Used
syringes, needles, and lancets should be placed in sharps
containers (such as red biohazard containers), hard plastic
containers (such as detergent bottles), or metal containers
(such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised: January 2012
Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930,
and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
LEVEMIR® FlexPen®
Please carefully read the following Instructions for use before using your LEVEMIR®
FlexPen® and each time you get a refill. You should read the instructions in this manual
even if you have used a LEVEMIR FlexPen before.
LEVEMIR FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to
60 units in increments of 1 unit. LEVEMIR FlexPen is designed to be used with
NovoFine® needles.
LEVEMIR FlexPen should not be used by people who are blind or have severe
eyesight problems without the help of a person who has good eyesight and who is
trained to use the LEVEMIR FlexPen the right way.
Getting ready
Make sure you have the following items:
LEVEMIR FlexPen
NovoFine disposable needles
Alcohol swab
PREPARING YOUR LEVEMIR FLEXPEN
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. LEVEMIR should
look clear and colorless.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab.
B. Attaching the needle
Remove the protective tab from a new disposable needle.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attach the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your LEVEMIR FlexPen
until you are ready to give your injection.
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and throw it away (see diagram
D).
Always use a new needle for each injection to cut down the chance of infection and to
prevent blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of needle sticks, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection, small amounts of air may collect in the cartridge during normal use.
To avoid injecting air and to ensure you take the right dose of insulin:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your LEVEMIR FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any
air bubbles collect at the top of the cartridge (see diagram F).
G. While you keep the needle pointing upwards, press the push-
button all the way in (see diagram G). The dose selector
returns to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use the
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6500.
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram H). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Wipe the skin with an alcohol swab and let the area dry.
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram I). Be careful only to
push the button after the needle is in the skin.
Turning the dose selector will not inject insulin.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has
been pulled out from the skin (see diagram J). This will make
sure that the full dose has been given.
You may see a drop of LEVEMIR at the needle tip. This is
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin,
press the injection site lightly with an alcohol swab. Do not
rub the area.
After the injection
Carefully remove the needle from the pen after each injection. This helps to
prevent infection and leakage of insulin. You can carefully recap the needle with
the bigger outer cap to help make it easier to remove the needle.
Do not recap the needle with the small inner cap. Recapping with this small part
can increase your chances of having a needle stick injury.
Put the needle in a sharps container or some type of hard plastic or metal
container with a screw top such as a detergent bottle or empty coffee can.
These containers should be sealed and thrown away the right way. Check
with your healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away used
needles and syringes. Do not throw away used needles and syringes in
household trash or recycling bins.
K. Put the pen cap on the LEVEMIR FlexPen and store the
LEVEMIR FlexPen without the needle attached (see diagram K).
The LEVEMIR FlexPen prevents the cartridge from being
completely emptied. It can deliver 300 units then you should
throw it away in a sharps container or some type of hard plastic
or metal container with a screw top, such as a detergent bottle
or empty coffee can.
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FUNCTION CHECK
L. If your LEVEMIR FlexPen is not working the right way, follow
the steps below:
Attach a new NovoFine needle.
Remove the big outer needle cap and the inner needle
cap.
Do an airshot as described in “Giving the airshot before
each injection” (see diagram E through G).
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
Turn the dose selector so the dose indicator window shows
20 units.
Hold the LEVEMIR FlexPen so the needle is pointing
down.
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap to the marker
(see diagram L). If LEVEMIR FlexPen has released too much or too little insulin,
do the function check again. If the same problem happens again, do not use your
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled with
care. If you drop your FlexPen it could get damaged. If you are concerned that
your FlexPen is damaged, use a new one. You can clean the outside of your
FlexPen by wiping it with a damp cloth. Do not soak or wash your FlexPen.
Soaking or washing the FlexPen could damage it. Do not refill your FlexPen.
Remove the needle from the LEVEMIR FlexPen after each injection. This
helps to cut down your chance of infection, prevent leakage of insulin. Be
careful when handling used needles to avoid needle sticks and transfer of
infections.
Keep your LEVEMIR FlexPen and needles out of the reach of children.
Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and
LEVEMIR FlexPen must not be shared.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a safety measure, always carry a spare insulin delivery device in case
your LEVEMIR FlexPen is lost or damaged.
Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave
it in a car or other location where it can get too hot or too cold.
Revised: January 2012
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered
trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007,
6,869,930, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3212923
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:30.871893 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021536s028lbl.pdf', 'application_number': 21536, 'submission_type': 'SUPPL ', 'submission_number': 28} |
4,547 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NovoLog Mix 70/30 safely and effectively. See full prescribing
information for NovoLog Mix 70/30.
NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30%
insulin aspart injection, [rDNA origin])
Suspension for subcutaneous injection
Initial U.S. Approval: 2001
---------------------------------RECENT MAJOR CHANGES-------------------------
Warnings and Precautions (5.8) 3/2013
----------------------------INDICATIONS AND USAGE---------------------------
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control
in patients with diabetes mellitus.
Important Limitations of Use: In premix insulins, such as NovoLog Mix 70/30,
the proportions of rapid acting and long acting insulins are fixed and do not
allow for basal versus prandial dose adjustments (1).
----------------------DOSAGE AND ADMINISTRATION-----------------------
Only for subcutaneous injection (2.1).
Type 1 DM: dose within 15 minutes before meal initiation.
Type 2 DM: dose within 15 minutes before or after starting a meal.
Do not administer intravenously (2.1).
Do not use in insulin infusion pumps (2.1).
Must be resuspended immediately before use (2.2).
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Each presentation contains 100 Units of insulin aspart per mL (U-100) (3)
10 mL vials
3 mL NovoLog Mix 70/30 FlexPen
-------------------------------CONTRAINDICATIONS------------------------------
Do not use during episodes of hypoglycemia (4).
Do not use in patients with hypersensitivity to NovoLog Mix 70/30 or
one of its excipients (4).
-----------------------WARNINGS AND PRECAUTIONS------------------------
NovoLog Mix 70/30 should not be mixed with any other insulin product
(5.1).
Hypoglycemia is the most common adverse effect of insulin therapy.
Glucose monitoring is recommended for all patients with diabetes. Any
change of insulin dose should be made cautiously and only under
medical supervision (5.1, 5.2).
Insulin, particularly when given in settings of poor glycemic control,
can cause hypokalemia. Use caution in patients predisposed to
hypokalemia (5.3).
Like all insulins, NovoLog Mix 70/30 requirements may be reduced
in patients with renal impairment or hepatic impairment (5.4, 5.5).
Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with insulin products, including NovoLog Mix 70/30 (5.6).
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and
insulin, including NovoLog Mix 70/30 (5.8).
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions observed with insulin therapy include hypoglycemia,
allergic reactions, local injection site reactions, lipodystrophy, rash and
pruritus (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
The following may increase the blood-glucose-lowering effect and
susceptibility to hypoglycemia: oral antidiabetic products, pramlintide,
ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g.
octreotide), sulfonamide antibiotics (7).
The following may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine
derivatives, somatropin, thyroid hormones, estrogens, progestogens
(e.g., in oral contraceptives), atypical antipsychotics (7).
Beta-blockers, clonidine, lithium salts, and alcohol may either
potentiate or weaken the blood-glucose-lowering effect of insulin (7).
Pentamidine may cause hypoglycemia, which may be followed by
hyperglycemia (7).
The signs of hypoglycemia may be reduced or absent in patients taking
sympatholytic products such as beta-blockers, clonidine, guanethidine,
and reserpine (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 3/2013
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Resuspension
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Renal Impairment
5.5 Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Antibody Production
5.8 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1
NovoLog Mix 70/30 versus Novolin 70/30
14.2
Combination Therapy: Insulin and Oral Agents in Patients with
Type 2 Diabetes
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Recommended Storage
17 PATIENT COUNSELING INFORMATION
17.1
Physician Instructions
*Sections or subsections omitted from the full prescribing information are not
listed.
8.5 Geriatric Use
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
____________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control in
patients with diabetes mellitus.
Important Limitations of Use:
In premix insulins, such as NovoLog Mix 70/30, the proportions of rapid acting and long
acting insulins are fixed and do not allow for basal versus prandial dose adjustments.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
NovoLog Mix 70/30 is an insulin analog with an earlier onset and intermediate duration
of action in comparison to the basal human insulin premix. The addition of protamine to the
rapid-acting aspart insulin analog (NovoLog) results in insulin activity that is 30% short-acting
and 70% long-acting. NovoLog Mix 70/30 is typically dosed on a twice-daily basis (with each
dose intended to cover 2 meals or a meal and a snack). The dosage of NovoLog Mix 70/30 must
be individualized. The written prescription for NovoLog Mix 70/30 should include the full
name, to avoid confusion with NovoLog (insulin aspart) and Novolin 70/30 (human premix).
NovoLog Mix 70/30 should appear uniformly white and cloudy. Do not use it if it looks
clear or if it contains solid particles. NovoLog Mix 70/30 should not be used after the printed
expiration date.
NovoLog Mix 70/30 should be administered by subcutaneous injection in the abdominal
region, buttocks, thigh, or upper arm. NovoLog Mix 70/30 has a faster onset of action than
human insulin premix 70/30 and should be dosed within 15 minutes before meal initiation for
patients with type 1 diabetes. For patients with type 2 diabetes, dosing should occur within 15
minutes before or after meal initiation. Injection sites should be rotated within the same region
to reduce the risk of lipodystrophy. As with all insulins, the duration of action may vary
according to the dose, injection site, blood flow, temperature, and level of physical activity.
NovoLog Mix 70/30 should not be administered intravenously or used in insulin
infusion pumps. Dose regimens of NovoLog Mix 70/30 will vary among patients and should be
determined by the health care professional familiar with the patient’s recommended glucose
treatment goals, metabolic needs, eating habits, and other lifestyle variables.
2.2
Resuspension
NovoLog Mix 70/30 is a suspension that must be visually inspected and resuspended
immediately before use.
The NovoLog Mix 70/30 vial should be rolled gently in your hands in a horizontal position 10
times to mix it. The rolling procedure must be repeated until the suspension appears uniformly
white and cloudy. Inject immediately. Resuspension is easier when the insulin has reached
room temperature.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The NovoLog Mix 70/30 FlexPen should be rolled 10 times gently between your hands in a
horizontal position. Thereafter, turn the NovoLog Mix 70/30 FlexPen upside down so that the
glass ball moves from one end of the reservoir to the other. Do this at least 10 times. The
rolling and turning procedure must be repeated until the suspension appears uniformly white
and cloudy. Inject immediately. Before each subsequent injection, turn the disposable NovoLog
Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to
the other at least 10 times and until the suspension appears uniformly white and cloudy. Inject
immediately.
3
DOSAGE FORMS AND STRENGTHS
NovoLog Mix 70/30 is available in the following package sizes: each presentation
contains 100 units of insulin aspart per mL (U-100).
10 mL vials
3 mL NovoLog Mix 70/30 FlexPen
4
CONTRAINDICATIONS
NovoLog Mix 70/30 is contraindicated
during episodes of hypoglycemia
in patients with hypersensitivity to NovoLog Mix 70/30 or one of its excipients.
5
WARNINGS AND PRECAUTIONS
5.1
Administration
The short and long-acting components of insulin mixes, including NovoLog Mix 70/30,
cannot be titrated independently. Because NovoLog Mix 70/30 has peak pharmacodynamic
activity between 1-4 hours after injection, it should be administered within 15 minutes of meal
initiation [see Clinical Pharmacology (12)]. The dose of insulin required to provide adequate
glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal.
The pharmacodynamic profile may also be inadequate for patients who require more frequent
meals.
NovoLog Mix 70/30 should not be mixed with any other insulin product.
NovoLog Mix 70/30 should not be used intravenously.
NovoLog Mix 70/30 should not be used in insulin infusion pumps.
Glucose monitoring is recommended for all patients with diabetes. Any change of
insulin dose should be made cautiously and only under medical supervision. Changing from one
insulin product to another or changing the insulin strength may result in the need for a change in
dosage. Changes may also be necessary during illness, emotional stress, and other physiologic
stress in addition to changes in meals and exercise.
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by
the site used for injection and the degree of vascularization of the site. Smoking, temperature,
and exercise contribute to variations in blood flow and insulin absorption. These and other
factors contribute to inter- and intra-patient variability.
Needles and NovoLog Mix 70/30 FlexPen must not be shared.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2
Hypoglycemia
Hypoglycemia is the most common adverse effect of insulin therapy, including
NovoLog Mix 70/30. Severe hypoglycemia may lead to unconsciousness and/or convulsions
and may result in temporary or permanent impairment of brain function or even death. Severe
hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or
glucagon administration has been observed in clinical trials with insulin, including trials with
NovoLog Mix 70/30.
The timing of hypoglycemia may reflect the time-action profile of the insulin
formulation [see Clinical Pharmacology (12)]. Other factors, such as changes in dietary intake
(e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications
may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all insulins, use
caution in patients with hypoglycemia unawareness and in patients who may be predisposed to
hypoglycemia (e.g. patients who are fasting or have erratic food intake). The patient’s ability to
concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in
situations where these abilities are especially important, such as driving or operating machinery.
Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as long
duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control [see Drug Interactions (7)].
5.3
Hypokalemia
All insulin products, including NovoLog Mix 70/30, cause a shift in potassium from the
extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may
cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may
be at risk for hypokalemia (e.g. patients using potassium-lowering medications or patients
taking medications sensitive to potassium concentrations).
5.4
Renal Impairment
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various
degrees of renal impairment have not been conducted. As with other insulins, the requirements
for NovoLog Mix 70/30 may be reduced in patients with renal impairment [see Clinical
Pharmacology (12.3)].
5.5
Hepatic Impairment
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with
various degrees of hepatic impairment have not been conducted. As with other insulins, the
requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic impairment [see
Clinical Pharmacology (12.3)].
5.6
Hypersensitivity and Allergic Reactions
Local Reactions- As with other insulin therapy, patients may experience reactions such
as erythema, edema or pruritus at the site of NovoLog Mix 70/30 injection. These reactions
usually resolve in a few days to a few weeks, but in some occasions, may require
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discontinuation of NovoLog Mix 70/30. In some instances, these reactions may be related to the
insulin molecule, other components in the insulin preparation including protamine and cresol,
components in skin cleansing agents, or injection techniques. Localized reactions and
generalized myalgias have been reported with the use of cresol as an injectable excipient.
Systemic Reactions- Less common, but potentially more serious, is generalized allergy to
insulin, which may cause rash (including pruritus) over the whole body, shortness of breath,
wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized
allergy, including anaphylactic reaction, may be life threatening.
5.7
Antibody Production
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were
monitored in a 3-month, open-label comparator trial as well as in a long-term extension trial.
Changes in cross-reactive antibodies were more common after NovoLog Mix 70/30 than with
Novolin 70/30 but these changes did not correlate with change in HbA1c or increase in insulin
dose. The clinical significance of these antibodies has not been established. Antibodies did not
increase further after long-term exposure (>6 months) to NovoLog Mix 70/30.
5.8
Fluid retention and heart failure can occur with concomitant use of PPAR-gamma
agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor
(PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients
treated with insulin, including NovoLog Mix 70/30, and a PPAR-gamma agonist should be
observed for signs and symptoms of heart failure. If heart failure develops, it should be managed
according to current standards of care, and discontinuation or dose reduction of the PPAR-
gamma agonist must be considered.
6
ADVERSE REACTIONS
Clinical Trial Experience
Clinical trials are conducted under widely varying designs, therefore, the adverse reaction
rates reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including NovoLog Mix 70/30 [see Warnings and Precautions (5.2)]. NovoLog Mix
70/30 should not be used during episodes of hypoglycemia [see Contraindications (4)
and Warnings and Precautions (5)].
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic
retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic
control decreases the risk of diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including NovoLog Mix 70/30, can cause lipodystrophy at the
site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of
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adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin
absorption. Rotate insulin injection sites within the same region to reduce the risk of
lipodystrophy.
Weight gain
Weight gain can occur with some insulin therapies, including NovoLog Mix 70/30, and
has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic
control is improved by intensified insulin therapy.
Frequencies of adverse drug reactions
The frequencies of adverse drug reactions during a clinical trial with NovoLog Mix 70/30
in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the
tables below. The trial was a three-month, open-label trial in patients with Type 1 or
Type 2 diabetes who were treated twice daily (before breakfast and before supper) with
NovoLog Mix 70/30.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 diabetes mellitus
(Adverse events with frequency ≥ 5% are included.)
NovoLog Mix 70/30
(N=55)
Novolin 70/30
(N=49)
Preferred Term
N
%
N
%
Hypoglycemia
38
69
37
76
Headache
19
35
6
12
Influenza-like symptoms
7
13
1
2
Dyspepsia
5
9
3
6
Back pain
4
7
2
4
Diarrhea
4
7
3
6
Pharyngitis
4
7
1
2
Rhinitis
3
5
6
12
Skeletal pain
3
5
2
4
Upper respiratory tract infection
3
5
1
2
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 diabetes mellitus
(Adverse events with frequency ≥ 5% are included.)
NovoLog Mix 70/30
(N=85)
Novolin 70/30
(N=102)
Preferred Term
N
%
N
%
Hypoglycemia
40
47
51
50
Upper respiratory tract infection
10
12
6
6
Headache
8
9
8
8
Diarrhea
7
8
2
2
Neuropathy
7
8
2
2
Pharyngitis
5
6
4
4
Abdominal pain
4
5
0
0
Rhinitis
4
5
2
2
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Postmarketing Data
Additional adverse reactions have been identified during post-approval use of NovoLog
Mix 70/30. Because these adverse reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their frequency. They include
medication errors in which other insulins have been accidentally substituted for NovoLog Mix
70/30 [see Patient Counseling Information (17)].
7
DRUG INTERACTIONS
A number of substances affect glucose metabolism and may require insulin dose
adjustment and particularly close monitoring.
The following are examples of substances that may increase the blood-glucose-
lowering effect and susceptibility to hypoglycemia: oral antidiabetic products,
pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase
(MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide),
sulfonamide antibiotics.
The following are examples of substances that may reduce the blood-glucose-
lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
atypical antipsychotics.
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken
the blood-glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
products such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B.
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. This background risk is increased in pregnancies complicated by
hyperglycemia and may be decreased with good metabolic control. It is essential for patients
with diabetes or history of gestational diabetes to maintain good metabolic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first
trimester, generally increase during the second and third trimesters, and rapidly decline after
delivery. Careful monitoring of glucose control is essential in such patients.
An open-label, randomized study compared the safety and efficacy of NovoLog (the
rapid-acting component of NovoLog Mix 70/30) versus human insulin in the treatment of
pregnant women with Type 1 diabetes (322 exposed pregnancies (NovoLog: 157, human
insulin: 165)). Two-thirds of the enrolled patients were already pregnant when they entered the
study. Since only one-third of the patients enrolled before conception, the study was not large
enough to evaluate the risk of congenital malformations. Mean HbA1c of ~ 6% was observed in
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both groups during pregnancy, and there was no significant difference in the incidence of
maternal hypoglycemia.
Animal reproduction studies have not been conducted with NovoLog Mix 70/30.
However, subcutaneous reproduction and teratology studies have been performed with
NovoLog (the rapid-acting component of NovoLog Mix 70/30) and regular human insulin in
rats and rabbits. In these studies, NovoLog was given to female rats before mating, during
mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of
NovoLog did not differ from those observed with subcutaneous regular human insulin.
NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal
abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the human
subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of
10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based
on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high
doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a
dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of
1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits
based on U/body surface area.
Female patients should be advised to discuss with their physician if they intend to, or if
they become pregnant. There are no adequate and well-controlled studies of the use of
NovoLog Mix 70/30 in pregnant women.
8.3
Nursing Mothers
It is unknown whether insulin aspart is excreted in human milk as occurs with human
insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 or
NovoLog in lactating women. Women with diabetes who are lactating may require adjustments
of their insulin doses.
8.4
Pediatric Use
Safety and effectiveness of NovoLog Mix 70/30 have not been established in pediatric
patients.
8.5
Geriatric Use
Clinical studies of NovoLog Mix 70/30 did not include sufficient numbers of patients
aged 65 and over to determine whether they respond differently than younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of
the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function,
and of concomitant disease or other drug therapy in this population.
10
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake,
energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral
glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe
episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery.
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11
DESCRIPTION
NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart
injection, [rDNA origin]) is a human insulin analog suspension containing 70% insulin aspart
protamine crystals and 30% soluble insulin aspart. NovoLog Mix 70/30 is a blood-glucose-
lowering agent with an earlier onset and an intermediate duration of action. Insulin aspart is
homologous with regular human insulin with the exception of a single substitution of the amino
acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology
utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin aspart (NovoLog) has the empirical
formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
Gly
Ile
Gln
Val Glu
Cys Cys
Cys
Glu
Gln
Thr
Ile
Ser
Cys Ser
Leu
Leu
Tyr
Tyr
Asn
Val
Gln
Leu Cys Gly Ser
Phe
Asn
His
His Leu
Val
Glu
Ala
Leu Tyr
Leu
Val
Cys Gly
Glu Arg
Gly
Phe Phe
Tyr
Thr
Asp Lys Thr
Asn
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
2
1
3
4
5
6
8
7
9
10
11
12
14
13
15
16
17
18
20
19
21
23
22
24
25
26
27
29
28
30
Asp
Pro
S
S
S
S
S
S
A-chain
B-chain
Figure 1. Structural formula of insulin aspart
NovoLog Mix 70/30 is a uniform, white, sterile suspension that contains insulin aspart
100 Units/mL.
Inactive ingredients are glycerol 16.0 mg/mL, phenol 1.50 mg/mL, metacresol 1.72
mg/mL, zinc 19.6 g/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium
chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL. NovoLog Mix 70/30 has a pH of
7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of NovoLog Mix 70/30 is the regulation of glucose metabolism.
Insulins, including NovoLog Mix 70/30, bind to the insulin receptors on muscle, liver and fat
cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously
inhibiting the output of glucose from the liver.
12.2
Pharmacodynamics
The two euglycemic clamp studies described below [see Clinical Pharmacology (12.3)]
assessed glucose utilization after dosing of healthy volunteers. NovoLog Mix 70/30 has an
earlier onset of action than human premix 70/30 in studies of normal volunteers and patients
with diabetes. The onset of action is between 10-20 minutes for NovoLog Mix 70/30 compared
to 30 minutes for Novolin 70/30. The mean SD time to peak activity for NovoLog Mix 70/30
is 2.4 hr 0.8 hr compared to 4.2 hr 0.4 hr for Novolin 70/30. The duration of action may be
as long as 24 hours (see Figure 2).
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NovoLog Mix 70/30
Novolin 70/30
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
Glucose Infusion Rate (mg/kg*min)
2
8
9
10
7
6
5
4
3
1
0
Figure 2. Pharmacodynamic Activity Profile of NovoLog Mix 70/30 and Novolin 70/30 in
healthy subjects.
12.3
Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in
insulin aspart (NovoLog) reduces the molecule’s tendency to form hexamers as observed with
regular human insulin. The rapid absorption characteristics of NovoLog are maintained by
NovoLog Mix 70/30. The insulin aspart in the soluble component of NovoLog Mix 70/30 is
absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining
70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile
after subcutaneous injection.
Bioavailability and Absorption- The relative bioavailability of NovoLog Mix 70/30
compared to NovoLog and Novolin 70/30 indicates that the insulins are absorbed to similar
extent. In euglycemic clamp studies in healthy volunteers (n=23) after dosing with NovoLog
Mix 70/30 (0.2 U/kg), a mean maximum serum concentration (Cmax) of 23.4 5.3 mU/L was
reached after 60 minutes. The mean half-life (t1/2) of NovoLog Mix 70/30 was about 8 to 9
hours. Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose of
NovoLog Mix 70/30. Similar data were seen in a separate euglycemic clamp study in healthy
volunteers (n=24) after dosing with NovoLog Mix 70/30 (0.3 U/kg). A Cmax of 61.3 20.1
mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12 hours after a
subcutaneous dose.
The Cmax and the area under the insulin concentration-time curve (AUC) after
administration of NovoLog Mix 70/30 was approximately 20% greater than those after
administration of Novolin 70/30, (see Fig. 3 for pharmacokinetic profiles).
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NovoLog Mix 70/30
Novolin 70/30
Mean Serum Insulin (mU/L)
Time (hours)
30
15
12
15
24
21
18
0
5
10
20
25
3
6
9
0
Points represent m ean 2 SEM
Figure 3. Pharmacokinetic Profiles of NovoLog Mix 70/30 and Novolin 70/30
Distribution and Elimination- NovoLog has a low binding to plasma proteins, 0 to 9%,
similar to regular human insulin. After subcutaneous administration in normal male volunteers
(n=24), NovoLog was more rapidly eliminated than regular human insulin with an average
apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
The effect of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy,
or smoking, on the pharmacodynamics and pharmacokinetics of NovoLog Mix 70/30 has not
been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate
the carcinogenic potential of NovoLog Mix 70/30. In 52-week studies, Sprague-Dawley rats
were dosed subcutaneously with NovoLog, the rapid-acting component of NovoLog Mix 70/30,
at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of
1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day,
NovoLog increased the incidence of mammary gland tumors in females when compared to
untreated controls. The incidence of mammary tumors found with NovoLog was not
significantly different from that found with regular human insulin. The relevance of these
findings to humans is not known.
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NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward
gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo
micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.
In fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day
(approximately 32 times the human subcutaneous dose, based on U/body surface area) had no
direct adverse effects on male and female fertility, or on general reproductive performance of
animals.
13.2
Animal Toxicology and/or Pharmacology
In standard biological assays in mice and rabbits, one unit of NovoLog has the same
glucose-lowering effect as one unit of regular human insulin. However, the effect of NovoLog
Mix 70/30 is more rapid in onset compared to Novolin (human insulin) 70/30 due to its faster
absorption after subcutaneous injection.
14
CLINICAL STUDIES
14.1
NovoLog Mix 70/30 versus Novolin 70/30
In a three-month, open-label trial, patients with Type 1 (n=104) or Type 2 (n=187)
diabetes were treated twice daily (before breakfast and before supper) with NovoLog Mix 70/30
or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral
hypoglycemic agents were not allowed within 1 month prior to the study or during the study.
The small changes in HbA1c were comparable across the treatment groups (see Table 3).
Table 3: Glycemic Parameters at the End of Treatment [Mean ± SD (N subjects)]
NovoLog Mix 70/30
Novolin 70/30
Type 1, N=104
Fasting Blood Glucose (mg/dL)
174 ± 64 (48)
142 ± 59 (44)
1.5 Hour Post Breakfast (mg/dL)
187 ± 82 (48)
200 ± 82 (42)
1.5 Hour Post Dinner (mg/dL)
162 ± 77 (47)
171 ± 66 (41)
HbA1c (%) Baseline
8.4 ± 1.2 (51)
8.5 ± 1.1 (46)
HbA1c (%) Week 12
8.4 ± 1.1 (51)
8.3 ± 1.0 (47)
Type 2, N=187
Fasting Blood Glucose (mg/dL)
153 ± 40 (76)
152 ± 69 (93)
1.5 Hour Post Breakfast (mg/dL)
182 ± 65 (75)
200 ± 80 (92)
1.5 Hour Post Dinner (mg/dL)
168 ± 51 (75)
191 ± 65 (93)
HbA1c (%) Baseline
8.1 ± 1.2 (82)
8.2 ± 1.3 (98)
HbA1c (%) Week 12
7.9 ± 1.0 (81)
8.1 ± 1.1 (96)
The significance, with respect to the long-term clinical sequelae of diabetes, of the
differences in postprandial hyperglycemia between treatment groups has not been established.
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were
monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial.
14.2
Combination Therapy: Insulin and Oral Agents in Patients with Type 2 Diabetes
Trial 1:
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In a 34-week, open-label trial, insulin-naïve patients with type 2 diabetes currently
treated with 2 oral antidiabetic agents were switched to treatment with metformin and
pioglitazone. During an 8-week optimization period metformin and pioglitazone were increased
to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period,
subjects were randomized to receive either NovoLog Mix 70/30 twice daily added on to the
metformin and pioglitazone regimen or continue the current optimized metformin and
pioglitazone therapy. NovoLog Mix 70/30 was started at a dose of 6 IU twice daily (before
breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110
mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 IU.
Table 4: Combination Therapy with Oral Agents and Insulin in Patients with Type 2
Diabetes Mellitus [Mean (SD)]
Treatment duration 24-weeks
NovoLog Mix
70/30 +
Metformin
+ Pioglitazone
Metformin +
Pioglitazone
HbA1c
Baseline mean ± SD (n)
8.1 ± 1.0 (102)
8.1 ± 1.0 (98)
End-of-study mean ± SD (n) - LOCF
6.6 ± 1.0 (93)
7.8 ± 1.2 (87)
Adjusted Mean change from baseline ± SE (n)*
-1.6 ± 0.1 (93)
-0.3 ± 0.1 (87)
Treatment difference mean ± SE*
95% CI*
-1.3 ± 0.1
(-1.6, -1.0)
Percentage of subjects reaching HbA1c 7.0%
76%
24%
Percentage of subjects reaching HbA1c ≤6.5%
59%
12%
Fasting Blood Glucose (mg/dL)
Baseline Mean ± SD (n)
173 ± 39.8 (93)
163 ± 35.4 (88)
End of Study Mean ± SD (n) – LOCF
130 ± 50.0 (90)
162 ± 40.8 (84)
Adjusted Mean change from baseline ± SE (n)*
-43.0 ± 5.3 (90)
-3.9 ± 5.3 (84)
End-of-Study Blood Glucose (Plasma) (mg/dL)
2 Hour Post Breakfast
138 ± 42.8 (86)
188 ± 57.7 (74)
2 Hour Post Lunch
150 ± 41.5 (86)
176 ± 56.5 (74)
2 Hour Post Dinner
141 ± 57.8 (86)
195 ± 60.1 (74)
% of patients with severe hypoglycemia**
3
0
% of patients with minor hypoglycemia**
52
3
Weight gain at end of study (kg)**
4.6 ± 4.3 (92)
0.8 ± 3.2 (86)
*Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with
treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.
**If metabolic control is improved by intensified insulin therapy, an increased risk of hypoglycemia and weight
gain may occur.
Trial 2:
In a 28-week, open-label trial, insulin-naïve patients with type 2 diabetes with fasting
plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy
were randomized to receive either NovoLog Mix 70/30 twice daily [before breakfast and before
supper] or insulin glargine once daily1 (see Table 5). NovoLog Mix 70/30 was started at an
average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and before supper), and
bedtime insulin glargine was started at 10-12 IU (0.13 ± 0.03 IU/kg). Insulin doses were titrated
weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of
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80-110 mg/dL. The metformin dose was adjusted to 2550 mg/day. Approximately one-third of
the patients in each group were also treated with pioglitazone (30 mg/day). Insulin
secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients
were Caucasian (53%), and the mean initial weight was 90 kg.
Table 5: Combination Therapy with Oral Agents and Two Types of Insulin in Patients
with Type 2 Diabetes Mellitus [Mean (SD)]
Treatment duration 28-weeks
NovoLog Mix 70/30
+ Metformin ±
Pioglitazone
Insulin
Glargine +
Metformin ±
Pioglitazone
Number of patients
117
116
HbA1c
Baseline mean (%)
9.7 ± 1.5 (117)
9.8 ± 1.4 (114)
End-of-study mean (± SD)
6.9 ± 1.2 (108)
7.4 ± 1.2 (114)
Mean change from baseline
-2.7 ± 1.6 (108)
-2.4 ± 1.5 (114)
Percentage of subjects reaching HbA1c 7.0%
66%
40%
Total Daily Insulin Dose at end of study (U)
78 ± 40 (117)
51 ± 27 (116)
% of patients with severe hypoglycemia
0
0
% of minor hypoglycemia
43
16
Weight gain at end of study
5.4 ± 4.8 (117)
3.5 ± 4.5 (116)
15
REFERENCES
1.
Raskin R, Allen E, Hollander P, et al. Initiating insulin therapy in type 2
diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care.
2005; 28:260-265.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
NovoLog Mix 70/30 is available in the following package sizes: each presentation
contains 100 Units of insulin aspart per mL (U-100).
10 mL vials
NDC 0169-3685-12
3 mL NovoLog Mix 70/30 FlexPen NDC 0169-3696-19
NovoLog Mix 70/30 vials and NovoLog Mix 70/30 FlexPen are latex free.
16.2
Recommended Storage
Unused NovoLog Mix 70/30 should be stored in a refrigerator between 2C and 8C
(36F to 46F). Do not store in the freezer or directly adjacent to the refrigerator cooling
element. Do not freeze NovoLog Mix 70/30 or use NovoLog Mix 70/30 if it has been frozen.
Vials: After initial use, a vial may be kept at temperatures below 30C (86F) for up to
28 days, but should not be exposed to excessive heat or sunlight. Open vials may be refrigerated.
Unpunctured vials can be used until the expiration date printed on the label if they are
stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected
from light.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NovoLog Mix 70/30 FlexPen: Once a NovoLog Mix 70/30 FlexPen is punctured, it
should be kept at temperatures below 30C (86F) for up to 14 days, but should not be exposed
to excessive heat or sunlight. A NovoLog Mix 70/30 FlexPen in use must NOT be stored in the
refrigerator. Keep the disposable NovoLog Mix 70/30 FlexPen away from direct heat and
sunlight. An unpunctured NovoLog Mix 70/30 FlexPen can be used until the expiration date
printed on the label if they are stored in a refrigerator. Keep any unused NovoLog Mix 70/30
FlexPen in the carton so it will stay clean and protected from light.
These storage conditions are summarized in the following table:
Not in-use (unopened)
Room Temperature
(below 30°C [86°F])
Not in-use (unopened)
Refrigerated
(2°C - 8°C [36°F- 46°F])
In-use (opened)
Room Temperature
(below 30°C [86°F])
10 mL vial
28 days
Until expiration date
28 days (refrigerated/room
temperature)
3 mL NovoLog Mix
70/30 FlexPen
14 days
Until expiration date
14 days (Do not refrigerate)
17
PATIENT COUNSELING INFORMATION
[see FDA-Approved Patient Labeling]
17.1
Physician Instructions
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes
mellitus and has been associated with a reduction in diabetic complications. Patients should be
informed about potential risks and advantages of NovoLog Mix 70/30 therapy including the
possible adverse reactions. Patients should also be offered continued education and advice on
insulin therapies, injection technique, life-style management, regular glucose monitoring,
periodic glycosylated hemoglobin testing, recognition and management of hypo- and
hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose,
instruction for use of injection devices, and proper storage of insulin. See Patient Information
supplied with the product. Patients should be informed that frequent, patient-performed blood
glucose measurements are needed to achieve optimal glycemic control and avoid both hyper-
and hypoglycemia, and diabetic ketoacidosis.
The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery. Patients who have frequent
hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental substitutions between NovoLog Mix 70/30 and other insulin products have
been reported. Patients should be instructed to always carefully check that they are
administering the appropriate insulin to avoid medication errors between NovoLog Mix 70/30
and any other insulin. The prescription for NovoLog Mix 70/30 should be written clearly in
order to avoid confusion with other insulin products, for example, NovoLog or Novolin
70/30. In addition, the written prescription should clearly indicate the presentation, for example
FlexPen or vial.
Rx only
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Date of Issue: XX-XX-20XX
Version: X
Novo Nordisk®, NovoLog®, FlexPen®, and Novolin® are registered trademarks of Novo
Nordisk® A/S.
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422,
5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004 and other patents
pending.
© 2002 – 20XX Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NovoLog® Mix 70/30
(NŌ-vō-log-MIX-SEV-en-tee-THIR-tee)
(70% insulin aspart protamine suspension and 30% insulin aspart injection,
[rDNA origin])
Read the Patient Information leaflet that comes with NovoLog® Mix 70/30
before you start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure you
know how to manage your diabetes. Ask your healthcare provider if you
have any questions about managing your diabetes.
What is NovoLog® Mix 70/30?
NovoLog® Mix 70/30 is a man-made insulin that is used to control high blood
sugar in adults with diabetes mellitus.
It is not known if NovoLog® Mix 70/30 is safe or effective in children.
Who should not use NovoLog® Mix 70/30?
Do not take NovoLog® Mix 70/30 if:
Your blood sugar is too low (hypoglycemia)
You are allergic to any of the ingredients in NovoLog® Mix 70/30.
See the end of this leaflet for a complete list of ingredients in
NovoLog® Mix 70/30. Check with your healthcare provider if you
are not sure.
What should I tell my healthcare provider before taking NovoLog®
Mix 70/30?
Before you use NovoLog® Mix 70/30, tell your healthcare provider if
you:
have kidney or liver problems
take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with NovoLog® Mix
70/30.
have any other medical conditions. Medical conditions can
affect your insulin needs and your dose of NovoLog® Mix 70/30.
are pregnant or plan to become pregnant. It is not known if
NovoLog® Mix 70/30 will harm your unborn baby. Talk to your
healthcare provider if you are pregnant or plan to become
Reference ID: 3273547
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For current labeling information, please visit https://www.fda.gov/drugsatfda
pregnant. You and your healthcare provider should decide about
the best way to manage your diabetes while you are pregnant.
are breastfeeding or plan to breastfeed. It is not known if
NovoLog® Mix 70/30 passes into your breast milk. You and your
healthcare provider should decide if you will take NovoLog® Mix
70/30 while you breastfeed.
Tell your healthcare provider about all medicines you take, including
prescriptions and non-prescription medicines, vitamins and herbal
supplements.
NovoLog® Mix 70/30 may affect the way other medicines work, and other
medicines may affect how NovoLog® Mix 70/30 works. Your NovoLog® Mix
70/30 dose may change if you take other medicines.
Know the medicines you take. Keep a list of your medicines with you to
show your healthcare providers and pharmacist when you get a new
medicine.
How should I take NovoLog® Mix 70/30?
Take NovoLog® Mix 70/30 exactly as your healthcare provider tells
you to take it.
Your healthcare provider will tell you how much NovoLog® Mix
70/30 to take and when to take it.
Do not make any changes to your dose or type of insulin unless
your healthcare provider tells you to.
NovoLog® Mix 70/30 starts acting fast. If you have Type 1
diabetes, inject it up to 15 minutes before you eat a meal.
Do not inject NovoLog® Mix 70/30 if you are not planning to eat
within 15 minutes.
If you have Type 2 diabetes, you may inject NovoLog® Mix
70/30 up to 15 minutes before or after starting your meal.
Do Not mix NovoLog® Mix 70/30 with other insulin products.
Do Not use NovoLog® Mix 70/30 in an insulin pump.
Inject NovoLog® Mix 70/30 under the skin
(subcutaneously) of your stomach area, upper arms,
buttocks or upper legs. NovoLog® Mix 70/30 may affect your
blood sugar levels faster if you inject it under the skin of your
stomach area. Never inject NovoLog® Mix 70/30 into a vein or into
a muscle.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Change (rotate) injection sites within the area you choose with
each dose. Do not inject into the exact same spot for each
injection.
Read the instructions for use that come with your NovoLog®
Mix 70/30. Talk to your healthcare provider if you have any
questions. Your healthcare provider should show you how to
inject NovoLog® Mix 70/30 before you start using it.
NovoLog® Mix 70/30 comes in:
o 10 mL vials for use with a syringe
o 3 mL NovoLog® Mix 70/30 FlexPen®
If you take too much NovoLog® Mix 70/30, your blood
sugar may fall too low (hypoglycemia). You can treat mild
low blood sugar (hypoglycemia) by drinking or eating something
sugary right away (fruit juice, sugar candies, or glucose tablets).
It is important to treat low blood sugar (hypoglycemia) right away
because it could get worse and you could pass out (loss of
consciousness).
If you forget to take your dose of NovoLog® Mix 70/30,
your blood sugar may go too high (hyperglycemia). If high
blood sugar (hyperglycemia) is not treated it can lead to serious
problems, like passing out (loss of consciousness), coma or even
death. Follow your healthcare provider’s instructions for treating
high blood sugar. Know your symptoms of high blood sugar which
may include:
increased thirst
frequent urination
drowsiness
loss of appetite
a hard time
breathing
fruity smell on the breath
high amounts of sugar and
ketones in your urine
nausea, vomiting (throwing
up) or stomach pain
Do not share needles, insulin pens or syringes with others.
Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check
your blood sugar levels.
Your insulin dosage may need to change because of:
illness
stress
other medicines you
take
change in diet
change in physical activity or
exercise
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
See the end of this patient information for instructions about preparing and
giving your injection.
What should I consider while using NovoLog® Mix 70/30?
Alcohol. Drinking alcohol may affect your blood sugar when you
take NovoLog® Mix 70/30.
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for you to
drive if you often have:
low blood sugar
decreased or no warning signs of low blood sugar
What are the possible side effects of NovoLog® Mix 70/30?
NovoLog® Mix 70/30 may cause serious side effects, including:
low blood sugar (hypoglycemia). Symptoms of low blood
sugar may include:
sweating
dizziness or
lightheadedness
shakiness
hunger
fast heart beat
tingling of lips and
tongue
trouble concentrating
or confusion
blurred vision
slurred speech
anxiety, irritability or
mood changes
headache
Very low blood sugar can cause you to pass out (loss of
consciousness), seizures, and death. Talk to your healthcare
provider about how to tell if you have low blood sugar and what to
do if this happens while taking NovoLog® Mix 70/30. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of NovoLog® Mix 70/30 may need to be changed.
Low potassium in your blood (hypokalemia)
Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious talk to your
healthcare provider.
Reference ID: 3273547
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Serious allergic reaction (whole body reaction). Get
medical help right away, if you have any of these symptoms
of an allergic reaction:
o a rash over your whole body
o have trouble breathing
o a fast heartbeat
o sweating
o feel faint
Swelling of your hands and feet
Heart Failure. Taking certain diabetes pills called thiazolidinediones
or “TZDs” with NovoLog® Mix 70/30 may cause heart failure in some
people. This can happen even if you have never had heart failure or
heart problems before. If you already have heart failure it may get
worse while you take TZDs with NovoLog® Mix 70/30. Your
healthcare provider should monitor you closely while you are taking
TZDs with NovoLog® Mix 70/30. Tell your healthcare provider if you
have any new or worse symptoms of heart failure including:
shortness of breath
swelling of your ankles or feet
sudden weight gain
Treatment with TZDs and NovoLog® Mix 70/30 may need to be
adjusted or stopped by your healthcare provider if you have new or
worse heart failure.
The most common side effects of NovoLog® Mix 70/30 include:
Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) where you inject your insulin to help to prevent
these skin changes from happening. Do not inject insulin into this
type of skin.
Weight gain
Swelling of your hands and feet
Vision changes
These are not all of the possible side effects from NovoLog® Mix 70/30. Ask
your healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store NovoLog® Mix 70/30?
All Unopened NovoLog® Mix 70/30:
Keep all unopened NovoLog® Mix 70/30 in the refrigerator
between 36F to 46F (2C to 8C).
Do not freeze or store next to the refrigerator cooling
element. Do not use NovoLog® Mix 70/30 if it has been frozen.
Keep unopened NovoLog® Mix 70/30 in the carton to protect from
light.
Unopened vials can be used until the expiration date on the
NovoLog® Mix 70/30 label, if the medicine has been stored in a
refrigerator.
Unused NovoLog® Mix 70/30 FlexPen® can be used until the
expiration date on the NovoLog® Mix 70/30 FlexPen® label, if the
medicine has been stored in a refrigerator.
After NovoLog® Mix 70/30 has been opened:
Vials
Keep in the refrigerator or at room temperature below 86F
(30C) for up to 28 days.
Keep vials away from direct heat or light.
Throw away an opened vial after 28 days of use, even if
there is insulin left in the vial.
NovoLog® Mix 70/30 FlexPen®
Keep at room temperature below 86F (30C) for up to 14
days.
Do not store a NovoLog® Mix 70/30 FlexPen® that you are
using in the refrigerator.
Keep NovoLog® Mix 70/30 FlexPen® away from direct heat or
light.
Throw away a used NovoLog® Mix 70/30 FlexPen® after 14
days, even if there is insulin left in the syringe.
Never use insulin after the expiration date that is printed on the label
and carton.
Keep NovoLog® Mix 70/30 and all medicines out of the reach of
children.
General advice about NovoLog® Mix 70/30
Medicines are sometimes prescribed for conditions that are not mentioned in
the patient leaflet. Do not use NovoLog® Mix 70/30 for a condition for which
it was not prescribed. Do not give NovoLog® Mix 70/30 to other people, even
if they have the same symptoms you have. It may harm them.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This leaflet summarizes the most important information about NovoLog® Mix
70/30. If you would like more information about NovoLog® Mix 70/30 or
diabetes, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about NovoLog® Mix 70/30 that is
written for healthcare professionals. For more information call 1-800-727-
6500 or go to www.novonordisk-us.com.
What are the ingredients in NovoLog® Mix 70/30?
Active Ingredients in NovoLog® Mix 70/30: 70% insulin aspart
protamine suspension and 30% insulin aspart injection (rDNA origin).
Inactive Ingredients in NovoLog® Mix 70/30: glycerol, phenol,
metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium
chloride, protamine sulfate, water for injection, hydrochloric acid or
sodium hydroxide.
All NovoLog® Mix 70/30 vials and NovoLog® Mix 70/30 FlexPen® are latex
free.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1701 N Beauregard Street, Alexandria, VA 22311 and
is available at www.diabetes.org.
Date of Issue: XXXX
Version: X
Novo Nordisk®, NovoLog®, and FlexPen® are registered trademarks of Novo
Nordisk A/S.
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913,
5,834,422, 5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004 and
other patents pending.
© 2002-201X Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
NovoLog® Mix 70/30 (NŌvōLog-MIX-SEV-en-tee-THIR-tee)
(70% insulin aspart protamine suspension and 30% insulin aspart [rDNA
origin] injection)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® Mix 70/30 and each
time you get a refill. There may be new information. This information does not
take the place of talking to your healthcare provider about your medical condition
or your treatment.
Supplies you will need to give your NovoLog® Mix 70/30 injection:
10 mL NovoLog® Mix 70/30 vial
insulin syringe and needle
alcohol swab
Preparing your NovoLog® Mix 70/30 dose:
Wash your hands with soap and water.
Before you start to prepare your injection, check the NovoLog® Mix 70/30
label to make sure that you are taking the right type of insulin. This is
especially important if you use more than 1 type of insulin.
NovoLog® Mix 70/30 should look white and cloudy after mixing. Do not use
NovoLog Mix 70/30 if it looks clear or contains any lumps or particles.
NovoLog® Mix 70/30 is easier to mix when it is at room temperature.
After mixing NovoLog® Mix 70/30, inject your dose right away. If you wait to
inject your dose, the insulin will need to be mixed again.
Do not use NovoLog® Mix 70/30 past the expiration date printed on the
label.
Reference ID: 3230601
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 1: If you are using a new vial, pull
off the tamper-resistant cap (See Figure
A).
Step 2: Wipe the rubber stopper with an
alcohol swab (See Figure B).
(Figure A Figure B)
Step 3: Roll the NovoLog Mix 70/30 vial
between your hands 10 times. Keep
the vial in a horizontal (flat) position
(See Figure C). Roll the vial between
your hands until the Novolog® Mix
70/30 looks white and cloudy. Do not
shake the vial.
(Figure C)
Step 4: Hold the syringe with the needle
pointing up. Pull down on the plunger
until the black tip reaches the line for
the number of units for your prescribed
dose (See Figure D).
(Figure D)
Reference ID: 3230601
Reference ID: 3273547
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5: Push the needle through the
rubber stopper of the NovoLog® Mix
70/30 vial (See Figure E).
(Figure E)
Step 6: Push the plunger all the way in.
This puts air into the NovoLog® Mix
70/30 vial (See Figure F).
(Figure F)
Step 7: Turn the NovoLog® Mix 70/30
vial and syringe upside down and slowly
pull the plunger down until the black tip
is a few units past the line for your dose
(See Figure G).
If there are air bubbles, tap the
syringe gently a few times to let any
air bubbles rise to the top (See
Figure H).
(Figure G)
(Figure H)
Step 8: Slowly push the plunger up until
the black tip reaches the line for your
NovoLog® Mix 70/30 dose
(See Figure I).
(Figure I)
Reference ID: 3230601
Reference ID: 3273547
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 9: Check the syringe to make sure
you have the right dose of NovoLog® Mix
70/30.
Step 10: Pull the syringe out of the
vial’s rubber stopper (See Figure J).
(Figure J)
Giving your injection:
Inject your NovoLog® Mix 70/30 exactly as your healthcare provider has shown
you. Your healthcare provider should tell you if you need to pinch the skin
before injecting.
NovoLog® Mix 70/30 is injected under the skin (subcutaneously) of your stomach
area, buttocks, upper legs, or upper arms.
Change (rotate) your injection sites within the area you choose for each dose.
Do not use the same injection site for each injection.
Step 11: Choose your injection site and
wipe the skin with an alcohol swab. Let
the injection site dry before you inject
your dose (See Figure K).
(Figure K)
Step 12: Insert the needle into your
skin. Push down on the plunger to inject
your dose (See Figure L). Needle should
remain in the skin for at least 6 seconds to
make sure you have injected all the
insulin.
(Figure L)
Reference ID: 3230601
Reference ID: 3273547
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 13: Pull the needle out of your
skin. After that, you may see a drop
of NovoLog® Mix 70/30 at the needle tip.
This is normal and does not affect the
dose you just received (See Figure M).
If you see blood after you take the
needle out of your skin, press the
injection site lightly with a piece of
gauze or an alcohol swab. Do not
rub the area.
(Figure M)
After your injection:
Do not recap the needle. Recapping the needle can lead to a needle stick
injury.
Throw away empty insulin vials, used syringes and needles in a sharps container
or some type of hard plastic or metal container with a screw on cap such as a
detergent bottle or coffee can. Check with your healthcare provider about the
right way to throw away the container. There may be local or state laws about
how to throw away used syringes and needles. Do not throw away used
syringes and needles in household trash or recycling bins.
How should I store NovoLog® Mix 70/30?
Do not freeze NovoLog® Mix 70/30. Do not use NovoLog® Mix 70/30 if it has
been frozen.
Keep NovoLog® Mix 70/30 away from heat or light.
Store opened and unopened NovoLog® Mix 70/30 vials in the refrigerator at
36OF to 46OF (2OC to 8OC). Opened NovoLog® Mix 70/30 vials can also be
stored out of the refrigerator below 86OF (30OC).
Unopened vials may be used until the expiration date printed on the label, if
they are kept in the refrigerator.
Opened NovoLog® Mix 70/30 vials should be thrown away after 28 days, even if
they still have insulin left in them.
General information about the safe and effective use of NovoLog® Mix
70/30
Always use a new syringe and needle for each injection.
Do not share syringes or needles.
Keep NovoLog® Mix 70/30 vials, syringes, and needles out of the reach of children.
Reference ID: 3230601
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Instructions for Use has been approved by the U.S. Food and Drug
Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
Revised: December 2012
NovoLog® is a registered trademark of Novo Nordisk A/S.
NovoLog® Mix 70/30 is covered by US Patent Nos. 5,547,930, 5,618,913,
5,834,422, 5,840,680, 5,866,538 and other patents pending.
© 2002-2012 Novo Nordisk A/S
For information about NovoLog® Mix 70/30 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3230601
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
NovoLog® Mix 70/30 FlexPen®
Read the following instructions carefully before you start using your NovoLog® Mix
70/30 FlexPen® and each time you get a refill. There may be new information. You
should read the instructions even if you have used Novolog® Mix 70/30 FlexPen®
before.
NovoLog® Mix 70/30 FlexPen® is a disposable dial-a-dose insulin pen. You can
select doses from 1 to 60 units in increments of 1 unit. NovoLog® Mix 70/30
FlexPen® is designed to be used with NovoFine® needles.
NovoLog Mix® 70/30 FlexPen® should not be used by people who are blind or have
severe visual problems without the help of a person who has good eyesight and
who is trained to use the NovoLog® Mix 70/30 FlexPen® the right way.
Getting ready
Make sure you have the following items:
NovoLog® Mix 70/30 FlexPen®
New NovoFine® needle
Alcohol swab
PREPARING YOUR NOVOLOG® MIX 70/30 FLEXPEN®
•
Wash your hands with soap and water.
•
Before you start to prepare your injection, check the label to make
sure that you are taking the right type of insulin. This is especially
important if you take more than 1 type of insulin. NovoLog® Mix
70/30 should look cloudy after mixing.
Before your first injection with a new NovoLog® Mix 70/30 FlexPen® you
must mix the insulin:
A. Let the insulin reach room temperature before you use it.
This makes it easier to mix.
Pull off the pen cap (see diagram A).
Reference ID: 3273547
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For current labeling information, please visit https://www.fda.gov/drugsatfda
B. Roll the pen between your palms 10 times – it is
important that the pen is kept horizontal (see diagram
B).
C. Then gently move the pen up and down ten times
between position 1 and 2 as shown, so the glass ball
moves from one end of the cartridge to the other (see
diagram C).
Repeat rolling and moving the pen until the liquid appears
white and cloudy.
For every following injection move the pen up and down between
positions 1 and 2 at least ten times until the liquid appears white and
cloudy.
After mixing, complete all the following steps of the injection right away. If
there is a delay, the insulin will need to be mixed again.
Wipe the rubber stopper with an alcohol swab.
Before you inject, there must be at least 12 units of insulin left in the cartridge to
make sure the remaining insulin is evenly mixed. If there are less than 12 units
left, use a new NovoLog® Mix 70/30 FlexPen®.
Attaching the needle
D. Remove the protective tab from a disposable needle.
Screw the needle tightly onto your NovoLog® Mix 70/30
FlexPen®. It is important that the needle is put on straight
(see diagram D).
Never place a disposable needle on your NovoLog® Mix 70/30
FlexPen® until you are ready to take your injection.
E. Pull off the big outer needle cap (see diagram E).
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
F. Pull off the inner needle cap and dispose of it (see diagram
F).
Always use a new needle for each injection to help ensure sterility and prevent
blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of a needle stick, never put the inner needle cap back on
the needle.
Giving the airshot before each injection:
Before each injection small amounts of air may collect in the cartridge during
normal use. To avoid injecting air and to make sure you take the right dose
of insulin:
G. Turn the dose selector to select 2 units (see diagram G).
H. Hold your NovoLog® Mix 70/30 FlexPen® with the needle
pointing up. Tap the cartridge gently with your finger a few
times to make any air bubbles collect at the top of the
cartridge (see diagram H).
I. Keep the needle pointing upwards, press the push-button
all the way in (see diagram I). The dose selector returns
to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use
the NovoLog Mix® 70/30 FlexPen® and contact Novo Nordisk
at 1-800-727-6500.
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
J. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram J). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set
the dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before
injecting. Wipe the skin with an alcohol swab and let the area dry.
K. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram K). Be careful only
to push the button when injecting.
Turning the dose selector will not inject insulin.
L. Keep the needle in the skin for at least 6 seconds, and
keep the push-button pressed all the way in until the
needle has been pulled out from the skin (see diagram L).
This will make sure that the full dose has been given.
You may see a drop of NovoLog® Mix 70/30 at the needle tip.
This is normal and has no effect on the dose you just
received. If blood appears after you take the needle out of
your skin, press the injection site lightly with an alcohol
swab. Do not rub the area.
After the injection
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not recap the needle. Recapping can lead to a needle stick injury.
Remove the needle from the NovoLog® Mix 70/30 FlexPen® after each
injection. This helps to prevent infection, leakage of insulin, and will help to
make sure you inject the right dose of insulin.
Put the needle and any empty NovoLog® Mix 70/30 FlexPen® or any
used NovoLog® Mix 70/30 FlexPen® still containing insulin in a sharps
container or some type of hard plastic or metal container with a screw
top such as a detergent bottle or empty coffee can. These containers
should be sealed and thrown away the right way. Check with your
healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away
used needles and syringes. Do not throw away used needles and
syringes in household trash or recycling bins.
The NovoLog® Mix 70/30 FlexPen® prevents the cartridge from being completely
emptied. It is designed to deliver 300 units.
M. Put the pen cap on the NovoLog® Mix 70/30 FlexPen® and
store the NovoLog® Mix 70/30 FlexPen® without the
needle attached (see diagram M).
FUNCTION CHECK
If your NovoLog® Mix 70/30 FlexPen® is not working the right way, follow
the steps below:
Screw on a new NovoFine® needle
Remove the big outer needle cap and the inner needle
cap
Do an airshot as described in “Giving the airshot before
each injection”.
Put the big outer needle cap onto the needle. Do not
put on the inner needle cap.
Turn the dose selector so the dose indicator window
shows 20 units.
Hold the NovoLog® Mix 70/30 FlexPen® so the needle is
pointing down
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap (see
diagram N). If NovoLog® Mix 70/30 FlexPen® has released too much or too
little insulin, do the function check again. If the same problem happens
again, do not use your NovoLog® Mix 70/30 FlexPen® and contact Novo
Nordisk at 1-800-727-6500.
Maintenance
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Your NovoLog® Mix 70/30 FlexPen® is designed to work accurately and
safely. It must be handled with care. Avoid dropping your NovoLog® Mix
70/30 FlexPen® as it may damage it. If you are concerned that your
NovoLog® Mix 70/30 FlexPen® is damaged, use a new one. You can clean
the outside of your NovoLog® Mix 70/30 FlexPen® by wiping it with a damp
cloth. Do not soak or wash your NovoLog® Mix 70/30 FlexPen® as it may
damage it. Do not refill your NovoLog® Mix 70/30 FlexPen®.
Remove the needle from the NovoLog® Mix 70/30 FlexPen® after each
injection. This helps to ensure sterility, prevent leakage of insulin, and
will help to make sure you inject the right dose of insulin for future
injections.
Be careful when handling used needles to avoid needle sticks and
transfer of infectious diseases.
Keep your NovoLog® Mix 70/30 FlexPen® and needles out of the reach of
children.
Use NovoLog® Mix 70/30 FlexPen® as directed to treat your diabetes.
Do not share it with anyone else even if they also have diabetes.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen
with products not recommended by Novo Nordisk.
As a precautionary measure, always carry a spare insulin delivery device
in case your NovoLog® Mix 70/30 FlexPen® is lost or damaged.
Remember to keep the disposable NovoLog® Mix 70/30 FlexPen® with
you. Do not leave it in a car or other location where it can get too hot or
too cold.
NovoLog®, FlexPen®, NovoFine®, are trademarks of Novo Nordisk A/S.
NovoLog® is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422,
5,840,680, 5,866,538 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004
and other patents pending.
© 2002-2010 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog Mix 70/30® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3273547
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:30.886349 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021172s053lbl.pdf', 'application_number': 21172, 'submission_type': 'SUPPL ', 'submission_number': 53} |
5,672 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LEVEMIR® safely and effectively. See full prescribing information
for LEVEMIR.
LEVEMIR® (insulin detemir [rDNA origin] injection) solution for
subcutaneous injection
Initial U.S. Approval: 2005
--------------------RECENT MAJOR CHANGES-------------------
• Warnings and Precautions (5.8) 3/2013
----------------------------INDICATIONS AND USAGE----------------------
LEVEMIR is a long-acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
Important Limitations of Use:
Not recommended for treating diabetic ketoacidosis. Use intravenous,
rapid acting or short-acting insulin instead.
----------------------DOSAGE AND ADMINISTRATION-------------------
The starting dose should be individualized based on the type of
diabetes and whether the patient is insulin-naïve (2.1, 2.2, 2.3)
Administer subcutaneously once daily or in divided doses twice daily.
Once daily administration should be given with the evening meal or at
bedtime (2.1)
Rotate injection sites within an injection area (abdomen, thigh, or
deltoid) to reduce the risk of lipodystrophy (2.1)
Converting from other insulin therapies may require adjustment of
timing and dose of LEVEMIR. Closely monitor glucoses especially
upon converting to LEVEMIR and during the initial weeks thereafter
(2.3)
---------------------DOSAGE FORMS AND STRENGTHS-----------------
Solution for injection 100 Units/mL (U-100) in
3 mL LEVEMIR FlexPen®
10 mL vial (3)
------------------------------CONTRAINDICATIONS-------------------------
Do not use in patients with hypersensitivity to LEVEMIR or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
Dose adjustment and monitoring: Monitor blood glucose in all patients
treated with insulin. Insulin regimens should be modified cautiously and
only under medical supervision (5.1)
Administration: Do not dilute or mix with any other insulin or solution.
Do not administer subcutaneously via an insulin pump, intramuscularly,
or intravenously because severe hypoglycemia can occur (5.2)
Hypoglycemia is the most common adverse reaction of insulin therapy
and may be life-threatening (5.3, 6.1)
Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur (5.4)
Renal or hepatic impairment: May require adjustment of the LEVEMIR
dose (5.5, 5.6)
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and
insulin, including LEVEMIR(5.8)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions associated with LEVEMIR include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, rash and pruritus (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Certain drugs may affect glucose metabolism requiring insulin dose
adjustment and close monitoring of blood glucose (7)
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine) (7)
----------------------USE IN SPECIFIC POPULATIONS-------------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not been
studied in children with type 1 diabetes < 2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 3/2013
__________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Initiation of LEVEMIR Therapy
2.3 Converting to LEVEMIR from Other Insulin Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Dosage Adjustment and Monitoring
5.2 Administration
5.3 Hypoglycemia
5.4 Hypersensitivity and Allergic Reactions
5.5 Renal Impairment
5.6 Hepatic Impairment
5.7 Drug Interactions
5.8 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Preparation and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Patients
17.2 Never Share a LEVEMIR FlexPen Between Patients
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus.
Important Limitations of Use:
LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting
or short-acting insulin is the preferred treatment for this condition.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration.
Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at
bedtime.
Patients who require twice-daily dosing can administer the evening dose with the evening meal, at
bedtime, or 12 hours after the morning dose.
The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is
essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].
In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting
insulin.
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid)
from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all
insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by
exercise and other variables, such as stress, intercurrent illness, or changes in co-administered
medications or meal patterns.
When using LEVEMIR with a glucagon-like peptide (GLP)-1 receptor agonist, administer as separate
injections. Never mix. It is acceptable to inject LEVEMIR and a GLP-1 receptor agonist in the same
body region but the injections should not be adjacent to each other.
2.2 Initiation of LEVEMIR therapy
Reference ID: 3273518
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately
one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be
used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on oral antidiabetic medications is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or
divided into a twice daily regimen.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on a GLP-1 receptor agonist is 10 Units given once daily in the evening.
LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages
of LEVEMIR should be individualized under the supervision of a healthcare provider.
2.3 Converting to LEVEMIR from other insulin therapies
If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients
with type 2 diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see
Clinical Studies (14)].
As with all insulins, close glucose monitoring is recommended during the transition and in the initial
weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other
concomitant antidiabetic treatment may need to be adjusted.
3 DOSAGE FORMS AND STRENGTHS
LEVEMIR solution for injection 100 Unit per mL is available as:
3 mL LEVEMIR FlexPen®
10 mL vial
4 CONTRAINDICATIONS
LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients.
Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen
should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a
change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different
individuals or at different times in the same individual and is dependent on many conditions, including
the local blood supply, local temperature, and physical activity.
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Administration
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of
LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular
administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and
Precautions (5.3)].
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the
pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR
and the mixed insulin may be altered in an unpredictable manner.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk
of hypoglycemia increases with intensive glycemic control.
When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need
to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see Adverse
Reactions (6.1)].
All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to
unconsciousness or convulsions and may result in temporary or permanent impairment of brain function
or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion,
or glucagon administration has been observed in clinical trials with insulin, including trials with
LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals),
exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions
(7)].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Reference ID: 3273518
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions,
such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products,
including LEVEMIR.
5.5 Renal impairment
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals
with renal impairment and healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with renal impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
renal impairment [see Clinical Pharmacology (12.3)].
5.6 Hepatic impairment
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin
detemir compared to healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with liver impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
hepatic impairment [see Clinical Pharmacology (12.3)].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia
or hyperglycemia [see Drug Interactions (7)].
5.8 Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma
agonists, can cause dose-related fluid retention, particularly when used in combination with insulin.
Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including
LEVEMIR, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If
heart failure develops, it should be managed according to current standards of care, and discontinuation
or dose reduction of the PPAR-gamma agonist must be considered.
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
Hypoglycemia [see Warnings and Precautions (5.3)]
Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in
one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not
reflect the rates actually observed in clinical practice.
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical
trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below.
See Tables 5 and 6 for the hypoglycemia findings.
In the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg +
metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled
total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of
gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only
those patients who completed the run-in period with inadequate glycemic control were randomized to 26
weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg +
metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in
≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated
with liraglutide 1.8 mg and metformin alone (6.9%).
In two pooled trials, a total of 1155 adults with type 1 diabetes were exposed to individualized doses of
LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and
the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are
summarized in Table 1.
Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and
24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 767)
NPH, %
(n = 388)
Upper respiratory tract infection
26.1
21.4
Headache
22.6
22.7
Pharyngitis
9.5
8.0
Influenza-like illness
7.8
7.0
Abdominal Pain
6.0
2.6
A total of 320 adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=161)
or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total
exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summarized in
Table 2.
Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart
+ LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions
with incidence ≥ 5%)
LEVEMIR, %
(n = 161)
Glargine, %
(n = 159)
Upper respiratory tract infection
26.7
32.1
Headache
14.3
19.5
Back pain
8.1
6.3
Influenza-like illness
6.2
8.2
Gastroenteritis
5.6
4.4
Bronchitis
5.0
1.9
Reference ID: 3273518
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In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of
LEVEMIR (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and
the total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions are
summarized in Table 3.
Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and
24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 432)
NPH, %
(n = 437)
Upper respiratory tract infection
12.5
11.2
Headache
6.5
5.3
A total of 347 children and adolescents (6-17 years) with type 1 diabetes were exposed to individualized
doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180
days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions
are summarized in Table 4.
Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and
adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 232)
NPH, %
(n = 115)
Upper respiratory tract infection
35.8
42.6
Headache
31.0
32.2
Pharyngitis
17.2
20.9
Gastroenteritis
16.8
11.3
Influenza-like illness
13.8
20.9
Abdominal pain
13.4
13.0
Pyrexia
10.3
6.1
Cough
8.2
4.3
Viral infection
7.3
7.8
Nausea
6.5
7.0
Rhinitis
6.5
3.5
Vomiting
6.5
10.4
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
LEVEMIR [see Warnings and Precautions (5.3)].
Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR
clinical trials.
For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an
event with symptoms consistent with hypoglycemia requiring assistance of another person and
Reference ID: 3273518
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For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or
prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other
pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness,
unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who
may have required glucagon or intravenous glucose.
For the adult trials and pediatric Study D, non-severe hypoglycemia was defined as an asymptomatic or
symptomatic plasma glucose < 56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A
and C) that was self-treated by the patient. For pediatric Study I, non-severe hypoglycemia included
asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient
could self-treat or treat by taking oral therapy provided by the caregiver.
The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study
designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see
Tables 5 and 6).
Table 5: Hypoglycemia in Patients with Type 1 Diabetes
Severe Hypoglycemia
Non-severe Hypoglycemia
Percent of
patients with at
least 1 event
(n/total N)
Event/patient/
year
Percent of patients
(n/total N)
Event/patient/
year
Twice-daily
LEVEMIR
8.7
(24/276)
0.52
88.0
(243/276)
26.4
Study A
Type 1 Diabetes
Adults
16 weeks
In combination
with
insulin aspart
Twice-daily
NPH
10.6
(14/132)
0.43
89.4
(118/132)
37.5
Twice-daily
LEVEMIR
5.0
(8/161)
0.13
82.0
(132/161)
20.2
Study B
Type 1 Diabetes
Adults
26 weeks
In combination
with
insulin aspart
Once-daily
Glargine
10.1
(16/159)
0.31
77.4
(123/159)
21.8
Once-daily
LEVEMIR
7.5
(37/491)
0.35
88.4
(434/491)
31.1
Study C
Type 1 Diabetes
Adults
24 weeks
In combination
with
regular insulin
Once-daily
NPH
10.2
(26/256)
0.32
87.9
(225/256)
33.4
Once- or
Twice-daily
LEVEMIR
15.9
(37/232)
0.91
93.1
(216/232)
31.6
Study D
Type 1 Diabetes
Pediatrics
26 weeks
In combination
with
insulin aspart
Once- or
Twice-daily
NPH
20.0
(23/115)
0.99
95.7
(110/115)
37.0
Study I
Once- or
1.7
0.02
94.9
56.1
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Twice-daily
LEVEMIR
(3/177)
(168/177)
Type 1 Diabetes
Pediatrics
52 weeks
In combination
with insulin aspart
Once- or
Twice-daily
NPH
7.1
(12/170)
0.09
97.6
(166/170)
70.7
Table 6: Hypoglycemia in Patients with Type 2 Diabetes
Study E
Type 2 Diabetes
Adults
24 weeks
In combination with
oral agents
Study F
Type 2 Diabetes
Adults
22 weeks
In combination with
insulin aspart
Study H
Type 2 Diabetes
Adults
26 weeks
In combination with
Liraglutide and Metformin
Twice-
daily
LEVEMIR
Twice-
daily
NPH
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily
NPH
Once- daily
LEVEMIR +
Liraglutide +
Metformin
Liraglutide
+
Metformin
Percent of patients
with at least 1 event
(n/total N)
0.4
(1/237)
2.5
(6/238)
1.5
(3/195)
4.0
(8/199)
0
0
Severe
hypoglycemia
Event/patient/year
0.01
0.08
0.04
0.13
0
0
Percent of patients
(n/total N)
40.5
(96/237)
64.3
(153/238)
32.3
(63/195)
32.2
(64/199)
9.2
(15/163)
1.3
(2/158*)
Non-severe
hypoglycemia
Event/patient/year
3.5
6.9
1.6
2.0
0.29
0.03
*One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a
history of frequent hypoglycemia prior to the study
Insulin Initiation and Intensification of Glucose Control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible
ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral
neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and
neuropathy.
Lipodystrophy
Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy
(thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection sites within the
same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].
Weight Gain
Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)].
Peripheral Edema
Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Allergic Reactions
Local Allergy
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As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions,
including localized erythema, pain, pruritus, urticaria, edema, and inflammation. In clinical studies in
adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one
patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in
discontinuation of therapy.
Rotation of the injection site within a given area from one injection to the next may help to reduce or
prevent these reactions. In some instances, these reactions may be related to factors other than insulin,
such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin
usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR,
and may be life-threatening [see Warnings and Precautions (5.4)].
Antibody Production
All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase
or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical
trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic
control.
6.2 Postmarketing experience
The following adverse reactions have been identified during post approval use of LEVEMIR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported during post-approval use of LEVEMIR in which other insulins,
particularly rapid-acting or short-acting insulins, have been accidentally administered instead of
LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR
and other insulins, patients should be instructed always to verify the insulin label before each injection.
7 DRUG INTERACTIONS
A number of medications affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
The following are examples of medications that may increase the blood-glucose-lowering effect of
insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral
antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline,
salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood-glucose-lowering effect of
insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid
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hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical
antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose-
lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as
beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all
pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant while taking
LEVEMIR. A randomized controlled clinical trial of pregnant women with type 1 diabetes using
LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive
toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups
indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and
teratogenicity that were attributed to maternal hypoglycemia.
Clinical Considerations
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased
with good glucose control before conception and throughout pregnancy. Because insulin requirements
vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is
essential in pregnant women.
Human Data
In an open-label clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of
gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or
NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of
152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the
study (total pregnant women = 310). Approximately one half of the study participants in each arm were
randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first
8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <
7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted
mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient
(n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically
significant.
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Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 7. The two
most common adverse reactions were nasopharyngitis and headache. These are consistent with findings
from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the
LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia,
eight (8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization.
The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by
diabetes. Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the
definition of pre-eclampsia was not standardized in the trial making it difficult to establish a link
between a given treatment and an increased risk of pre-eclampsia. All events were considered unlikely
related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants.
Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group
than in the NPH insulin group as a whole. There was no difference between the treatment groups in
mean blood pressure during pregnancy and there was no indication of a general increase in blood
pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following
placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of
placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the
LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6%
and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’,
‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.
Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR to
insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with
incidence ≥ 5%)
LEVEMIR, %
(n = 152)
NPH, %
(n = 158)
Anemia
13.2
10.8
Diarrhea
11.8
5.1
Pre-eclampsia
10.5
7.0
Urinary tract infection
9.9
5.7
Gastroenteritis
8.6
5.1
Abdominal pain upper
5.9
3.8
Vomiting
5.3
4.4
Abortion spontaneous
5.3
2.5
Abdominal pain
5.3
6.3
Oropharyngeal pain
5.3
6.3
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be
easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and
NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patient-
year in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe
episodes of hypoglycemia were similar in both treatment groups (Table 8).
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Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes
Study G Type 1
Diabetes
Pregnancy
In combination with
insulin aspart
LEVEMIR
NPH
Percent of patients
with at least 1
event (n/total N)
16.4
(25/152)
20.9
(33/158)
Severe
hypoglycemia*
Events/patient/year
1.1
1.2
Percent of patients
with at least 1
event (n/total N)
94.7
(144/152)
92.4
(146/158)
Non-severe
hypoglycemia*
Events/patient/year
114.2
108.4
* For definition regarding severe and non-severe hypoglycemia see section 6, Hypoglycemia.
In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower
level of quantification (<25 pmol/L).
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR
use.
Animal Data
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300
nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day
(approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits
during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder
abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of
900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human
insulin control groups indicated that insulin detemir and human insulin had similar effects regarding
embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia
resulting from insulin exposure in normal animals.
8.3
Nursing Mothers
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It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human
insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman.
Women with diabetes who are lactating may require adjustments of their insulin doses.
8.4
Pediatric Use
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been
established in pediatric patients (age 2 to 17 years) with type 1 diabetes [see Clinical Pharmacology
(12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than 2
years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2
diabetes.
The dose recommendation when converting to LEVEMIR is the same as that described for adults [see
Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood
glucose.
8.5
Geriatric Use
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients
(3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were
≥65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥75 years of age. No
overall differences in safety or effectiveness were observed between these patients and younger patients,
but small sample sizes, particularly for patients ≥65 years of age in the type 1 diabetes trials and for
patients ≥75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals
cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and
maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to
recognize in the elderly.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].
11 DESCRIPTION
LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a
subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant
human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae followed by chemical modification.
Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been
omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a
molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:
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Figure 1: Structural Formula of insulin detemir
(A1)
(A21)
(B1)
(B29)
Gly
Ile Val Glu Gln Cys Cys Thr Ser
Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
Cys
Leu
His
Gln
Asn
Val
Phe
Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr
Pro Lys
NH
C
O
S
S
S
S
S
S
LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains
100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg
phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection.
Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of
approximately 7.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including
insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin
lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue
and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits
proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of
action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir
molecules from the injection site due to self-association of the drug molecules. In addition, the
distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24
hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection
and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to > 24 hours (24 hours
was the end of the observation period).
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Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum
effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2
diabetes. The clamp study was terminated at 16 hours according to protocol.
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Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study
12.3 Pharmacokinetics
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin
detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the
maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more
slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and
AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and
abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in
vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin
detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous
administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours
depending on dose.
Specific Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children
(6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir
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plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as
compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose
of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir
AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin
preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed
between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there
were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and
pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2
diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR
were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate,
severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics
of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with
human insulin have shown increased circulating levels of insulin in patients with renal impairment.
Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in
patients with renal impairment [see Warnings and Precautions (5.5)].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate
and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic
impairment with a corresponding increase in apparent clearance. However, some studies with human
insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful
glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients
with hepatic impairment [see Warnings and Precautions (5.6)].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR
has not been studied [see Use in Specific Populations (8.1)].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not
been studied.
Liraglutide -No pharmacokinetic interaction was observed between liraglutide and LEVEMIR when
separate subcutaneous injections of LEVEMIR 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady
state) were administered in patients with type 2 diabetes.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested
negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral
blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
14 CLINICAL STUDIES
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and
at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of
once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with
type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2
diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily
insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The
evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood
glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials
that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin
(HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to
treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and
bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered
before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar
HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9).
Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose
(FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized
to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine
(administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated
patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, open-label clinical study (Study C, n=749), adults with type 1 diabetes were randomized
to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination
with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on
HbA1c.
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Table 9: Type 1 Diabetes Mellitus – Adult
Study A
Study B
Study C
Treatment duration
16 weeks
26 weeks
24 weeks
Treatment in combination with
NovoLog®
(insulin aspart)
NovoLog®
(insulin aspart)
Human Soluble Insulin
(regular insulin)
Twice-daily
LEVEMIR
Twice-daily
NPH
Twice-daily
LEVEMIR
Once-
daily
insulin
glargine
Once-daily
LEVEMIR
Once-
daily
NPH
Number of patients treated
276
133
161
159
492
257
HbA1c (%)
Baseline HbA1c
8.6
8.5
8.9
8.8
8.4
8.3
Adj. mean change from baseline
-0.8*
-0.7*
-0.6**
-0.5**
-0.1*
0.0*
LEVEMIR – NPH
95% CI for treatment difference
-0.2
(-0.3, -0.0)
-0.0
(-0.2, 0.2)
-0.1
(-0.3, 0.0)
Basal insulin dose (units/day)
Baseline mean
21
24
27
23
12
24
Mean change from baseline
16
10
10
4
9
2
Total insulin dose (units/day)
Baseline mean
48
54
56
51
46
57
Mean change from baseline
17
10
9
6
11
3
Fasting blood glucose (mg/dL)
Baseline mean
209
220
153
150
213
206
Adj. mean change from baseline
-44*
-9*
-38**
-41**
-30*
-9*
Body weight (kg)
Baseline mean
74.6
75.5
77.5
75.1
76.5
76.9
Adj.mean change from baseline
0.2*
0.8*
0.5**
1.0**
-0.3*
0.3*
*From an ANCOVA model adjusted for baseline value and country.
**From an ANCOVA model adjusted for baseline value and study site.
Type 1 Diabetes – Pediatric
Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with
type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6-17 years of age. The other
study was 52 weeks in duration and enrolled patients 2-16 years of age. In both studies, LEVEMIR and
NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each
meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of
NPH insulin (Table 10). In the 52-week study, the randomization was stratified by age (2-5 years, n=82,
and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in
the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
Study D
Study I
Treatment duration
26 weeks
52 weeks
Treatment in combination with
NovoLog®
(insulin aspart)
NovoLog®
(insulin aspart)
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily NPH
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily
NPH
Number of subjects treated
232
115
177
170
HbA1c (%)
Reference ID: 3273518
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Baseline HbA1c
8.8
8.8
8.4
8.4
Adj. mean change from baseline
-0.7*
-0.8*
0.3**
0.2**
LEVEMIR – NPH
95% CI for treatment difference
0.1
(-0.1, 0.3)
0.1
(-0.1, 0.4)
Basal insulin dose (units/day)
Baseline mean
24
26
17
17
Mean change from baseline
8
6
8
7
Total insulin dose (units/day)
Baseline mean
48
50
35
34
Mean change from baseline
9
7
10
8
Fasting blood glucose (mg/dL)
Baseline mean
181
181
135
141
Adj. mean change from baseline
-39
-21
-10**
0**
Body weight (kg)
Baseline mean
Adj.mean change from baseline
46.3
1.6*
46.2
2.7*
37.4
2.7**
36.5
3.6**
*From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).
**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).
Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-
daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before
breakfast and evening) as part of a regimen of stable combination therapy with one or two of the
following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase
inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin
similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes,
LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with
insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
Study E
Study F
Treatment duration
24 weeks
22 weeks
Treatment in combination with
oral agents
insulin aspart
Twice-daily
LEVEMIR
Twice-
daily
NPH
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily
NPH
Number of subjects treated
237
239
195
200
HbA1c (%)
Baseline HbA1c
8.6
8.5
8.2
8.1
Adj. mean change from baseline
-2.0*
-2.1*
-0.6**
-0.6**
LEVEMIR – NPH
95% CI for treatment difference
0.1
(-0.0, 0.3)
-0.1
(-0.2, 0.1)
Basal insulin dose (units/day)
Baseline mean
18
17
22
22
Mean change from baseline
48
28
26
15
Total insulin dose1 (units/day)
Baseline mean
-
-
22
22
Mean change from baseline
-
-
57
42
Fasting blood glucose2 (mg/dL)
Reference ID: 3273518
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Baseline mean
179
173
-
-
Adj. mean change from baseline
-69*
-74*
-
-
Body weight (kg)
Baseline mean
82.5
82.3
82.0
79.6
Adj.mean change from baseline
1.2*
2.8*
0.5**
1.2**
1Study E – Conducted in insulin-naïve patients
2Study F - Fasting blood glucose data not collected
*From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.
**From an ANCOVA model adjusted for baseline value and country.
Combination Therapy with Metformin and Liraglutide
This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on
metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (≥1500
mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the
sulfonylurea then all patients entered a 12-week run-in period during which they received add-on
therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%)
achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-
randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in
period with approximately one-half of these patients doing so because of gastrointestinal adverse
reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those
who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in
the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and
metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of
the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the
percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized
to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-
on therapy with LEVEMIR.
Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically
significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide
1.8 mg + metformin alone (Table 12). From a mean baseline body weight of 96 kg after randomization,
there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared
to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8
mg + metformin alone.
Table 12: Results of a 26-week open-label trial of LEVEMIR as add on to liraglutide + metformin
compared to continued treatment with liraglutide + metformin alone in patients not achieving
HbA1c < 7% after 12 weeks of metformin and liraglutide
Study H
LEVEMIR +
Liraglutide
+Metformin
Liraglutide+
Metformin
Intent-to-Treat Population (N)ª
162
157
HbA1c (%) (Mean)
Baseline (week 0)
7.6
7.6
Adjusted mean change from baseline
-0.5*
0*
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Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence interval
-0.5***
(-0.7, -0.4)
Percentage of patients achieving A1c <7%
43**
17**
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline (week 0)
166
159
Adjusted mean change from baseline
-38*
-7*
Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence interval
-31***
(-39, -23)
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
*From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.
**From a logistic regression model adjusted for baseline HbA1c.
***p-value <0.0001
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin
detemir per mL (U-100).
3 mL LEVEMIR FlexPen® NDC 0169-6439-10
10 mL vial
NDC 0169-3687-12
FlexPen is for use with NovoFine® disposable needles. Each FlexPen is for use by a single patient.
LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.
16.2 Storage:
Unused (unopened) LEVEMIR should be stored in the refrigerator between 2° and 8°C (36° to 46°F).
Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not
use LEVEMIR if it has been frozen.
Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in
a refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.
If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room
temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and
light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator,
even if the FlexPen or vial still contains insulin.
Vials:
After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not
possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it
Reference ID: 3273518
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is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be
discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after
they are first kept out of the refrigerator.
LEVEMIR FlexPen:
After initial use, the LEVEMIR FlexPen must NOT be stored in a refrigerator and must NOT be stored
with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at
room temperature, below 30°C (86°F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days
after they are first kept out of the refrigerator.
The storage conditions are summarized in Table 13:
Table 13: Storage Conditions for LEVEMIR FlexPen and vial
Not in-use
(unopened)
Refrigerated
Not in-use
(unopened)
Room Temperature
(below 30°C)
In-use
(opened)
3 mL
LEVEMIR
FlexPen
Until expiration date
42 days*
42 days*
Room Temperature
(below 30°C)
(Do not refrigerate)
10 mL vial
Until expiration date
42 days*
42 days*
Refrigerated or Room
Temperature (below 30°C)
*The total time allowed at room temperature (below 30°C) is 42 days regardless of whether the product is in-use or not in-use.
16.3 Preparation and handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to
administration and should only be used if the solution appears clear and colorless.
Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See
Warnings and Precautions (5.2)].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1 Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under
medical supervision. Patients should be informed about the potential side effects of insulin therapy,
including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the
same body region), and allergic reactions. Patients should be informed that the ability to concentrate and
react may be impaired as a result of hypoglycemia. This may present a risk in situations where these
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abilities are especially important, such as driving or operating other machinery. Patients who have
frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been
reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to
always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients
must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
Patients should be instructed on self-management procedures including glucose monitoring, proper
injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional
disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin
dose, inadequate food intake, and skipped meals.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or
are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional
information.
17.2 Never Share a LEVEMIR FlexPen Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen with another person, even if the
needle is changed. Sharing of the FlexPen between patients may pose a risk of transmission of
infection.
Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo
Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents
pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.
© 2005-201x Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3273518
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Patient Information
LEVEMIR® (LEV–uh-mere)
(insulin detemir [rDNA origin] injection)
solution for subcutaneous injection
Read the Patient Information that comes with LEVEMIR® before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure
that you know how to manage your diabetes. Ask your healthcare
provider, if you have any questions about managing your diabetes.
What is LEVEMIR®?
LEVEMIR® is a man-made long-acting insulin used to control high
blood sugar in adults and children with diabetes mellitus.
It is not recommended to use LEVEMIR® to treat diabetic ketoacidosis.
Who should not use LEVEMIR®?
Do not use LEVEMIR® if:
you are allergic to any of the ingredients in LEVEMIR®. See the end
of this leaflet for a complete list of ingredients in LEVEMIR®.
What should I tell my healthcare provider before using
LEVEMIR®?
Before you use LEVEMIR®, tell your healthcare provider if you:
have liver or kidney problems
take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with LEVEMIR®.
have any other medical conditions. Some medical conditions can
affect your insulin needs and your dose of LEVEMIR®.
are pregnant or plan to become pregnant. It is not known, if
LEVEMIR® would harm your unborn baby. Talk to your healthcare
provider, if you are pregnant or plan to become pregnant. You and
your healthcare provider should talk about the best way to manage
your diabetes while you are pregnant.
are breastfeeding or plan to breast-feed. It is not known if
LEVEMIR® passes into breast milk. You and your healthcare
provider should decide if you will take LEVEMIR® while you
breastfeed.
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Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins and
herbal supplements. LEVEMIR® may affect the way other medicines
work, and other medicines may affect how LEVEMIR® works.
Know the medicines you take. Keep a list of your medicines with
you to show your healthcare provider and pharmacist when you get a
new medicine.
How should I use LEVEMIR®?
Use LEVEMIR® exactly as your healthcare provider told you to use
it.
Your healthcare provider will tell you how much LEVEMIR® to use
and when to use it.
Do not make any changes to your dose or type of insulin unless you
are told to do so by your healthcare provider.
Know your insulin. Make sure you know:
the type and strength of insulin prescribed for you.
the amount of insulin you take.
the best time for you to take your insulin. This may change if
you take a different type of insulin.
Do not dilute or mix LEVEMIR® with any other insulin or injectable
diabetes medicine. Your LEVEMIR® will not work the right way and
you may lose control of your blood sugar, which can be serious.
Give yourself separate injections. You may give the separate
injections in the same body area (for example, your stomach area),
but you should not give the injections right next to each other.
Do not use LEVEMIR® in an insulin pump.
Inject LEVEMIR® under your skin (subcutaneously) in your upper
arm, abdomen (stomach area), or thigh. Never inject LEVEMIR®
into a vein or muscle.
Change injection sites within the area you choose with each dose.
Do not inject into the exact same spot for each injection.
Read the instructions for use that comes with your
LEVEMIR®. Talk to your healthcare provider if you have any
questions. Your healthcare provider should show you how to inject
LEVEMIR® before you start taking it.
Reference ID: 3273518
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Your healthcare provider will decide which type of LEVEMIR® to
prescribe for you.
LEVEMIR® comes in:
10 mL vials (small bottles) for use with a syringe
3 mL LEVEMIR® FlexPen®
Ask your healthcare provider how you should use LEVEMIR®.
If you use too much LEVEMIR®, your blood sugar may fall
low (hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away
(fruit juice, sugar candies, or glucose tablets). It is important to
treat low blood sugar (hypoglycemia) right away because it could
get worse and you could pass out (lose consciousness).
If you pass out you will need help from another person or
emergency medical services right away. See “What are the
possible side effects of LEVEMIR®?” for more information on
low blood sugar (hypoglycemia).
If you forget to take your dose of LEVEMIR®, your blood
sugar may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death.
Follow your healthcare provider’s instructions for treating high
blood sugar.
Know your symptoms of high blood sugar, which may include:
increased thirst
frequent urination
drowsiness
loss of appetite
a hard time breathing
fruity smell on the breath
high amounts of sugar and
ketones in your urine
nausea, vomiting (throwing
up) or stomach pain
Do not share needles, insulin pens or syringes with others.
Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check your
blood sugar levels.
Your insulin dosage may need to change because of:
illness
stress
other medicines you
take
change in diet
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change in physical activity
or exercise
What should I avoid while taking LEVEMIR®?
Alcohol. Drinking alcohol may affect your blood sugar when
you use LEVEMIR®.
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for
you to drive if you often have:
low blood sugar (hypoglycemia)
decreased or no warning signs of low blood sugar
What are the possible side effects of LEVEMIR®?
LEVEMIR® can cause serious side effects, including:
Low blood sugar (hypoglycemia). Signs and symptoms of low
blood sugar may include:
dizziness or
lightheadedness
shakiness
hunger
fast heart beat
tingling in your hands,
feet, lips or tongue
trouble concentrating or
confusion
blurred vision
slurred speech
anxiety or mood changes
headache
sweating
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, and death. In some people their blood sugar
may get so low that they need another person to help them. Talk to
your healthcare provider about how to tell if you have low blood sugar
and what to do if this happens while taking LEVEMIR®. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
If you are using LEVEMIR® with another diabetes medicine, your
LEVEMIR® dose may need to be changed to reduce your chance of
getting low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of LEVEMIR® may need to be changed.
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Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) the area where you inject your insulin to help
prevent these skin changes from happening. Do not inject insulin
into areas of skin that have thickening or pits.
Serious allergic reactions. LEVEMIR® can cause life
threatening symptoms. Get medical help right away if you have
any of these symptoms of an allergic reaction:
a rash all over your body
itching
shortness of breath
trouble breathing
(wheezing)
fast heartbeat
sweating
feel faint
Swelling of your hands and feet
Heart Failure. Taking certain diabetes pills called
thiazolidinediones or “TZDs” with LEVEMIR® may cause heart
failure in some people. This can happen even if you have never
had heart failure or heart problems before. If you already have
heart failure it may get worse while you take TZDs with LEVEMIR®.
Your healthcare provider should monitor you closely while you are
taking TZDs with LEVEMIR®. Tell your healthcare provider if you
have any new or worse symptoms of heart failure including:
shortness of breath
swelling of your ankles or feet
sudden weight gain
Treatment with TZDs and LEVEMIR® may need to be adjusted or
stopped by your healthcare provider if you have new or worse heart
failure.
Common side effects of LEVEMIR® include:
Low blood sugar (hypoglycemia). See “What are the possible
side effects of LEVEMIR®?” for more information on low
blood sugar (hypoglycemia).
Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious, talk to your
healthcare provider.
Weight gain. This can occur with any insulin therapy. Talk to your
healthcare provider about how LEVEMIR® can affect your weight.
Tell your healthcare provider if you have any side effect that bothers
you or does not go away.
Reference ID: 3273518
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These are not all of the possible side effects from LEVEMIR®. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store LEVEMIR®?
Unopened LEVEMIR®:
Keep all unopened LEVEMIR® in the refrigerator
between 36F to 46F (2C to 8C).
Unopened LEVEMIR® can be kept until the expiration date on
the label if the medicine has been stored in a refrigerator.
If refrigeration is not possible, you can keep the unopened
LEVEMIR® at room temperature below 86°F (30C).
Throw away LEVEMIR® 42 days after it is first kept out of the
refrigerator.
Do not freeze. Do not use LEVEMIR® if it has been frozen.
Keep unopened LEVEMIR® in the carton to protect it from
light.
LEVEMIR® in use:
Vials
Keep opened vials of LEVEMIR® in the refrigerator or at
room temperature below 86F (30C) away from direct
heat or light.
Throw away a vial that has always been kept in the
refrigerator after 42 days of use, even if there is insulin
left in the vial.
Throw away a vial that has been kept at room
temperature 42 days after it is first kept out of the
refrigerator, even if there is insulin left in the vial.
LEVEMIR® FlexPen
Keep at room temperature below 86F (30C) for up to
42 days.
Do not store a LEVEMIR® FlexPen® that you are using in
the refrigerator.
Reference ID: 3273518
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not store LEVEMIR® with the needle attached.
Keep LEVEMIR® FlexPen® away from direct heat or
light.
Throw away used LEVEMIR® FlexPens after 42 days,
even if there is insulin left in them.
Keep LEVEMIR® and all medicines out of the reach of children.
General information about LEVEMIR®
Medicines are sometimes prescribed for conditions that are not
mentioned in the patient leaflet. Do not use LEVEMIR® for a condition
for which it was not prescribed. Do not give LEVEMIR® to other
people, even if they have the same symptoms you have. It may harm
them.
This leaflet summarizes the most important information about
LEVEMIR®. If you would like more information about LEVEMIR® or
diabetes, talk with your healthcare provider. You can ask your
healthcare provider for information about LEVEMIR® that is written for
healthcare professionals.
For more information about LEVEMIR®, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in LEVEMIR®?
Active Ingredient: Insulin detemir
Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium
phosphate dihydrate, sodium chloride and water for injection.
Hydrochloric acid or sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks of
Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538,
6,011,007, 6,869,930 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297,
6,235,004 and other patents pending.
© 2005-201x Novo Nordisk
Manufactured by:
Novo Nordisk A/S
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Revised: Month2012
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions For Use
LEVEMIR® 10 mL vial
Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial
and each time you get a refill. You should read the instructions in this manual even if you have
used an insulin 10 mL vial before.
How should I use the LEVEMIR 10 mL vial?
Using the 10 mL vial:
1. Check to make sure that you have the correct type of insulin.
This is especially important if you use different types of insulin.
2. Look at the vial and the insulin. The LEVEMIR insulin should
be clear and colorless. The tamper-resistant cap should be in
place before the first use. If the cap has been removed before
your first use of the vial, or if the insulin is cloudy or colored,
Do not use the insulin and return it to your pharmacy.
3. Wash your hands with soap and water.
4. If you are using a new vial, pull off the tamper-resistant cap.
Before each use, wipe the rubber stopper with an alcohol
wipe.
4A
4B
5. Do not roll or shake the vial. Shaking the vial right before the
dose is drawn into the syringe may cause bubbles or foam.
This can cause you to draw up the wrong dose of insulin. The
insulin should be used only if it is clear and colorless.
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Pull back the plunger on your syringe until the black tip
reaches the marking for the number of units you will inject.
6
7. Push the needle through the rubber stopper into the vial.
7
8. Push the plunger all the way in. This inserts air into the vial.
8
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose that you
need.
9
10. If there are air bubbles, tap the syringe gently with your finger
to raise the air bubbles to the top of the needle. Then slowly
push the plunger to the correct unit marking for your dose.
10
11. Check to make sure you have the right dose of LEVEMIR in
the syringe.
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12. Pull the syringe out of the vial.
13. Inject your LEVEMIR right away as instructed by your
healthcare provider.
How should I inject LEVEMIR with a syringe?
If you clean your injection site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider about how to rotate injection sites and how to give an
injection.
1. Pinch your skin between two fingers, push the needle into the
skinfold, using a dart-like motion and push the plunger to inject
the insulin under your skin. The needle will be straight in.
1
2. Keep the needle under your skin for at least 6 seconds to
make sure you have injected all the insulin. After you pull the
needle from your skin you may see a drop of Levemir at the
needle tip. This is normal and has no effect on the dose you
just received.
3. If blood appears after you pull the needle from your skin, press
the injection site lightly with an alcohol swab. Do not rub the
area.
4. After each injection, remove the needle without recapping
and dispose of it in a puncture-resistant container. Used
syringes, needles, and lancets should be placed in sharps
containers (such as red biohazard containers), hard plastic
containers (such as detergent bottles), or metal containers
(such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised: January 2012
Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930,
and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
LEVEMIR® FlexPen®
Please carefully read the following Instructions for use before using your LEVEMIR®
FlexPen® and each time you get a refill. You should read the instructions in this manual
even if you have used a LEVEMIR FlexPen before.
LEVEMIR FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to
60 units in increments of 1 unit. LEVEMIR FlexPen is designed to be used with
NovoFine® needles.
LEVEMIR FlexPen should not be used by people who are blind or have severe
eyesight problems without the help of a person who has good eyesight and who is
trained to use the LEVEMIR FlexPen the right way.
Getting ready
Make sure you have the following items:
LEVEMIR FlexPen
NovoFine disposable needles
Alcohol swab
PREPARING YOUR LEVEMIR FLEXPEN
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. LEVEMIR should
look clear and colorless.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab.
B. Attaching the needle
Remove the protective tab from a new disposable needle.
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attach the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your LEVEMIR FlexPen
until you are ready to give your injection.
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and throw it away (see diagram
D).
Always use a new needle for each injection to cut down the chance of infection and to
prevent blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of needle sticks, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection, small amounts of air may collect in the cartridge during normal use.
To avoid injecting air and to ensure you take the right dose of insulin:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your LEVEMIR FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any
air bubbles collect at the top of the cartridge (see diagram F).
G. While you keep the needle pointing upwards, press the push-
button all the way in (see diagram G). The dose selector
returns to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use the
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6500.
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram H). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Wipe the skin with an alcohol swab and let the area dry.
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram I). Be careful only to
push the button after the needle is in the skin.
Turning the dose selector will not inject insulin.
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has
been pulled out from the skin (see diagram J). This will make
sure that the full dose has been given.
You may see a drop of LEVEMIR at the needle tip. This is
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin,
press the injection site lightly with an alcohol swab. Do not
rub the area.
After the injection
Carefully remove the needle from the pen after each injection. This helps to
prevent infection and leakage of insulin. You can carefully recap the needle with
the bigger outer cap to help make it easier to remove the needle.
Do not recap the needle with the small inner cap. Recapping with this small part
can increase your chances of having a needle stick injury.
Put the needle in a sharps container or some type of hard plastic or metal
container with a screw top such as a detergent bottle or empty coffee can.
These containers should be sealed and thrown away the right way. Check
with your healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away used
needles and syringes. Do not throw away used needles and syringes in
household trash or recycling bins.
K. Put the pen cap on the LEVEMIR FlexPen and store the
LEVEMIR FlexPen without the needle attached (see diagram K).
The LEVEMIR FlexPen prevents the cartridge from being
completely emptied. It can deliver 300 units then you should
throw it away in a sharps container or some type of hard plastic
or metal container with a screw top, such as a detergent bottle
or empty coffee can.
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FUNCTION CHECK
L. If your LEVEMIR FlexPen is not working the right way, follow
the steps below:
Attach a new NovoFine needle.
Remove the big outer needle cap and the inner needle
cap.
Do an airshot as described in “Giving the airshot before
each injection” (see diagram E through G).
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
Turn the dose selector so the dose indicator window shows
20 units.
Hold the LEVEMIR FlexPen so the needle is pointing
down.
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap to the marker
(see diagram L). If LEVEMIR FlexPen has released too much or too little insulin,
do the function check again. If the same problem happens again, do not use your
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled with
care. If you drop your FlexPen it could get damaged. If you are concerned that
your FlexPen is damaged, use a new one. You can clean the outside of your
FlexPen by wiping it with a damp cloth. Do not soak or wash your FlexPen.
Soaking or washing the FlexPen could damage it. Do not refill your FlexPen.
Remove the needle from the LEVEMIR FlexPen after each injection. This
helps to cut down your chance of infection, prevent leakage of insulin. Be
careful when handling used needles to avoid needle sticks and transfer of
infections.
Keep your LEVEMIR FlexPen and needles out of the reach of children.
Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and
LEVEMIR FlexPen must not be shared.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a safety measure, always carry a spare insulin delivery device in case
your LEVEMIR FlexPen is lost or damaged.
Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave
it in a car or other location where it can get too hot or too cold.
Revised: January 2012
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered
trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007,
6,869,930, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3079224
Reference ID: 3273518
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:31.025515 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021536s035lbl.pdf', 'application_number': 21536, 'submission_type': 'SUPPL ', 'submission_number': 35} |
5,674 |
__________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LEVEMIR® safely and effectively. See full prescribing information
for LEVEMIR.
LEVEMIR® (insulin detemir [rDNA origin] injection) solution for
subcutaneous injection
Initial U.S. Approval: 2005
----------------------------INDICATIONS AND USAGE---------------------
LEVEMIR is a long-acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
Important Limitations of Use:
• Not recommended for treating diabetic ketoacidosis. Use intravenous,
rapid acting or short-acting insulin instead.
----------------------DOSAGE AND ADMINISTRATION-------------------
• The starting dose should be individualized based on the type of
diabetes and whether the patient is insulin-naïve (2.1, 2.2, 2.3)
• Administer subcutaneously once daily or in divided doses twice daily.
Once daily administration should be given with the evening meal or at
bedtime (2.1)
• Rotate injection sites within an injection area (abdomen, thigh, or
deltoid) to reduce the risk of lipodystrophy (2.1)
• Converting from other insulin therapies may require adjustment of
timing and dose of LEVEMIR. Closely monitor glucoses especially
upon converting to LEVEMIR and during the initial weeks thereafter
(2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------
Solution for injection 100 Units/mL (U-100) in
• 3 mL LEVEMIR FlexPen®
• 10 mL vial (3)
------------------------------CONTRAINDICATIONS------------------------
• Do not use in patients with hypersensitivity to LEVEMIR or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Dose adjustment and monitoring: Monitor blood glucose in all patients
treated with insulin. Insulin regimens should be modified cautiously and
only under medical supervision (5.1)
• Administration: Do not dilute or mix with any other insulin or solution.
Do not administer subcutaneously via an insulin pump, intramuscularly,
or intravenously because severe hypoglycemia can occur (5.2)
• Hypoglycemia is the most common adverse reaction of insulin therapy
and may be life-threatening (5.3, 6.1)
• Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur (5.4)
• Renal or hepatic impairment: May require adjustment of the LEVEMIR
dose (5.5, 5.6)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions associated with LEVEMIR include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, rash and pruritus (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• Certain drugs may affect glucose metabolism requiring insulin dose
adjustment and close monitoring of blood glucose (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine) (7)
----------------------USE IN SPECIFIC POPULATIONS-------------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not been
studied in children with type 1 diabetes < 6 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 4/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Initiation of LEVEMIR Therapy
2.3 Converting to LEVEMIR from Other Insulin Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Dosage Adjustment and Monitoring
5.2 Administration
5.3 Hypoglycemia
5.4 Hypersensitivity and Allergic Reactions
5.5 Renal Impairment
5.6 Hepatic Impairment
5.7 Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Preparation and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Patients
17.2 Never Share a LEVEMIR FlexPen Between Patients
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus.
Important Limitations of Use:
• LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting
or short-acting insulin is the preferred treatment for this condition.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration.
Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at
bedtime.
Patients who require twice-daily dosing can administer the evening dose with the evening meal, at
bedtime, or 12 hours after the morning dose.
The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is
essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].
In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting
insulin.
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid)
from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all
insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by
exercise and other variables, such as stress, intercurrent illness, or changes in co-administered
medications or meal patterns.
When using LEVEMIR with a glucagon-like peptide (GLP)-1 receptor agonist, administer as separate
injections. Never mix. It is acceptable to inject LEVEMIR and a GLP-1 receptor agonist in the same
body region but the injections should not be adjacent to each other.
2.2 Initiation of LEVEMIR Therapy
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately
one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be
used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on oral antidiabetic medications is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or
divided into a twice daily regimen.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on a GLP-1 receptor agonist is 10 Units given once daily in the evening.
LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages
of LEVEMIR should be individualized under the supervision of a healthcare provider.
2.3 Converting to LEVEMIR from other insulin therapies
If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients
with type 2 diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see
Clinical Studies (14)].
As with all insulins, close glucose monitoring is recommended during the transition and in the initial
weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other
concomitant antidiabetic treatment may need to be adjusted.
3 DOSAGE FORMS AND STRENGTHS
LEVEMIR solution for injection 100 Unit per mL is available as:
•
3 mL LEVEMIR FlexPen®
•
10 mL vial
4 CONTRAINDICATIONS
LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients.
Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen
should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a
change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different
individuals or at different times in the same individual and is dependent on many conditions, including
the local blood supply, local temperature, and physical activity.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Administration
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of
LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular
administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and
Precautions (5.3)].
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the
pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR
and the mixed insulin may be altered in an unpredictable manner.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk
of hypoglycemia increases with intensive glycemic control.
When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need
to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see Adverse
Reactions (6.1)].
All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to
unconsciousness or convulsions and may result in temporary or permanent impairment of brain function
or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion,
or glucagon administration has been observed in clinical trials with insulin, including trials with
LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals),
exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions
(7)].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions,
such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products,
including LEVEMIR.
5.5 Renal Impairment
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals
with renal impairment and healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with renal impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
renal impairment [see Clinical Pharmacology (12.3)].
5.6 Hepatic Impairment
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin
detemir compared to healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with liver impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
hepatic impairment [see Clinical Pharmacology (12.3)].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia
or hyperglycemia [see Drug Interactions (7)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions (5.3)]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in
one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not
reflect the rates actually observed in clinical practice.
The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical
trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below.
See Tables 5 and 6 for the hypoglycemia findings.
In the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg +
metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled
total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of
gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only
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those patients who completed the run-in period with inadequate glycemic control were randomized to 26
weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg +
metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in
≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated
with liraglutide 1.8 mg and metformin alone (6.9%).
Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and
24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 767)
NPH, %
(n = 388)
Upper respiratory tract infection
26.1
21.4
Headache
22.6
22.7
Pharyngitis
9.5
8.0
Influenza-like illness
7.8
7.0
Abdominal Pain
6.0
2.6
Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart
+ LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions
with incidence ≥ 5%)
LEVEMIR, %
(n = 161)
Glargine, %
(n = 159)
Upper respiratory tract infection
26.7
32.1
Headache
14.3
19.5
Back pain
8.1
6.3
Influenza-like illness
6.2
8.2
Gastroenteritis
5.6
4.4
Bronchitis
5.0
1.9
Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and
24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 432)
NPH, %
(n = 437)
Upper respiratory tract infection
12.5
11.2
Headache
6.5
5.3
Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and
adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 232)
NPH, %
(n = 115)
Upper respiratory tract infection
35.8
42.6
Headache
31.0
32.2
Pharyngitis
17.2
20.9
Gastroenteritis
16.8
11.3
Influenza-like illness
13.8
20.9
Abdominal pain
13.4
13.0
Pyrexia
10.3
6.1
Cough
8.2
4.3
Viral infection
7.3
7.8
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Nausea
6.5
7.0
Rhinitis
6.5
3.5
Vomiting
6.5
10.4
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
• Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
LEVEMIR [see Warnings and Precautions (5.3)].
Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR
clinical trials. Severe hypoglycemia was defined as an event with symptoms consistent with
hypoglycemia requiring assistance of another person and associated with either a plasma glucose value
below 56 mg/dL (blood glucose below 50 mg/dL) or prompt recovery after oral carbohydrate,
intravenous glucose or glucagon administration. Non-severe hypoglycemia was defined as an
asymptomatic or symptomatic plasma glucose < 56 mg/dL (or equivalently blood glucose <50 mg/dL as
used in Study A and C) that was self-treated by the patient.
The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study
designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see
Tables 5 and 6).
Table 5: Hypoglycemia in Patients with Type 1 Diabetes
Study A
Type 1 Diabetes
Adults
16 weeks
In combination with
insulin aspart
Study B
Type 1 Diabetes
Adults
26 weeks
In combination with
insulin aspart
Study C
Type 1 Diabetes
Adults
24 weeks
In combination with
regular insulin
Study D
Type 1 Diabetes
Pediatrics
26 weeks
In combination with
insulin aspart
Twice-
Daily
LEVEMIR
Twice-
Daily
NPH
Twice-
Daily
LEVEMIR
Once-
Daily
Glargine
Once-Daily
LEVEMIR
Once-
Daily
NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
Severe
hypoglycemia
Percent of
patients with
at least 1
event
(n/total N)
8.7
(24/276)
10.6
(14/132)
5.0
(8/161)
10.1
(16/159)
7.5
(37/491)
10.2
(26/256)
15.9
(37/232)
20.0
(23/115)
Event/patient/
year
0.52
0.43
0.13
0.31
0.35
0.32
0.91
0.99
Non-severe
hypoglycemia
Percent of
patients
(n/total N)
88.0
(243/276)
89.4
(118/132)
82.0
(132/161)
77.4
(123/159)
88.4
(434/491)
87.9
(225/256)
93.1
(216/232)
95.7
(110/115)
Event/patient/
year
26.4
37.5
20.2
21.8
31.1
33.4
31.6
37.0
Table 6: Symptomatic Hypoglycemia in Patients with Type 2 Diabetes
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Study E
Type 2 Diabetes
Adults
24 weeks
In combination with
oral agents
Study F
Type 2 Diabetes
Adults
22 weeks
In combination with
insulin aspart
Study H
Type 2 Diabetes
Adults
26 weeks in combination
with Liraglutide and
Metformin
Twice-
Daily
LEVEMIR
Twice-
Daily
NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
Once Daily
LEVEMIR +
Liraglutide +
Metformin
Liraglutide
+
Metformin
Severe
hypoglycemia
Percent of patients
with at least 1 event
(n/total N)
0.4
(1/237)
2.5
(6/238)
1.5
(3/195)
4.0
(8/199)
0
0
Event/patient/year
0.01
0.08
0.04
0.13
0
0
Non-severe
hypoglycemia
Percent of patients
(n/total N)
40.5
(96/237)
64.3
(153/238)
32.3
(63/195)
32.2
(64/199)
9.2
(15/163)
1.3
(2/158*)
Event/patient/year
3.5
6.9
1.6
2.0
0.29
0.03
*One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a
history of frequent hypoglycemia prior to the study
Insulin Initiation and Intensification of Glucose Control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible
ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral
neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and
neuropathy.
• Lipodystrophy
Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy
(thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the
same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].
• Weight Gain
Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)].
• Peripheral Edema
Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
• Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions,
including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in
adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one
patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in
discontinuation of therapy.
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Rotation of the injection site within a given area from one injection to the next may help to reduce or
prevent these reactions. In some instances, these reactions may be related to factors other than insulin,
such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin
usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR,
and may be life-threatening [see Warnings and Precautions (5.4)].
• Antibody Production
All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase
or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical
trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic
control.
6.2 Postmarketing experience
The following adverse reactions have been identified during post approval use of LEVEMIR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported during post-approval use of LEVEMIR in which other insulins,
particularly rapid-acting or short-acting insulins, have been accidentally administered instead of
LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR
and other insulins, patients should be instructed always to verify the insulin label before each injection.
7 DRUG INTERACTIONS
A number of medications affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
The following are examples of medications that may increase the blood-glucose-lowering effect of
insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral
antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline,
salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood-glucose-lowering effect of
insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid
hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical
antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose
lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
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The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as
beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all
pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant while taking
LEVEMIR. A randomized controlled clinical trial of pregnant women with type I diabetes using
LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive
toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups
indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and
teratogenicity that were attributed to maternal hypoglycemia.
Clinical Considerations
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased
with good glucose control before conception and throughout pregnancy. Because insulin requirements
vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is
essential in pregnant women.
Human Data
In an, open-label, clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of
gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or
NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of
152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the
study (Total pregnant women = 310). Approximately one half of the study participants in each arm were
randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first
8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <
7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted
mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient
(n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically
significant.
Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 7. The two
most common adverse reactions were nasopharyngitis and headache. These are consistent with findings
from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the
Levemir and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia, eight
(8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization. The rates
of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by diabetes.
Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the definition of pre-
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eclampsia was not standardized in the trial making it difficult to establish a link between a given
treatment and an increased risk of pre-eclampsia. All events were considered unlikely related to trial
treatment. In all nine (9) cases requiring hospitalization the women had healthy infants. Events of
hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group than in the
NPH insulin group as a whole. There was no difference between the treatment groups in mean blood
pressure during pregnancy and there was no indication of a general increase in blood pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following
placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of
placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the
LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6%
and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’,
‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.
Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR to
insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with
incidence ≥ 5%)*
LEVEMIR, %
(n = 152)
NPH, %
(n = 158)
Anemia
13.2
10.8
Diarrhea
11.8
5.1
Pre-eclampsia
10.5
7.0
Urinary tract infection
9.9
5.7
Gastroenteritis
8.6
5.1
Abdominal pain upper
5.9
3.8
Vomiting
5.3
4.4
Abortion spontaneous
5.3
2.5
Abdominal pain
5.3
6.3
Oropharyngeal pain
5.3
6.3
* Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be
easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and
NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patient-
year in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe
episodes of hypoglycemia were similar in both treatment groups (Table 8).
Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes
Study G Type 1
Diabetes
Pregnancy
In combination with
insulin aspart
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LEVEMIR
NPH
Severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
16.4
(25/152)
20.9
(33/158)
Events/patient/year
1.1
1.2
Non-severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
94.7
(144/152)
92.4
(146/158)
Events/patient/year
114.2
108.4
* For definition regarding severe and non-severe hypoglycemia see section 6, Hypoglycemia.
In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower
level of quantification (<25 pmol/L).
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR
use.
Animal Data
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300
nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day
(approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits
during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder
abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of
900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human
insulin control groups indicated that insulin detemir and human insulin had similar effects regarding
embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia
resulting from insulin exposure in normal animals.
8.3
Nursing Mothers
It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human
insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman.
Women with diabetes who are lactating may require adjustments of their insulin doses.
8.4
Pediatric Use
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been
established in pediatric patients (age 6 to 17 years) with type 1 diabetes [see Clinical Pharmacology
(12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than 6
years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2
diabetes.
The dose recommendation when converting to LEVEMIR is the same as that described for adults [see
Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood
glucose.
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8.5
Geriatric Use
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients
(3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were
≥65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥75 years of age. No
overall differences in safety or effectiveness were observed between these patients and younger patients,
but small sample sizes, particularly for patients ≥65 years of age in the type 1 diabetes trials and for
patients ≥75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals
cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and
maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to
recognize in the elderly.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].
11 DESCRIPTION
LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a
subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant
human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae followed by chemical modification.
Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been
omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a
molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:
Figure 1: Structural Formula of insulin detemir
S
S
(A1)
(A21)
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
S
S
S
S
(B1)
(B29)
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys
C NH structural formula
O
LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains
100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg
phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection.
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Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of
approximately 7.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including
insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin
lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue
and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits
proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of
action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir
molecules from the injection site due to self-association of the drug molecules. In addition, the
distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24
hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection
and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to > 24 hours (24 hours
was the end of the observation period).
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Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study graph
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum
effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2
diabetes. The clamp study was terminated at 16 hours according to protocol.
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Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study graph
12.3 Pharmacokinetics
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin
detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the
maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more
slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and
AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and
abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in
vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin
detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous
administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours
depending on dose.
Specific Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children
(6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir
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plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as
compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose
of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir
AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin
preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed
between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there
were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and
pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2
diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR
were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate,
severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics
of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with
human insulin have shown increased circulating levels of insulin in patients with renal impairment.
Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in
patients with renal impairment [see Warnings and Precautions (5.5)].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate
and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic
impairment with a corresponding increase in apparent clearance. However, some studies with human
insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful
glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients
with hepatic impairment [see Warnings and Precautions (5.6)].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR
has not been studied [see Use in Specific Populations (8.1)].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not
been studied.
Liraglutide -No pharmacokinetic interaction was observed between liraglutide and LEVEMIR when
separate subcutaneous injections of LEVEMIR 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady
state) were administered in patients with type 2 diabetes.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested
negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral
blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
14 CLINICAL STUDIES
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and
at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of
once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with
type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2
diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily
insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The
evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood
glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials
that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin
(HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to
treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and
bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered
before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar
HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9).
Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose
(FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized
to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine
(administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated
patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, non-blinded clinical study (Study C, n=749), adults with type 1 diabetes were randomized
to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination
with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on
HbA1c.
Reference ID: 3123025
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Study D
Treatment duration
26 weeks
Treatment in combination with
®
NovoLog
(insulin aspart)
Once- or
Once- or
Twice
Twice
Daily
Daily
LEVEMIR
NPH
Number of subjects treated
232
115
HbA1c (%)
Baseline HbA1c
8.8
8.8
Adj. mean change from baseline
-0.7
-0.8
LEVEMIR – NPH
0.1
95% CI for Treatment difference
(-0.1, 0.3)
Basal insulin dose (units/day)
Table 9: Type 1 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of patients treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for Treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose (mg/dL)
Baseline mean
Adj. mean change from baseline
Body weight (kg)
Baseline mean
Mean change from baseline
Study A
16 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Twice-daily
NPH
276
133
8.6
8.5
-0.8
-0.7
-0.2
(-0.3, -0.0)
21
24
16
10
48
54
17
10
209
220
-44
-9
74.6
75.5
0.2
0.8
Study B
26 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Once-
daily
insulin
glargine
161
159
8.9
8.8
-0.6
-0.5
-0.0
(-0.2, 0.2)
27
23
10
4
56
51
9
6
153
150
-38
-41
77.5
75.1
0.5
1.0
Study C
24 weeks
Human Soluble Insulin
(regular insulin)
Once-daily
LEVEMIR
Once-
daily
NPH
492
257
8.4
8.3
-0.1
0.0
-0.1
(-0.3, 0.0)
12
24
9
2
46
57
11
3
213
206
-30
-9
76.5
76.9
-0.3
0.3
Baseline values were included as covariates in an ANCOVA analysis.
Type 1 Diabetes – Pediatric
In an open-label clinical study (Study D, n=347), pediatric patients (age range 6 to 17) with type 1
diabetes were randomized to 26 weeks of treatment with LEVEMIR or NPH insulin both of which were
administered either once- or twice-daily (bedtime or morning and bedtime), at a dosing frequency
consistent with the number of daily basal insulin injections a patient was taking prior to trial entry.
Insulin aspart was administered before each meal. LEVEMIR-treated patients had a decrease in HbA1c
similar to that of NPH insulin (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
Reference ID: 3123025
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Baseline mean
24
26
Mean change from baseline
8
6
Total insulin dose (units/day)
Baseline mean
48
50
Mean change from baseline
9
7
Fasting blood glucose (mg/dL)
Baseline mean
181
181
Adj. mean change from baseline
-39
-21
Body weight (kg)
Baseline mean
46.3
46.2
Mean change from baseline
1.6
2.7
Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-
daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before
breakfast and evening) as part of a regimen of stable combination therapy with one or two of the
following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase
inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin
similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes,
LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with
insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for Treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose1 (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose2 (mg/dL)
Baseline mean
Adj. mean change from baseline
Body weight (kg)
Baseline mean
Mean change from baseline
Study E
24 weeks
oral agents
Twice-daily
LEVEMIR
Twice-
daily
NPH
237
239
8.6
8.5
-2.0
-2.1
0.1
(-0.0, 0.3)
18
17
48
28
-
-
-
-
179
173
-69
-74
82.7
82.5
1.2
2.7
Study F
22 weeks
insulin aspart
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
195
200
8.2
8.1
-0.6
-0.6
-0.1
(-0.2, 0.1)
22
22
26
15
22
22
57
42
-
-
-
-
82.0
79.6
0.5
1.2
1Study E – Conducted in insulin-naïve patients
2Study F - Fasting blood glucose data not collected
Reference ID: 3123025
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Combination Therapy with Metformin and Liraglutide
This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%)
on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin
(≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued
the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on
therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%)
achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-
randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in
period with approximately one-half of these patients doing so because of gastrointestinal adverse
reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those
who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in
the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and
metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of
the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the
percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized
to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-
on therapy with LEVEMIR.
Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically
significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide
1.8 mg + metformin alone (Table 12). From a mean baseline body weight of 96 kg after randomization,
there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared
to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8
mg + metformin alone.
Table 12 Results of a 26-week open-label trial of LEVEMIR as add on to liraglutide + metformin
compared to continued treatment with liraglutide + metformin alone in patients not achieving
HbA1c < 7% after 12 weeks of Metformin and Liraglutide
Study H
LEVEMIR +
Liraglutide
+Metformin
Liraglutide+
Metformin
Intent-to-Treat Population (N)ª
162
157
HbA1c (%) (Mean)
Baseline (week 0)
Adjusted mean change from baseline
Difference from liraglutide + metformin arm (LS mean) b
95% Confidence Interval
7.6
-0.5
-0.5*
(-0.7, -0.4)
7.6
0
Percentage of patients achieving A1c <7%
43
17
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline (week 0)
Adjusted mean change from baseline
Difference from liraglutide + metformin arm (LS mean) b
95% Confidence Interval
166
-38
-31*
(-39 , -23)
159
-7
Reference ID: 3123025
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For current labeling information, please visit https://www.fda.gov/drugsatfda
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
*p-value <0.0001
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin
detemir per mL (U-100).
3 mL LEVEMIR FlexPen®
NDC 0169-6439-10
10 mL vial
NDC 0169-3687-12
FlexPen is for use with NovoFine® disposable needles. Each FlexPen is for use by a single patient.
LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.
16.2 Storage:
Unused (unopened) LEVEMIR should be stored in the refrigerator between 2° and 8°C (36° to 46°F).
Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not
use LEVEMIR if it has been frozen.
Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in
a refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.
If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room
temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and
light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator,
even if the FlexPen or vial still contains insulin.
Vials:
After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not
possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it
is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be
discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after
they are first kept out of the refrigerator.
LEVEMIR FlexPen:
After initial use, the LEVEMIR FlexPen must NOT be stored in a refrigerator and must NOT be stored
with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at
room temperature, below 30°C (86°F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days
after they are first kept out of the refrigerator.
The storage conditions are summarized in Table 13:
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 13: Storage Conditions for LEVEMIR FlexPen and vial
Not in-use
(unopened)
Refrigerated
Not in-use
(unopened)
Room Temperature
(below 30°C)
In-use
(opened)
3 mL
LEVEMIR
FlexPen
Until expiration date
42 days*
42 days*
Room Temperature
(below 30°C)
(Do not refrigerate)
42 days*
10 mL vial
Until expiration date
42 days*
Refrigerated or Room
Temperature (below 30°C)
*The total time allowed at room temperature (below 30°C) is 42 days regardless of whether the product
is in-use or not in-use.
16.3 Preparation and handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to
administration and should only be used if the solution appears clear and colorless.
Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See
Warnings and Precautions (5.2)].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1 Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under
medical supervision. Patients should be informed about the potential side effects of insulin therapy,
including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the
same body region), and allergic reactions. Patients should be informed that the ability to concentrate and
react may be impaired as a result of hypoglycemia. This may present a risk in situations where these
abilities are especially important, such as driving or operating other machinery. Patients who have
frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been
reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to
always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients
must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
Reference ID: 3123025
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be instructed on self-management procedures including glucose monitoring, proper
injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional
disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin
dose, inadequate food intake, and skipped meals.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or
are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional
information.
17.2 Never Share a LEVEMIR FlexPen Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen with another person, even if the
needle is changed. Sharing of the FlexPen between patients may pose a risk of transmission of
infection.
Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo
Nordisk A/S.
LEVEMIR is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents
pending.
FlexPen is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3123025
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
LEVEMIR® (LEV–uh-mere)
(insulin detemir [rDNA origin] injection)
solution for subcutaneous injection
Read the Patient Information that comes with LEVEMIR® before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure
that you know how to manage your diabetes. Ask your healthcare
provider, if you have any questions about managing your diabetes.
What is LEVEMIR?
LEVEMIR is a man-made long-acting insulin used to control high blood
sugar in adults and children with diabetes mellitus.
It is not recommended to use LEVEMIR to treat diabetic ketoacidosis.
Who should not use LEVEMIR?
Do not use LEVEMIR if:
• you are allergic to any of the ingredients in LEVEMIR. See the end
of this leaflet for a complete list of ingredients in LEVEMIR.
What should I tell my healthcare provider before using
LEVEMIR?
Before you use LEVEMIR, tell your healthcare provider if you:
• have liver or kidney problems
• have any other medical conditions. Some medical conditions can
affect your insulin needs and your dose of LEVEMIR.
• are pregnant or plan to become pregnant. It is not known, if
LEVEMIR would harm your unborn baby. Talk to your healthcare
provider, if you are pregnant or plan to become pregnant. You and
your healthcare provider should talk about the best way to manage
your diabetes while you are pregnant.
• are breastfeeding or plan to breast-feed. It is not known if
LEVEMIR passes into breast milk. You and your healthcare provider
should decide if you will take LEVEMIR while you breastfeed.
Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins and
herbal supplements. LEVEMIR may affect the way other medicines
work, and other medicines may affect how LEVEMIR works.
Reference ID: 3123025
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with
you to show your healthcare provider and pharmacist when you get a
new medicine.
How should I use LEVEMIR?
• Use LEVEMIR exactly as your healthcare provider told you to use it.
• Your healthcare provider will tell you how much LEVEMIR to use and
when to use it.
• Do not make any changes to your dose or type of insulin unless you
are told to do so by your healthcare provider.
Know your insulin. Make sure you know:
• the type and strength of insulin prescribed for you.
• the amount of insulin you take.
• the best time for you to take your insulin. This may change if
you take a different type of insulin.
• Do not dilute or mix LEVEMIR with any other insulin or injectable
diabetes medicine. Your LEVEMIR will not work the right way and
you may lose control of your blood sugar, which can be serious.
Give yourself separate injections. You may give the separate
injections in the same body area (for example, your stomach area),
but you should not give the injections right next to each other.
• Do not use LEVEMIR in an insulin pump.
• Inject LEVEMIR under your skin (subcutaneously) in your upper
arm, abdomen (stomach area), or thigh. Never inject LEVEMIR into
a vein or muscle.
• Change injection sites within the area you choose with each dose.
Do not inject into the exact same spot for each injection.
• Read the instructions for use that comes with your LEVEMIR.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject LEVEMIR before
you start taking it.
• Your healthcare provider will decide which type of LEVEMIR to
prescribe for you.
LEVEMIR comes in:
• 10 mL vials (small bottles) for use with a syringe
• 3 mL LEVEMIR FlexPen®
Ask your healthcare provider how you should use LEVEMIR.
Reference ID: 3123025
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you use too much LEVEMIR, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away
(fruit juice, sugar candies, or glucose tablets). It is important to
treat low blood sugar (hypoglycemia) right away because it could
get worse and you could pass out (lose consciousness).
If you pass out you will need help from another person or
emergency medical services right away. See “What are the
possible side effects of LEVEMIR?” for more information on
low blood sugar (hypoglycemia).
• If you forget to take your dose of LEVEMIR, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death.
Follow your healthcare provider’s instructions for treating high
blood sugar.
Know your symptoms of high blood sugar, which may include:
• increased thirst
• high amounts of sugar and
• frequent urination
ketones in your urine
• drowsiness
• nausea, vomiting (throwing
• loss of appetite
up) or stomach pain
• a hard time breathing
• fruity smell on the breath
• Do not share needles, insulin pens or syringes with others.
• Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check your
blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
change in diet
•
stress
•
change in physical activity
•
other medicines you
or exercise
take
What should I avoid while taking LEVEMIR?
•
Alcohol. Drinking alcohol may affect your blood sugar when
you use LEVEMIR.
Reference ID: 3123025
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•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for
you to drive if you often have:
• low blood sugar (hypoglycemia)
• decreased or no warning signs of low blood sugar
What are the possible side effects of LEVEMIR?
LEVEMIR can cause serious side effects, including:
• Low blood sugar (hypoglycemia). Signs and symptoms of low
blood sugar may include:
• dizziness or
• trouble concentrating or
lightheadedness
confusion
• shakiness
• blurred vision
• hunger
• slurred speech
• fast heart beat
• anxiety or mood changes
• tingling in your hands,
• headache
feet, lips or tongue
• sweating
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, and death. In some people their blood sugar
may get so low that they need another person to help them. Talk to
your healthcare provider about how to tell if you have low blood sugar
and what to do if this happens while taking LEVEMIR. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
If you are using LEVEMIR with another diabetes medicine, your
LEVEMIR dose may need to be changed to reduce your chance of
getting low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of LEVEMIR may need to be changed.
• Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) the area where you inject your insulin to help
prevent these skin changes from happening. Do not inject insulin
into areas of skin that have thickening or pits.
• Serious allergic reactions. LEVEMIR can cause life
threatening symptoms. Get medical help right away if you have
any of these symptoms of an allergic reaction:
Reference ID: 3123025
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• a rash all over your body
• fast heartbeat
• itching
• sweating
• shortness of breath
• feel faint
• trouble breathing
(wheezing)
Common side effects of LEVEMIR include:
• Low blood sugar (hypoglycemia). See “What are the possible
side effects of LEVEMIR?” for more information on low blood
sugar (hypoglycemia).
• Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious, talk to your
healthcare provider.
• Weight gain. This can occur with any insulin therapy. Talk to your
healthcare provider about how LEVEMIR can affect your weight.
Tell your healthcare provider if you have any side effect that bothers
you or does not go away.
These are not all of the possible side effects from LEVEMIR. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store LEVEMIR?
Unopened LEVEMIR:
•
Keep all unopened LEVEMIR in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Unopened LEVEMIR can be kept until the expiration date on
the label if the medicine has been stored in a refrigerator.
•
If refrigeration is not possible, you can keep the unopened
LEVEMIR at room temperature below 86°F (30°C).
•
Throw away LEVEMIR 42 days after it is first kept out of the
refrigerator.
•
Do not freeze. Do not use LEVEMIR if it has been frozen.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Keep unopened LEVEMIR in the carton to protect it from
light.
LEVEMIR in use:
•
Vials
• Keep opened vials of LEVEMIR in the refrigerator or at
room temperature below 86°F (30°C) away from direct
heat or light.
• Throw away a vial that has always been kept in the
refrigerator after 42 days of use, even if there is insulin
left in the vial.
• Throw away a vial that has been kept at room
temperature 42 days after it is first kept out of the
refrigerator, even if there is insulin left in the vial.
•
LEVEMIR FlexPen
• Keep at room temperature below 86°F (30°C) for up to
42 days.
• Do not store a LEVEMIR FlexPen that you are using in
the refrigerator.
• Do not store LEVEMIR with the needle attached.
• Keep LEVEMIR FlexPen away from direct heat or light.
• Throw away used LEVEMIR FlexPens after 42 days, even
if there is insulin left in them.
Keep LEVEMIR and all medicines out of the reach of children.
General information about LEVEMIR
Medicines are sometimes prescribed for conditions that are not
mentioned in the patient leaflet. Do not use LEVEMIR for a condition
for which it was not prescribed. Do not give LEVEMIR to other people,
even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about
LEVEMIR. If you would like more information about LEVEMIR or
diabetes, talk with your healthcare provider. You can ask your
healthcare provider for information about LEVEMIR that is written for
healthcare professionals.
For more information about LEVEMIR, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in LEVEMIR?
Active Ingredient: Insulin detemir
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium
phosphate dihydrate, sodium chloride and water for injection.
Hydrochloric acid or sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks of
Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538,
6,011,007, 6,869,930 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297,
6,235,004 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Revised: April 2012
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions For Use
LEVEMIR® 10 mL vial
Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial
and each time you get a refill. You should read the instructions in this manual even if you have
used an insulin 10 mL vial before.
How should I use the LEVEMIR 10 mL vial?
Using the 10 mL vial:
1. Check to make sure that you have the correct type of insulin.
This is especially important if you use different types of insulin.
2. Look at the vial and the insulin. The LEVEMIR insulin should
be clear and colorless. The tamper-resistant cap should be in
place before the first use. If the cap has been removed before
your first use of the vial, or if the insulin is cloudy or colored,
Do not use the insulin and return it to your pharmacy.
3. Wash your hands with soap and water.
4. If you are using a new vial, pull off the tamper-resistant cap.
usa
ge illustration
Before each use, wipe the rubber stopper with an alcohol
wipe.
5. Do not roll or shake the vial. Shaking the vial right before the
dose is drawn into the syringe may cause bubbles or foam.
This can cause you to draw up the wrong dose of insulin. The
insulin should be used only if it is clear and colorless.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Pull back the plunger on your syringe until the black tip
reaches the marking for the number of units you will inject.
7. Push the needle through the rubber stopper into the vial.
8. Push the plunger all the way in. This inserts air into the vial.
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose that you
need.
10. If there are air bubbles, tap the syringe gently with your finger
to raise the air bubbles to the top of the needle. Then slowly
push the plunger to the correct unit marking for your dose.
us
ag
e
il
lustration
11. Check to make sure you have the right dose of LEVEMIR in
the syringe.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12. Pull the syringe out of the vial.
13. Inject your LEVEMIR right away as instructed by your
healthcare provider.
How should I inject LEVEMIR with a syringe?
If you clean your injection site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider about how to rotate injection sites and how to give an
injection.
1. Pinch your skin between two fingers, push the needle into the
skinfold, using a dart-like motion and push the plunger to inject
the insulin under your skin. The needle will be straight in.
usage illustration
2. Keep the needle under your skin for at least 6 seconds to
make sure you have injected all the insulin. After you pull the
needle from your skin you may see a drop of Levemir at the
needle tip. This is normal and has no effect on the dose you
just received.
3. If blood appears after you pull the needle from your skin, press
the injection site lightly with an alcohol swab. Do not rub the
area.
4. After each injection, remove the needle without recapping
and dispose of it in a puncture-resistant container. Used
syringes, needles, and lancets should be placed in sharps
containers (such as red biohazard containers), hard plastic
containers (such as detergent bottles), or metal containers
(such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised: January 2012
Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930,
and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
LEVEMIR® FlexPen®
Please carefully read the following Instructions for use before using your LEVEMIR®
FlexPen® and each time you get a refill. You should read the instructions in this manual
even if you have used a LEVEMIR FlexPen before.
LEVEMIR FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to
60 units in increments of 1 unit. LEVEMIR FlexPen is designed to be used with
NovoFine® needles.
LEVEMIR FlexPen should not be used by people who are blind or have severe
eyesight problems without the help of a person who has good eyesight and who is
trained to use the LEVEMIR FlexPen the right way.
Getting ready
Make sure you have the following items:
•
LEVEMIR FlexPen
•
NovoFine disposable needles
•
Alcohol swab usage illustration
PREPARING YOUR LEVEMIR FLEXPEN
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. LEVEMIR should
look clear and colorless.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustration
B. Attaching the needle
Remove the protective tab from a new disposable needle.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attach the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your LEVEMIR FlexPen
until you are ready to give your injection. usage illustration
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and throw it away (see diagram
D). usage illustration
Always use a new needle for each injection to cut down the chance of infection and to
prevent blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of needle sticks, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection, small amounts of air may collect in the cartridge during normal use.
To avoid injecting air and to ensure you take the right dose of insulin:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your LEVEMIR FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any
air bubbles collect at the top of the cartridge (see diagram F).
G. While you keep the needle pointing upwards, press the push-
button all the way in (see diagram G). The dose selector
returns to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use the
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727
Reference ID: 3123025 usage illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6500.
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram H). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Wipe the skin with an alcohol swab and let the area dry. usage illustration
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram I). Be careful only to
push the button after the needle is in the skin. usage illustration
Turning the dose selector will not inject insulin.
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has
been pulled out from the skin (see diagram J). This will make
sure that the full dose has been given.
You may see a drop of LEVEMIR at the needle tip. This is
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin,
press the injection site lightly with an alcohol swab. Do not
rub the area. usage illustration
After the injection
Carefully remove the needle from the pen after each injection. This helps to
prevent infection and leakage of insulin. You can carefully recap the needle with
the bigger outer cap to help make it easier to remove the needle.
Do not recap the needle with the small inner cap. Recapping with this small part
can increase your chances of having a needle stick injury.
Put the needle in a sharps container or some type of hard plastic or metal
container with a screw top such as a detergent bottle or empty coffee can.
These containers should be sealed and thrown away the right way. Check
with your healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away used
needles and syringes. Do not throw away used needles and syringes in
household trash or recycling bins.
K. Put the pen cap on the LEVEMIR FlexPen and store the
LEVEMIR FlexPen without the needle attached (see diagram K).
The LEVEMIR FlexPen prevents the cartridge from being
completely emptied. It can deliver 300 units then you should
throw it away in a sharps container or some type of hard plastic
or metal container with a screw top, such as a detergent bottle
or empty coffee can. usage illustration
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FUNCTION CHECK
L. If your LEVEMIR FlexPen is not working the right way, follow
the steps below:
•
Attach a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap. usage illustration
•
Do an airshot as described in “Giving the airshot before
each injection” (see diagram E through G).
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the LEVEMIR FlexPen so the needle is pointing
down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap to the marker
(see diagram L). If LEVEMIR FlexPen has released too much or too little insulin,
do the function check again. If the same problem happens again, do not use your
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled with
care. If you drop your FlexPen it could get damaged. If you are concerned that
your FlexPen is damaged, use a new one. You can clean the outside of your
FlexPen by wiping it with a damp cloth. Do not soak or wash your FlexPen.
Soaking or washing the FlexPen could damage it. Do not refill your FlexPen.
Remove the needle from the LEVEMIR FlexPen after each injection. This
helps to cut down your chance of infection, prevent leakage of insulin. Be
careful when handling used needles to avoid needle sticks and transfer of
infections.
Keep your LEVEMIR FlexPen and needles out of the reach of children.
Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and
LEVEMIR FlexPen must not be shared.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a safety measure, always carry a spare insulin delivery device in case
your LEVEMIR FlexPen is lost or damaged.
Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave
it in a car or other location where it can get too hot or too cold.
Revised: January 2012
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered
trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007,
6,869,930, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3123025
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:31.397568 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021536S039lbl.pdf', 'application_number': 21536, 'submission_type': 'SUPPL ', 'submission_number': 39} |
5,675 |
__________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LEVEMIR® safely and effectively. See full prescribing information
for LEVEMIR.
LEVEMIR® (insulin detemir [rDNA origin] injection) solution for
subcutaneous injection
Initial U.S. Approval: 2005
----------------------------INDICATIONS AND USAGE---------------------
LEVEMIR is a long-acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
Important Limitations of Use:
• Not recommended for treating diabetic ketoacidosis. Use intravenous,
rapid acting or short-acting insulin instead.
----------------------DOSAGE AND ADMINISTRATION-------------------
• The starting dose should be individualized based on the type of
diabetes and whether the patient is insulin-naïve (2.1, 2.2, 2.3)
• Administer subcutaneously once daily or in divided doses twice daily.
Once daily administration should be given with the evening meal or at
bedtime (2.1)
• Rotate injection sites within an injection area (abdomen, thigh, or
deltoid) to reduce the risk of lipodystrophy (2.1)
• Converting from other insulin therapies may require adjustment of
timing and dose of LEVEMIR. Closely monitor glucoses especially
upon converting to LEVEMIR and during the initial weeks thereafter
(2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------
Solution for injection 100 Units/mL (U-100) in
• 3 mL LEVEMIR FlexPen®
• 10 mL vial (3)
------------------------------CONTRAINDICATIONS------------------------
• Do not use in patients with hypersensitivity to LEVEMIR or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Dose adjustment and monitoring: Monitor blood glucose in all patients
treated with insulin. Insulin regimens should be modified cautiously and
only under medical supervision (5.1)
• Administration: Do not dilute or mix with any other insulin or solution.
Do not administer subcutaneously via an insulin pump, intramuscularly,
or intravenously because severe hypoglycemia can occur (5.2)
• Hypoglycemia is the most common adverse reaction of insulin therapy
and may be life-threatening (5.3, 6.1)
• Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur (5.4)
• Renal or hepatic impairment: May require adjustment of the LEVEMIR
dose (5.5, 5.6)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions associated with LEVEMIR include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, rash and pruritus (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• Certain drugs may affect glucose metabolism requiring insulin dose
adjustment and close monitoring of blood glucose (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine) (7)
----------------------USE IN SPECIFIC POPULATIONS-------------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not been
studied in children with type 1 diabetes < 2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 5/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Initiation of LEVEMIR Therapy
2.3 Converting to LEVEMIR from Other Insulin Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Dosage Adjustment and Monitoring
5.2 Administration
5.3 Hypoglycemia
5.4 Hypersensitivity and Allergic Reactions
5.5 Renal Impairment
5.6 Hepatic Impairment
5.7 Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Preparation and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Patients
17.2 Never Share a LEVEMIR FlexPen Between Patients
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus.
Important Limitations of Use:
• LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting
or short-acting insulin is the preferred treatment for this condition.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration.
Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at
bedtime.
Patients who require twice-daily dosing can administer the evening dose with the evening meal, at
bedtime, or 12 hours after the morning dose.
The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is
essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].
In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting
insulin.
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid)
from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all
insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by
exercise and other variables, such as stress, intercurrent illness, or changes in co-administered
medications or meal patterns.
When using LEVEMIR with a glucagon-like peptide (GLP)-1 receptor agonist, administer as separate
injections. Never mix. It is acceptable to inject LEVEMIR and a GLP-1 receptor agonist in the same
body region but the injections should not be adjacent to each other.
2.2 Initiation of LEVEMIR Therapy
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately
one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be
used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on oral antidiabetic medications is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or
divided into a twice daily regimen.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on a GLP-1 receptor agonist is 10 Units given once daily in the evening.
LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages
of LEVEMIR should be individualized under the supervision of a healthcare provider.
2.3 Converting to LEVEMIR from other insulin therapies
If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients
with type 2 diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see
Clinical Studies (14)].
As with all insulins, close glucose monitoring is recommended during the transition and in the initial
weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other
concomitant antidiabetic treatment may need to be adjusted.
3 DOSAGE FORMS AND STRENGTHS
LEVEMIR solution for injection 100 Unit per mL is available as:
•
3 mL LEVEMIR FlexPen®
•
10 mL vial
4 CONTRAINDICATIONS
LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients.
Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen
should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a
change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different
individuals or at different times in the same individual and is dependent on many conditions, including
the local blood supply, local temperature, and physical activity.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Administration
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of
LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular
administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and
Precautions (5.3)].
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the
pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR
and the mixed insulin may be altered in an unpredictable manner.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk
of hypoglycemia increases with intensive glycemic control.
When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need
to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see Adverse
Reactions (6.1)].
All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to
unconsciousness or convulsions and may result in temporary or permanent impairment of brain function
or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion,
or glucagon administration has been observed in clinical trials with insulin, including trials with
LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals),
exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions
(7)].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions,
such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products,
including LEVEMIR.
5.5 Renal Impairment
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals
with renal impairment and healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with renal impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
renal impairment [see Clinical Pharmacology (12.3)].
5.6 Hepatic Impairment
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin
detemir compared to healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with liver impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
hepatic impairment [see Clinical Pharmacology (12.3)].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia
or hyperglycemia [see Drug Interactions (7)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions (5.3)]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in
one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not
reflect the rates actually observed in clinical practice.
The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical
trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below.
See Tables 5 and 6 for the hypoglycemia findings.
In the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg +
metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled
total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of
gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only
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those patients who completed the run-in period with inadequate glycemic control were randomized to 26
weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg +
metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in
≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated
with liraglutide 1.8 mg and metformin alone (6.9%).
In two pooled trials, a total of 1155 adults with type 1 diabetes were exposed to individualized doses of
LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and
the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are
summarized in Table 1.
Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and
24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 767)
NPH, %
(n = 388)
Upper respiratory tract infection
26.1
21.4
Headache
22.6
22.7
Pharyngitis
9.5
8.0
Influenza-like illness
7.8
7.0
Abdominal Pain
6.0
2.6
A total of 320 adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=161)
or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total
exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summized in
Table 2.
Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart
+ LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions
with incidence ≥ 5%)
LEVEMIR, %
(n = 161)
Glargine, %
(n = 159)
Upper respiratory tract infection
26.7
32.1
Headache
14.3
19.5
Back pain
8.1
6.3
Influenza-like illness
6.2
8.2
Gastroenteritis
5.6
4.4
Bronchitis
5.0
1.9
In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of
Levemir (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and the
total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions are
summarized in Table 3.
Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and
24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 432)
NPH, %
(n = 437)
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Upper respiratory tract infection
12.5
11.2
Headache
6.5
5.3
A total of 347 children and adolescents (6-17 years) with type 1 diabetes were exposed to individualized
doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180
days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions
are summarized in Table 4.
Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and
adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 232)
NPH, %
(n = 115)
Upper respiratory tract infection
35.8
42.6
Headache
31.0
32.2
Pharyngitis
17.2
20.9
Gastroenteritis
16.8
11.3
Influenza-like illness
13.8
20.9
Abdominal pain
13.4
13.0
Pyrexia
10.3
6.1
Cough
8.2
4.3
Viral infection
7.3
7.8
Nausea
6.5
7.0
Rhinitis
6.5
3.5
Vomiting
6.5
10.4
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
• Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
LEVEMIR [see Warnings and Precautions (5.3)].
Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR
clinical trials.
For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an
event with symptoms consistent with hypoglycemia requiring assistance of another person and
associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or
prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other
pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness,
unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who
may have required glucagon or intravenous glucose.
For the adult trials and pediatric Study D, non-severe hypoglycemia was defined as an asymptomatic or
symptomatic plasma glucose < 56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A
and C) that was self-treated by the patient. For pediatric Study I, non-severe hypoglycemia included
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asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient
could self-treat or treat by taking oral therapy provided by the caregiver.
The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study
designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see
Tables 5 and 6).
Table 5: Hypoglycemia in Patients with Type 1 Diabetes
Severe Hypoglycemia
Non-Severe Hypoglycemia
Percent of
patients with at
least 1 event
(n/total N)
Event/patient/
year
Percent of patients
(n/total N)
Event/patient/
year
Study A
Type 1 Diabetes
Adults
16 weeks
In combination
with
insulin aspart
Twice-Daily
LEVEMIR
8.7
(24/276)
0.52
88.0
(243/276)
26.4
Twice-Daily
NPH
10.6
(14/132)
0.43
89.4
(118/132)
37.5
Study B
Type 1 Diabetes
Adults
26 weeks
In combination
with
insulin aspart
Twice-Daily
LEVEMIR
5.0
(8/161)
0.13
82.0
(132/161)
20.2
Once-Daily
Glargine
10.1
(16/159)
0.31
77.4
(123/159)
21.8
Study C
Type 1 Diabetes
Adults
24 weeks
In combination
with
regular insulin
Once-Daily
LEVEMIR
7.5
(37/491)
0.35
88.4
(434/491)
31.1
Once-Daily
NPH
10.2
(26/256)
0.32
87.9
(225/256)
33.4
Study D
Type 1 Diabetes
Pediatrics
26 weeks
In combination
with
insulin aspart
Once- or
Twice Daily
LEVEMIR
15.9
(37/232)
0.91
93.1
(216/232)
31.6
Once- or
Twice Daily
NPH
20.0
(23/115)
0.99
95.7
(110/115)
37.0
Study I
Type 1 Diabetes
Pediatrics
52 weeks
In combination
with insulin aspart
Once- or
Twice Daily
LEVEMIR
1.7
(3/177)
0.02
94.9
(168/177)
56.1
Once- or
Twice Daily
NPH
7.1
(12/170)
0.09
97.6
(166/170)
70.7
Table 6: Hypoglycemia in Patients with Type 2 Diabetes
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Study E
Type 2 Diabetes
Adults
24 weeks
In combination with
oral agents
Study F
Type 2 Diabetes
Adults
22 weeks
In combination with
insulin aspart
Study H
Type 2 Diabetes
Adults
26 weeks in combination
with Liraglutide and
Metformin
Twice-
Daily
LEVEMIR
Twice-
Daily
NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
Once Daily
LEVEMIR +
Liraglutide +
Metformin
Liraglutide
+
Metformin
Severe
hypoglycemia
Percent of patients
with at least 1 event
(n/total N)
0.4
(1/237)
2.5
(6/238)
1.5
(3/195)
4.0
(8/199)
0
0
Event/patient/year
0.01
0.08
0.04
0.13
0
0
Non-severe
hypoglycemia
Percent of patients
(n/total N)
40.5
(96/237)
64.3
(153/238)
32.3
(63/195)
32.2
(64/199)
9.2
(15/163)
1.3
(2/158*)
Event/patient/year
3.5
6.9
1.6
2.0
0.29
0.03
*One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a
history of frequent hypoglycemia prior to the study
• Insulin Initiation and Intensification of Glucose Control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible
ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral
neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and
neuropathy.
• Lipodystrophy
Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy
(thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection sites within the
same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].
• Weight Gain
Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)].
• Peripheral Edema
Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
• Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions,
including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in
adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one
patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in
discontinuation of therapy.
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Rotation of the injection site within a given area from one injection to the next may help to reduce or
prevent these reactions. In some instances, these reactions may be related to factors other than insulin,
such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin
usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR,
and may be life-threatening [see Warnings and Precautions (5.4)].
• Antibody Production
All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase
or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical
trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic
control.
6.2 Postmarketing experience
The following adverse reactions have been identified during post approval use of LEVEMIR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported during post-approval use of LEVEMIR in which other insulins,
particularly rapid-acting or short-acting insulins, have been accidentally administered instead of
LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR
and other insulins, patients should be instructed always to verify the insulin label before each injection.
7 DRUG INTERACTIONS
A number of medications affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
The following are examples of medications that may increase the blood-glucose-lowering effect of
insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral
antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline,
salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood-glucose-lowering effect of
insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid
hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical
antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose
lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
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The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as
beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all
pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant while taking
LEVEMIR. A randomized controlled clinical trial of pregnant women with type I diabetes using
LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive
toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups
indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and
teratogenicity that were attributed to maternal hypoglycemia.
Clinical Considerations
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased
with good glucose control before conception and throughout pregnancy. Because insulin requirements
vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is
essential in pregnant women.
Human Data
In an, open-label, clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of
gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or
NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of
152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the
study (Total pregnant women = 310). Approximately one half of the study participants in each arm were
randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first
8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <
7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted
mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient
(n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically
significant.
Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 7. The two
most common adverse reactions were nasopharyngitis and headache. These are consistent with findings
from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the
LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia,
eight (8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization.
The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by
diabetes. Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the
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definition of pre-eclampsia was not standardized in the trial making it difficult to establish a link
between a given treatment and an increased risk of pre-eclampsia. All events were considered unlikely
related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants.
Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group
than in the NPH insulin group as a whole. There was no difference between the treatment groups in
mean blood pressure during pregnancy and there was no indication of a general increase in blood
pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following
placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of
placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the
LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6%
and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’,
‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.
Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR to
insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with
incidence ≥ 5%)D
LEVEMIR, %
(n = 152)
NPH, %
(n = 158)
Anemia
13.2
10.8
Diarrhea
11.8
5.1
Pre-eclampsia
10.5
7.0
Urinary tract infection
9.9
5.7
Gastroenteritis
8.6
5.1
Abdominal pain upper
5.9
3.8
Vomiting
5.3
4.4
Abortion spontaneous
5.3
2.5
Abdominal pain
5.3
6.3
Oropharyngeal pain
5.3
6.3
D Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be
easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and
NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patient-
year in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe
episodes of hypoglycemia were similar in both treatment groups (Table 8).
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Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes
Study G Type 1
Diabetes
Pregnancy
In combination with
insulin aspart
LEVEMIR
NPH
Severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
16.4
(25/152)
20.9
(33/158)
Events/patient/year
1.1
1.2
Non-severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
94.7
(144/152)
92.4
(146/158)
Events/patient/year
114.2
108.4
* For definition regarding severe and non-severe hypoglycemia see section 6, Hypoglycemia.
In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower
level of quantification (<25 pmol/L).
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR
use.
Animal Data
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300
nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day
(approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits
during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder
abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of
900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human
insulin control groups indicated that insulin detemir and human insulin had similar effects regarding
embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia
resulting from insulin exposure in normal animals.
8.3
Nursing Mothers
It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human
insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman.
Women with diabetes who are lactating may require adjustments of their insulin doses.
8.4
Pediatric Use
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been
established in pediatric patients (age 2 to 17 years) with type 1 diabetes [see Clinical Pharmacology
(12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than 2
years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2
diabetes.
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The dose recommendation when converting to LEVEMIR is the same as that described for adults [see
Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood
glucose.
8.5
Geriatric Use
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients
(3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were
≥65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥75 years of age. No
overall differences in safety or effectiveness were observed between these patients and younger patients,
but small sample sizes, particularly for patients ≥65 years of age in the type 1 diabetes trials and for
patients ≥75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals
cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and
maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to
recognize in the elderly.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].
11 DESCRIPTION
LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a
subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant
human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae followed by chemical modification.
Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been
omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a
molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:
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Figure 1: Structural Formula of insulin detemir
S
S
(A1)
(A21)
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
S
S
S
S
(B1)
(B29)
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys
C NH structural formula
O
LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains
100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg
phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection.
Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of
approximately 7.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including
insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin
lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue
and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits
proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of
action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir
molecules from the injection site due to self-association of the drug molecules. In addition, the
distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24
hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection
and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to > 24 hours (24 hours
was the end of the observation period).
Reference ID: 3132940
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study graph
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum
effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2
diabetes. The clamp study was terminated at 16 hours according to protocol.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study graph
12.3 Pharmacokinetics
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin
detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the
maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more
slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and
AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and
abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in
vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin
detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous
administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours
depending on dose.
Specific Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children
(6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir
Reference ID: 3132940
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For current labeling information, please visit https://www.fda.gov/drugsatfda
plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as
compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose
of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir
AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin
preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed
between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there
were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and
pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2
diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR
were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate,
severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics
of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with
human insulin have shown increased circulating levels of insulin in patients with renal impairment.
Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in
patients with renal impairment [see Warnings and Precautions (5.5)].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate
and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic
impairment with a corresponding increase in apparent clearance. However, some studies with human
insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful
glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients
with hepatic impairment [see Warnings and Precautions (5.6)].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR
has not been studied [see Use in Specific Populations (8.1)].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not
been studied.
Liraglutide -No pharmacokinetic interaction was observed between liraglutide and LEVEMIR when
separate subcutaneous injections of LEVEMIR 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady
state) were administered in patients with type 2 diabetes.
Reference ID: 3132940
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For current labeling information, please visit https://www.fda.gov/drugsatfda
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested
negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral
blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
14 CLINICAL STUDIES
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and
at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of
once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with
type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2
diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily
insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The
evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood
glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials
that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin
(HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to
treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and
bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered
before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar
HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9).
Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose
(FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized
to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine
(administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated
patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, open-label clinical study (Study C, n=749), adults with type 1 diabetes were randomized
to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination
with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on
HbA1c.
Reference ID: 3132940
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Table 9: Type 1 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of patients treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for Treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose (mg/dL)
Baseline mean
Adj. mean change from baseline
Body weight (kg)
Baseline mean
Adj.Mean change from baseline
Study A
16 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Twice-daily
NPH
276
133
8.6
8.5
-0.8*
-0.7*
-0.2
(-0.3, -0.0)
21
24
16
10
48
54
17
10
209
220
-44*
-9*
74.6
75.5
0.2*
0.8*
Study B
26 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Once-
daily
insulin
glargine
161
159
8.9
8.8
-0.6**
-0.5**
-0.0
(-0.2, 0.2)
27
23
10
4
56
51
9
6
153
150
-38**
-41**
77.5
75.1
0.5**
1.0**
Study C
24 weeks
Human Soluble Insulin
(regular insulin)
Once-daily
LEVEMIR
Once-
daily
NPH
492
257
8.4
8.3
-0.1*
0.0*
-0.1
(-0.3, 0.0)
12
24
9
2
46
57
11
3
213
206
-30*
-9*
76.5
76.9
-0.3*
0.3*
*From an ANCOVA model adjusted for baseline value and country.
**From an ANCOVA model adjusted for baseline value and study site.
Type 1 Diabetes – Pediatric
Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with
type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6-17 years of age. The other
study was 52 weeks in duration and enrolled patients 2-16 years of age. In both studies, LEVEMIR and
NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each
meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of
NPH insulin (Table 10). In the 52-week study, the randomization was stratified by age (2-5 years, n=82,
and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in
the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Baseline HbA1c
Study D
26 weeks
NovoLog®
(insulin aspart)
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily NPH
232
115
8.8
8.8
Study I
52 weeks
NovoLog®
(insulin aspart)
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily NPH
177
170
8.4
8.4
Reference ID: 3132940
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Adj. mean change from baseline
-0.7*
-0.8*
0.3**
0.2**
LEVEMIR – NPH
0.1
0.1
95% CI for Treatment difference
Basal insulin dose (units/day)
-0.1;0.3
-0.1; 0.4
Baseline mean
24
26
17
17
Mean change from baseline
Total insulin dose (units/day)
8
6
8
7
Baseline mean
48
50
35
34
Mean change from baseline
Fasting blood glucose (mg/dL)
9
7
10
8
Baseline mean
181
181
135
141
Adj. mean change from baseline
Body weight (kg)
-39
-21
-10**
0**
Baseline mean
46.3
46.2
37.4
36.5
Adj.Mean change from baseline
1.6*
2.7*
2.7**
3.6**
*From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).
**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).
Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-
daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before
breakfast and evening) as part of a regimen of stable combination therapy with one or two of the
following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase
inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin
similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes,
LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with
insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for Treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose1 (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose2 (mg/dL)
Baseline mean
Study E
24 weeks
oral agents
Twice-daily
LEVEMIR
Twice-
daily
NPH
237
239
8.6
8.5
-2.0*
-2.1*
0.1
(-0.0, 0.3)
18
17
48
28
-
-
-
-
179
173
Study F
22 weeks
insulin aspart
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
195
200
8.2
8.1
-0.6**
-0.6**
-0.1
(-0.2, 0.1)
22
22
26
15
22
22
57
42
-
-
Reference ID: 3132940
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Adj. mean change from baseline
Body weight (kg)
Baseline mean
Adj.Mean change from baseline
-69*
82.5
1.2*
-74*
82.3
2.8*
-
82.0
0.5**
-
79.6
1.2**
1Study E – Conducted in insulin-naïve patients
2Study F - Fasting blood glucose data not collected
*From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.
**From an ANCOVA model adjusted for baseline value and country.
Combination Therapy with Metformin and Liraglutide
This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%)
on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin
(≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued
the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on
therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%)
achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-
randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in
period with approximately one-half of these patients doing so because of gastrointestinal adverse
reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those
who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in
the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and
metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of
the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the
percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized
to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-
on therapy with LEVEMIR.
Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically
significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide
1.8 mg + metformin alone (Table 12). From a mean baseline body weight of 96 kg after randomization,
there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared
to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8
mg + metformin alone.
Table 12: Results of a 26-week open-label trial of LEVEMIR as add on to liraglutide + metformin
compared to continued treatment with liraglutide + metformin alone in patients not achieving
HbA1c < 7% after 12 weeks of Metformin and Liraglutide
Study H
LEVEMIR +
Liraglutide
+Metformin
Liraglutide+
Metformin
Intent-to-Treat Population (N)ª
162
157
HbA1c (%) (Mean)
Baseline (week 0)
Adjusted mean change from baseline
7.6
-0.5*
7.6
0*
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Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence Interval
-0.5***
(-0.7, -0.4)
Percentage of patients achieving A1c <7%
43**
17**
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline (week 0)
Adjusted mean change from baseline
Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence Interval
166
-38*
-31***
(-39 , -23)
159
-7*
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
*From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.
**From a logistic regression model adjusted for baseline HbA1c.
***p-value <0.0001
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin
detemir per mL (U-100).
3 mL LEVEMIR FlexPen®
NDC 0169-6439-10
10 mL vial
NDC 0169-3687-12
FlexPen is for use with NovoFine® disposable needles. Each FlexPen is for use by a single patient.
LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.
16.2 Storage:
Unused (unopened) LEVEMIR should be stored in the refrigerator between 2° and 8°C (36° to 46°F).
Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not
use LEVEMIR if it has been frozen.
Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in
a refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.
If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room
temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and
light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator,
even if the FlexPen or vial still contains insulin.
Vials:
After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not
possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it
Reference ID: 3132940
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is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be
discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after
they are first kept out of the refrigerator.
LEVEMIR FlexPen:
After initial use, the LEVEMIR FlexPen must NOT be stored in a refrigerator and must NOT be stored
with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at
room temperature, below 30°C (86°F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days
after they are first kept out of the refrigerator.
The storage conditions are summarized in Table 13:
Table 13: Storage Conditions for LEVEMIR FlexPen and vial
Not in-use
(unopened)
Refrigerated
Not in-use
(unopened)
Room Temperature
(below 30°C)
In-use
(opened)
3 mL
LEVEMIR
FlexPen
Until expiration date
42 days*
42 days*
Room Temperature
(below 30°C)
(Do not refrigerate)
42 days*
10 mL vial
Until expiration date
42 days*
Refrigerated or Room
Temperature (below 30°C)
*The total time allowed at room temperature (below 30°C) is 42 days regardless of whether the product is in-use or not in-use.
16.3 Preparation and handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to
administration and should only be used if the solution appears clear and colorless.
Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See
Warnings and Precautions (5.2)].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1 Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under
medical supervision. Patients should be informed about the potential side effects of insulin therapy,
including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the
same body region), and allergic reactions. Patients should be informed that the ability to concentrate and
react may be impaired as a result of hypoglycemia. This may present a risk in situations where these
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abilities are especially important, such as driving or operating other machinery. Patients who have
frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been
reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to
always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients
must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
Patients should be instructed on self-management procedures including glucose monitoring, proper
injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional
disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin
dose, inadequate food intake, and skipped meals.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or
are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional
information.
17.2 Never Share a LEVEMIR FlexPen Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen with another person, even if the
needle is changed. Sharing of the FlexPen between patients may pose a risk of transmission of
infection.
Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo
Nordisk A/S.
LEVEMIR is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents
pending.
FlexPen is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-800-727-6500
Reference ID: 3132940
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For current labeling information, please visit https://www.fda.gov/drugsatfda
www.novonordisk-us.com
Reference ID: 3132940
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
LEVEMIR® (LEV–uh-mere)
(insulin detemir [rDNA origin] injection)
solution for subcutaneous injection
Read the Patient Information that comes with LEVEMIR® before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure
that you know how to manage your diabetes. Ask your healthcare
provider, if you have any questions about managing your diabetes.
What is LEVEMIR?
LEVEMIR is a man-made long-acting insulin used to control high blood
sugar in adults and children with diabetes mellitus.
It is not recommended to use LEVEMIR to treat diabetic ketoacidosis.
Who should not use LEVEMIR?
Do not use LEVEMIR if:
• you are allergic to any of the ingredients in LEVEMIR. See the end
of this leaflet for a complete list of ingredients in LEVEMIR.
What should I tell my healthcare provider before using
LEVEMIR?
Before you use LEVEMIR, tell your healthcare provider if you:
• have liver or kidney problems
• have any other medical conditions. Some medical conditions can
affect your insulin needs and your dose of LEVEMIR.
• are pregnant or plan to become pregnant. It is not known, if
LEVEMIR would harm your unborn baby. Talk to your healthcare
provider, if you are pregnant or plan to become pregnant. You and
your healthcare provider should talk about the best way to manage
your diabetes while you are pregnant.
• are breastfeeding or plan to breast-feed. It is not known if
LEVEMIR passes into breast milk. You and your healthcare provider
should decide if you will take LEVEMIR while you breastfeed.
Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins and
herbal supplements. LEVEMIR may affect the way other medicines
work, and other medicines may affect how LEVEMIR works.
Reference ID: 3132940
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with
you to show your healthcare provider and pharmacist when you get a
new medicine.
How should I use LEVEMIR?
• Use LEVEMIR exactly as your healthcare provider told you to use it.
• Your healthcare provider will tell you how much LEVEMIR to use and
when to use it.
• Do not make any changes to your dose or type of insulin unless you
are told to do so by your healthcare provider.
Know your insulin. Make sure you know:
• the type and strength of insulin prescribed for you.
• the amount of insulin you take.
• the best time for you to take your insulin. This may change if
you take a different type of insulin.
• Do not dilute or mix LEVEMIR with any other insulin or injectable
diabetes medicine. Your LEVEMIR will not work the right way and
you may lose control of your blood sugar, which can be serious.
Give yourself separate injections. You may give the separate
injections in the same body area (for example, your stomach area),
but you should not give the injections right next to each other.
• Do not use LEVEMIR in an insulin pump.
• Inject LEVEMIR under your skin (subcutaneously) in your upper
arm, abdomen (stomach area), or thigh. Never inject LEVEMIR into
a vein or muscle.
• Change injection sites within the area you choose with each dose.
Do not inject into the exact same spot for each injection.
• Read the instructions for use that comes with your LEVEMIR.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject LEVEMIR before
you start taking it.
• Your healthcare provider will decide which type of LEVEMIR to
prescribe for you.
LEVEMIR comes in:
• 10 mL vials (small bottles) for use with a syringe
• 3 mL LEVEMIR FlexPen®
Ask your healthcare provider how you should use LEVEMIR.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you use too much LEVEMIR, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away
(fruit juice, sugar candies, or glucose tablets). It is important to
treat low blood sugar (hypoglycemia) right away because it could
get worse and you could pass out (lose consciousness).
If you pass out you will need help from another person or
emergency medical services right away. See “What are the
possible side effects of LEVEMIR?” for more information on
low blood sugar (hypoglycemia).
• If you forget to take your dose of LEVEMIR, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death.
Follow your healthcare provider’s instructions for treating high
blood sugar.
Know your symptoms of high blood sugar, which may include:
• increased thirst
• high amounts of sugar and
• frequent urination
ketones in your urine
• drowsiness
• nausea, vomiting (throwing
• loss of appetite
up) or stomach pain
• a hard time breathing
• fruity smell on the breath
• Do not share needles, insulin pens or syringes with others.
• Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check your
blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
change in diet
•
stress
•
change in physical activity
•
other medicines you
or exercise
take
What should I avoid while taking LEVEMIR?
•
Alcohol. Drinking alcohol may affect your blood sugar when
you use LEVEMIR.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for
you to drive if you often have:
• low blood sugar (hypoglycemia)
• decreased or no warning signs of low blood sugar
What are the possible side effects of LEVEMIR?
LEVEMIR can cause serious side effects, including:
• Low blood sugar (hypoglycemia). Signs and symptoms of low
blood sugar may include:
• dizziness or
• trouble concentrating or
lightheadedness
confusion
• shakiness
• blurred vision
• hunger
• slurred speech
• fast heart beat
• anxiety or mood changes
• tingling in your hands,
• headache
feet, lips or tongue
• sweating
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, and death. In some people their blood sugar
may get so low that they need another person to help them. Talk to
your healthcare provider about how to tell if you have low blood sugar
and what to do if this happens while taking LEVEMIR. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
If you are using LEVEMIR with another diabetes medicine, your
LEVEMIR dose may need to be changed to reduce your chance of
getting low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of LEVEMIR may need to be changed.
• Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) the area where you inject your insulin to help
prevent these skin changes from happening. Do not inject insulin
into areas of skin that have thickening or pits.
• Serious allergic reactions. LEVEMIR can cause life
threatening symptoms. Get medical help right away if you have
any of these symptoms of an allergic reaction:
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• a rash all over your body
• fast heartbeat
• itching
• sweating
• shortness of breath
• feel faint
• trouble breathing
(wheezing)
Common side effects of LEVEMIR include:
• Low blood sugar (hypoglycemia). See “What are the possible
side effects of LEVEMIR?” for more information on low blood
sugar (hypoglycemia).
• Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious, talk to your
healthcare provider.
• Weight gain. This can occur with any insulin therapy. Talk to your
healthcare provider about how LEVEMIR can affect your weight.
Tell your healthcare provider if you have any side effect that bothers
you or does not go away.
These are not all of the possible side effects from LEVEMIR. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store LEVEMIR?
Unopened LEVEMIR:
•
Keep all unopened LEVEMIR in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Unopened LEVEMIR can be kept until the expiration date on
the label if the medicine has been stored in a refrigerator.
•
If refrigeration is not possible, you can keep the unopened
LEVEMIR at room temperature below 86°F (30°C).
•
Throw away LEVEMIR 42 days after it is first kept out of the
refrigerator.
•
Do not freeze. Do not use LEVEMIR if it has been frozen.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Keep unopened LEVEMIR in the carton to protect it from
light.
LEVEMIR in use:
•
Vials
• Keep opened vials of LEVEMIR in the refrigerator or at
room temperature below 86°F (30°C) away from direct
heat or light.
• Throw away a vial that has always been kept in the
refrigerator after 42 days of use, even if there is insulin
left in the vial.
• Throw away a vial that has been kept at room
temperature 42 days after it is first kept out of the
refrigerator, even if there is insulin left in the vial.
•
LEVEMIR FlexPen
• Keep at room temperature below 86°F (30°C) for up to
42 days.
• Do not store a LEVEMIR FlexPen that you are using in
the refrigerator.
• Do not store LEVEMIR with the needle attached.
• Keep LEVEMIR FlexPen away from direct heat or light.
• Throw away used LEVEMIR FlexPens after 42 days, even
if there is insulin left in them.
Keep LEVEMIR and all medicines out of the reach of children.
General information about LEVEMIR
Medicines are sometimes prescribed for conditions that are not
mentioned in the patient leaflet. Do not use LEVEMIR for a condition
for which it was not prescribed. Do not give LEVEMIR to other people,
even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about
LEVEMIR. If you would like more information about LEVEMIR or
diabetes, talk with your healthcare provider. You can ask your
healthcare provider for information about LEVEMIR that is written for
healthcare professionals.
For more information about LEVEMIR, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in LEVEMIR?
Active Ingredient: Insulin detemir
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium
phosphate dihydrate, sodium chloride and water for injection.
Hydrochloric acid or sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks of
Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538,
6,011,007, 6,869,930 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297,
6,235,004 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Revised: April 2012
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions For Use
LEVEMIR® 10 mL vial
Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial
and each time you get a refill. You should read the instructions in this manual even if you have
used an insulin 10 mL vial before.
How should I use the LEVEMIR 10 mL vial?
Using the 10 mL vial:
1. Check to make sure that you have the correct type of insulin.
This is especially important if you use different types of insulin.
2. Look at the vial and the insulin. The LEVEMIR insulin should
be clear and colorless. The tamper-resistant cap should be in
place before the first use. If the cap has been removed before
your first use of the vial, or if the insulin is cloudy or colored,
Do not use the insulin and return it to your pharmacy.
3. Wash your hands with soap and water.
4. If you are using a new vial, pull off the tamper-resistant cap.
usa
ge illustration
Before each use, wipe the rubber stopper with an alcohol
wipe.
5. Do not roll or shake the vial. Shaking the vial right before the
dose is drawn into the syringe may cause bubbles or foam.
This can cause you to draw up the wrong dose of insulin. The
insulin should be used only if it is clear and colorless.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Pull back the plunger on your syringe until the black tip
reaches the marking for the number of units you will inject.
7. Push the needle through the rubber stopper into the vial.
8. Push the plunger all the way in. This inserts air into the vial.
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose that you
need.
10. If there are air bubbles, tap the syringe gently with your finger
to raise the air bubbles to the top of the needle. Then slowly
push the plunger to the correct unit marking for your dose.
us
ag
e
il
lustration
11. Check to make sure you have the right dose of LEVEMIR in
the syringe.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12. Pull the syringe out of the vial.
13. Inject your LEVEMIR right away as instructed by your
healthcare provider.
How should I inject LEVEMIR with a syringe?
If you clean your injection site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider about how to rotate injection sites and how to give an
injection.
1. Pinch your skin between two fingers, push the needle into the
skinfold, using a dart-like motion and push the plunger to inject
the insulin under your skin. The needle will be straight in.
usage illustration
2. Keep the needle under your skin for at least 6 seconds to
make sure you have injected all the insulin. After you pull the
needle from your skin you may see a drop of Levemir at the
needle tip. This is normal and has no effect on the dose you
just received.
3. If blood appears after you pull the needle from your skin, press
the injection site lightly with an alcohol swab. Do not rub the
area.
4. After each injection, remove the needle without recapping
and dispose of it in a puncture-resistant container. Used
syringes, needles, and lancets should be placed in sharps
containers (such as red biohazard containers), hard plastic
containers (such as detergent bottles), or metal containers
(such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised: January 2012
Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930,
and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LEVEMIR FlexPen should not be used by people who are blind or have severe
eyesight problems without the help of a person who has good eyesight and who is
trained to use the LEVEMIR FlexPen the right way.
Instructions For Use
LEVEMIR® FlexPen®
Please carefully read the following Instructions for use before using your LEVEMIR®
FlexPen® and each time you get a refill. You should read the instructions in this manual
even if you have used a LEVEMIR FlexPen before.
LEVEMIR FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to
60 units in increments of 1 unit. LEVEMIR FlexPen is designed to be used with
NovoFine® needles.
Getting ready
Make sure you have the following items:
•
LEVEMIR FlexPen
•
NovoFine disposable needles
•
Alcohol swab usage illustration
PREPARING YOUR LEVEMIR FLEXPEN
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. LEVEMIR should
look clear and colorless.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustration
B. Attaching the needle
Remove the protective tab from a new disposable needle.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attach the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your LEVEMIR FlexPen
until you are ready to give your injection. usage illustration
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and throw it away (see diagram
D). usage illustration
Always use a new needle for each injection to cut down the chance of infection and to
prevent blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of needle sticks, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection, small amounts of air may collect in the cartridge during normal use.
To avoid injecting air and to ensure you take the right dose of insulin:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your LEVEMIR FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any
air bubbles collect at the top of the cartridge (see diagram F).
G. While you keep the needle pointing upwards, press the push-
button all the way in (see diagram G). The dose selector
returns to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use the
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727
Reference ID: 3132940 usage illustration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6500.
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram H). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Wipe the skin with an alcohol swab and let the area dry. usage illustration
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram I). Be careful only to
push the button after the needle is in the skin. usage illustration
Turning the dose selector will not inject insulin.
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has
been pulled out from the skin (see diagram J). This will make
sure that the full dose has been given.
You may see a drop of LEVEMIR at the needle tip. This is
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin,
press the injection site lightly with an alcohol swab. Do not
rub the area. usage illustration
After the injection
Carefully remove the needle from the pen after each injection. This helps to
prevent infection and leakage of insulin. You can carefully recap the needle with
the bigger outer cap to help make it easier to remove the needle.
Do not recap the needle with the small inner cap. Recapping with this small part
can increase your chances of having a needle stick injury.
Put the needle in a sharps container or some type of hard plastic or metal
container with a screw top such as a detergent bottle or empty coffee can.
These containers should be sealed and thrown away the right way. Check
with your healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away used
needles and syringes. Do not throw away used needles and syringes in
household trash or recycling bins.
K. Put the pen cap on the LEVEMIR FlexPen and store the
LEVEMIR FlexPen without the needle attached (see diagram K).
The LEVEMIR FlexPen prevents the cartridge from being
completely emptied. It can deliver 300 units then you should
throw it away in a sharps container or some type of hard plastic
or metal container with a screw top, such as a detergent bottle
or empty coffee can. usage illustration
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FUNCTION CHECK
L. If your LEVEMIR FlexPen is not working the right way, follow
the steps below:
•
Attach a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap. usage illustration
•
Do an airshot as described in “Giving the airshot before
each injection” (see diagram E through G).
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the LEVEMIR FlexPen so the needle is pointing
down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap to the marker
(see diagram L). If LEVEMIR FlexPen has released too much or too little insulin,
do the function check again. If the same problem happens again, do not use your
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled with
care. If you drop your FlexPen it could get damaged. If you are concerned that
your FlexPen is damaged, use a new one. You can clean the outside of your
FlexPen by wiping it with a damp cloth. Do not soak or wash your FlexPen.
Soaking or washing the FlexPen could damage it. Do not refill your FlexPen.
Remove the needle from the LEVEMIR FlexPen after each injection. This
helps to cut down your chance of infection, prevent leakage of insulin. Be
careful when handling used needles to avoid needle sticks and transfer of
infections.
Keep your LEVEMIR FlexPen and needles out of the reach of children.
Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and
LEVEMIR FlexPen must not be shared.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a safety measure, always carry a spare insulin delivery device in case
your LEVEMIR FlexPen is lost or damaged.
Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave
it in a car or other location where it can get too hot or too cold.
Revised: January 2012
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered
trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007,
6,869,930, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3132940
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:31.488388 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021536s041lbl.pdf', 'application_number': 21536, 'submission_type': 'SUPPL ', 'submission_number': 41} |
5,676 |
__________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LEVEMIR® safely and effectively. See full prescribing information
for LEVEMIR.
LEVEMIR® (insulin detemir [rDNA origin] injection) solution for
subcutaneous injection
Initial U.S. Approval: 2005
--------------------RECENT MAJOR CHANGES-------------------
• Warnings and Precautions (5.8)
3/2013
----------------------------INDICATIONS AND USAGE---------------------
LEVEMIR is a long-acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
Important Limitations of Use:
Not recommended for treating diabetic ketoacidosis. Use intravenous,
rapid acting or short-acting insulin instead.
----------------------DOSAGE AND ADMINISTRATION-------------------
The starting dose should be individualized based on the type of
diabetes and whether the patient is insulin-naïve (2.1, 2.2, 2.3)
Administer subcutaneously once daily or in divided doses twice daily.
Once daily administration should be given with the evening meal or at
bedtime (2.1)
Rotate injection sites within an injection area (abdomen, thigh, or
deltoid) to reduce the risk of lipodystrophy (2.1)
Converting from other insulin therapies may require adjustment of
timing and dose of LEVEMIR. Closely monitor glucoses especially
upon converting to LEVEMIR and during the initial weeks thereafter
(2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------
Solution for injection 100 Units/mL (U-100) in
3 mL LEVEMIR FlexPen®
10 mL vial (3)
------------------------------CONTRAINDICATIONS------------------------
Do not use in patients with hypersensitivity to LEVEMIR or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
Dose adjustment and monitoring: Monitor blood glucose in all patients
treated with insulin. Insulin regimens should be modified cautiously and
only under medical supervision (5.1)
Administration: Do not dilute or mix with any other insulin or solution.
Do not administer subcutaneously via an insulin pump, intramuscularly,
or intravenously because severe hypoglycemia can occur (5.2)
Hypoglycemia is the most common adverse reaction of insulin therapy
and may be life-threatening (5.3, 6.1)
Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur (5.4)
Renal or hepatic impairment: May require adjustment of the LEVEMIR
dose (5.5, 5.6)
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and
insulin, including LEVEMIR(5.8)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions associated with LEVEMIR include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, rash and pruritus (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Certain drugs may affect glucose metabolism requiring insulin dose
adjustment and close monitoring of blood glucose (7)
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine) (7)
----------------------USE IN SPECIFIC POPULATIONS-------------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not been
studied in children with type 1 diabetes < 2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 3/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Initiation of LEVEMIR Therapy
2.3 Converting to LEVEMIR from Other Insulin Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Dosage Adjustment and Monitoring
5.2 Administration
5.3 Hypoglycemia
5.4 Hypersensitivity and Allergic Reactions
5.5 Renal Impairment
5.6 Hepatic Impairment
5.7 Drug Interactions
5.8 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Preparation and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Patients
17.2 Never Share a LEVEMIR FlexPen Between Patients
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3273518
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus.
Important Limitations of Use:
LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting
or short-acting insulin is the preferred treatment for this condition.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration.
Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at
bedtime.
Patients who require twice-daily dosing can administer the evening dose with the evening meal, at
bedtime, or 12 hours after the morning dose.
The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is
essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].
In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting
insulin.
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid)
from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all
insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by
exercise and other variables, such as stress, intercurrent illness, or changes in co-administered
medications or meal patterns.
When using LEVEMIR with a glucagon-like peptide (GLP)-1 receptor agonist, administer as separate
injections. Never mix. It is acceptable to inject LEVEMIR and a GLP-1 receptor agonist in the same
body region but the injections should not be adjacent to each other.
2.2 Initiation of LEVEMIR therapy
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The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately
one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be
used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on oral antidiabetic medications is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or
divided into a twice daily regimen.
The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled
on a GLP-1 receptor agonist is 10 Units given once daily in the evening.
LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages
of LEVEMIR should be individualized under the supervision of a healthcare provider.
2.3 Converting to LEVEMIR from other insulin therapies
If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients
with type 2 diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see
Clinical Studies (14)].
As with all insulins, close glucose monitoring is recommended during the transition and in the initial
weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other
concomitant antidiabetic treatment may need to be adjusted.
3 DOSAGE FORMS AND STRENGTHS
LEVEMIR solution for injection 100 Unit per mL is available as:
3 mL LEVEMIR FlexPen®
10 mL vial
4 CONTRAINDICATIONS
LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients.
Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen
should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a
change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different
individuals or at different times in the same individual and is dependent on many conditions, including
the local blood supply, local temperature, and physical activity.
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5.2 Administration
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of
LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular
administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and
Precautions (5.3)].
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the
pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR
and the mixed insulin may be altered in an unpredictable manner.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk
of hypoglycemia increases with intensive glycemic control.
When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need
to be lowered or more conservatively titrated to minimize the risk of hypoglycemia [see Adverse
Reactions (6.1)].
All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to
unconsciousness or convulsions and may result in temporary or permanent impairment of brain function
or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion,
or glucagon administration has been observed in clinical trials with insulin, including trials with
LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals),
exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions
(7)].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
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Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions,
such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products,
including LEVEMIR.
5.5 Renal impairment
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals
with renal impairment and healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with renal impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
renal impairment [see Clinical Pharmacology (12.3)].
5.6 Hepatic impairment
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin
detemir compared to healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with liver impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
hepatic impairment [see Clinical Pharmacology (12.3)].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia
or hyperglycemia [see Drug Interactions (7)].
5.8 Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma
agonists, can cause dose-related fluid retention, particularly when used in combination with insulin.
Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including
LEVEMIR, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If
heart failure develops, it should be managed according to current standards of care, and discontinuation
or dose reduction of the PPAR-gamma agonist must be considered.
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
Hypoglycemia [see Warnings and Precautions (5.3)]
Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in
one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not
reflect the rates actually observed in clinical practice.
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The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical
trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below.
See Tables 5 and 6 for the hypoglycemia findings.
In the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg +
metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled
total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of
gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only
those patients who completed the run-in period with inadequate glycemic control were randomized to 26
weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg +
metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in
≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated
with liraglutide 1.8 mg and metformin alone (6.9%).
In two pooled trials, a total of 1155 adults with type 1 diabetes were exposed to individualized doses of
LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and
the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are
summarized in Table 1.
Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and
24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 767)
NPH, %
(n = 388)
Upper respiratory tract infection
26.1
21.4
Headache
22.6
22.7
Pharyngitis
9.5
8.0
Influenza-like illness
7.8
7.0
Abdominal Pain
6.0
2.6
A total of 320 adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=161)
or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total
exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summarized in
Table 2.
Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart
+ LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions
with incidence ≥ 5%)
LEVEMIR, %
(n = 161)
Glargine, %
(n = 159)
Upper respiratory tract infection
26.7
32.1
Headache
14.3
19.5
Back pain
8.1
6.3
Influenza-like illness
6.2
8.2
Gastroenteritis
5.6
4.4
Bronchitis
5.0
1.9
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In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of
LEVEMIR (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and
the total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions are
summarized in Table 3.
Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and
24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 432)
NPH, %
(n = 437)
Upper respiratory tract infection
12.5
11.2
Headache
6.5
5.3
A total of 347 children and adolescents (6-17 years) with type 1 diabetes were exposed to individualized
doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180
days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions
are summarized in Table 4.
Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and
adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 232)
NPH, %
(n = 115)
Upper respiratory tract infection
35.8
42.6
Headache
31.0
32.2
Pharyngitis
17.2
20.9
Gastroenteritis
16.8
11.3
Influenza-like illness
13.8
20.9
Abdominal pain
13.4
13.0
Pyrexia
10.3
6.1
Cough
8.2
4.3
Viral infection
7.3
7.8
Nausea
6.5
7.0
Rhinitis
6.5
3.5
Vomiting
6.5
10.4
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
LEVEMIR [see Warnings and Precautions (5.3)].
Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR
clinical trials.
For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an
event with symptoms consistent with hypoglycemia requiring assistance of another person and
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Severe Hypoglycemia
Non-severe Hypoglycemia
Percent of
patients with at
least 1 event
(n/total N)
Event/patient/
year
Percent of patients
(n/total N)
Event/patient/
year
Study A
Type 1 Diabetes
Adults
16 weeks
In combination
with
insulin aspart
Twice-daily
LEVEMIR
8.7
(24/276)
0.52
88.0
(243/276)
26.4
Twice-daily
NPH
10.6
(14/132)
0.43
89.4
(118/132)
37.5
Study B
Type 1 Diabetes
Adults
26 weeks
In combination
with
insulin aspart
Twice-daily
LEVEMIR
5.0
(8/161)
0.13
82.0
(132/161)
20.2
Once-daily
Glargine
10.1
(16/159)
0.31
77.4
(123/159)
21.8
Study C
Type 1 Diabetes
Adults
24 weeks
In combination
with
regular insulin
Once-daily
LEVEMIR
7.5
(37/491)
0.35
88.4
(434/491)
31.1
Once-daily
NPH
10.2
(26/256)
0.32
87.9
(225/256)
33.4
Study D
Type 1 Diabetes
Pediatrics
26 weeks
In combination
with
insulin aspart
Once- or
Twice-daily
LEVEMIR
15.9
(37/232)
0.91
93.1
(216/232)
31.6
Once- or
Twice-daily
NPH
20.0
(23/115)
0.99
95.7
(110/115)
37.0
Study I
Once- or
associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or
prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other
pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness,
unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who
may have required glucagon or intravenous glucose.
For the adult trials and pediatric Study D, non-severe hypoglycemia was defined as an asymptomatic or
symptomatic plasma glucose < 56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A
and C) that was self-treated by the patient. For pediatric Study I, non-severe hypoglycemia included
asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient
could self-treat or treat by taking oral therapy provided by the caregiver.
The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study
designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see
Tables 5 and 6).
Table 5: Hypoglycemia in Patients with Type 1 Diabetes
1.7
0.02
94.9
56.1
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Type 1 Diabetes
Pediatrics
Twice-daily
LEVEMIR
(3/177)
(168/177)
52 weeks
In combination
with insulin aspart
Once- or
Twice-daily
NPH
7.1
(12/170)
0.09
97.6
(166/170)
70.7
Table 6: Hypoglycemia in Patients with Type 2 Diabetes
Study E
Type 2 Diabetes
Adults
24 weeks
In combination with
oral agents
Study F
Type 2 Diabetes
Adults
22 weeks
In combination with
insulin aspart
Study H
Type 2 Diabetes
Adults
26 weeks
In combination with
Liraglutide and Metformin
Twice-
daily
LEVEMIR
Twice-
daily
NPH
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily
NPH
Once- daily
LEVEMIR +
Liraglutide +
Metformin
Liraglutide
+
Metformin
Severe
hypoglycemia
Percent of patients
with at least 1 event
(n/total N)
0.4
(1/237)
2.5
(6/238)
1.5
(3/195)
4.0
(8/199)
0
0
Event/patient/year
0.01
0.08
0.04
0.13
0
0
Non-severe
hypoglycemia
Percent of patients
(n/total N)
40.5
(96/237)
64.3
(153/238)
32.3
(63/195)
32.2
(64/199)
9.2
(15/163)
1.3
(2/158*)
Event/patient/year
3.5
6.9
1.6
2.0
0.29
0.03
*One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a
history of frequent hypoglycemia prior to the study
Insulin Initiation and Intensification of Glucose Control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible
ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral
neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and
neuropathy.
Lipodystrophy
Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy
(thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection sites within the
same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].
Weight Gain
Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)].
Peripheral Edema
Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
Allergic Reactions
Local Allergy
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As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions,
including localized erythema, pain, pruritus, urticaria, edema, and inflammation. In clinical studies in
adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one
patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in
discontinuation of therapy.
Rotation of the injection site within a given area from one injection to the next may help to reduce or
prevent these reactions. In some instances, these reactions may be related to factors other than insulin,
such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin
usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR,
and may be life-threatening [see Warnings and Precautions (5.4)].
Antibody Production
All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase
or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical
trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic
control.
6.2 Postmarketing experience
The following adverse reactions have been identified during post approval use of LEVEMIR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported during post-approval use of LEVEMIR in which other insulins,
particularly rapid-acting or short-acting insulins, have been accidentally administered instead of
LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR
and other insulins, patients should be instructed always to verify the insulin label before each injection.
7 DRUG INTERACTIONS
A number of medications affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
The following are examples of medications that may increase the blood-glucose-lowering effect of
insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral
antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline,
salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood-glucose-lowering effect of
insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid
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hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical
antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose
lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as
beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all
pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant while taking
LEVEMIR. A randomized controlled clinical trial of pregnant women with type 1 diabetes using
LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive
toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups
indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and
teratogenicity that were attributed to maternal hypoglycemia.
Clinical Considerations
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased
with good glucose control before conception and throughout pregnancy. Because insulin requirements
vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is
essential in pregnant women.
Human Data
In an open-label clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of
gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or
NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of
152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the
study (total pregnant women = 310). Approximately one half of the study participants in each arm were
randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first
8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <
7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted
mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient
(n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically
significant.
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Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 7. The two
most common adverse reactions were nasopharyngitis and headache. These are consistent with findings
from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the
LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia,
eight (8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization.
The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by
diabetes. Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the
definition of pre-eclampsia was not standardized in the trial making it difficult to establish a link
between a given treatment and an increased risk of pre-eclampsia. All events were considered unlikely
related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants.
Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group
than in the NPH insulin group as a whole. There was no difference between the treatment groups in
mean blood pressure during pregnancy and there was no indication of a general increase in blood
pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following
placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of
placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the
LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6%
and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’,
‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.
Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR to
insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with
incidence ≥ 5%)
LEVEMIR, %
(n = 152)
NPH, %
(n = 158)
Anemia
13.2
10.8
Diarrhea
11.8
5.1
Pre-eclampsia
10.5
7.0
Urinary tract infection
9.9
5.7
Gastroenteritis
8.6
5.1
Abdominal pain upper
5.9
3.8
Vomiting
5.3
4.4
Abortion spontaneous
5.3
2.5
Abdominal pain
5.3
6.3
Oropharyngeal pain
5.3
6.3
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be
easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and
NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patient-
year in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe
episodes of hypoglycemia were similar in both treatment groups (Table 8).
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Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes
Study G Type 1
Diabetes
Pregnancy
In combination with
insulin aspart
LEVEMIR
NPH
Severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
16.4
(25/152)
20.9
(33/158)
Events/patient/year
1.1
1.2
Non-severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
94.7
(144/152)
92.4
(146/158)
Events/patient/year
114.2
108.4
* For definition regarding severe and non-severe hypoglycemia see section 6, Hypoglycemia.
In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower
level of quantification (<25 pmol/L).
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR
use.
Animal Data
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300
nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day
(approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits
during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder
abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of
900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human
insulin control groups indicated that insulin detemir and human insulin had similar effects regarding
embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia
resulting from insulin exposure in normal animals.
8.3
Nursing Mothers
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It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human
insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman.
Women with diabetes who are lactating may require adjustments of their insulin doses.
8.4
Pediatric Use
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been
established in pediatric patients (age 2 to 17 years) with type 1 diabetes [see Clinical Pharmacology
(12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than 2
years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2
diabetes.
The dose recommendation when converting to LEVEMIR is the same as that described for adults [see
Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood
glucose.
8.5
Geriatric Use
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients
(3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were
≥65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥75 years of age. No
overall differences in safety or effectiveness were observed between these patients and younger patients,
but small sample sizes, particularly for patients ≥65 years of age in the type 1 diabetes trials and for
patients ≥75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals
cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and
maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to
recognize in the elderly.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].
11 DESCRIPTION
LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a
subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant
human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae followed by chemical modification.
Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been
omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a
molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:
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s
t
ru
ctura
l form
ula
Figure 1: Structural Formula of insulin detemir
LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains
100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg
phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection.
Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of
approximately 7.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including
insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin
lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue
and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits
proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of
action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir
molecules from the injection site due to self-association of the drug molecules. In addition, the
distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24
hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection
and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to > 24 hours (24 hours
was the end of the observation period).
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Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study graph
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum
effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2
diabetes. The clamp study was terminated at 16 hours according to protocol.
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Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study graph
12.3 Pharmacokinetics
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin
detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the
maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more
slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and
AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and
abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in
vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin
detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous
administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours
depending on dose.
Specific Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children
(6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir
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plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as
compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose
of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir
AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin
preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed
between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there
were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and
pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2
diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR
were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate,
severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics
of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with
human insulin have shown increased circulating levels of insulin in patients with renal impairment.
Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in
patients with renal impairment [see Warnings and Precautions (5.5)].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate
and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic
impairment with a corresponding increase in apparent clearance. However, some studies with human
insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful
glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients
with hepatic impairment [see Warnings and Precautions (5.6)].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR
has not been studied [see Use in Specific Populations (8.1)].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not
been studied.
Liraglutide -No pharmacokinetic interaction was observed between liraglutide and LEVEMIR when
separate subcutaneous injections of LEVEMIR 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady
state) were administered in patients with type 2 diabetes.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested
negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral
blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
14 CLINICAL STUDIES
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and
at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of
once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with
type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2
diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily
insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The
evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood
glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials
that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin
(HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to
treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and
bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered
before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar
HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9).
Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose
(FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized
to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine
(administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated
patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, open-label clinical study (Study C, n=749), adults with type 1 diabetes were randomized
to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination
with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on
HbA1c.
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Table 9: Type 1 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of patients treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose (mg/dL)
Baseline mean
Adj. mean change from baseline
Body weight (kg)
Baseline mean
Adj.mean change from baseline
Study A
16 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Twice-daily
NPH
276
133
8.6
8.5
-0.8*
-0.7*
-0.2
(-0.3, -0.0)
21
24
16
10
48
54
17
10
209
220
-44*
-9*
74.6
75.5
0.2*
0.8*
Study B
26 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Once-
daily
insulin
glargine
161
159
8.9
8.8
-0.6**
-0.5**
-0.0
(-0.2, 0.2)
27
23
10
4
56
51
9
6
153
150
-38**
-41**
77.5
75.1
0.5**
1.0**
Study C
24 weeks
Human Soluble Insulin
(regular insulin)
Once-daily
LEVEMIR
Once-
daily
NPH
492
257
8.4
8.3
-0.1*
0.0*
-0.1
(-0.3, 0.0)
12
24
9
2
46
57
11
3
213
206
-30*
-9*
76.5
76.9
-0.3*
0.3*
*From an ANCOVA model adjusted for baseline value and country.
**From an ANCOVA model adjusted for baseline value and study site.
Type 1 Diabetes – Pediatric
Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with
type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6-17 years of age. The other
study was 52 weeks in duration and enrolled patients 2-16 years of age. In both studies, LEVEMIR and
NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each
meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of
NPH insulin (Table 10). In the 52-week study, the randomization was stratified by age (2-5 years, n=82,
and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in
the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Study D
26 weeks
NovoLog®
(insulin aspart)
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily NPH
232
115
Study I
52 weeks
NovoLog®
(insulin aspart)
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily
NPH
177
170
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Baseline HbA1c
8.8
8.8
8.4
8.4
Adj. mean change from baseline
-0.7*
-0.8*
0.3**
0.2**
LEVEMIR – NPH
0.1
0.1
95% CI for treatment difference
Basal insulin dose (units/day)
(-0.1, 0.3)
(-0.1, 0.4)
Baseline mean
24
26
17
17
Mean change from baseline
Total insulin dose (units/day)
8
6
8
7
Baseline mean
48
50
35
34
Mean change from baseline
Fasting blood glucose (mg/dL)
9
7
10
8
Baseline mean
181
181
135
141
Adj. mean change from baseline
Body weight (kg)
-39
-21
-10**
0**
Baseline mean
46.3
46.2
37.4
36.5
Adj.mean change from baseline
1.6*
2.7*
2.7**
3.6**
*From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).
**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).
Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-
daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before
breakfast and evening) as part of a regimen of stable combination therapy with one or two of the
following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase
inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin
similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes,
LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with
insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose1 (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose2 (mg/dL)
Study E
24 weeks
oral agents
Twice-daily
LEVEMIR
Twice-
daily
NPH
237
239
8.6
8.5
-2.0*
-2.1*
0.1
(-0.0, 0.3)
18
17
48
28
-
-
-
-
Study F
22 weeks
insulin aspart
Once- or
Twice-
daily
LEVEMIR
Once- or
Twice-
daily
NPH
195
200
8.2
8.1
-0.6**
-0.6**
-0.1
(-0.2, 0.1)
22
22
26
15
22
22
57
42
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Baseline mean
179
173
-
-
Adj. mean change from baseline
-69*
-74*
-
-
Body weight (kg)
Baseline mean
82.5
82.3
82.0
79.6
Adj.mean change from baseline
1.2*
2.8*
0.5**
1.2**
1Study E – Conducted in insulin-naïve patients
2Study F - Fasting blood glucose data not collected
*From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.
**From an ANCOVA model adjusted for baseline value and country.
Combination Therapy with Metformin and Liraglutide
This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on
metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (≥1500
mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the
sulfonylurea then all patients entered a 12-week run-in period during which they received add-on
therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%)
achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-
randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in
period with approximately one-half of these patients doing so because of gastrointestinal adverse
reactions [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥7% (33% of those
who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in
the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and
metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of
the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the
percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized
to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-
on therapy with LEVEMIR.
Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically
significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide
1.8 mg + metformin alone (Table 12). From a mean baseline body weight of 96 kg after randomization,
there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared
to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8
mg + metformin alone.
Table 12: Results of a 26-week open-label trial of LEVEMIR as add on to liraglutide + metformin
compared to continued treatment with liraglutide + metformin alone in patients not achieving
HbA1c < 7% after 12 weeks of metformin and liraglutide
Study H
LEVEMIR +
Liraglutide
+Metformin
Liraglutide+
Metformin
Intent-to-Treat Population (N)ª
162
157
HbA1c (%) (Mean)
Baseline (week 0)
Adjusted mean change from baseline
7.6
-0.5*
7.6
0*
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Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence interval
-0.5***
(-0.7, -0.4)
Percentage of patients achieving A1c <7%
43**
17**
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline (week 0)
Adjusted mean change from baseline
Difference from liraglutide + metformin arm (LS
mean) b
95% Confidence interval
166
-38*
-31***
(-39, -23)
159
-7*
aIntent-to-treat population using last observation on study
bLeast squares mean adjusted for baseline value
*From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.
**From a logistic regression model adjusted for baseline HbA1c.
***p-value <0.0001
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin
detemir per mL (U-100).
3 mL LEVEMIR FlexPen®
NDC 0169-6439-10
10 mL vial
NDC 0169-3687-12
FlexPen is for use with NovoFine® disposable needles. Each FlexPen is for use by a single patient.
LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.
16.2 Storage:
Unused (unopened) LEVEMIR should be stored in the refrigerator between 2° and 8°C (36° to 46°F).
Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not
use LEVEMIR if it has been frozen.
Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in
a refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.
If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room
temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and
light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator,
even if the FlexPen or vial still contains insulin.
Vials:
After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not
possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it
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is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be
discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after
they are first kept out of the refrigerator.
LEVEMIR FlexPen:
After initial use, the LEVEMIR FlexPen must NOT be stored in a refrigerator and must NOT be stored
with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at
room temperature, below 30°C (86°F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days
after they are first kept out of the refrigerator.
The storage conditions are summarized in Table 13:
Table 13: Storage Conditions for LEVEMIR FlexPen and vial
Not in-use
(unopened)
Refrigerated
Not in-use
(unopened)
Room Temperature
(below 30°C)
In-use
(opened)
3 mL
LEVEMIR
FlexPen
Until expiration date
42 days*
42 days*
Room Temperature
(below 30°C)
(Do not refrigerate)
42 days*
10 mL vial
Until expiration date
42 days*
Refrigerated or Room
Temperature (below 30°C)
*The total time allowed at room temperature (below 30°C) is 42 days regardless of whether the product is in-use or not in-use.
16.3 Preparation and handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to
administration and should only be used if the solution appears clear and colorless.
Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See
Warnings and Precautions (5.2)].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1 Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under
medical supervision. Patients should be informed about the potential side effects of insulin therapy,
including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the
same body region), and allergic reactions. Patients should be informed that the ability to concentrate and
react may be impaired as a result of hypoglycemia. This may present a risk in situations where these
Reference ID: 3273518
Reference ID: 3290419
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For current labeling information, please visit https://www.fda.gov/drugsatfda
abilities are especially important, such as driving or operating other machinery. Patients who have
frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been
reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to
always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients
must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
Patients should be instructed on self-management procedures including glucose monitoring, proper
injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional
disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin
dose, inadequate food intake, and skipped meals.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or
are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional
information.
17.2 Never Share a LEVEMIR FlexPen Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen with another person, even if the
needle is changed. Sharing of the FlexPen between patients may pose a risk of transmission of
infection.
Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo
Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents
pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.
© 2005-201x Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3273518
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
LEVEMIR® (LEV–uh-mere)
(insulin detemir [rDNA origin] injection)
solution for subcutaneous injection
Read the Patient Information that comes with LEVEMIR® before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure
that you know how to manage your diabetes. Ask your healthcare
provider, if you have any questions about managing your diabetes.
What is LEVEMIR®?
LEVEMIR® is a man-made long-acting insulin used to control high blood
sugar in adults and children with diabetes mellitus.
It is not recommended to use LEVEMIR® to treat diabetic ketoacidosis.
Who should not use LEVEMIR®?
Do not use LEVEMIR® if:
• you are allergic to any of the ingredients in LEVEMIR®. See the end
of this leaflet for a complete list of ingredients in LEVEMIR®.
What should I tell my healthcare provider before using
LEVEMIR®?
Before you use LEVEMIR®, tell your healthcare provider if you:
• have liver or kidney problems
• take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
• have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with LEVEMIR®.
• have any other medical conditions. Some medical conditions can
affect your insulin needs and your dose of LEVEMIR®.
• are pregnant or plan to become pregnant. You and your healthcare
provider should talk about the best way to manage your diabetes
while you are pregnant.
• are breastfeeding or plan to breast-feed. It is not known if
LEVEMIR® passes into breast milk. You and your healthcare
provider should decide if you will take LEVEMIR® while you
breastfeed.
Reference ID: 3290419
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Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins and
herbal supplements. LEVEMIR® may affect the way other medicines
work, and other medicines may affect how LEVEMIR® works.
Know the medicines you take. Keep a list of your medicines with
you to show your healthcare provider and pharmacist when you get a
new medicine.
How should I use LEVEMIR®?
• Use LEVEMIR® exactly as your healthcare provider told you to use
it.
• Your healthcare provider will tell you how much LEVEMIR® to use
and when to use it.
• Do not make any changes to your dose or type of insulin unless you
are told to do so by your healthcare provider.
Know your insulin. Make sure you know:
• the type and strength of insulin prescribed for you.
• the amount of insulin you take.
• the best time for you to take your insulin. This may change if
you take a different type of insulin.
• Do not dilute or mix LEVEMIR® with any other insulin or injectable
diabetes medicine. Your LEVEMIR® will not work the right way and
you may lose control of your blood sugar, which can be serious.
Give yourself separate injections. You may give the separate
injections in the same body area (for example, your stomach area),
but you should not give the injections right next to each other.
• Do not use LEVEMIR® in an insulin pump.
• Inject LEVEMIR® under your skin (subcutaneously) in your upper
arm, abdomen (stomach area), or thigh. Never inject LEVEMIR®
into a vein or muscle.
• Change injection sites within the area you choose with each dose.
Do not inject into the exact same spot for each injection.
• Read the instructions for use that comes with your
LEVEMIR®. Talk to your healthcare provider if you have any
questions. Your healthcare provider should show you how to inject
LEVEMIR® before you start taking it.
• Your healthcare provider will decide which type of LEVEMIR® to
prescribe for you.
Reference ID: 3290419
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LEVEMIR® comes in:
• 10 mL vials (small bottles) for use with a syringe
• 3 mL LEVEMIR® FlexPen®
Ask your healthcare provider how you should use LEVEMIR®.
• If you use too much LEVEMIR® , your blood sugar may fall
low (hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away
(fruit juice, sugar candies, or glucose tablets). It is important to
treat low blood sugar (hypoglycemia) right away because it could
get worse and you could pass out (lose consciousness).
If you pass out you will need help from another person or
emergency medical services right away. See “What are the
possible side effects of LEVEMIR®?” for more information on
low blood sugar (hypoglycemia).
• If you forget to take your dose of LEVEMIR®, your blood
sugar may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death.
Follow your healthcare provider’s instructions for treating high blood
sugar.
Know your symptoms of high blood sugar, which may include:
• increased thirst
• fruity smell on the breath
• frequent urination
• high amounts of sugar and
• drowsiness
ketones in your urine
• loss of appetite
• nausea, vomiting (throwing
• a hard time breathing
up) or stomach pain
• Do not share needles, insulin pens or syringes with others.
• Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check your
blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
change in diet
•
stress
•
change in physical activity
•
other medicines you
or exercise
take
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What should I avoid while taking LEVEMIR®?
•
Alcohol. Drinking alcohol may affect your blood sugar when
you use LEVEMIR®.
•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for
you to drive if you often have:
• low blood sugar (hypoglycemia)
• decreased or no warning signs of low blood sugar
What are the possible side effects of LEVEMIR®?
LEVEMIR® can cause serious side effects, including:
• Low blood sugar (hypoglycemia). Signs and symptoms of low
blood sugar may include:
• dizziness or
• trouble concentrating or
lightheadedness
confusion
• shakiness
• blurred vision
• hunger
• slurred speech
• fast heart beat
• anxiety or mood changes
• tingling in your hands,
• headache
feet, lips or tongue
• sweating
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, and death. In some people their blood sugar
may get so low that they need another person to help them. Talk to
your healthcare provider about how to tell if you have low blood sugar
and what to do if this happens while taking LEVEMIR®. Know your
symptoms of low blood sugar. Follow your healthcare provider’s
instructions for treating low blood sugar.
If you are using LEVEMIR® with another diabetes medicine, your
LEVEMIR® dose may need to be changed to reduce your chance of
getting low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of LEVEMIR® may need to be changed.
• Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) the area where you inject your insulin to help
prevent these skin changes from happening. Do not inject insulin
into areas of skin that have thickening or pits.
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• Serious allergic reactions. LEVEMIR® can cause life
threatening symptoms. Get medical help right away if you have
any of these symptoms of an allergic reaction:
• a rash all over your body
• fast heartbeat
• itching
• sweating
• shortness of breath
• feel faint
• trouble breathing
(wheezing)
• Swelling of your hands and feet
• Heart Failure. Taking certain diabetes pills called
thiazolidinediones or “TZDs” with LEVEMIR® may cause heart failure
in some people. This can happen even if you have never had heart
failure or heart problems before. If you already have heart failure
it may get worse while you take TZDs with LEVEMIR®. Your
healthcare provider should monitor you closely while you are taking
TZDs with LEVEMIR®. Tell your healthcare provider if you have any
new or worse symptoms of heart failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and LEVEMIR® may need to be adjusted or
stopped by your healthcare provider if you have new or worse heart
failure.
Common side effects of LEVEMIR® include:
• Low blood sugar (hypoglycemia). See “What are the possible
side effects of LEVEMIR®?” for more information on low
blood sugar (hypoglycemia).
• Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious, talk to your
healthcare provider.
• Weight gain. This can occur with any insulin therapy. Talk to your
healthcare provider about how LEVEMIR® can affect your weight.
Tell your healthcare provider if you have any side effect that bothers
you or does not go away.
These are not all of the possible side effects from LEVEMIR®. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects.
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You may report side effects to FDA at 1-800-FDA-1088.
How should I store LEVEMIR®?
Unopened LEVEMIR®:
•
Keep all unopened LEVEMIR® in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Unopened LEVEMIR® can be kept until the expiration date on
the label if the medicine has been stored in a refrigerator.
•
If refrigeration is not possible, you can keep the unopened
LEVEMIR® at room temperature below 86°F (30°C).
•
Throw away LEVEMIR® 42 days after it is first kept out of the
refrigerator.
•
Do not freeze. Do not use LEVEMIR® if it has been frozen.
•
Keep unopened LEVEMIR® in the carton to protect it from
light.
LEVEMIR® in use:
•
Vials
• Keep opened vials of LEVEMIR® in the refrigerator or at
room temperature below 86°F (30°C) away from direct
heat or light.
• Throw away a vial that has always been kept in the
refrigerator after 42 days of use, even if there is insulin
left in the vial.
• Throw away a vial that has been kept at room
temperature 42 days after it is first kept out of the
refrigerator, even if there is insulin left in the vial.
•
LEVEMIR® FlexPen
• Keep at room temperature below 86°F (30°C) for up to
42 days.
• Do not store a LEVEMIR® FlexPen® that you are using in
the refrigerator.
• Do not store LEVEMIR® with the needle attached.
• Keep LEVEMIR® FlexPen® away from direct heat or
light.
• Throw away used LEVEMIR® FlexPens after 42 days,
even if there is insulin left in them.
Reference ID: 3290419
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Keep LEVEMIR® and all medicines out of the reach of children.
General information about LEVEMIR®
Medicines are sometimes prescribed for conditions that are not
mentioned in the patient leaflet. Do not use LEVEMIR® for a condition
for which it was not prescribed. Do not give LEVEMIR® to other
people, even if they have the same symptoms you have. It may harm
them.
This leaflet summarizes the most important information about
LEVEMIR®. If you would like more information about LEVEMIR® or
diabetes, talk with your healthcare provider. You can ask your
healthcare provider for information about LEVEMIR® that is written for
healthcare professionals.
For more information about LEVEMIR®, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in LEVEMIR®?
Active Ingredient: Insulin detemir
Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium
phosphate dihydrate, sodium chloride and water for injection.
Hydrochloric acid or sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks of
Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538,
6,011,007, 6,869,930 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297,
6,235,004 and other patents pending.
© 2005-2013 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Plainsboro, New Jersey 08536
www.novonordisk-us.com
1-800-727-6500
Revised: March 2013
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions For Use
LEVEMIR® 10 mL vial
Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial
and each time you get a refill. You should read the instructions in this manual even if you have
used an insulin 10 mL vial before.
How should I use the LEVEMIR 10 mL vial?
Using the 10 mL vial:
1. Check to make sure that you have the correct type of insulin.
This is especially important if you use different types of insulin.
2. Look at the vial and the insulin. The LEVEMIR insulin should
be clear and colorless. The tamper-resistant cap should be in
place before the first use. If the cap has been removed before
your first use of the vial, or if the insulin is cloudy or colored,
Do not use the insulin and return it to your pharmacy.
3. Wash your hands with soap and water.
4. If you are using a new vial, pull off the tamper-resistant cap.
usa
ge illustration
Before each use, wipe the rubber stopper with an alcohol
wipe.
5. Do not roll or shake the vial. Shaking the vial right before the
dose is drawn into the syringe may cause bubbles or foam.
This can cause you to draw up the wrong dose of insulin. The
insulin should be used only if it is clear and colorless.
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6. Pull back the plunger on your syringe until the black tip
reaches the marking for the number of units you will inject.
7. Push the needle through the rubber stopper into the vial.
8. Push the plunger all the way in. This inserts air into the vial.
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose that you
need.
10. If there are air bubbles, tap the syringe gently with your finger
to raise the air bubbles to the top of the needle. Then slowly
push the plunger to the correct unit marking for your dose.
us
ag
e
il
lustration
11. Check to make sure you have the right dose of LEVEMIR in
the syringe.
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12. Pull the syringe out of the vial.
13. Inject your LEVEMIR right away as instructed by your
healthcare provider.
How should I inject LEVEMIR with a syringe?
If you clean your injection site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider about how to rotate injection sites and how to give an
injection.
1. Pinch your skin between two fingers, push the needle into the
skinfold, using a dart-like motion and push the plunger to inject
the insulin under your skin. The needle will be straight in.
usage illustration
2. Keep the needle under your skin for at least 6 seconds to
make sure you have injected all the insulin. After you pull the
needle from your skin you may see a drop of Levemir at the
needle tip. This is normal and has no effect on the dose you
just received.
3. If blood appears after you pull the needle from your skin, press
the injection site lightly with an alcohol swab. Do not rub the
area.
4. After each injection, remove the needle without recapping
and dispose of it in a puncture-resistant container. Used
syringes, needles, and lancets should be placed in sharps
containers (such as red biohazard containers), hard plastic
containers (such as detergent bottles), or metal containers
(such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Reference ID: 3079224
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised: January 2012
Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930,
and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3079224
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LEVEMIR FlexPen should not be used by people
Instructions For Use
LEVEMIR® FlexPen®
Please carefully read the following Instructions for use before using your LEVEMIR®
FlexPen® and each time you get a refill. You should read the instructions in this manual
even if you have used a LEVEMIR FlexPen before.
LEVEMIR FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to
60 units in increments of 1 unit. LEVEMIR FlexPen is designed to be used with
NovoFine® needles.
who are blind or have severe
eyesight problems without the help of a person who has good eyesight and who is
trained to use the LEVEMIR FlexPen the right way.
Getting ready
Make sure you have the following items:
•
LEVEMIR FlexPen
•
NovoFine disposable needles
•
Alcohol swab usage illustration
PREPARING YOUR LEVEMIR FLEXPEN
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. LEVEMIR should
look clear and colorless.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. usage illustration
B. Attaching the needle
Remove the protective tab from a new disposable needle.
Reference ID: 3079224
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Attach the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your LEVEMIR FlexPen
until you are ready to give your injection. usage illustration
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and throw it away (see diagram
D). usage illustration
Always use a new needle for each injection to cut down the chance of infection and to
prevent blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of needle sticks, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection, small amounts of air may collect in the cartridge during normal use.
To avoid injecting air and to ensure you take the right dose of insulin:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your LEVEMIR FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any
air bubbles collect at the top of the cartridge (see diagram F).
G. While you keep the needle pointing upwards, press the push-
button all the way in (see diagram G). The dose selector
returns to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use the
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727usage illustration
Reference ID: 3079224
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6500.
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram H). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Wipe the skin with an alcohol swab and let the area dry. usage illustration
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram I). Be careful only to
push the button after the needle is in the skin. usage illustration
Turning the dose selector will not inject insulin.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has
been pulled out from the skin (see diagram J). This will make
sure that the full dose has been given.
You may see a drop of LEVEMIR at the needle tip. This is
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin,
press the injection site lightly with an alcohol swab. Do not
rub the area. usage illustration
After the injection
Carefully remove the needle from the pen after each injection. This helps to
prevent infection and leakage of insulin. You can carefully recap the needle with
the bigger outer cap to help make it easier to remove the needle.
Do not recap the needle with the small inner cap. Recapping with this small part
can increase your chances of having a needle stick injury.
Put the needle in a sharps container or some type of hard plastic or metal
container with a screw top such as a detergent bottle or empty coffee can.
These containers should be sealed and thrown away the right way. Check
with your healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away used
needles and syringes. Do not throw away used needles and syringes in
household trash or recycling bins.
K. Put the pen cap on the LEVEMIR FlexPen and store the
LEVEMIR FlexPen without the needle attached (see diagram K).
The LEVEMIR FlexPen prevents the cartridge from being
completely emptied. It can deliver 300 units then you should
throw it away in a sharps container or some type of hard plastic
or metal container with a screw top, such as a detergent bottle
or empty coffee can. usage illustration
Reference ID: 3079224
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FUNCTION CHECK
L. If your LEVEMIR FlexPen is not working the right way, follow
the steps below:
•
Attach a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap. usage illustration
•
Do an airshot as described in “Giving the airshot before
each injection” (see diagram E through G).
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the LEVEMIR FlexPen so the needle is pointing
down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap to the marker
(see diagram L). If LEVEMIR FlexPen has released too much or too little insulin,
do the function check again. If the same problem happens again, do not use your
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled with
care. If you drop your FlexPen it could get damaged. If you are concerned that
your FlexPen is damaged, use a new one. You can clean the outside of your
FlexPen by wiping it with a damp cloth. Do not soak or wash your FlexPen.
Soaking or washing the FlexPen could damage it. Do not refill your FlexPen.
Remove the needle from the LEVEMIR FlexPen after each injection. This
helps to cut down your chance of infection, prevent leakage of insulin. Be
careful when handling used needles to avoid needle sticks and transfer of
infections.
Keep your LEVEMIR FlexPen and needles out of the reach of children.
Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and
LEVEMIR FlexPen must not be shared.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a safety measure, always carry a spare insulin delivery device in case
your LEVEMIR FlexPen is lost or damaged.
Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave
it in a car or other location where it can get too hot or too cold.
Revised: January 2012
Reference ID: 3079224
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered
trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007,
6,869,930, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3079224
Reference ID: 3290419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:31.649743 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021536s044lbl.pdf', 'application_number': 21536, 'submission_type': 'SUPPL ', 'submission_number': 44} |
5,673 |
__________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LEVEMIR® safely and effectively. See full prescribing information
for LEVEMIR.
LEVEMIR® (insulin detemir [rDNA origin] injection) solution for
subcutaneous injection
Initial U.S. Approval: 2005
----------------------------INDICATIONS AND USAGE---------------------
LEVEMIR is a long-acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
Important Limitations of Use:
• Not recommended for treating diabetic ketoacidosis. Use intravenous,
rapid acting or short-acting insulin instead.
----------------------DOSAGE AND ADMINISTRATION-------------------
• The starting dose should be individualized based on the type of
diabetes and whether the patient is insulin-naïve (2.1, 2.2, 2.3)
• Administer subcutaneously once daily or in divided doses twice daily.
Once daily administration should be given with the evening meal or at
bedtime (2.1)
• Rotate injection sites within an injection area (abdomen, thigh, or
deltoid) to reduce the risk of lipodystrophy (2.1)
• Converting from other insulin therapies may require adjustment of
timing and dose of LEVEMIR. Closely monitor glucoses especially
upon converting to LEVEMIR and during the initial weeks thereafter
(2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------
Solution for injection 100 Units/mL (U-100) in
• 3 mL LEVEMIR FlexPen®
• 10 mL vial (3)
------------------------------CONTRAINDICATIONS------------------------
• Do not use in patients with hypersensitivity to LEVEMIR or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Dose adjustment and monitoring: Monitor blood glucose in all patients
treated with insulin. Insulin regimens should be modified cautiously and
only under medical supervision (5.1)
• Administration: Do not dilute or mix with any other insulin or solution.
Do not administer subcutaneously via an insulin pump, intramuscularly,
or intravenously because severe hypoglycemia can occur (5.2)
• Hypoglycemia is the most common adverse reaction of insulin therapy
and may be life-threatening (5.3, 6.1)
• Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur (5.4)
• Renal or hepatic impairment: May require adjustment of the LEVEMIR
dose (5.5, 5.6)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions associated with LEVEMIR include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, rash and pruritus (6)
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• Certain drugs may affect glucose metabolism requiring insulin dose
adjustment and close monitoring of blood glucose (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine) (7)
----------------------USE IN SPECIFIC POPULATIONS-------------------------
Pediatric: Has not been studied in children with type 2 diabetes. Has not been
studied in children with type 1 diabetes < 6 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 3/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Initiation of LEVEMIR Therapy
2.3 Converting to LEVEMIR from Other Insulin Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Dosage Adjustment and Monitoring
5.2 Administration
5.3 Hypoglycemia
5.4 Hypersensitivity and Allergic Reactions
5.5 Renal Impairment
5.6 Hepatic Impairment
5.7 Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Preparation and Handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Patients
17.2 Never Share a LEVEMIR FlexPen Between Patients
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus.
Important Limitations of Use:
• LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting
or short-acting insulin is the preferred treatment for this condition.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration.
Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at
bedtime.
Patients who require twice-daily dosing can administer the evening dose with the evening meal, at
bedtime, or 12 hours after the morning dose.
The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is
essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LEVEMIR should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1)].
In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting
insulin.
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid)
from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].
LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all
insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by
exercise and other variables, such as stress, intercurrent illness, or changes in co-administered
medications or meal patterns.
2.2 Initiation of LEVEMIR Therapy
The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately
one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be
used to satisfy the remainder of the daily insulin requirements.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The recommended starting dose of LEVEMIR in patients with type 2 diabetes who are not currently
treated with insulin is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or divided into a
twice daily regimen.
LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages
of LEVEMIR should be individualized under the supervision of a healthcare provider.
2.3 Converting to LEVEMIR from other insulin therapies
If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients
with type 2 diabetes may require more LEVEMIR than NPH insulin, as observed in one trial [see
Clinical Studies (14)].
As with all insulins, close glucose monitoring is recommended during the transition and in the initial
weeks thereafter. Doses and timing of concurrent rapid-acting or short-acting insulins or other
concomitant antidiabetic treatment may need to be adjusted.
3 DOSAGE FORMS AND STRENGTHS
LEVEMIR solution for injection 100 Unit per mL is available as:
•
3 mL LEVEMIR FlexPen®
•
10 mL vial
4 CONTRAINDICATIONS
LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients.
Reactions have included anaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen
should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a
change in the insulin dose or an adjustment of concomitant anti-diabetic treatment.
As with all insulin preparations, the time course of action for LEVEMIR may vary in different
individuals or at different times in the same individual and is dependent on many conditions, including
the local blood supply, local temperature, and physical activity.
5.2 Administration
LEVEMIR should only be administered subcutaneously.
Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of
LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and
Precautions (5.3)].
Do not use LEVEMIR in insulin infusion pumps.
Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the
pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR
and the mixed insulin may be altered in an unpredictable manner.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk
of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and
manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result
in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the
assistance of another person or parenteral glucose infusion, or glucagon administration has been
observed in clinical trials with insulin, including trials with LEVEMIR.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals),
exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions
(7)].
The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia.
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be
predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food
intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions,
such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or
intensified glycemic control [see Drug Interactions (7)]. These situations may result in severe
hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products,
including LEVEMIR.
5.5 Renal Impairment
No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals
with renal impairment and healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with renal impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
renal impairment [see Clinical Pharmacology (12.3)].
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.6 Hepatic Impairment
Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin
detemir compared to healthy volunteers. However, some studies with human insulin have shown
increased circulating insulin concentrations in patients with liver impairment. Careful glucose
monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with
hepatic impairment [see Clinical Pharmacology (12.3)].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia
or hyperglycemia [see Drug Interactions (7)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions (5.3)]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in
one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not
reflect the rates actually observed in clinical practice.
The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical
trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below.
See Tables 5 and 6 for the hypoglycemia findings.
Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and
24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 767)
NPH, %
(n = 388)
Upper respiratory tract infection
26.1
21.4
Headache
22.6
22.7
Pharyngitis
9.5
8.0
Influenza-like illness
7.8
7.0
Abdominal Pain
6.0
2.6
Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart
+ LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions
with incidence ≥ 5%)
LEVEMIR, %
(n = 161)
Glargine, %
(n = 159)
Upper respiratory tract infection
26.7
32.1
Headache
14.3
19.5
Back pain
8.1
6.3
Influenza-like illness
6.2
8.2
Gastroenteritis
5.6
4.4
Bronchitis
5.0
1.9
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and
24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 432)
NPH, %
(n = 437)
Upper respiratory tract infection
12.5
11.2
Headache
6.5
5.3
Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and
adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)
LEVEMIR, %
(n = 232)
NPH, %
(n = 115)
Upper respiratory tract infection
35.8
42.6
Headache
31.0
32.2
Pharyngitis
17.2
20.9
Gastroenteritis
16.8
11.3
Influenza-like illness
13.8
20.9
Abdominal pain
13.4
13.0
Pyrexia
10.3
6.1
Cough
8.2
4.3
Viral infection
7.3
7.8
Nausea
6.5
7.0
Rhinitis
6.5
3.5
Vomiting
6.5
10.4
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
• Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
LEVEMIR [see Warnings and Precautions (5.3)].
Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR
clinical trials. Severe hypoglycemia was defined as an event with symptoms consistent with
hypoglycemia requiring assistance of another person and associated with either a plasma glucose value
below 56 mg/dL (blood glucose below 50 mg/dL) or prompt recovery after oral carbohydrate,
intravenous glucose or glucagon administration. Non-severe hypoglycemia was defined as an
asymptomatic or symptomatic plasma glucose < 56 mg/dL (or equivalently blood glucose <50 mg/dL as
used in Study A and C) that was self-treated by the patient.
The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study
designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see
Tables 5 and 6).
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5: Hypoglycemia in Patients with Type 1 Diabetes
Study A
Type 1 Diabetes
Adults
16 weeks
In combination with
insulin aspart
Study B
Type 1 Diabetes
Adults
26 weeks
In combination with
insulin aspart
Study C
Type 1 Diabetes
Adults
24 weeks
In combination with
regular insulin
Study D
Type 1 Diabetes
Pediatrics
26 weeks
In combination with
insulin aspart
Twice-
Daily
LEVEMIR
Twice-
Daily
NPH
Twice-
Daily
LEVEMIR
Once-
Daily
Glargine
Once-Daily
LEVEMIR
Once-
Daily
NPH
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
Severe
hypoglycemia
Percent of
patients with
at least 1
event
(n/total N)
8.7
(24/276)
10.6
(14/132)
5.0
(8/161)
10.1
(16/159)
7.5
(37/491)
10.2
(26/256)
15.9
(37/232)
20.0
(23/115)
Event/patient/
year
0.52
0.43
0.13
0.31
0.35
0.32
0.91
0.99
Non-severe
hypoglycemia
Percent of
patients
(n/total N)
88.0
(243/276)
89.4
(118/132)
82.0
(132/161)
77.4
(123/159)
88.4
(434/491)
87.9
(225/256)
93.1
(216/232)
95.7
(110/115)
Event/patient/
year
26.4
37.5
20.2
21.8
31.1
33.4
31.6
37.0
Table 6: Hypoglycemia in Patients with Type 2 Diabetes
Study E
Type 2 Diabetes
Adults
24 weeks
In combination with
oral agents
Study F
Type 2 Diabetes
Adults
22 weeks
In combination with
insulin aspart
Twice-Daily
LEVEMIR
Twice-Daily
NPH
Once- or
Twice Daily
LEVEMIR
Once- or
Twice Daily
NPH
Severe hypoglycemia
Percent of patients
with at least 1 event
(n/total N)
0.4
(1/237)
2.5
(6/238)
1.5
(3/195)
4.0
(8/199)
Event/patient/year
0.01
0.08
0.04
0.13
Non-severe
hypoglycemia
Percent of patients
(n/total N)
40.5
(96/237)
64.3
(153/238)
32.3
(63/195)
32.2
(64/199)
Event/patient/year
3.5
6.9
1.6
2.0
• Insulin Initiation and Intensification of Glucose Control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible
ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral
neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and
neuropathy.
• Lipodystrophy
Long-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin
injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy
(thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the
same region to reduce the risk of lipodystrophy [see Dosage and Administration (2.1)].
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Weight Gain
Weight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
• Peripheral Edema
Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor
metabolic control is improved by intensified insulin therapy.
• Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking LEVEMIR may experience injection site reactions,
including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in
adults, three patients treated with LEVEMIR reported injection site pain (0.25%) compared to one
patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in
discontinuation of therapy.
Rotation of the injection site within a given area from one injection to the next may help to reduce or
prevent these reactions. In some instances, these reactions may be related to factors other than insulin,
such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin
usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR,
and may be life-threatening [see Warnings and Precautions (5.4)].
• Antibody Production
All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase
or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical
trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic
control.
6.2 Postmarketing experience
The following adverse reactions have been identified during post approval use of LEVEMIR. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported during post-approval use of LEVEMIR in which other insulins,
particularly rapid-acting or short-acting insulins, have been accidentally administered instead of
LEVEMIR [see Patient Counseling Information (17)]. To avoid medication errors between LEVEMIR
and other insulins, patients should be instructed always to verify the insulin label before each injection.
7 DRUG INTERACTIONS
A number of medications affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The following are examples of medications that may increase the blood-glucose-lowering effect of
insulins including LEVEMIR and, therefore, increase the susceptibility to hypoglycemia: oral
antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors,
disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, pentoxifylline,
salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood-glucose-lowering effect of
insulins including LEVEMIR: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g.,
epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid
hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical
antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose
lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by
hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as
beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Risk Summary
The background risk of birth defects, pregnancy loss, or other adverse events that exists for all
pregnancies is increased in pregnancies complicated by hyperglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant while taking
LEVEMIR. A randomized controlled clinical trial of pregnant women with type I diabetes using
LEVEMIR during pregnancy did not show an increase in the risk of fetal abnormalities. Reproductive
toxicology studies in non-diabetic rats and rabbits that included concurrent human insulin control groups
indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and
teratogenicity that were attributed to maternal hypoglycemia.
Clinical Considerations
The increased risk of adverse events in pregnancies complicated by hyperglycemia may be decreased
with good glucose control before conception and throughout pregnancy. Because insulin requirements
vary throughout pregnancy and in the post-partum period, careful monitoring of glucose control is
essential in pregnant women.
Human Data
In an, open-label, clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of
gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or
NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. 152
women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the
Reference ID: 3109199
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For current labeling information, please visit https://www.fda.gov/drugsatfda
study (Total pregnant women = 310). Approximately one half of the study participants in each arm were
randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first
8 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <
7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted
mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient
(n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically
significant.
Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 7. The two
most common adverse reactions were nasopharyngitis and headache. These are consistent with findings
from other type 1 diabetes trials (see Table 1, Section 6.1.),and are not repeated in Table 7.
The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the
Levemir and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia, eight
(8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization. The rates
of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by diabetes.
Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the definition of pre-
eclampsia was not standardized in the trial making it difficult to establish a link between a given
treatment and an increased risk of pre-eclampsia. All events were considered unlikely related to trial
treatment. In all nine (9) cases requiring hospitalization the women had healthy infants. Events of
hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group than in the
NPH insulin group as a whole. There was no difference between the treatment groups in mean blood
pressure during pregnancy and there was no indication of a general increase in blood pressure.
In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following
placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of
placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the
LEVEMIR group.
The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6%
and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’,
‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.
Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR to
insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with
incidence ≥ 5%)*
LEVEMIR, %
(n = 152)
NPH, %
(n = 158)
Anaemia
13.2
10.8
Diarrhoea
11.8
5.1
Pre-eclampsia
10.5
7.0
Urinary tract infection
9.9
5.7
Gastroenteritis
8.6
5.1
Abdominal pain upper
5.9
3.8
Vomiting
5.3
4.4
Abortion spontaneous
5.3
2.5
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Abdominal pain
5.3
6.3
Oropharyngeal pain
5.3
6.3
* Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be
easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The proportion of subjects experiencing severe hypoglycemia was 16.4% and 20.9% in LEVEMIR and
NPH treated patients respectively. The rate of severe hypoglycemia was 1.1 and 1.2 events per patient-
year in LEVEMIR and NPH treated patients respectively. Proportion and incidence rates for non-severe
episodes of hypoglycemia were similar in both treatment groups (Table 8).
Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes
Study G Type 1
Diabetes
Pregnancy
In combination with
insulin aspart
LEVEMIR
NPH
Severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
16.4
(25/152)
20.9
(33/158)
Events/patient/year
1.1
1.2
Non-severe
hypoglycemia*
Percent of patients
with at least 1
event (n/total N)
94.7
(144/152)
92.4
(146/158)
Events/patient/year
114.2
108.4
* For definition regarding severe and non-severe hypoglycemia see section 6, Hypoglycemia.
In about a quarter of infants,, LEVEMIR was detected in the infant cord blood at levels above the lower
level of quantification (<25 pmol/L).
No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR
use.
Animal Data
In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300
nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day
(approximately 135 times a human dose of 0.5 Units/kg/day based on AUC ratio) were given to rabbits
during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder
abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of
900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human
insulin control groups indicated that insulin detemir and human insulin had similar effects regarding
embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia
resulting from insulin exposure in normal animals.
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8.3
Nursing Mothers
It is unknown whether LEVEMIR is excreted in human milk. Because many drugs, including human
insulin, are excreted in human milk, use caution when administering LEVEMIR to a nursing woman.
Women with diabetes who are lactating may require adjustments of their insulin doses.
8.4
Pediatric Use
The pharmacokinetics, safety and effectiveness of subcutaneous injections of LEVEMIR have been
established in pediatric patients (age 6 to 17 years) with type 1 diabetes [see Clinical Pharmacology
(12.3) and Clinical Studies (14)]. LEVEMIR has not been studied in pediatric patients younger than 6
years of age with type 1 diabetes. LEVEMIR has not been studied in pediatric patients with type 2
diabetes.
The dose recommendation when converting to LEVEMIR is the same as that described for adults [see
Dosage and Administration (2) and Clinical Studies (14)]. As in adults, the dosage of LEVEMIR must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood
glucose.
8.5
Geriatric Use
In controlled clinical trials comparing LEVEMIR to NPH insulin or insulin glargine, 64 of 1624 patients
(3.9%) in the type 1 diabetes trials and 309 of 1082 patients (28.6%) in the type 2 diabetes trials were
≥65 years of age. A total of 52 (7 type 1 and 45 type 2) patients (1.9%) were ≥75 years of age. No
overall differences in safety or effectiveness were observed between these patients and younger patients,
but small sample sizes, particularly for patients ≥65 years of age in the type 1 diabetes trials and for
patients ≥75 years of age in all trials limits conclusions. Greater sensitivity of some older individuals
cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and
maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to
recognize in the elderly.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be
treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia [see Warnings and Precautions (5.3)].
11 DESCRIPTION
LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a
subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant
human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant
DNA in Saccharomyces cerevisiae followed by chemical modification.
Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been
omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a
molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:
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Figure 1: Structural Formula of insulin detemir
S
S
(A1)
(A21)
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
S
S
S
S
(B1)
(B29)
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys
C NH Structural Formula of insulin detemir
O
LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains
100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg
phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection.
Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of
approximately 7.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including
insulin detemir, exert their specific action through binding to insulin receptors. Receptor-bound insulin
lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue
and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits
proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of
action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir
molecules from the injection site due to self-association of the drug molecules. In addition, the
distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24
hours after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection
and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to > 24 hours (24 hours
was the end of the observation period).
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Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum
effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2
diabetes. The clamp study was terminated at 16 hours according to protocol.
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Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study
12.3 Pharmacokinetics
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin
detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the
maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more
slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and
AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and
abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in
vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin
detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous
administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours
depending on dose.
Specific Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children
(6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir
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plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as
compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose
of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir
AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin
preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed
between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there
were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and
pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2
diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR
were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate,
severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics
of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with
human insulin have shown increased circulating levels of insulin in patients with renal impairment.
Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in
patients with renal impairment [see Warnings and Precautions (5.5)].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was
administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate
and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic
impairment with a corresponding increase in apparent clearance. However, some studies with human
insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful
glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients
with hepatic impairment [see Warnings and Precautions (5.6)].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR
has not been studied [see Use in Specific Populations (8.1)].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not
been studied.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested
negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral
blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.
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In a fertility and embryonic development study, insulin detemir was administered to female rats before
mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose
of 0.5 Units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.
14 CLINICAL STUDIES
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and
at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of
once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with
type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2
diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily
insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The
evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood
glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials
that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin
(HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to
treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and
bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered
before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar
HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9).
Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose
(FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized
to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine
(administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated
patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, non-blinded clinical study (Study C, n=749), adults with type 1 diabetes were randomized
to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination
with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on
HbA1c.
Table 9: Type 1 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of patients treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
Study A
16 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Twice-daily
NPH
276
133
8.6
8.5
-0.8
-0.7
Study B
26 weeks
NovoLog®
(insulin aspart)
Twice-daily
LEVEMIR
Once-
daily
insulin
glargine
161
159
8.9
8.8
-0.6
-0.5
Study C
24 weeks
Human Soluble Insulin
(regular insulin)
Once-daily
LEVEMIR
Once-
daily
NPH
492
257
8.4
8.3
-0.1
0.0
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LEVEMIR – NPH
-0.2
-0.0
-0.1
95% CI for Treatment difference
Basal insulin dose (units/day)
(-0.3, -0.0)
(-0.2, 0.2)
(-0.3, 0.0)
Baseline mean
21
24
27
23
12
24
Mean change from baseline
Total insulin dose (units/day)
16
10
10
4
9
2
Baseline mean
48
54
56
51
46
57
Mean change from baseline
Fasting blood glucose (mg/dL)
17
10
9
6
11
3
Baseline mean
209
220
153
150
213
206
Adj. mean change from baseline
Body weight (kg)
-44
-9
-38
-41
-30
-9
Baseline mean
74.6
75.5
77.5
75.1
76.5
76.9
Mean change from baseline
0.2
0.8
0.5
1.0
-0.3
0.3
Baseline values were included as covariates in an ANCOVA analysis.
Type 1 Diabetes – Pediatric
In an open-label clinical study (Study D, n=347), pediatric patients (age range 6 to 17) with type 1
diabetes were randomized to 26 weeks of treatment with LEVEMIR or NPH insulin both of which were
administered either once- or twice-daily (bedtime or morning and bedtime), at a dosing frequency
consistent with the number of daily basal insulin injections a patient was taking prior to trial entry.
Insulin aspart was administered before each meal. LEVEMIR-treated patients had a decrease in HbA1c
similar to that of NPH insulin (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for Treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose (mg/dL)
Baseline mean
Adj. mean change from baseline
Body weight (kg)
Baseline mean
Mean change from baseline
Study D
26 weeks
NovoLog®
(insulin aspart)
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
232
115
8.8
8.8
-0.7
-0.8
0.1
(-0.1, 0.3)
24
26
8
6
48
50
9
7
181
181
-39
-21
46.3
46.2
1.6
2.7
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Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-
daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before
breakfast and evening) as part of a regimen of stable combination therapy with one or two of the
following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase
inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin
similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes,
LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with
insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
Treatment duration
Treatment in combination with
Number of subjects treated
HbA1c (%)
Baseline HbA1c
Adj. mean change from baseline
LEVEMIR – NPH
95% CI for Treatment difference
Basal insulin dose (units/day)
Baseline mean
Mean change from baseline
Total insulin dose1 (units/day)
Baseline mean
Mean change from baseline
Fasting blood glucose2 (mg/dL)
Baseline mean
Adj. mean change from baseline
Body weight (kg)
Baseline mean
Mean change from baseline
Study E
24 weeks
oral agents
Twice-daily
LEVEMIR
Twice-
daily
NPH
237
239
8.6
8.5
-2.0
-2.1
0.1
(-0.0, 0.3)
18
17
48
28
-
-
-
-
179
173
-69
-74
82.7
82.5
1.2
2.7
Study F
22 weeks
insulin aspart
Once- or
Twice
Daily
LEVEMIR
Once- or
Twice
Daily
NPH
195
200
8.2
8.1
-0.6
-0.6
-0.1
(-0.2, 0.1)
22
22
26
15
22
22
57
42
-
-
-
-
82.0
79.6
0.5
1.2
1Study E – Conducted in insulin-naïve patients
2Study F - Fasting blood glucose data not collected
Pregnancy
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1
diabetes. [see Use in Specific Populations (8.1)]
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin
detemir per mL (U-100).
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3 mL LEVEMIR FlexPen®
NDC 0169-6439-10
10 mL vial
NDC 0169-3687-12
FlexPen is for use with NovoFine® disposable needles. Each FlexPen is for use by a single patient.
LEVEMIR FlexPen should never be shared between patients, even if the needle is changed.
16.2 Storage:
Unused (unopened) LEVEMIR should be stored in the refrigerator between 2° and 8°C (36° to 46°F).
Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not
use LEVEMIR if it has been frozen.
Unused (unopened) LEVEMIR can be kept until the expiration date printed on the label if it is stored in
a refrigerator. Keep unused LEVEMIR in the carton so that it stays clean and protected from light.
If refrigeration is not possible, unused (unopened) LEVEMIR can be kept unrefrigerated at room
temperature, below 30°C (86°F) as long as it is kept as cool as possible and away from direct heat and
light. Unrefrigerated LEVEMIR should be discarded 42 days after it is first kept out of the refrigerator,
even if the FlexPen or vial still contains insulin.
Vials:
After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not
possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F) as long as it
is kept as cool as possible and away from direct heat and light. Refrigerated LEVEMIR vials should be
discarded 42 days after initial use. Unrefrigerated LEVEMIR vials should be discarded 42 days after
they are first kept out of the refrigerator.
LEVEMIR FlexPen:
After initial use, the LEVEMIR FlexPen must NOT be stored in a refrigerator and must NOT be stored
with the needle in place. Keep the opened (in use) LEVEMIR FlexPen away from direct heat and light at
room temperature, below 30°C (86°F). Unrefrigerated LEVEMIR FlexPens should be discarded 42 days
after they are first kept out of the refrigerator.
The storage conditions are summarized in Table 12:
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Table 12: Storage Conditions for LEVEMIR FlexPen and vial
Not in-use
(unopened)
Refrigerated
Not in-use
(unopened)
Room Temperature
(below 30°C)
In-use
(opened)
3 mL
LEVEMIR
FlexPen
Until expiration date
42 days*
42 days*
Room Temperature
(below 30°C)
(Do not refrigerate)
42 days*
10 mL vial
Until expiration date
42 days*
Refrigerated or Room
Temperature (below 30°C)
*The total time allowed at room temperature (below 30°C) is 42 days regardless of whether the product
is in-use or not in-use.
16.3 Preparation and handling
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. LEVEMIR should be inspected visually prior to
administration and should only be used if the solution appears clear and colorless.
Mixing and diluting: LEVEMIR must NOT be mixed or diluted with any other insulin or solution [See
Warnings and Precautions (5.2)].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1 Instructions for Patients
Patients should be informed that changes to insulin regimens must be made cautiously and only under
medical supervision. Patients should be informed about the potential side effects of insulin therapy,
including hypoglycemia, weight gain, lipodystrophy (and the need to rotate injection sites within the
same body region), and allergic reactions. Patients should be informed that the ability to concentrate and
react may be impaired as a result of hypoglycemia. This may present a risk in situations where these
abilities are especially important, such as driving or operating other machinery. Patients who have
frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use
caution when driving or operating machinery.
Accidental mix-ups between LEVEMIR and other insulins, particularly short-acting insulins, have been
reported. To avoid medication errors between LEVEMIR and other insulins, patients should be instructed to
always check the insulin label before each injection.
LEVEMIR must only be used if the solution is clear and colorless with no particles visible. Patients
must be advised that LEVEMIR must NOT be diluted or mixed with any other insulin or solution.
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Patients should be instructed on self-management procedures including glucose monitoring, proper
injection technique, and management of hypoglycemia and hyperglycemia. Patients should be instructed
on handling of special situations such as intercurrent conditions (illness, stress, or emotional
disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin
dose, inadequate food intake, and skipped meals.
Patients with diabetes should be advised to inform their healthcare professional if they are pregnant or
are contemplating pregnancy. Refer patients to the LEVEMIR "Patient Information" for additional
information.
17.2 Never Share a LEVEMIR FlexPen Between Patients
Counsel patients that they should never share a LEVEMIR FlexPen with another person, even if the
needle is changed. Sharing of the FlexPen between patients may pose a risk of transmission of
infection.
Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo
Nordisk A/S.
LEVEMIR is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents
pending.
FlexPen is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
LEVEMIR® (LEV–uh-mere)
(insulin detemir [rDNA origin] injection)
solution for subcutaneous injection
Read the Patient Information that comes with LEVEMIR® before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
healthcare provider about your diabetes or your treatment. Make sure
that you know how to manage your diabetes. Ask your healthcare
provider, if you have any questions about managing your diabetes.
What is LEVEMIR?
LEVEMIR is a man-made long-acting insulin, that is used to control
high blood sugar in adults and children with diabetes mellitus.
It is not recommended to use LEVEMIR to treat diabetic ketoacidosis.
Who should not use LEVEMIR?
Do not take LEVEMIR if:
• you are allergic to any of the ingredients in LEVEMIR. See the end
of this leaflet for a complete list of ingredients in LEVEMIR.
What should I tell my healthcare provider before taking
LEVEMIR?
Before you take LEVEMIR, tell your healthcare provider if you:
• have liver or kidney problems
• have any other medical conditions. Some medical conditions can
affect your insulin needs and your dose of LEVEMIR.
• are pregnant or plan to become pregnant. It is not known, if
LEVEMIR would harm your unborn baby. Talk to your healthcare
provider, if you are pregnant or plan to become pregnant. You and
your healthcare provider should talk about the best way to manage
your diabetes while you are pregnant.
• are breastfeeding or plan to breast-feed. It is not known if
LEVEMIR passes into breast milk. You and your healthcare provider
should decide if you will take LEVEMIR while you breastfeed.
Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins and
herbal supplements. LEVEMIR may affect the way other medicines
work, and other medicines may affect how LEVEMIR works.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with
you to show your healthcare provider and pharmacist when you get a
new medicine.
How should I take LEVEMIR?
• Take LEVEMIR exactly as your healthcare provider told you to take
it.
• Your healthcare provider will tell you how much LEVEMIR to take
and when to take it.
• Do not make any changes to your dose or type of insulin unless you
are told to do so by your healthcare provider.
Know your insulin. Make sure you know:
• the type and strength of insulin prescribed for you.
• the amount of insulin you take.
• the best time for you to take your insulin. This may change if
you take a different type of insulin.
• Do not dilute or mix LEVEMIR with any other insulin or solution.
Your LEVEMIR will not work the right way and you may lose blood
sugar control, which can be serious.
• Do not use LEVEMIR in an insulin pump.
• Inject LEVEMIR under your skin (subcutaneously) in your upper
arm, abdomen (stomach area), or thigh. Never inject LEVEMIR into
a vein or muscle.
• Change injection sites within the area you choose with each dose.
Do not inject into the exact same spot for each injection.
• Read the instructions for use that comes with your LEVEMIR.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject LEVEMIR before
you start taking it.
• Your healthcare provider will decide which type of LEVEMIR to
prescribe for you.
LEVEMIR comes in:
• 10 mL vials (small bottles) for use with a syringe
• 3 mL LEVEMIR FlexPen®
Ask your healthcare provider how you should use LEVEMIR.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you take too much LEVEMIR, your blood sugar may fall low
(hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away
(fruit juice, sugar candies, or glucose tablets). It is important to
treat low blood sugar (hypoglycemia) right away because it could
get worse and you could pass out (lose consciousness).
If you pass out you will need help from another person or
emergency medical services right away. See “What are the
possible side effects of LEVEMIR?” for more information on
low blood sugar (hypoglycemia).
• If you forget to take your dose of LEVEMIR, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like
loss of consciousness (passing out), coma or even death.
Follow your healthcare provider’s instructions for treating high
blood sugar.
Know your symptoms of high blood sugar, which may include:
• increased thirst
• high amounts of sugar and
• frequent urination
ketones in your urine
• drowsiness
• nausea, vomiting (throwing
• loss of appetite
up) or stomach pain
• a hard time breathing
• fruity smell on the breath
• Do not share needles, insulin pens or syringes with others.
• Check your blood sugar levels. Ask your healthcare provider
what your blood sugars should be and when you should check your
blood sugar levels.
Your insulin dosage may need to change because of:
•
illness
•
change in diet
•
stress
•
change in physical activity
•
other medicines you
or exercise
take
What should I avoid while taking LEVEMIR?
•
Alcohol. Drinking alcohol may affect your blood sugar when
you take LEVEMIR.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Driving and operating machinery. You may have trouble
paying attention or reacting if you have low blood sugar
(hypoglycemia). Be careful when you drive a car or operate
machinery. Ask your healthcare provider if it is alright for
you to drive if you often have:
• low blood sugar (hypoglycemia)
• decreased or no warning signs of low blood sugar
What are the possible side effects of LEVEMIR?
LEVEMIR can cause serious side effects, including:
• Low blood sugar (hypoglycemia). Symptoms of low blood sugar
may include:
• dizziness or
• trouble concentrating or
lightheadedness
confusion
• shakiness
• blurred vision
• hunger
• slurred speech
• fast heart beat
• anxiety or mood changes
• tingling in your hands,
• headache
feet, lips or tongue
• sweating
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, and death. Talk to your healthcare provider
about how to tell if you have low blood sugar and what to do if this
happens while taking LEVEMIR. Know your symptoms of low blood
sugar. Follow your healthcare provider’s instructions for treating low
blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for
you. Your dose of LEVEMIR may need to be changed.
• Skin thickening or pits at the injection site (lipodystrophy).
Change (rotate) the area where you inject your insulin to help
prevent these skin changes from happening. Do not inject insulin
into areas of skin that have thickening or pits.
• Serious allergic reactions. LEVEMIR can cause life
threatening symptoms. Get medical help right away if you have
any of these symptoms of an allergic reaction:
• a rash all over your body
• fast heartbeat
• itching
• sweating
• shortness of breath
• feel faint
• trouble breathing
(wheezing)
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Common side effects of LEVEMIR include:
• Low blood sugar (hypoglycemia). See “What are the possible
side effects of LEVEMIR?” for more information on low blood
sugar (hypoglycemia).
• Reactions at the injection site (local allergic reaction). You
may get redness, swelling, and itching at the injection site. If you
keep having skin reactions or they are serious, talk to your
healthcare provider.
• Weight gain. This can occur with any insulin therapy. Talk to your
healthcare provider about how LEVEMIR can affect your weight.
Tell your healthcare provider if you have any side effect that bothers
you or does not go away.
These are not all of the possible side effects from LEVEMIR. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store LEVEMIR?
Unopened LEVEMIR:
•
Keep all unopened LEVEMIR in the refrigerator
between 36°F to 46°F (2°C to 8°C).
•
Unopened LEVEMIR can be kept until the expiration date on
the label if the medicine has been stored in a refrigerator.
•
If refrigeration is not possible, you can keep the unopened
LEVEMIR at room temperature below 86°F (30°C).
•
Throw away LEVEMIR 42 days after it is first kept out of the
refrigerator.
•
Do not freeze. Do not use LEVEMIR if it has been frozen.
•
Keep unopened LEVEMIR in the carton to protect it from
light.
LEVEMIR in use:
•
Vials
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Keep opened vials of LEVEMIR in the refrigerator or at
room temperature below 86°F (30°C) away from direct
heat or light.
• Throw away a vial that has always been kept in the
refrigerator after 42 days of use, even if there is insulin
left in the vial.
• Throw away a vial that has been kept at room
temperature 42 days after it is first kept out of the
refrigerator, even if there is insulin left in the vial.
•
LEVEMIR FlexPen
• Keep at room temperature below 86°F (30°C) for up to
42 days.
• Do not store a LEVEMIR FlexPen that you are using in
the refrigerator.
• Do not store LEVEMIR with the needle attached.
• Keep LEVEMIR FlexPen away from direct heat or light.
• Throw away used LEVEMIR FlexPens after 42 days, even
if there is insulin left in them.
Keep LEVEMIR and all medicines out of the reach of children.
General information about LEVEMIR
Medicines are sometimes prescribed for conditions that are not
mentioned in the patient leaflet. Do not use LEVEMIR for a condition
for which it was not prescribed. Do not give LEVEMIR to other people,
even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about
LEVEMIR. If you would like more information about LEVEMIR or
diabetes, talk with your healthcare provider. You can ask your
healthcare provider for information about LEVEMIR that is written for
healthcare professionals.
For more information about LEVEMIR, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in LEVEMIR?
Active Ingredient: Insulin detemir
Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium
phosphate dehydrate, sodium chloride and water for injection.
Hydrochloric acid or sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Administration.
Revised: January 2012
Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks
of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538,
6,011,007, 6,869,930 and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297,
6,235,004 and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions For Use
LEVEMIR® 10 mL vial
Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial
and each time you get a refill. You should read the instructions in this manual even if you have
used an insulin 10 mL vial before.
How should I use the LEVEMIR 10 mL vial?
Using the 10 mL vial:
1. Check to make sure that you have the correct type of insulin.
This is especially important if you use different types of insulin.
2. Look at the vial and the insulin. The LEVEMIR insulin should
be clear and colorless. The tamper-resistant cap should be in
place before the first use. If the cap has been removed before
your first use of the vial, or if the insulin is cloudy or colored,
Do not use the insulin and return it to your pharmacy.
3. Wash your hands with soap and water.
4. If you are using a new vial, pull off the tamper-resistant cap.
bot
tle
Before each use, wipe the rubber stopper with an alcohol
wipe.
5. Do not roll or shake the vial. Shaking the vial right before the
dose is drawn into the syringe may cause bubbles or foam.
This can cause you to draw up the wrong dose of insulin. The
insulin should be used only if it is clear and colorless.
Reference ID: 3109199
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Pull back the plunger on your syringe until the black tip
reaches the marking for the number of units you will inject.
7. Push the needle through the rubber stopper into the vial.
8. Push the plunger all the way in. This inserts air into the vial.
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose that you
need.
10. If there are air bubbles, tap the syringe gently with your finger
to raise the air bubbles to the top of the needle. Then slowly
push the plunger to the correct unit marking for your dose.
bo
tt
le
a
nd syringe
11. Check to make sure you have the right dose of LEVEMIR in
the syringe.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12. Pull the syringe out of the vial.
13. Inject your LEVEMIR right away as instructed by your
healthcare provider.
How should I inject LEVEMIR with a syringe?
If you clean your injection site with an alcohol swab, let the injection site dry before you inject.
Talk with your healthcare provider about how to rotate injection sites and how to give an
injection.
1. Pinch your skin between two fingers, push the needle into the
skinfold, using a dart-like motion and push the plunger to inject
the insulin under your skin. The needle will be straight in.
injecting needle
2. Keep the needle under your skin for at least 6 seconds to
make sure you have injected all the insulin. After you pull the
needle from your skin you may see a drop of Levemir at the
needle tip. This is normal and has no effect on the dose you
just received.
3. If blood appears after you pull the needle from your skin, press
the injection site lightly with an alcohol swab. Do not rub the
area.
4. After each injection, remove the needle without recapping
and dispose of it in a puncture-resistant container. Used
syringes, needles, and lancets should be placed in sharps
containers (such as red biohazard containers), hard plastic
containers (such as detergent bottles), or metal containers
(such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised: January 2012
Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930,
and other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
LEVEMIR® FlexPen®
Please carefully read the following Instructions for use before using your LEVEMIR®
FlexPen® and each time you get a refill. You should read the instructions in this manual
even if you have used a LEVEMIR FlexPen before.
LEVEMIR FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to
60 units in increments of 1 unit. LEVEMIR FlexPen is designed to be used with
NovoFine® needles.
LEVEMIR FlexPen should not be used by people who are blind or have severe
eyesight problems without the help of a person who has good eyesight and who is
trained to use the LEVEMIR FlexPen the right way.
Getting ready
Make sure you have the following items:
•
LEVEMIR FlexPen
•
NovoFine disposable needles
•
Alcohol swab FlexPen items
PREPARING YOUR LEVEMIR FLEXPEN
Wash your hands with soap and water. Before you start to prepare your injection,
check the label to make sure that you are taking the right type of insulin. This is
especially important if you take more than 1 type of insulin. LEVEMIR should
look clear and colorless.
A. Pull off the pen cap (see diagram A).
Wipe the rubber stopper with an alcohol swab. pen
B. Attaching the needle
Remove the protective tab from a new disposable needle.
Reference ID: 3109199
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Attach the needle tightly onto your FlexPen. It is important that
the needle is put on straight (see diagram B).
Never place a disposable needle on your LEVEMIR FlexPen
until you are ready to give your injection. FlexPen
C. Pull off the big outer needle cap (see diagram C).
D. Pull off the inner needle cap and throw it away (see diagram
D). FlexPen
Always use a new needle for each injection to cut down the chance of infection and to
prevent blocked needles.
Be careful not to bend or damage the needle before use.
To reduce the risk of needle sticks, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection, small amounts of air may collect in the cartridge during normal use.
To avoid injecting air and to ensure you take the right dose of insulin:
E. Turn the dose selector to select 2 units (see diagram E).
F. Hold your LEVEMIR FlexPen with the needle pointing up. Tap
the cartridge gently with your finger a few times to make any
air bubbles collect at the top of the cartridge (see diagram F).
G. While you keep the needle pointing upwards, press the push-
button all the way in (see diagram G). The dose selector
returns to 0.
A drop of insulin should appear at the needle tip. If not,
change the needle and repeat the procedure no more than 6
times.
If you do not see a drop of insulin after 6 times, do not use the
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727FlexPen
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6500.
A small air bubble may remain at the needle tip, but it will not
be injected.
SELECTING YOUR DOSE
Check and make sure that the dose selector is set at 0.
H. Turn the dose selector to the number of units you need to
inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the
dose selector in either direction until the correct dose lines up
with the pointer (see diagram H). When turning the dose
selector, be careful not to press the push-button as insulin will
come out.
You cannot select a dose larger than the number of units left
in the cartridge.
You will hear a click for every single unit dialed. Do not set the
dose by counting the number of clicks you hear.
Do not use the cartridge scale printed on the cartridge to
measure your dose of insulin.
GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. Your
healthcare provider should tell you if you need to pinch the skin before injecting.
Wipe the skin with an alcohol swab and let the area dry. FlexPen dose
I. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until
the 0 lines up with the pointer (see diagram I). Be careful only to
push the button after the needle is in the skin. FlexPen
Turning the dose selector will not inject insulin.
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
J. Keep the needle in the skin for at least 6 seconds, and keep
the push-button pressed all the way in until the needle has
been pulled out from the skin (see diagram J). This will make
sure that the full dose has been given.
You may see a drop of LEVEMIR at the needle tip. This is
normal and has no effect on the dose you just received. If
blood appears after you take the needle out of your skin,
press the injection site lightly with an alcohol swab. Do not
rub the area. needle
After the injection
Carefully remove the needle from the pen after each injection. This helps to
prevent infection and leakage of insulin. You can carefully recap the needle with
the bigger outer cap to help make it easier to remove the needle.
Do not recap the needle with the small inner cap. Recapping with this small part
can increase your chances of having a needle stick injury.
Put the needle in a sharps container or some type of hard plastic or metal
container with a screw top such as a detergent bottle or empty coffee can.
These containers should be sealed and thrown away the right way. Check
with your healthcare provider about the right way to throw away used syringes
and needles. There may be local or state laws about how to throw away used
needles and syringes. Do not throw away used needles and syringes in
household trash or recycling bins.
K. Put the pen cap on the LEVEMIR FlexPen and store the
LEVEMIR FlexPen without the needle attached (see diagram K).
The LEVEMIR FlexPen prevents the cartridge from being
completely emptied. It can deliver 300 units then you should
throw it away in a sharps container or some type of hard plastic
or metal container with a screw top, such as a detergent bottle
or empty coffee can. FlexPen
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FUNCTION CHECK
L. If your LEVEMIR FlexPen is not working the right way, follow
the steps below:
•
Attach a new NovoFine needle.
•
Remove the big outer needle cap and the inner needle
cap. FlexPen
•
Do an airshot as described in “Giving the airshot before
each injection” (see diagram E through G).
•
Put the big outer needle cap onto the needle. Do not put
on the inner needle cap.
•
Turn the dose selector so the dose indicator window shows
20 units.
•
Hold the LEVEMIR FlexPen so the needle is pointing
down.
•
Press the push-button all the way in.
The insulin should fill the lower part of the big outer needle cap to the marker
(see diagram L). If LEVEMIR FlexPen has released too much or too little insulin,
do the function check again. If the same problem happens again, do not use your
LEVEMIR FlexPen and contact Novo Nordisk at 1-800-727-6500.
Maintenance
Your FlexPen is designed to work accurately and safely. It must be handled with
care. If you drop your FlexPen it could get damaged. If you are concerned that
your FlexPen is damaged, use a new one. You can clean the outside of your
FlexPen by wiping it with a damp cloth. Do not soak or wash your FlexPen.
Soaking or washing the FlexPen could damage it. Do not refill your FlexPen.
Remove the needle from the LEVEMIR FlexPen after each injection. This
helps to cut down your chance of infection, prevent leakage of insulin. Be
careful when handling used needles to avoid needle sticks and transfer of
infections.
Keep your LEVEMIR FlexPen and needles out of the reach of children.
Use LEVEMIR FlexPen as directed to treat your diabetes. Needles and
LEVEMIR FlexPen must not be shared.
Always use a new needle for each injection.
Novo Nordisk is not responsible for harm due to using this insulin pen with
products not recommended by Novo Nordisk.
As a safety measure, always carry a spare insulin delivery device in case
your LEVEMIR FlexPen is lost or damaged.
Remember to keep the disposable LEVEMIR FlexPen with you. Do not leave
it in a car or other location where it can get too hot or too cold.
Revised: January 2012
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered
trademarks of Novo Nordisk A/S.
LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007,
6,869,930, and other patents pending.
FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and
other patents pending.
© 2005-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about LEVEMIR® contact:
Novo Nordisk Inc.
100 College Road West,
Princeton, New Jersey 08540
Reference ID: 3109199
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:31.778349 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021536s037lbl.pdf', 'application_number': 21536, 'submission_type': 'SUPPL ', 'submission_number': 37} |
5,879 |
_______________________________________________________________________________________________________________________________________
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
-----------------------WARNINGS AND PRECAUTIONS------------------------
APIDRA safely and effectively. See full prescribing information for
• Dose adjustment and monitoring: Closely monitor blood glucose in all
APIDRA.
patients treated with insulin. Change insulin regimens cautiously and only
under medical supervision.(5.1)
APIDRA (insulin glulisine [rDNA origin] injection) solution for injection
Initial U.S. Approval: 2004
----------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
10/2008
----------------------------INDICATIONS AND USAGE---------------------------
APIDRA is a rapid acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
The dosage of APIDRA must be individualized (2.1)
Subcutaneous
Injection
Administer within 15 minutes before a meal or within 20
minutes after starting a meal. Use in a regimen with an
intermediate or long-acting insulin. (2.1, 2.2)
Continuous
Subcutaneous
Infusion Pump
APIDRA must not be mixed or diluted when used in an
external insulin infusion pump. (2.3)
Intravenous
Infusion
Infuse intravenously (0.05 Units/mL to 1 Units/mL APIDRA
in 0.9% sodium chloride using polyvinyl chloride infusion
bags) only under strict medical supervision with close
monitoring of blood glucose and potassium. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
APIDRA 100 units/mL (U-100) is available as: (3)
• 10 mL vials
• 3 mL cartridge system for use in OptiClik ® (Insulin Delivery Device)
-------------------------------CONTRAINDICATIONS------------------------------
• Do not use during episodes of hypoglycemia (4)
• Do not use in patients with hypersensitivity to APIDRA or any of its
excipients (4)
• Hypoglycemia: Most common adverse reaction of insulin therapy and may
be life-threatening (5.2)
• Allergic reactions: Severe, life-threatening, generalized allergy, including
anaphylaxis, can occur with any insulin, including APIDRA (5.3)
• Hypokalemia: All insulins, including APIDRA can cause hypokalemia,
which if untreated, may result in respiratory paralysis, ventricular
arrhythmia, and death (5.4)
• Renal or hepatic impairment: Like all insulins, may require a reduction in
the APIDRA dose (5.5)
• Mixing: APIDRA for subcutaneous injection should not be mixed with insulins
other than NPH insulin. Do not mix APIDRA with any insulin for intravenous
administration or for use in a continuous infusion pump (5.6)
• Pump use: Change the APIDRA in the pump reservoir every 48 hours (5.7)
• Intravenous use: Frequently monitor for hypoglycemia and hypokalemia. (5.8)
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions commonly associated with APIDRA include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• Certain drugs affect glucose metabolism and may necessitate insulin dose
adjustment (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine). (7)
-----------------------USE IN SPECIFIC POPULATIONS------------------------
• APIDRA has not been studied in children under 4 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: October 2008
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosage considerations
2.2 Subcutaneous administration
2.3 Continuous subcutaneous infusion (insulin pump)
2.4 Intravenous administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Dose adjustment and monitoring
5.2 Hypoglycemia
5.3 Hypersensitivity and allergic reactions
5.4 Hypokalemia
5.5 Renal or hepatic impairment
5.6 Mixing of insulins
5.7 Subcutaneous insulin infusion pumps
5.8 Intravenous administration
5.9 Drug interactions
6 ADVERSE REACTIONS
6.1 Clinical trial experience
6.2 Postmarketing experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing mothers
8.4 Pediatric use
8.5 Geriatric use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4 Clinical pharmacology in specific populations
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, mutagenesis, impairment of fertility
14 CLINICAL STUDIES
14.1
Type 1 Diabetes-Adults
14.2
Type 2 Diabetes-Adults
14.3
Type 1 Diabetes-Adults: Pre-and post-meal administration
14.4
Type 1 Diabetes-Pediatric patients
14.5
Type 1 Diabetes-Adults: Continuous subcutaneous insulin infusion
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How supplied
16.2
Storage
16.3
Preparation and handling
17 PATIENT COUNSELING INFORMATION
17.1
Instructions for all patients
17.2
For patients using continuous subcutaneous insulin pumps
*Sections or subsections omitted from the full prescribing information are not
listed.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
APIDRA is indicated to improve glycemic control in adults and children with diabetes mellitus.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage considerations
APIDRA is a recombinant insulin analog that is equipotent to human insulin (i.e. one unit of
APIDRA has the same glucose-lowering effect as one unit of regular human insulin) when given
intravenously. When given subcutaneously, APIDRA has a more rapid onset of action and a
shorter duration of action than regular human insulin.
The dosage of APIDRA must be individualized. Blood glucose monitoring is essential in all
patients receiving insulin therapy.
The total daily insulin requirement may vary and is usually between 0.5 to 1 Unit/kg/day. Insulin
requirements may be altered during stress, major illness, or with changes in exercise, meal
patterns, or coadministered drugs.
2.2 Subcutaneous administration
APIDRA should be given within 15 minutes before a meal or within 20 minutes after starting a
meal.
APIDRA given by subcutaneous injection should generally be used in regimens with an
intermediate or long-acting insulin.
APIDRA should be administered by subcutaneous injection in the abdominal wall, thigh, or
upper arm. Injection sites should be rotated within the same region (abdomen, thigh or upper
arm) from one injection to the next to reduce the risk of lipodystrophy [See Adverse Reactions
(6.1)].
2.3 Continuous subcutaneous infusion (insulin pump)
APIDRA may be administered by continuous subcutaneous infusion in the abdominal wall. Do
not use diluted or mixed insulins in external insulin pumps. Infusion sites should be rotated
within the same region to reduce the risk of lipodystrophy [See Adverse Reactions (6.1)]. The
initial programming of the external insulin infusion pump should be based on the total daily
insulin dose of the previous regimen.
The following insulin pumps† have been used in APIDRA clinical trials conducted by sanofi
aventis, the manufacturer of APIDRA:
• Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™,
Rapid C™, Rapid D™, and Tender™)
• MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate
QR™, and Quick-set™).
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Before using a different insulin pump with APIDRA, read the pump label to make sure the pump
has been evaluated with APIDRA.
Physicians and patients should carefully evaluate information on pump use in the APIDRA
prescribing information, Patient Information Leaflet, and the pump manufacturer’s manual.
APIDRA-specific information should be followed for in-use time, frequency of changing
infusion sets, or other details specific to APIDRA usage, because APIDRA-specific information
may differ from general pump manual instructions.
Based on in vitro studies which have shown loss of the preservative, metacresol and insulin
degradation, APIDRA in the reservoir should be changed at least every 48 hours. APIDRA in
clinical use should not be exposed to temperatures greater than 98.6°F (37°C). [See Warnings
and Precautions (5.7) and How Supplied/Storage and Handling (16.2)].
2.4 Intravenous administration
APIDRA can be administered intravenously under medical supervision for glycemic control with
close monitoring of blood glucose and serum potassium to avoid hypoglycemia and
hypokalemia. For intravenous use, APIDRA should be used at concentrations of 0.05 Units/mL
to 1 Unit/mL insulin glulisine in infusion systems using polyvinyl chloride (PVC) bags.
APIDRA has been shown to be stable only in normal saline solution (0.9% sodium chloride).
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Do not administer insulin
mixtures intravenously.
3 DOSAGE FORMS AND STRENGTHS
APIDRA 100 units per mL (U-100) is available as:
• 10 mL vials
• 3 mL cartridges for use in the OptiClik
® Insulin Delivery Device
4 CONTRAINDICATIONS
APIDRA is contraindicated:
• during episodes of hypoglycemia
• in patients who are hypersensitive to APIDRA or to any of its excipients
When used in patients with known hypersensitivity to APIDRA or its excipients, patients
may develop localized or generalized hypersensitivity reactions [See Adverse Reactions
(6.1)].
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin
regimen should be made cautiously and only under medical supervision. Changes in insulin
strength, manufacturer, type, or method of administration may result in the need for a change in
insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.
As with all insulin preparations, the time course of action for APIDRA may vary in different
individuals or at different times in the same individual and is dependent on many conditions,
including the site of injection, local blood supply, or local temperature. Patients who change their
level of physical activity or meal plan may require adjustment of insulin dosages.
5.2 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including APIDRA. The
risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to
recognize and manage hypoglycemia. Severe hypoglycemia may lead to unconsciousness and/or
convulsions and may result in temporary or permanent impairment of brain function or death.
Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose
infusion or glucagon administration has been observed in clinical trials with insulin, including
trials with APIDRA.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of
meals), injection site, exercise, and concomitant medications may also alter the risk of
hypoglycemia [See Drug Interactions (7)].
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who
may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have
erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery.
Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia
may be different or less pronounced under certain conditions, such as longstanding diabetes,
diabetic nerve disease, use of medications such as beta-blockers [See Drug Interactions (7)], or
intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly,
loss of consciousness) prior to the patient’s awareness of hypoglycemia.
Intravenously administered insulin has a more rapid onset of action than subcutaneously
administered insulin, requiring closer monitoring for hypoglycemia.
5.3 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including APIDRA [See Adverse reactions (6.1)].
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.4 Hypokalemia
All insulin products, including APIDRA, cause a shift in potassium from the extracellular to
intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations). Monitor glucose and potassium
frequently when APIDRA is administered intravenously.
5.5 Renal or hepatic impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or
hepatic impairment [See Clinical Pharmacology (12.4)].
5.6 Mixing of insulins
APIDRA for subcutaneous injection should not be mixed with insulin preparations other than
NPH insulin. If APIDRA is mixed with NPH insulin, APIDRA should be drawn into the syringe
first. Injection should occur immediately after mixing.
Do not mix APIDRA with other insulins for intravenous administration or for use in a
continuous subcutaneous infusion pump.
APIDRA for intravenous administration should not be diluted with solutions other than 0.9%
sodium chloride (normal saline). The efficacy and safety of mixing APIDRA with diluents or
other insulins for use in external subcutaneous infusion pumps have not been established.
5.7 Subcutaneous insulin infusion pumps
When used in an external insulin pump for subcutaneous infusion, APIDRA should not be
diluted or mixed with any other insulin. APIDRA in the reservoir should be changed at least
every 48 hours. APIDRA should not be exposed to temperatures greater than 98.6°F (37°C).
Malfunction of the insulin pump or infusion set or insulin degradation can rapidly lead to
hyperglycemia and ketosis. Prompt identification and correction of the cause of hyperglycemia
or ketosis is necessary. Interim subcutaneous injections with APIDRA may be required. Patients
using continuous subcutaneous insulin infusion pump therapy must be trained to administer
insulin by injection and have alternate insulin therapy available in case of pump failure. [See
Dosage and Administration (2.3), How Supplied/Storage and Handling (16), and Patient
Counseling Information (17.2)].
5.8 Intravenous administration
When APIDRA is administered intravenously, glucose and potassium levels must be closely
monitored to avoid potentially fatal hypoglycemia and hypokalemia.
Do not mix APIDRA with other insulins for intravenous administration. APIDRA may be diluted
only in normal saline solution.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9 Drug interactions
Some medications may alter insulin requirements and the risk for hypoglycemia or
hyperglycemia [See Drug Interactions (7)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [See Warnings and Precautions (5.2)]
• Hypokalemia [See Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates
reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
The frequencies of adverse drug reactions during APIDRA clinical trials in patients with type 1
diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Treatment –emergent adverse events in pooled studies of adults with type 1
diabetes (adverse events with frequency ≥ 5%)
APIDRA, %
(n=950)
All comparatorsa, %
(n=641)
Nasopharyngitis
10.6
12.9
Hypoglycemiab
6.8
6.7
Upper respiratory tract infection
6.6
5.6
Influenza
4.0
5.0
a Insulin lispro, regular human insulin, insulin aspart
b Only severe symptomatic hypoglycemia
Table 2: Treatment –emergent adverse events in pooled studies of adults with type 2
diabetes (adverse events with frequency ≥ 5%)
APIDRA, %
(n=883)
Regular human insulin, %
(n=883)
Upper respiratory tract infection
10.5
7.7
Nasopharyngitis
7.6
8.2
Edema peripheral
7.5
7.8
Influenza
6.2
4.2
Arthralgia
5.9
6.3
Hypertension
3.9
5.3
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Pediatrics
Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical
study in children and adolescents with type 1 diabetes treated with APIDRA (n=277) or insulin
lispro (n=295).
Table 3: Treatment –emergent adverse events in children and adolescents with type 1
diabetes (adverse reactions with frequency ≥ 5%)
APIDRA, %
(n=277)
Lispro, %
(n=295)
Nasopharyngitis
9.0
9.5
Upper respiratory tract infection
8.3
10.8
Headache
6.9
11.2
Hypoglycemic seizure
6.1
4.7
•
Severe symptomatic hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including APIDRA [See Warnings and Precautions (5.2)]. The rates and incidence of severe
symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party,
were comparable for all treatment regimens (see Table 4). In the phase 3 clinical trial, children
and adolescents with type 1 diabetes had a higher incidence of severe symptomatic
hypoglycemia in the two treatment groups compared to adults with type 1 diabetes. (see Table 4)
[See Clinical Studies (14)].
Table 4: Severe Symptomatic Hypoglycemia*
Type 1 Diabetes
Adults
12 weeks
with insulin glargine
Type 1 Diabetes
Adults
26 weeks
with insulin glargine
Type 2 Diabetes
Adults
26 weeks
with NPH human insulin
Type 1 Diabetes
Pediatrics
26 weeks
APIDRA
Pre-meal
APIDRA
Post-meal
Regular
Human
Insulin
APIDRA
Insulin
Lispro
APIDRA
Regular
Human
Insulin
APIDRA
Insulin
Lispro
Events per
month per
patient
0.05
0.05
0.13
0.02
0.02
0.00
0.00
0.09
0.08
Percent of
patients
(n/total N)
8.4%
(24/286)
8.4%
(25/296)
10.1%
(28/278)
4.8%
(16/339)
4.0%
(13/333)
1.4%
(6/416)
1.2%
(5/420)
16.2%
(45/277)
19.3%
(57/295)
* Severe symptomatic hypoglycemia defined as a hypoglycemic event requiring the assistance of another person
that met one of the following criteria:
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
the event was associated with a whole blood referenced blood glucose <36mg/dL or the event was associated
with prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.
• Insulin initiation and intensification of glucose control
Intensification or rapid improvement in glucose control has been associated with
a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy,
and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk
of diabetic retinopathy and neuropathy.
• Lipodystrophy
Long-term use of insulin, including APIDRA, can cause lipodystrophy at the site of repeated
insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose
tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate
insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See
Dosage and Administration (2.2, 2.3)].
• Weight gain
Weight gain can occur with insulin therapy, including APIDRA, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
• Peripheral Edema
Insulin, including APIDRA, may cause sodium retention and edema, particularly if previously
poor metabolic control is improved by intensified insulin therapy.
• Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)
In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter
occlusions and infusion site reactions were similar for APIDRA and insulin aspart treated
patients (Table 5).
Table 5: Catheter Occlusions and Infusion Site Reactions.
APIDRA
(n=29)
insulin aspart
(n=30)
Catheter occlusions/month
0.08
0.15
Infusion site reactions
10.3% (3/29)
13.3% (4/30)
• Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking APIDRA may experience redness, swelling, or
itching at the site of injection. These minor reactions usually resolve in a few days to a few
weeks, but in some occasions may require discontinuation of APIDRA. In some instances, these
reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or
poor injection technique.
Systemic Allergy
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin,
including APIDRA. Generalized allergy to insulin may cause whole body rash (including
pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
In controlled clinical trials up to 12 months duration, potential systemic allergic reactions were
reported in 79 of 1833 patients (4.3%) who received APIDRA and 58 of 1524 patients (3.8%)
who received the comparator short-acting insulins. During these trials treatment with APIDRA
was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.
Localized reactions and generalized myalgias have been reported with the use of metacresol,
which is an excipient of APIDRA.
Antibody Production
In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that
react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained
near baseline during the first 6 months of the study in the patients treated with APIDRA. A
decrease in antibody concentration was observed during the following 6 months of the study. In a
study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin
antibody concentration was observed in the patients treated with APIDRA and in the patients
treated with human insulin during the first 9 months of the study. Thereafter the concentration of
antibodies decreased in the APIDRA patients and remained stable in the human insulin patients.
There was no correlation between cross-reactive insulin antibody concentration and changes in
HbA1c, insulin doses, or incidence of hypoglycemia. The clinical significance of these
antibodies is not known.
APIDRA did not elicit a significant antibody response in a study of children and adolescents
with type 1 diabetes.
6.2 Postmarketing experience
The following adverse reactions have been identified during post-approval use of APIDRA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to estimate reliably their frequency or establish a causal relationship to drug
exposure.
Medication errors have been reported in which other insulins, particularly long-acting insulins,
have been accidentally administered instead of APIDRA [See Patient Counseling Information
(17)].
7 DRUG INTERACTIONS
A number of drugs affect glucose metabolism and may necessitate insulin dose adjustment and
particularly close monitoring.
Drugs that may increase the blood glucose-lowering effect of insulins including APIDRA, and
therefore increase the risk of hypoglycemia, include oral antidiabetic products, pramlintide, ACE
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene,
pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.
Drugs that may reduce the blood-glucose-lowering effect of APIDRA include corticosteroids,
niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline),
glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens,
progestogens (e.g., in oral contraceptives), protease inhibitors, and atypical antipsychotics.
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood
glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs
such as beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: Reproduction and teratology studies have been performed with insulin
glulisine in rats and rabbits using regular human insulin as a comparator. Insulin glulisine was
given to female rats throughout pregnancy at subcutaneous doses up to 10 U/kg once daily (dose
resulting in an exposure 2 times the average human dose, based on body surface area
comparison) and did not have any remarkable toxic effects on embryo-fetal development.
Insulin glulisine was given to female rabbits throughout pregnancy at subcutaneous doses up to
1.5 Units/kg/day (dose resulting in an exposure 0.5 times the average human dose, based on body
surface area comparison). Adverse effects on embryo-fetal development were only seen at
maternal toxic dose levels inducing hypoglycemia. Increased incidence of post-implantation
losses and skeletal defects were observed at a dose level of 1.5 Units/kg once daily (dose
resulting in an exposure 0.5 times the average human dose, based on body surface area
comparison) that also caused mortality in dams. A slight increased incidence of post-
implantation losses was seen at the next lower dose level of 0.5 Units/kg once daily (dose
resulting in an exposure 0.2 times the average human dose, based on body surface area
comparison) which was also associated with severe hypoglycemia but there were no defects at
that dose. No effects were observed in rabbits at a dose of 0.25 Units/kg once daily (dose
resulting in an exposure 0.1 times the average human dose, based on body surface area
comparison). The effects of insulin glulisine did not differ from those observed with
subcutaneous regular human insulin at the same doses and were attributed to secondary effects of
maternal hypoglycemia.
There are no well-controlled clinical studies of the use of APIDRA in pregnant women. Because
animal reproduction studies are not always predictive of human response, this drug should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is
essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic
control before conception and throughout pregnancy. Insulin requirements may decrease during
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the first trimester, generally increase during the second and third trimesters, and rapidly decline
after delivery. Careful monitoring of glucose control is essential in these patients.
8.3 Nursing mothers
It is unknown whether insulin glulisine is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when APIDRA is administered to a nursing
woman. Use of APIDRA is compatible with breastfeeding, but women with diabetes who are
lactating may require adjustments of their insulin doses.
8.4 Pediatric use
The safety and effectiveness of subcutaneous injections of APIDRA have been established in
pediatric patients (age 4 to 17 years) with type 1 diabetes [See Clinical Studies (14.4)]. APIDRA
has not been studied in pediatric patients with type 1 diabetes younger than 4 years of age and in
pediatric patients with type 2 diabetes.
As in adults, the dosage of APIDRA must be individualized in pediatric patients based on
metabolic needs and frequent monitoring of blood glucose.
8.5 Geriatric use
In clinical trials (n=2408), APIDRA was administered to 147 patients ≥65 years of age and 27
patients ≥75 years of age. The majority of this small subset of elderly patients had type 2
diabetes. The change in HbA1c values and hypoglycemia frequencies did not differ by age.
Nevertheless, caution should be exercised when APIDRA is administered to geriatric patients.
10 OVERDOSAGE
Excess insulin may cause hypoglycemia and, particularly when given intravenously,
hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes of
hypoglycemia with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11 DESCRIPTION
APIDRA® (insulin glulisine [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. Insulin glulisine is produced by recombinant DNA technology
utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine differs
from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the
lysine in position B29 is replaced by glutamic acid. Chemically, insulin glulisine is 3B-lysine
29B-glutamic acid-human insulin, has the empirical formula C258H384N64O78S6 and a molecular
weight of 5823 and has the following structural formula:
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A-chain
Stru
ctur
al
Fo
rmu
la
B-chain
APIDRA is a sterile, aqueous, clear, and colorless solution. Each milliliter of APIDRA contains
100 units (3.49 mg) insulin glulisine, 3.15 mg metacresol, 6 mg tromethamine, 5 mg sodium
chloride, 0.01 mg polysorbate 20, and water for injection. APIDRA has a pH of approximately
7.3. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium
hydroxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Regulation of glucose metabolism is the primary activity of insulins and insulin analogs,
including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake
by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis
and proteolysis, and enhance protein synthesis.
The glucose lowering activities of APIDRA and of regular human insulin are equipotent when
administered by the intravenous route. After subcutaneous administration, the effect of APIDRA
is more rapid in onset and of shorter duration compared to regular human insulin. [See
Pharmacodynamics (12.2)].
12.2 Pharmacodynamics
Studies in healthy volunteers and patients with diabetes demonstrated that APIDRA has a more
rapid onset of action and a shorter duration of activity than regular human insulin when given
subcutaneously.
In a study in patients with type 1 diabetes (n= 20), the glucose-lowering profiles of APIDRA and
regular human insulin were assessed at various times in relation to a standard meal at a dose of
0.15 Units/kg. (Figure 1.)
The maximum blood glucose excursion (ΔGLUmax; baseline subtracted glucose concentration)
for APIDRA injected 2 minutes before a meal was 65 mg/dL compared to 64 mg/dL for regular
human insulin injected 30 minutes before a meal (see Figure 1A), and 84 mg/dL for regular
human insulin injected 2 minutes before a meal (see Figure 1B). The maximum blood glucose
excursion for APIDRA injected 15 minutes after the start of a meal was 85 mg/dL compared to
84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1C).
12
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Meal
Gra
ph
Figure 1. Serial mean blood glucose collected up to 6 hours following a single dose of APIDRA
and regular human insulin. APIDRA given 2 minutes (APIDRA - pre) before the start of a meal
compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal
(Figure 1A) and compared to regular human insulin (Regular - pre) given 2 minutes before a
meal (Figure 1B). APIDRA given 15 minutes (APIDRA - post) after start of a meal compared to
regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 1C). On the x-axis
zero (0) is the start of a 15-minute meal.
In a randomized, open-label, two-way crossover study, 16 healthy male subjects received an
intravenous infusion of APIDRA or regular human insulin with saline diluent at a rate of 0.8
milliUnits/kg/min for two hours. Infusion of the same dose of APIDRA or regular human insulin
produced equivalent glucose disposal at steady state.
12.3 Pharmacokinetics
Absorption and bioavailability
Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2)
demonstrated that absorption of insulin glulisine was faster than that of regular human insulin.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
P h
arm
aco
kinetic P
rofile
Gr
ap
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P h
a
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m a c
o
k
i
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eti
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Prof
ile
Graph
In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15
Units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120
minutes) and the peak concentration (Cmax) was 83 microUnits/mL (range 40 to 131
microUnits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239
minutes) and a Cmax of 50 microUnits/mL (range 35 to 71 microUnits/mL) for regular human
insulin. (Figure 2)
Figure 2. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with
type 1 diabetes after a dose of 0.15 Units/kg.
Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.2
Units/kg in an euglycemic clamp study in patients with type 2 diabetes (n=24) and a body mass
index (BMI) between 20 and 36 kg/m2. The median time to maximum concentration (Tmax) was
100 minutes (range 40 to 120 minutes) and the median peak concentration (Cmax) was 84
microUnits/mL (range 53 to 165 microUnits/mL) for insulin glulisine compared to a median Tmax
of 240 minutes (range 80 to 360 minutes) and a median Cmax of 41 microUnits/mL (range 33 to
61 microUnits/mL) for regular human insulin. (Figure 3.)
Figure 3. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with
type 2 diabetes after a subcutaneous dose of 0.2 Units/kg.
When APIDRA was injected subcutaneously into different areas of the body, the time-
concentration profiles were similar. The absolute bioavailability of insulin glulisine after
subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%,
deltoid 71%, thigh 68%).
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was
similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the
syringe) and following separate simultaneous subcutaneous injections. There was 27%
attenuation of the maximum concentration (Cmax) of APIDRA after premixing; however, the time
to maximum concentration (Tmax) was not affected. No data are available on mixing APIDRA
with insulin preparations other than NPH insulin. [See Clinical Studies (14)].
Distribution and elimination
The distribution and elimination of insulin glulisine and regular human insulin after intravenous
administration are similar with volumes of distribution of 13 and 21 L and half-lives of 13 and
17 minutes, respectively. After subcutaneous administration, insulin glulisine is eliminated more
rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86
minutes.
12.4
Clinical pharmacology in specific populations
Pediatric patients
The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin
were assessed in a study conducted in children 7 to 11 years old (n=10) and adolescents 12 to 16
years old (n=10) with type 1 diabetes. The relative differences in pharmacokinetics and
pharmacodynamics between APIDRA and regular human insulin in these patients with type 1
diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.
Race
A study in 24 healthy Caucasians and Japanese subjects compared the pharmacokinetics and
pharmacodynamics after subcutaneous injection of insulin glulisine, insulin lispro, and regular
human insulin. With subcutaneous injection of insulin glulisine, Japanese subjects had a greater
initial exposure (33%) for the ratio of AUC(0-1h) to AUC(0-clamp end) than Caucasians (21%)
although the total exposures were similar. There were similar findings with insulin lispro and
regular human insulin.
Obesity
Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.3
Units/kg in a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass
index (BMI) between 30 and 40 kg/m2. The median time to maximum concentration (Tmax) was
85 minutes (range 49 to 150 minutes) and the median peak concentration (Cmax) was 192
microUnits/mL (range 98 to 380 microUnits/mL) for insulin glulisine compared to a median Tmax
of 150 minutes (range 90 to 240 minutes) and a median Cmax of 86 microUnits/mL (range 43 to
175 microUnits/mL) for regular human insulin.
The more rapid onset of action and shorter duration of activity of APIDRA and insulin lispro
compared to regular human insulin were maintained in an obese non-diabetic population (n= 18).
(Figure 4.)
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
G l
u
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I n
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s
ion
R
at
e
Gr
ap
h
Figure 4. Glucose infusion rates (GIR) in a euglycemic clamp study after subcutaneous injection
of 0.3 Units/kg of APIDRA, insulin lispro or regular human insulin in an obese population.
Renal impairment
Studies with human insulin have shown increased circulating levels of insulin in patients with
renal failure. In a study performed in 24 non-diabetic subjects with normal renal function
(ClCr >80 mL/min), moderate renal impairment (30-50 mL/min) and severe renal impairment
(<30 mL/min), the subjects with moderate and severe renal impairment had increased exposure
to insulin glulisine by 29% to 40% and reduced clearance of insulin glulisine by 20% to 25%
compared to subjects with normal renal function. [See Warnings and Precautions (5.4)].
Hepatic impairment
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of APIDRA
has not been studied. Some studies with human insulin have shown increased circulating levels
of insulin in patients with liver failure. [See Warnings and Precautions (5.4)].
Gender
The effect of gender on the pharmacokinetics and pharmacodynamics of APIDRA has not been
studied.
Pregnancy
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of APIDRA has not
been studied.
Smoking
The effect of smoking on the pharmacokinetics and pharmacodynamics of APIDRA has not been
studied.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
Standard 2-year carcinogenicity studies in animals have not been performed. In Sprague Dawley
rats, a 12-month repeat dose toxicity study was conducted with insulin glulisine at subcutaneous
doses of 2.5, 5, 20 or 50 Units/kg twice daily (dose resulting in an exposure 1, 2, 8, and 20 times
the average human dose, based on body surface area comparison).
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There was a non-dose dependent higher incidence of mammary gland tumors in female rats
administered insulin glulisine compared to untreated controls. The incidence of mammary
tumors for insulin glulisine and regular human insulin was similar. The relevance of these
findings to humans is not known. Insulin glulisine was not mutagenic in the following tests:
Ames test, in vitro mammalian chromosome aberration test in V79 Chinese hamster cells, and in
vivo mammalian erythrocyte micronucleus test in rats.
In fertility studies in male and female rats at subcutaneous doses up to 10 Units/kg once daily
(dose resulting in an exposure 2 times the average human dose, based on body surface area
comparison), no clear adverse effects on male and female fertility, or general reproductive
performance of animals were observed.
14 CLINICAL STUDIES
The safety and efficacy of APIDRA was studied in adult patients with type 1 and type 2 diabetes
(n =1833) and in children and adolescent patients (4 to 17 years) with type 1 diabetes (n=572).
The primary efficacy parameter in these trials was glycemic control, assessed using glycated
hemoglobin (GHb reported as HbA1c equivalent).
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.1 Type 1 Diabetes-Adults
A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
patients with type 1 diabetes to assess the safety and efficacy of APIDRA (n= 339) compared to
insulin lispro (n= 333) when administered subcutaneously within 15 minutes before a meal.
Insulin glargine was administered once daily in the evening as the basal insulin. There was a 4
week run-in period with insulin lispro and insulin glargine prior to randomization. Most patients
were Caucasian (97%). Fifty eight percent of the patients were men. The mean age was 39 years
(range 18 to 74 years). Glycemic control, the number of daily short-acting insulin injections and
the total daily doses of APIDRA and insulin lispro were similar in the two treatment groups
(Table 6).
Table 6: Type 1 Diabetes Mellitus–Adult
Treatment duration
26 weeks
Treatment in combination with:
Insulin glargine
APIDRA
Insulin Lispro
Glycated hemoglobin (GHb)* (%)
Number of patients
331
322
Baseline mean
7.6
7.6
Adjusted mean change from baseline
-0.1
-0.1
Treatment difference: APIDRA – Insulin Lispro
0.0
95% CI for treatment difference
(-0.1; 0.1)
Basal insulin dose (Units/day)
Baseline mean
24
24
Adjusted mean change from baseline
0
2
Short-acting insulin dose (Units/day)
Baseline mean
30
31
Adjusted mean change from baseline
-1
-1
Mean number of short-acting insulin injections per day
3
3
Body weight (kg)
Baseline mean
73.9
74.1
Mean change from baseline
0.6
0.3
*GHb reported as HbA1c equivalent
14.2 Type 2 Diabetes-Adults
A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
insulin-treated patients with type 2 diabetes to assess the safety and efficacy of APIDRA (n=
435) given within 15 minutes before a meal compared to regular human insulin (n=441)
administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the
basal insulin. All patients participated in a 4-week run-in period with regular human insulin and
NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The
mean age was 58 years (range 26 to 84 years). The average body mass index (BMI) was 34.6
kg/m2. At randomization, 58% of the patients were taking an oral antidiabetic agent. These
patients were instructed to continue use of their oral antidiabetic agent at the same dose
throughout the trial. The majority of patients (79%) mixed their short-acting insulin with NPH
human insulin immediately prior to injection. The reductions from baseline in GHb were similar
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
between the 2 treatment groups (see Table 7). No differences between APIDRA and regular
human insulin groups were seen in the number of daily short-acting insulin injections or basal or
short-acting insulin doses. (See Table 7.)
Table 7: Type 2 Diabetes Mellitus–Adult
Treatment duration
26 weeks
Treatment in combination with:
NPH human insulin
APIDRA
Regular Human
Insulin
Glycated hemoglobin (GHb)* (%)
Number of patients
404
403
Baseline mean
7.6
7.5
Adjusted mean change from baseline
-0.5
-0.3
Treatment difference: APIDRA – Regular Human Insulin
-0.2
95% CI for treatment difference
(-0.3; -0.1)
Basal insulin dose (Units/day)
Baseline mean
59
57
Adjusted mean change from baseline
6
6
Short-acting insulin dose (Units/day)
Baseline mean
32
31
Adjusted mean change from baseline
4
5
Mean number of short-acting insulin injections per day
2
2
Body weight (kg)
Baseline mean
100.5
99.2
Mean change from baseline
1.8
2.0
*GHb reported as HbA1c equivalent
14.3 Type 1 Diabetes-Adults: Pre- and post-meal administration
A 12-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
patients with type 1 diabetes to assess the safety and efficacy of APIDRA administered at
different times with respect to a meal. APIDRA was administered subcutaneously either within
15 minutes before a meal (n=286) or immediately after a meal (n=296) and regular human
insulin (n= 278) was administered subcutaneously 30 to 45 minutes prior to a meal. Insulin
glargine was administered once daily at bedtime as the basal insulin. There was a 4-week run-in
period with regular human insulin and insulin glargine followed by randomization. Most patients
were Caucasian (94%). The mean age was 40 years (range 18 to 73 years). Glycemic control
(see Table 8) was comparable for the 3 treatment regimens. No changes from baseline between
the treatments were seen in the total daily number of short-acting insulin injections. (See Table
8.)
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8: Pre- and Post-Meal Administration in Type 1 Diabetes Mellitus–Adult
Treatment duration
Treatment in combination with:
Glycated hemoglobin (GHb)* (%)
Number of patients
Baseline mean
Adjusted mean change from baseline**
Basal insulin dose (Units/day)
Baseline mean
Adjusted mean change from baseline
Short-acting insulin dose (Units/day)
Baseline mean
Adjusted mean change from baseline
Mean number of short-acting insulin injections per day
Body weight (kg)
Baseline mean
Mean change from baseline
12 weeks
insulin glargine
12 weeks
insulin glargine
12 weeks
insulin glargine
APIDRA
pre meal
APIDRA
post meal
Regular Human
Insulin
268
276
257
7.7
7.7
7.6
-0.3
-0.1
-0.1
29
29
28
1
0
1
29
29
27
-1
-1
2
3
3
3
79.2
80.3
78.9
0.3
-0.3
0.3
*GHb reported as HbA1c equivalent
**Adjusted mean change from baseline treatment difference (98.33% CI for treatment difference):
APIDRA pre meal vs. Regular Human Insulin - 0.1 (-0.3; 0.0)
APIDRA post meal vs. Regular Human Insulin 0.0 (-0.1; 0.2)
APIDRA post meal vs. pre meal 0.2 (0.0; 0.3)
14.4 Type 1 Diabetes-Pediatric patients
A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
children and adolescents older than 4 years of age with type 1 diabetes mellitus to assess the
safety and efficacy of APIDRA (n= 277) compared to insulin lispro (n= 295) when administered
subcutaneously within 15 minutes before a meal. Patients also received insulin glargine
(administered once daily in the evening) or NPH insulin (administered once in the morning and
once in the evening). There was a 4-week run-in period with insulin lispro and insulin glargine or
NPH prior to randomization. Most patients were Caucasian (91%). Fifty percent of the patients
were male. The mean age was 12.5 years (range 4 to 17 years). Mean BMI was 20.6 kg/m2.
Glycemic control (see Table 9) was comparable for the two treatment regimens.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 9: Results from a 26-week study in pediatric patients with type 1 diabetes mellitus
Number of patients
Basal Insulin
Glycated hemoglobin (GHb)* (%)
Baseline mean
Adjusted mean change from Baseline
Treatment Difference: Mean (95% confidence interval)
Basal insulin dose (Units/kg/day)
Baseline mean
Mean change from baseline
Short-acting insulin dose (Units/kg/day)
Baseline mean
Mean change from baseline
Mean number of short-acting insulin injections per day
Baseline mean body weight (kg)
Mean weight change from baseline (kg)
APIDRA
Lispro
271
291
NPH or insulin glargine
NPH or insulin glargine
8.2
8.2
0.1
0.2
-0.1 (-0.2, 0.1)
0.5
0.5
0.0
0.0
0.5
0.5
0.0
0.0
3
3
51.5
2.2
50.8
2.2
*GHb reported as HbA1c equivalent
14.5 Type 1 Diabetes-Adults: Continuous subcutaneous insulin infusion
A 12-week randomized, active control study (APIDRA versus insulin aspart) conducted in adults
with type 1 diabetes (APIDRA n= 29, insulin aspart n=30) evaluated the use of APIDRA in an
external continuous subcutaneous insulin pump. All patients were Caucasian. The mean age was
46 years (range 21 to 73 years). The mean GHb increased from baseline to endpoint in both
treatment groups (from 6.8% to 7.0% for APIDRA; from 7.1% to 7.2% for insulin aspart).
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How supplied
APIDRA 100 units per mL (U-100) is available as:
10 mL vials
NDC 0088-2500-33
3 mL cartridge system*, package of 5
NDC 0088-2500-52
* Cartridge systems are for use only in OptiClik® (Insulin Delivery Device)
16.2 Storage
Do not use after the expiration date.
Unopened Vial/Cartridge System
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Unopened APIDRA vials and cartridge systems should be stored in a refrigerator, 36°F-46°F
(2°C-8°C). Protect from light. APIDRA should not be stored in the freezer and it should not be
allowed to freeze. Discard if it has been frozen.
Unopened vials/cartridge systems not stored in a refrigerator must be used within 28 days.
Open (In-Use) Vial:
Opened vials, whether or not refrigerated, must be used within 28 days. If refrigeration is not
possible, the open vial in use can be kept unrefrigerated for up to 28 days away from direct heat
and light, as long as the temperature is not greater than 77°F (25°C).
Open (In-Use) Cartridge System:
The opened (in-use) cartridge system inserted in OptiClik
® should NOT be refrigerated but
should be kept below 77◦F (25◦C) away from direct heat and light. The opened (in-use) cartridge
system must be discarded after 28 days. Do not store OptiClik
®, with or without cartridge
system, in a refrigerator at any time.
Infusion sets:
Infusion sets (reservoirs, tubing, and catheters) and the APIDRA in the reservoir should be
discarded after 48 hours of use or after exposure to temperatures that exceed 98.6°F (37°C).
Intravenous use:
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION (2.4) are stable
at room temperature for 48 hours.
16.3 Preparation and Handling
After dilution for intravenous use, the solution should be inspected visually for particulate matter
and discoloration prior to administration. Do not use the solution if it has become cloudy or
contains particles; use only if it is clear and colorless. APIDRA is not compatible with Dextrose
solution and Ringers solution and, therefore, cannot be used with these solution fluids. The use
of APIDRA with other solutions has not been studied and is, therefore, not recommended.
Cartridge system: If OptiClik
® (the Insulin Delivery Device for APIDRA) malfunctions,
APIDRA may be drawn from the cartridge system into a U-100 syringe and injected.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
17.1 Instructions for all patients
Patients should be instructed on self-management procedures including glucose monitoring,
proper injection technique, and management of hypoglycemia and hyperglycemia.
Patients must be instructed on handling of special situations such as intercurrent conditions
(illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent
administration of an increased insulin dose, inadequate food intake, and skipped meals.
Refer patients to the APIDRA Patient Information Leaflet for additional information.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Women with diabetes should be advised to inform their doctor if they are pregnant or are
contemplating pregnancy.
Accidental mix-ups between APIDRA and other insulins, particularly long-acting insulins, have
been reported. To avoid medication errors between APIDRA and other insulins, patients should
be instructed to always check the insulin label before each injection.
17.2 For patients using continuous subcutaneous insulin pumps
Patients using external pump infusion therapy should be trained appropriately.
The following insulin pumps† have been used in APIDRA clinical trials conducted by sanofi
aventis, the manufacturer of APIDRA:
• Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™,
Rapid C™, Rapid D™, and Tender™)
• MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate
QR™, and Quick-set™).
Before using a different insulin pump with APIDRA, read the pump label to make sure the pump
has been evaluated with APIDRA.
To minimize insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), the infusion sets (reservoir, tubing, and catheter) and the APIDRA in the reservoir
should be replaced every 48 hours and a new infusion site should be selected. The temperature of
the insulin may exceed ambient temperature when the pump housing, cover, tubing or sport case
is exposed to sunlight or radiant heat. Insulin exposed to temperatures higher than 98.6°F (37°C)
should be discarded. Infusion sites that are erythematous, pruritic, or thickened should be
reported to the healthcare professional, and a new site selected because continued infusion may
increase the skin reaction or alter the absorption of APIDRA.
Pump or infusion set malfunctions or insulin degradation can lead to rapid hyperglycemia and
ketosis. This is especially pertinent for rapid-acting insulin analogs that are more rapidly
absorbed through skin and have a shorter duration of action. Prompt identification and correction
of the cause of hyperglycemia or ketosis is necessary. Problems include pump malfunction,
infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Less commonly,
hypoglycemia from pump malfunction may occur. If these problems cannot be promptly
corrected, patients should resume therapy with subcutaneous insulin injection and contact their
healthcare professional. [See Dosage and Administration (2.3), Warnings and Precautions (5.7),
and How Supplied/Storage and Handling (16)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2008 sanofi-aventis U.S. LLC
†The brands listed are the registered trademarks of their respective owners and are not trademarks
of sanofi-aventis U.S. LLC
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
APIDRA® 10 mL vial (1000 units per vial) 100 units per mL (U-100)
(insulin glulisine [recombinant DNA origin] injection)
Read the “Patient Information” that comes with APIDRA (uh-PEE-druh) before you start using it
and each time you get a refill. There may be new information. This leaflet does not take the
place of talking with your healthcare provider about your diabetes or treatment. If you have
questions about APIDRA or about diabetes, talk with your healthcare provider.
What is the most important information I should know about APIDRA?
• Do not change the insulin you use without talking to your healthcare provider. Any
change in insulin strength, manufacturer, type (regular, NPH, analog), species (beef,
pork, beef-pork, human) or method of manufacture (recombinant DNA versus animal-
source insulin) may need a change in the dose you are using. This dose change may be
needed right away or later on. Sometimes this dose change may happen during the first
several weeks or months on the new insulin. Doses of oral anti-diabetic medicines may
also need to change, if your insulin is changed.
• You must test your blood sugar levels while using an insulin such as APIDRA. Your
healthcare provider will tell you how often you should test your blood sugar level, and
what to do if it is high or low.
• When used in a pump do not mix APIDRA with any other insulin or liquid.
• APIDRA comes as U-100 insulin. It contains 10 milliliters (mL) of APIDRA. One
milliliter (mL) of U-100 insulin contains 100 units of insulin. (1 mL = 1 cc).
What is diabetes?
• Your body needs insulin to turn sugar (glucose) into energy. If your body does not make
enough insulin, you need to take more insulin so you will not have too much sugar in
your blood.
• Insulin injections are important in keeping your diabetes under control. But other factors
can have an effect on your diabetes, such as the foods you eat, how often you check your
blood sugars, and your exercise level.
What is APIDRA?
• APIDRA (insulin glulisine [recombinant DNA origin]) is a rapid-acting man-made
insulin. APIDRA is used to treat patients with diabetes for the control of high blood
sugar.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• APIDRA is a clear, colorless, sterile solution for injection under the skin
(subcutaneously). APIDRA may also be given by infusion into one of your veins
(intravenously) by healthcare providers only.
• You need a prescription to get APIDRA. Always be sure you receive the right insulin
from the pharmacy.
Who should not take APIDRA?
Do not take APIDRA if:
• your blood sugar is too low (hypoglycemia). After treating your low blood sugar, follow
your healthcare provider's instructions on the use of Apidra.
• you are allergic to insulin glulisine or any of the inactive ingredients in APIDRA.
Check with your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking APIDRA?
Tell your healthcare provider:
• about all of your medical conditions, including liver or kidney problems. Your dose
may need to be adjusted.
• if you are pregnant or plan to become pregnant. It is not known if APIDRA may
harm your unborn baby. It is very important to maintain control of your blood sugar
levels during pregnancy. Your healthcare provider will decide which insulin is best for
you during your pregnancy.
• if you are breast-feeding or plan to breast-feed. It is not known whether APIDRA
passes into your milk. Many medicines, including insulin, pass into human milk, and
could affect your baby. Talk to your healthcare provider about the best way to feed your
baby.
• about all the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. Your APIDRA dose may change if you
take other medicines. For more information look under Medicines, under the heading
“What can affect how much insulin I need?”.
How should I use APIDRA?
See "Instructions for Use" including the sections "How do I draw the insulin into the
syringe?" and “How should I infuse APIDRA with an external subcutaneous insulin
infusion pump?" for additional information.
• Follow the instructions given by your healthcare provider about the type or types of
insulin you are using. Do not make any changes with your insulin unless you have talked
to your healthcare provider. Your insulin needs may change because of illness, stress,
other medicines, or changes in diet or activity level. Talk to your healthcare provider
about how to adjust your insulin dose.
• You should take APIDRA within 15 minutes before a meal or within 20 minutes after
starting a meal.
• Only use APIDRA that is clear and colorless. If your APIDRA is cloudy or colored,
return it to your pharmacy for a replacement.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Follow your healthcare provider's instructions for testing your blood sugar.
• Inject APIDRA under your skin (subcutaneously) in your upper arm, abdomen (stomach
area), or thigh (upper leg). Never inject it into a vein or muscle.
• If you use a pump, infuse APIDRA through the skin of your abdomen.
• Change (rotate) injection sites within the same body area.
What kind of syringe should I use?
• Always use a syringe that is marked for U-100 insulin. If you use a wrong syringe, you
may get the wrong dose. You could get a blood sugar level that is too low or too high.
Mixing with APIDRA
• If you are mixing APIDRA with NPH human insulin, draw APIDRA into the syringe
first. Inject the mixture right away. Do not mix APIDRA with any other type of
insulin than NPH.
• Do not mix APIDRA with any other insulin when used in a pump.
Instructions for Use
How do I draw the insulin into the syringe?
• The syringe must be new and does not contain any other medicine.
• Do not mix APIDRA with any other type of insulin than NPH. If you are mixing
APIDRA with NPH human insulin, draw APIDRA into the syringe first. Inject the
mixture right away.
Follow these steps:
1. Wash your hands.
2. Check the insulin to make sure it is clear and colorless. Do not use the insulin after the
expiration date stamped on the label, if it is colored or cloudy or if you see particles in the
solution.
3. If you are using a new vial, remove the protective cap. Do not remove the stopper. Usage Illustration
4. Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of
APIDRA before use. Usage Illustration
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Use a new needle and syringe every time you give an injection. Use disposable syringes
and needles only once. Throw them away properly. Never share needles and syringes.
6. Draw air into the syringe equal to your insulin dose. Usage Illustration
7. Put the needle through the rubber top of the vial and push the plunger to inject the air into
the vial. Usage Illustration
8. Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly
in one hand.
9. Make sure the tip of the needle is in the insulin. With your free hand, pull the plunger to
withdraw the correct dose into the syringe. Usage Illustration
10. Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles
are in the syringe, hold the syringe straight up and tap the side of the syringe until the
bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in
until you have the correct dose. If you are mixing APIDRA with NPH insulin, check with
your healthcare provider on how to mix. Usage Illustration
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11. Remove the needle from the vial. Do not let the needle touch anything. You are now
ready to inject.
For information on mixing insulins, see section “Mixing with Apidra”.
How do I inject APIDRA?
Inject APIDRA under your skin. Take APIDRA as prescribed by your healthcare provider.
Follow these steps:
1. Decide on an injection area - either upper arm, thigh or abdomen. Injection sites within
an injection area must be different from one injection to the next.
2. Use alcohol or soap and water to clean the injection site. The injection site should be dry
before you inject. Usage Illustration
3. Pinch the skin. Stick the needle in the way your healthcare provider showed you. Release
the skin.
4. Slowly push in the plunger of the syringe all the way, making sure you have injected all
the insulin. Leave the needle in the skin for about 10 seconds. Usage Illustration
Pull the needle straight out and gently press on the spot where you injected yourself for
several seconds. Do not rub the area.
5. Follow your healthcare provider’s instructions for throwing away the needle and syringe.
Do not recap the used needle. The used needle and syringe should be placed in sharps
containers (such as red biohazard containers), hard plastic containers (such as detergent
bottles), or metal containers (such as an empty coffee can). Such containers should be
sealed and disposed of properly.
How should I infuse APIDRA with an external subcutaneous insulin infusion pump?
Do not mix APIDRA with any other insulin or liquid when used in a pump.
• APIDRA is recommended for use in the following pumps and infusion sets: Disetronic®
H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™, Rapid C™, Rapid
D™, and Tender™); MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(Sof-set Ultimate QR™, and Quick-set™)‡. See the instruction manual of your specific
pump on proper use of insulin in a pump. Call your healthcare provider if you have
questions about using the pump.
• If the pump or infusion set does not work right, you may not receive the right amount of
insulin. Hypoglycemia (blood sugar that is too low), hyperglycemia (blood sugar that is
too high), or ketosis (when fats instead of sugar are broken down for energy because of
lack of insulin, chemicals called ketones appear in the blood) can happen. See
instruction manual for your pump. You may have less time to identify and correct the
problem than with regular insulin. This is because APIDRA starts working faster and
does not work as long.
• If you start using APIDRA by pump infusion, you may need to adjust your insulin doses.
Check with your healthcare provider.
• You must use insulin from a new vial of APIDRA if unexplained hyperglycemia
happens, or if pump alarms do not respond to all of the following:
•
a repeat dose (injection or bolus) of APIDRA
•
a change in the infusion set, including the reservoir with APIDRA
•
a change in the infusion site.
If these actions do not work, you may need to restart your injections with syringes and
you must call your healthcare provider. Continue to check your blood sugar often.
The infusion set, reservoir with insulin, and infusion site should be changed:
• every 48 hours or less
• when unexpected hyperglycemia or ketosis occurs
• when alarms sound, as specified by your pump manual
• if the insulin has been exposed to temperatures over 98.6°F (37°C). If the insulin or
pump could have absorbed radiant heat, for example from sunlight, that would heat
the insulin to over 98.6°F (37°C). Dark colored pump cases or sport covers can
increase this type of heat. The location where the pump is worn may affect the
temperature.
• Patients who get skin reactions at the infusion site may need to change infusion sites
more often.
What can affect how much insulin I need?
Illness. Illness may change how much insulin you need. It is a good idea to think ahead and
make a "sick day" plan with your healthcare provider in advance so you will be ready when this
happens. Be sure to test your blood sugar more often and call your healthcare provider if you are
sick.
Medicines. Many medicines can affect your insulin needs. Other medicines, including
prescription and non-prescription medicines, vitamins and herbal supplements, can change the
way insulin works. You may need a different dose of insulin when you are taking certain other
medicines. Know all the medicines you take, including prescription and non-prescription
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
medicines, vitamins and herbal supplements. You may want to keep a list of the medicines you
take. You can show this list to all your healthcare providers and pharmacists anytime you get a
new medicine or refill. Your healthcare provider will tell you if your insulin dose needs to be
changed.
Meals. The amount of food you eat can affect your insulin needs. If you eat less food, skip
meals, or eat more food than usual, you may need a different dose of insulin. Talk to your
healthcare provider if you change your diet so that you know how to adjust your APIDRA and
other insulin doses.
Alcohol. Alcohol, including beer and wine, may affect the way APIDRA works and affect your
blood sugar levels. Talk to your healthcare provider about drinking alcohol.
Exercise or Activity level. Exercise or activity level may change the way your body uses
insulin. Check with your healthcare provider before you start an exercise program because your
dose may need to be changed.
Travel. If you travel across time zones, talk with your healthcare provider about how to time
your injections. When you travel, wear your medical alert identification. Take extra insulin and
supplies with you.
Pregnancy or nursing. The effects of APIDRA on an unborn child or on a nursing baby are
unknown. Therefore, tell your healthcare provider if you are planning to have a baby, are
pregnant, or nursing a baby. Good control of diabetes is especially important during pregnancy
and nursing.
What are the possible side effects of APIDRA and other insulins?
Insulins, including APIDRA, can cause hypoglycemia (low blood sugar), hyperglycemia (high
blood sugar), allergy, and skin reactions.
Hypoglycemia (low blood sugar):
Hypoglycemia is often called an "insulin reaction" or "low blood sugar". It may happen when
you do not have enough sugar in your blood. Common causes of hypoglycemia are illness,
emotional or physical stress, too much insulin, too little food or missed meals, and too much
exercise or activity.
Early warning signs of hypoglycemia may be different, less noticeable or not noticeable at all
in some people. That is why it is important to check your blood sugar as you have been
advised by your healthcare provider.
Hypoglycemia can happen with:
• Taking too much insulin. This can happen when too much insulin is injected. For pump
users, it could happen if the pump dose is too high.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Not enough carbohydrate (sugar or starch) intake. This can happen if a meal or snack
is missed or delayed.
• Vomiting or diarrhea that decreases the amount of sugar absorbed by your body.
• Intake of alcohol.
• Medicines that affect insulin. Be sure to discuss all your medicines with your healthcare
provider. Do not start any new medicines until you know how they may affect your
insulin dose.
• Medical conditions that can affect your blood sugar levels or insulin. These
conditions include diseases of the adrenal glands, the pituitary, the thyroid gland, the
liver, and the kidney.
• Too much glucose use by the body. This can happen if you exercise too much or have a
fever.
• Injecting insulin the wrong way or in the wrong injection area.
Hypoglycemia can be mild to severe. Its onset may be rapid. Some patients have few or no
warning symptoms, including:
• patients with diabetes for a long time
• patients with diabetic neuropathy (nerve problems)
• patients using certain medicines for high blood pressure or heart problems.
Hypoglycemia may reduce your ability to drive a car or use mechanical equipment and you may
risk injury to yourself or others.
Severe hypoglycemia can be dangerous and can cause temporary or permanent harm to your
heart or brain. It may cause unconsciousness, seizures, or death.
Symptoms of hypoglycemia may include:
• anxiety, irritability, restlessness, trouble concentrating, personality changes, mood changes,
or other abnormal behavior
• tingling in your hands, feet, lips, or tongue
• dizziness, light-headedness, or drowsiness
• nightmares or trouble sleeping
• headache
• blurred vision
• slurred speech
• palpitations (fast heart beat)
• sweating
• tremor (shaking)
• unsteady gait (walking).
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you have hypoglycemia often or it is hard for you to know if you have the symptoms of
hypoglycemia, talk to your healthcare provider.
Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates such as fruit juice,
raisins, sugar candies, milk, or glucose tablets. Talk to your healthcare provider about the amount
of carbohydrates you should eat to treat mild to moderate hypoglycemia.
Severe hypoglycemia may require the help of another person or emergency medical people. A
person with hypoglycemia who is unable to take foods or liquids with sugar by mouth, or is
unconscious needs medical help fast and will need treatment with a glucagon injection or glucose
given intravenously (IV). Without medical help right away, serious reactions or even death could
happen.
Hyperglycemia (high blood sugar):
Hyperglycemia happens when you have too much sugar in your blood. Usually, it means
there is not enough insulin to break down the food you eat into energy your body can use.
Hyperglycemia can be caused by a fever, an infection, stress, eating more than you should,
taking less insulin than prescribed, or it can mean your diabetes is getting worse.
Hyperglycemia can happen with:
• Insufficient (too little) insulin. This can happen from:
- injecting too little or no insulin
- incorrect storage (freezing, excessive heat)
- use after the expiration date.
For pump users, this can also be caused when the bolus dose of APIDRA infusion or the
basal infusion is set too low or the pump is delivering too little insulin.
• Too much carbohydrate intake. This can happen if you eat larger meals, eat more often
or increase the amount of carbohydrate in your meals.
• Medicines that affect insulin. Be sure to discuss all your medicines with your
healthcare provider. Do not start any new medicines until you know how they may
affect your insulin dose.
• Medical conditions that affect insulin. These medical conditions include fevers,
infections, heart attacks, and stress.
• Injecting insulin the wrong way or in the wrong injection area.
Testing your blood or urine often will let you know if you have hyperglycemia. If your tests are
often high, tell your healthcare provider so your dose of insulin can be changed.
Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA) or very
high glucose levels (hyperosmolar coma) and result in unconsciousness and death.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Although diabetic ketoacidosis occurs most often in patients with type 1 diabetes, it can also
happen in patients with type 2 diabetes who become very sick. Because some patients get few
symptoms of hyperglycemia, it is important to check your blood/urine sugar and ketones
regularly.
Symptoms of hyperglycemia include:
• confusion or drowsiness
• increased thirst
• decreased appetite, nausea, or vomiting
• rapid heart rate
• increased urination and dehydration (too little fluid in your body).
Symptoms of DKA also include:
• fruity smelling breath
• fast, deep breathing
• stomach area (abdominal) pain.
Severe or continuing hyperglycemia or DKA needs evaluation and treatment right away by
your healthcare provider.
Other possible side effects of APIDRA include:
Serious allergic reactions:
Some times severe, life-threatening allergic reactions can happen with insulin. If you think you
are having a severe allergic reaction, get medical help right away. Signs of insulin allergy
include:
• rash all over your body
• shortness of breath
• wheezing (trouble breathing)
• fast pulse
• sweating
• low blood pressure.
Reactions at the injection site:
Injecting insulin can cause the following reactions on the skin at the injection site:
• little depression in the skin (lipoatrophy)
• skin thickening (lipohypertrophy)
• red, swelling, itchy skin (injection site reaction).
You can reduce the chance of getting an injection site reaction if you change (rotate) the
injection site each time. An injection site reaction should clear up in a few days or a few weeks.
If injection site reactions do not go away or keep happening call your healthcare provider.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These are not all the side effects of APIDRA. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-332-1088.
How should I store APIDRA?
Unopened APIDRA:
• Do not use APIDRA after the expiration date stamped on the label.
• Store all unopened APIDRA in a refrigerator (not the freezer) between 36°F to 46°F (2°C
to 8°C). Do not allow it to freeze. Do not use APIDRA if it has been frozen.
• Keep APIDRA out of direct heat and light.
• Do not use APIDRA if it has been overheated.
• Do not use APIDRA if it is cloudy, colored, or if you see particles.
Opened APIDRA:
Vial:
• Store in a refrigerator or below 77°F (25°C) and away from direct heat and light.
• Throw the vial away 28 days after the first use even if it still contains APIDRA.
Insulin pump infusion sets:
• Change the infusion sets (reservoirs, tubing, and catheters) and the APIDRA in the
reservoir at least every 48 hours. Change all these parts sooner if they have been exposed
to temperatures higher than 98.6°F (37°C).
• Do not use a vial of APIDRA after the expiration date stamped on the label.
• Do not use APIDRA if it is colored, cloudy or if you see particles.
General Information about APIDRA
• Use APIDRA only to treat your diabetes. Do not give or share APIDRA with another person,
even if they have diabetes also. It may harm them.
• The active ingredient in APIDRA is insulin glulisine. The concentration of insulin glulisine
is 100 units per milliliter (mL) or U-100. APIDRA also contains metacresol, tromethamine,
sodium chloride, polysorbate 20, and water for injection. Hydrochloric acid and/or sodium
hydroxide may be added to adjust the pH.
• This leaflet summarizes the most important information about APIDRA. If you would like
more information, talk with your healthcare provider. You can ask your healthcare provider
for information about APIDRA that is written for healthcare providers. For more information
about APIDRA call 1-800-633-1610 or go to website www.apidra.com.
ADDITIONAL INFORMATION
DIABETES FORECAST is a national magazine designed especially for patients with diabetes
and their families and is available by subscription from the American Diabetes Association,
National Service Center, 1701 N. Beauregard Street, Alexandria, Virginia 22311, 1-800
DIABETES (1-800-342-2383). You may also visit the ADA website at www.diabetes.org.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research
Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1
800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdrf.org.
To get more information about diabetes, check with your healthcare provider or diabetes
educator or visit www.DiabetesWatch.com.
Rev. August 2008
sanofi-aventis U.S. LLC
Bridgewater NJ 08807
©2008 sanofi-aventis U.S. LLC
‡
The brands listed are the registered trademarks of their respective owners and are not
trademarks of sanofi-aventis U.S. LLC
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
APIDRA® 3 mL cartridge system (300 units per cartridge system)
100 units per mL (U-100)
(insulin glulisine [recombinant DNA origin] injection)
Read the “Patient Information” that comes with APIDRA (uh-PEE-druh) before you start using it
and each time you get a refill. There may be new information. This leaflet does not take the place
of talking with your healthcare provider about your diabetes or treatment. If you have questions
about APIDRA or about diabetes, talk with your healthcare provider.
What is the most important information I should know about APIDRA?
• Do not change the insulin you use without talking to your healthcare provider. Any
change in insulin strength, manufacturer, type (for example: regular, NPH, analogs),
species (beef, pork, beef-pork, human) or method of manufacture (recombinant DNA
versus animal-source insulin) may need a change in the dose you are using. This dose
change may be needed right away or later on. Sometimes this dose change may happen
during the first several weeks or months on the new insulin. Doses of oral anti-diabetic
medicines may also need to change, if your insulin is changed.
• You must test your blood sugar levels while using an insulin, such as APIDRA.
Your healthcare provider will tell you how often you should test your blood sugar level,
and what to do if it is high or low.
• APIDRA comes as U-100 insulin. It contains 3 milliliters (mL) of APIDRA. One
milliliter of U-100 insulin contains 100 units of insulin. (1 mL = 1 cc).
What is Diabetes?
• Your body needs insulin to turn sugar (glucose) into energy. If your body does not make
enough insulin, you need to take more insulin so you will not have too much sugar in
your blood.
• Insulin injections are important in keeping your diabetes under control. But other factors
can have an effect on your diabetes, such as the foods you eat, how often you check your
blood sugars, and your exercise level.
What is APIDRA?
• APIDRA (insulin glulisine [recombinant DNA origin]) is a rapid-acting man-made
insulin. APIDRA is used to treat patients with diabetes for the control of high blood
sugar.
• APIDRA is a clear, colorless, sterile solution for injection under the skin
(subcutaneously). APIDRA may also be given by infusion into one of your veins
(intravenously) by healthcare providers only.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• APIDRA starts working faster than regular insulin and does not work as long. APIDRA
is used with a longer-acting insulin or by itself as insulin pump therapy to maintain
proper blood sugar control.
• You need a prescription to get APIDRA. Always be sure you receive the right insulin
from the pharmacy.
Who should NOT take APIDRA?
Do not take APIDRA if:
• your blood sugar is too low (hypoglycemia). After treating your low blood sugar, follow
your healthcare provider's instructions on the use of Apidra.
• you are allergic to insulin glulisine or any of the inactive ingredients in APIDRA.
Check with your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking APIDRA?
Tell your healthcare provider:
• about all of your medical conditions, including liver or kidney problems. Your dose
may need to be adjusted.
• if you are pregnant or plan to become pregnant. It is not known if APIDRA may
harm your unborn baby. It is very important to maintain control of your blood sugar
levels during pregnancy. Your healthcare provider will decide which insulin is best for
you during your pregnancy.
• if you are breast-feeding or plan to breast-feed. It is not known whether APIDRA
passes into your milk. Many medicines, including insulin, pass into human milk, and
could affect your baby. Talk to your healthcare provider about the best way to feed your
baby.
• about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements. Your APIDRA dose may change if you
take other medicines. For more information look under Medicines, under the heading
“What can affect how much insulin I need?”.
How should I use APIDRA?
See the "Instructions for OptiClik® Use" section for additional information.
• Follow the instructions given by your healthcare provider about the type or types of
insulin you are using. Do not make any changes with your insulin unless you have talked
to your healthcare provider. Your insulin needs may change because of illness, stress,
other medicines, or changes in diet or activity level. Talk to your healthcare provider
about how to adjust your insulin dose.
• You should take APIDRA within 15 minutes before a meal or within 20 minutes after
starting a meal. Only use APIDRA that is clear and colorless. If your APIDRA is cloudy
or colored, return it to your pharmacy for a replacement.
• Follow your healthcare provider's instructions for testing your blood sugar.
• Inject APIDRA under your skin (subcutaneously) in your upper arm, abdomen (stomach
area), or thigh (upper leg). Never inject it into a vein or muscle.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Change (rotate) injection sites within the same body area.
What kind of insulin Pen should I use with APIDRA cartridge system?
• Always use OptiClik® device distributed by sanofi-aventis U.S. LLC with your APIDRA
cartridge system. If you use any other device than OptiClik® insulin Pen with APIDRA
cartridge system, you may get the wrong dose of insulin causing serious problems for
you, such as a blood sugar level that is too low or too high. Always use a new needle
each time you give APIDRA injection.
• NEEDLES AND INSULIN PEN MUST NOT BE SHARED.
• Disposable needle should be used only once. Used needle should be placed in sharps
containers (such as red biohazard containers), hard plastic containers (such as detergent
bottles), or metal containers (such as an empty coffee can). Such containers should be
sealed and disposed of properly.
Instructions for OptiClik® Use
It is important to read, understand, and follow the step-by-step instructions in the
“OptiClik® Instruction Leaflet” before using OptiClik® insulin Pen. Failure to follow the
instructions may result in getting too much or too little insulin. If you have lost your leaflet
or have a question, go to www.opticlik.com or call 1-800-633-1610.
OptiClik® insulin Pen is for use with BD Ultra-Fine needles.
The following general notes should be taken into consideration before injecting APIDRA:
• Always wash your hands before handling the cartridge system and/or the OptiClik® insulin
Pen.
• Always attach a new needle before use.
• Always perform the safety test before use.
• Check the insulin solution in the cartridge system to make sure it is clear, colorless, and free
of particles. If it is not, throw it away.
• Decide on an injection area - either upper arm, thigh, or abdomen. Do not use the same
injection site as your last injection.
• After injecting APIDRA, leave the needle in the skin for an additional 10 seconds. Then pull
the needle straight out. Gently press on the spot where you injected yourself for a few
seconds. Do not rub the area.
• Do not drop the OptiClik® insulin Pen.
If your blood glucose reading is high or low, tell your healthcare provider so the dose can be
adjusted.
What can affect how much insulin I need?
Illness. Illness may change how much insulin you need. It is a good idea to think ahead and
make a "sick day" plan with your healthcare provider in advance so you will be ready when this
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
happens. Be sure to test your blood sugar more often and call your healthcare provider if you are
sick.
Medicines.
Many medicines can affect your insulin needs. Other medicines, including
prescription and non-prescription medicines, vitamins and herbal supplements, can change the
way insulin works. You may need a different dose of insulin when you are taking certain other
medicines. Know all the medicines you take, including prescription and non-prescription
medicines, vitamins and herbal supplements. You may want to keep a list of the medicines you
take. You can show this list to all your healthcare providers and pharmacists anytime you get a
new medicine or refill. Your healthcare provider will tell you if your insulin dose needs to be
changed.
Meals. The amount of food you eat can affect your insulin needs. If you eat less food, skip
meals, or eat more food than usual, you may need a different dose of insulin. Talk to your
healthcare provider if you change your diet so that you know how to adjust your APIDRA and
other insulin doses.
Alcohol. Alcohol, including beer and wine, may affect the way APIDRA works and affect your
blood sugar levels. Talk to your healthcare provider about drinking alcohol.
Exercise or Activity level. Exercise or activity level may change the way your body uses
insulin. Check with your healthcare provider before you start an exercise program because your
dose may need to be changed.
Travel. If you travel across time zones, talk with your healthcare provider about how to time
your injections. When you travel, wear your medical alert identification. Take extra insulin and
supplies with you.
Pregnancy or nursing. The effects of APIDRA on an unborn child or on a nursing baby are
unknown. Therefore, tell your healthcare provider if you are planning to have a baby, are
pregnant, or nursing a baby. Good control of diabetes is especially important during pregnancy
and nursing.
What are the possible side effects of APIDRA and other insulins?
Insulins, including APIDRA, can cause hypoglycemia (low blood sugar), hyperglycemia (high
blood sugar), allergy, and skin reactions.
Hypoglycemia (low blood sugar):
Hypoglycemia is often called an "insulin reaction" or "low blood sugar". It may happen when
you do not have enough sugar in your blood. Common causes of hypoglycemia are illness,
emotional or physical stress, too much insulin, too little food or missed meals, and too much
exercise or activity.
Early warning signs of hypoglycemia may be different, less noticeable or not noticeable at all in
some people. That is why it is important to check your blood sugar as you have been advised by
your healthcare provider.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypoglycemia can happen with:
• Taking too much insulin. This can happen when too much insulin is injected. For pump
users it could happen if the pump dose is too high.
• Not enough carbohydrate (sugar or starch) intake. This can happen if: a meal or snack
is missed or delayed.
• Vomiting or diarrhea that decreases the amount of sugar absorbed by your body.
• Intake of alcohol.
• Medicines that affect insulin. Be sure to discuss all your medicines with your healthcare
provider. Do not start any new medicines until you know how they may affect your
insulin dose.
• Medical conditions that can affect your blood sugar levels or insulin. These
conditions include diseases of the adrenal glands, the pituitary, the thyroid gland, the
liver, and the kidney.
• Too much glucose use by the body. This can happen if you exercise too much or have a
fever.
• Injecting insulin the wrong way or in the wrong injection area.
Hypoglycemia can be mild to severe. Its onset may be rapid. Some patients have few or no
warning symptoms, including:
• patients with diabetes for a long time
•
patients with diabetic neuropathy (nerve problems)
•
or patients using certain medicines for high blood pressure or heart problems.
Hypoglycemia may reduce your ability to drive a car or use mechanical equipment and you may
risk injury to yourself or others.
Severe hypoglycemia can be dangerous and can cause temporary or permanent harm to your
heart or brain. It may cause unconsciousness, seizures, or death.
Symptoms of hypoglycemia may include:
• anxiety, irritability, restlessness, trouble concentrating, personality changes, mood changes,
or other abnormal behavior
• tingling in your hands, feet, lips, or tongue
• dizziness, light-headedness, or drowsiness
• nightmares or trouble sleeping
• headache
• blurred vision
• slurred speech
• palpitations (fast heart beat)
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• sweating
• tremor (shaking)
• unsteady gait (walking).
If you have hypoglycemia often or it is hard for you to know if you have the symptoms of
hypoglycemia, talk to your healthcare provider.
Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates such as fruit juice,
raisins, sugar candies, milk or glucose tablets. Talk to your healthcare provider about the amount
of carbohydrates you should eat to treat mild to moderate hypoglycemia.
Severe hypoglycemia may require the help of another person or emergency medical people. A
person with hypoglycemia who is unable to take foods or liquids with sugar by mouth, or is
unconscious needs medical help fast and will need treatment with a glucagon injection or glucose
given intravenously (IV). Without medical help right away, serious reactions or even death could
happen.
Hyperglycemia (high blood glucose):
Hyperglycemia happens when you have too much sugar in your blood. Usually, it means there is
not enough insulin to break down the food you eat into energy your body can use.
Hyperglycemia can be caused by a fever, an infection, stress, eating more than you should,
taking less insulin than prescribed, or it can mean your diabetes is getting worse.
Hyperglycemia can happen with:
• Insufficient (too little) insulin. This can happen from:
- injecting too little or no insulin
- incorrect storage (freezing, excessive heat)
- use after the expiration date.
For pump users this can also be caused when the bolus dose of APIDRA infusion or the basal
infusion is set too low or the pump is delivering too little insulin.
• Too much carbohydrate intake. This can happen if you eat larger meals, eat more often
or increase the amount of carbohydrate in your meals.
• Medicines that affect insulin. Be sure to discuss all your medicines with your healthcare
provider. Do not start any new medicines until you know how they may affect your
insulin dose.
• Medical conditions that affect insulin. These medical conditions include fevers,
infections, heart attacks, and stress.
• Injecting insulin the wrong way or in the wrong injection area.
Testing your blood or urine often will let you know if you have hyperglycemia. If your tests are
often high, tell your healthcare provider so your dose of insulin can be changed.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA) or very
high glucose levels (hyperosmolar coma) and result in unconsciousness and death.
Although diabetic ketoacidosis occurs most often in patients with type 1 diabetes, it can also
happen in patients with type 2 diabetes who become very sick. Because some patients get few
symptoms of hyperglycemia, it is important to check your blood sugar regularly.
Symptoms of hyperglycemia include:
• confusion or drowsiness
• increased thirst
• decreased appetite, nausea, or vomiting
• rapid heart rate
• increased urination and dehydration (too little fluid in your body).
Symptoms of DKA also include:
• fruity smelling breath
• fast, deep breathing
• stomach area (abdominal) pain.
Severe or continuing hyperglycemia or DKA needs evaluation and treatment right away by
your healthcare provider.
Other possible side effects of APIDRA include:
Serious allergic reactions:
Some times severe, life-threatening allergic reactions can happen with insulin. If you think you
are having a severe allergic reaction, get medical help right away. Signs of insulin allergy
include:
• rash all over your body
• shortness of breath
• wheezing (trouble breathing)
• fast pulse
• sweating
• low blood pressure.
Reactions at the injection site:
Injecting insulin can cause the following reactions on the skin at the injection site:
• little depression in the skin (lipoatrophy)
• skin thickening (lipohypertrophy)
• red, swelling, itchy skin (injection site reaction).
You can reduce the chance of getting an injection site reaction if you change (rotate) the
injection site each time. An injection site reaction should clear up in a few days or a few weeks.
If injection site reactions do not go away or keep happening, call your healthcare provider.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These are not all the side effects of APIDRA. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-332-1088.
How should I store APIDRA?
Unopened APIDRA:
• Do not use APIDRA after the expiration date stamped on the label.
• Store all unopened APIDRA in a refrigerator (not the freezer) between 36°F to 46°F (2°C
to 8°C). Do not allow it to freeze. Do not use APIDRA if it has been frozen.
• Keep APIDRA out of direct heat and light.
• Do not use APIDRA if it has been overheated.
• Do not use APIDRA if it is cloudy, colored, or if you see particles.
Opened APIDRA:
Cartridge:
• Store the opened cartridge system below 77°F (25°C) and away from direct heat and
light.
• Throw away the cartridge system 28 days after the first use even if it still contains
APIDRA.
• Do not store an opened cartridge system or OptiClik® insulin Pen in a refrigerator.
• Do not use APIDRA if it is cloudy, colored, or if you see particles.
General Information about APIDRA
• Use APIDRA only to treat your diabetes. Do not give or share APIDRA with another
person, even if they have diabetes also. It may harm them.
• The active ingredient in APIDRA is insulin glulisine. The concentration of insulin glulisine is
100 units per milliliter (mL), or U-100. APIDRA also contains metacresol, tromethamine,
sodium chloride, polysorbate 20, and water for injection as inactive ingredients.
Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH.
• This leaflet summarizes the most important information about APIDRA. If you would like
more information, talk with your healthcare provider. You can ask your healthcare provider
for information about APIDRA that is written for healthcare providers. For more
information about APIDRA call 1-800-633-1610 or go to website www.apidra.com.
ADDITIONAL INFORMATION
DIABETES FORECAST is a national magazine designed especially for patients with diabetes
and their families and is available by subscription from the American Diabetes Association,
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(ADA), P.O. Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). You
may also visit the ADA website at www.diabetes.org.
Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research
Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1
800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdf.org.
To get more information about diabetes, check with your healthcare provider or diabetes
educator or visit www.DiabetesWatch.com.
Additional information about APIDRA or OptiClik® can be obtained by calling 1-800-633-1610
or by visiting www.apidra.com or www.opticlik.com.
Rev. August 2008
sanofi-aventis U.S. LLC
Bridgewater NJ 08807
©2008 sanofi-aventis U.S. LLC
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:32.030017 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021629s015lbl.pdf', 'application_number': 21629, 'submission_type': 'SUPPL ', 'submission_number': 15} |
5,945 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
MENOPUR® safely and effectively. See full prescribing information
for MENOPUR® .
MENOPUR® (menotropins for injection) for subcutaneous use.
Initial U.S. Approval: 1975
----------------------------RECENT MAJOR CHANGES---------------------------
Dosage and Administration (2.2)
2/2014
Contraindications (4)
2/2014
Warnings and Precautions
Ovarian Hyperstimulation Syndrome (OHSS) (5.2)
2/2014
Pulmonary and Vascular Complications (5.3)
2/2014
Ovarian Torsion (5.4)
2/2014
Multi-fetal Gestation and Birth (5.5)
2/2014
Congenital Malformations (5.6)
2/2014
Ectopic Pregnancy (5.7)
2/2014
Spontaneous Abortion (5.8)
2/2014
Ovarian Neoplasms (5.9)
2/2014
-----------------------------INDICATIONS AND USAGE---------------------------
MENOPUR® (menotropins for injection) is a gonadotropin indicated for:
• Development of multiple follicles and pregnancy in ovulatory women
as part of an Assisted Reproductive Technology (ART) cycle (1)
-------------------------DOSAGE AND ADMINISTRATION-----------------------
• Initial starting dose of the first cycle - 225 International Units per day,
administered subcutaneously (2.2)
• Dosage adjustments after 5 days and by no more than 150
International Units at each adjustment (2.2)
• Do not administer doses greater than 450 International Units per day
(2.2)
• MENOPUR® may be administered together with BRAVELLE®
(urofollitropin for injection, purified). Only the total starting dose of 225
International Units (150 International Units of MENOPUR® and 75
International Units of BRAVELLE® or 75 International Units of
MENOPUR® and 150 International Units of BRAVELLE®) was studied
in a clinical trial. (2.2)
----------------------DOSAGE FORMS AND STRENGTHS----------------------
Lyophilized powder for injection: containing 75 IU FSH and 75 IU of LH
activity, supplied as lyophilized powder or pellet in sterile vials with
diluent vials and Q-Cap® vial adapters. (3)
-------------------------------CONTRAINDICATIONS-------------------------------
MENOPUR® is contraindicated in women who exhibit:
• Prior hypersensitivity to MENOPUR® or menotropins products or one
of their excipients (4)
• High levels of FSH indicating primary ovarian failure (4)
• Pregnancy (4)
• Presence of uncontrolled non-gonadal endocrinopathies (4)
• Sex hormone dependent tumors of the reproductive tract and
accessory organ (4)
• Tumors of pituitary gland or hypothalamus (4)
• Abnormal uterine bleeding of undetermined origin (4)
• Ovarian cyst or enlargement of undetermined origin, not due to
polycystic ovary syndrome (4)
------------------------WARNINGS AND PRECAUTIONS------------------------
• Abnormal Ovarian Enlargement (5.1)
• Ovarian Hyperstimulation Syndrome (5.2)
• Pulmonary and Vascular Complications (5.3)
• Ovarian Torsion (5.4)
• Multi-fetal Gestation and Birth (5.5)
• Congenital Malformation (5.6)
• Ectopic Pregnancy (5.7)
• Spontaneous Abortion (5.8)
• Ovarian Neoplasms (5.9)
-------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions (≥2%) in ART include: abdominal
cramps; abdomen enlarged; abdominal pain; headache; injection site
pain and reaction; injection site inflammation; OHSS (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Ferring
Pharmaceuticals Inc. at 1-888-FERRING (1-888-337-7464) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS-------------------------------
No drug/drug interaction studies have been conducted for MENOPUR®
in humans. (7)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
• Pregnancy Category X. Do not use MENOPUR® in pregnant women.
(4, 8.1)
• Nursing Mothers: It is not known whether this drug is excreted in
human milk. (8.3)
• Pediatric Use: Safety and efficacy not established. (8.4)
• Renal and Hepatic Insufficiency: Safety, efficacy, and
pharmacokinetics of MENOPUR® in women with renal or hepatic
insufficiency have not been established. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: February 2014
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
Development of Multiple Follicles and Pregnancy in Ovulatory
Women as Part of an Assisted Reproductive Technology (ART)
Cycle
2
DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Recommended Dosing for Assisted Reproductive
Technology
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Abnormal Ovarian Enlargement
5.2
Ovarian Hyperstimulation Syndrome (OHSS)
5.3
Pulmonary and Vascular Complications
5.4
Ovarian Torsion
5.5
Multi-fetal Gestation and Birth
5.6
Congenital Malformations
5.7
Ectopic Pregnancy
5.8
Spontaneous Abortion
5.9
Ovarian Neoplasms
5.10
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.6
Renal and Hepatic Insufficiency
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOCOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
17.1
Dosing and Use
17.2
Duration and Monitoring Required
17.3
Instructions Regarding a Missed Dose
17.4
Ovarian Hyperstimulation Syndrome
17.5
Multi-fetal Gestation and Birth
*Sections or subsections omitted from the Full Prescribing information
are not listed
2
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Development of Multiple Follicles and Pregnancy in Ovulatory Women as Part of an Assisted
Reproductive Technology (ART) Cycle
Prior to initiation of treatment with MENOPUR®:
•
Perform a complete gynecologic and endocrinologic evaluation, and diagnose the cause of
infertility
•
Exclude the possibility of pregnancy
•
Evaluate the fertility status of the male partner
•
Exclude a diagnosis of primary ovarian failure
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
•
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
• Administer MENOPUR® subcutaneously in the abdomen as described in Instructions for Use.
•
MENOPUR® may be administered together with BRAVELLE® (urofollitropin for injection,
purified).
2.2 Recommended Dosing for Assisted Reproductive Technology
The recommended dosing scheme for patients undergoing IVF follows a stepwise approach and is
individualized for each woman. The recommended initial dose of MENOPUR® for women who have
received a GnRH agonist for pituitary suppression is 225 International Units. MENOPUR® may be
administered together with BRAVELLE® (urofollitropin for injection, purified) and the total initial dose
when the products are combined should not exceed 225 International Units (150 International Units of
MENOPUR® and 75 International Units of BRAVELLE® or 75 International Units of MENOPUR® and
150 International Units of BRAVELLE®).
•
Beginning on cycle day 2 or 3, a starting dose of 225 International Units of MENOPUR® is
administered subcutaneously daily. Adjust the dose after 5 days based on the woman’s ovarian
response, as determined by ultrasound evaluation of follicular growth and serum estradiol levels.
•
Do not make additional dosage adjustments more frequently than every 2 days or by more than
150 International Units at each adjustment.
•
Continue treatment until adequate follicular development is evident, and then administer hCG.
Withhold the administration of hCG in cases where the ovarian monitoring suggests an increased
risk of OHSS on the last day of MENOPUR® therapy [see Warnings and Precautions (5.1, 5.2,
5.10)].
•
Do not administer daily doses of MENOPUR® or MENOPUR® in combination with BRAVELLE®
that exceed 450 International Units.
•
Therapy should not exceed 20 days.
3 DOSAGE FORMS AND STRENGTHS
Lyophilized powder for Injection containing 75 International Units FSH and 75 International Units of
LH activity, supplied as lyophilized powder or pellet in sterile vials with diluent vials and Q•Cap® vial
adapters.
3
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
MENOPUR® is contraindicated in women who exhibit:
•
Prior hypersensitivity to MENOPUR® or menotropins products or one of their excipients
•
High levels of FSH indicating primary ovarian failure [see Indications and Usage (1)]
•
Pregnancy
MENOPUR® may cause fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. MENOPUR® is contraindicated in women who are pregnant. If this
drug is used during pregnancy, or if the woman becomes pregnant while taking this drug, the
woman should be apprised of the potential hazard to a fetus.
•
Presence of uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary
disorders) [see Indications and Usage (1)]
•
Sex hormone dependent tumors of the reproductive tract and accessory organs
•
Tumors of pituitary gland or hypothalamus
•
Abnormal uterine bleeding of undetermined origin
•
Ovarian cyst or enlargement of undetermined origin, not due to polycystic ovary syndrome
5 WARNINGS AND PRECAUTIONS
MENOPUR® should only be used by physicians who are experienced in infertility treatment. MENOPUR®
contains gonadotropic substances capable of causing in women, Ovarian Hyperstimulation Syndrome
(OHSS) with or without pulmonary or vascular complications [see Warnings and Precautions (5.2, 5.3)]
and multiple births [see Warnings and Precautions (5.5)]. Gonadotropin therapy requires the availability of
appropriate monitoring facilities [see Warnings and Precautions (5.10)]. Use the lowest effective dose.
5.1
Abnormal Ovarian Enlargement
In order to minimize the hazards associated with abnormal ovarian enlargement that may occur with
MENOPUR® therapy, treatment should be individualized and the lowest effective dose should be used
[see Dosage and Administration (2.2)]. Use of ultrasound monitoring of ovarian response and/or
measurement of serum estradiol levels is important to minimize the risk of ovarian stimulation [see
Warnings and Precautions (5.10)].
If the ovaries are abnormally enlarged on the last day of MENOPUR® therapy, hCG should not be
administered in order to reduce the chance of developing Ovarian Hyperstimulation Syndrome (OHSS)
[see Warnings and Precautions (5.2)]. Prohibit intercourse in women with significant ovarian enlargement
because of the danger of hemoperitoneum resulting from rupture of ovarian cysts [see Warnings and
Precautions (5.2)].
5.2
Ovarian Hyperstimulation Syndrome (OHSS)
OHSS is a medical event distinct from uncomplicated ovarian enlargement and may progress rapidly to
become a serious medical event. OHSS is characterized by a dramatic increase in vascular permeability,
which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the
pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting,
and weight gain. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea,
vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria have been
reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte
imbalances, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute pulmonary distress, and
thromboembolic reactions [see Warnings and Precautions (5.3)]. Transient liver function test
abnormalities suggestive of hepatic dysfunction, with or without morphologic changes on liver biopsy,
have been reported in association with OHSS.
OHSS occurs after gonadotropin treatment has been discontinued and it can develop rapidly, reaching its
maximum about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the
onset of menses. If there is evidence that OHSS may be developing prior to hCG administration [see
Warnings and Precautions (5.1)], the hCG must be withheld.
4
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore,
women should be assessed for the development of OHSS for at least two weeks after hCG
administration.
If serious OHSS occurs, gonadotropins, including hCG, should be stopped and consideration should be
given as to whether the woman needs to be hospitalized. Treatment is primarily symptomatic and overall
should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the
use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except
in the late phase of resolution as described below. The management of OHSS may be divided into three
phases as follows:
•
Acute Phase:
Management should be directed at preventing hemoconcentration due to loss of intravascular
volume to the third space and minimizing the risk of thromboembolic phenomena and kidney
damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine
specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation
studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be
thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of
limited intravenous fluids, electrolytes, human serum albumin, is intended to normalize
electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full
correction of the intravascular volume deficit may lead to an unacceptable increase in the
amount of third space fluid accumulation.
•
Chronic Phase:
After the acute phase is successfully managed as above, excessive fluid accumulation in the
third space should be limited by instituting severe potassium, sodium, and fluid restriction.
•
Resolution Phase:
As third space fluid returns to the intravascular compartment, a fall in hematocrit and increasing
urinary output are observed in the absence of any increase in intake. Peripheral and/or
pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as
it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat
pulmonary edema.
Do not remove ascitic, pleural, and pericardial fluid unless there is the necessity to relieve symptoms such
as pulmonary distress or cardiac tamponade.
OHSS increases the risk of injury to the ovary. Pelvic examination or intercourse may cause rupture of an
ovarian cyst, which may result in hemoperitoneum, and should be avoided.
If bleeding occurs and requires surgical intervention, the clinical objective should be to control the
bleeding and retain as much ovarian tissue as possible. A physician experienced in the management of
this syndrome, or who is experienced in the management of fluid and electrolyte imbalances, should be
consulted.
In the IVF clinical trial for MENOPUR
®, OHSS occurred in 7.2% of the 373 MENOPUR® treated women.
5.3
Pulmonary and Vascular Complications
Serious pulmonary conditions (e.g. atelectasis, acute respiratory distress syndrome and exacerbation of
asthma) have been reported in women treated with gonadotropins. In addition, thromboembolic events
both in association with, and separate from the Ovarian Hyperstimulation Syndrome (OHSS) have been
reported in women treated with gonadotropins. Intravascular thrombosis and embolism, which may
originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the
extremities. Women with generally recognized risk factors for thrombosis, such as personal or family
history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial
thromboembolic events during or following treatment with gonadotropins. Sequelae of such reactions
5
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular
occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarctions. In
rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women
with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology need
to be weighed against the risks. Pregnancy also carries an increased risk of thrombosis.
5.4
Ovarian Torsion
Ovarian torsion has been reported after treatment with gonadotropins. This may be related to OHSS,
pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst
and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early
diagnosis and immediate detorsion.
5.5
Multi-fetal Gestation and Birth
Multi-fetal gestation and births have been reported with all gonadotropin therapy including therapy
with MENOPUR® .
In the IVF clinical trial of MENOPUR®, multiple pregnancy as diagnosed by ultrasound occurred in
35.3% (n=30) of 85 total pregnancies.
Before beginning treatment with MENOPUR®, advise the woman and her partner of the potential risk of
multi-fetal gestation and birth.
5.6
Congenital Malformations
The incidence of congenital malformations after some ART [specifically in vitro fertilization (IVF) or
intracytoplasmic sperm injection (ICSI)] may be slightly higher than after spontaneous conception. This
slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal
age, maternal and paternal genetic background, sperm characteristics) and to the higher incidence of
multi-fetal gestations after IVF or ICSI. There are no indications that the use of gonadotropins during IVF
or ICSI is associated with an increased risk of congenital malformations.
5.7
Ectopic Pregnancy
Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy
may be increased. Early confirmation of intrauterine pregnancy should be determined by β-hCG testing
and transvaginal ultrasound.
5.8
Spontaneous Abortion
The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products. However,
causality has not been established. The increased risk may be a factor of the underlying infertility.
5.9
Ovarian Neoplasms
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who
have had multiple drug therapy for controlled ovarian stimulation; however, a causal relationship has not
been established.
5.10 Laboratory Tests
In most instances, treatment of women with MENOPUR® will result only in follicular growth and
maturation. In the absence of an endogenous LH surge, hCG is given when monitoring of the woman
indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone
or in combination with measurement of serum estradiol levels. The combination of both ultrasound and
serum estradiol measurement are useful for monitoring follicular growth and maturation, timing of the
ovulatory trigger, detecting ovarian enlargement and minimizing the risk of the OHSS and multiple
gestation.
The clinical confirmation of ovulation is obtained by direct or indirect indices of progesterone production
as well as sonographic evidence of ovulation.
6
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Direct or indirect indices of progesterone production:
•
Urinary or serum luteinizing hormone (LH) rise
•
A rise in basal body temperature
•
Increase in serum progesterone
•
Menstruation following the shift in basal body temperature
Sonographic evidence of ovulation:
•
Collapsed follicle
•
Fluid in the cul-de-sac
•
Features consistent with corpus luteum formation
•
Secretory endometrium
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
• Abnormal Ovarian Enlargement [see Warnings and Precautions (5.1)]
• Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2)]
• Atelectasis, acute respiratory distress syndrome and exacerbation of asthma [see Warnings and
Precautions (5.3)]
• Thromboembolic events [see Warnings and Precautions (5.3)]
• Ovarian Torsion [see Warnings and Precautions (5.4)]
• Multi-fetal Gestation and Birth [see Warnings and Precautions (5.5)]
• Congenital Malformations [see Warnings and Precautions (5.6)]
• Ectopic Pregnancy [see Warnings and Precautions (5.7)]
• Spontaneous Abortion [see Warnings and Precautions (5.8)]
• Ovarian Neoplasms [see Warnings and Precautions (5.9)]
6.1
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and
may not reflect the rates observed in practice.
In two single cycle, open label, multinational, multicenter, comparative trials, a total of 434 normal
ovulatory infertile women were randomized and received subcutaneously administered MENOPUR® as
part of an in vitro fertilization (IVF) cycle (both trials) or intracytoplasmic sperm injection (ICSI)] cycle (one
of the two trials). All women received pituitary down-regulation with gonadotropin releasing hormone
(GnRH) agonist before stimulation. Adverse Reactions occurring at an incidence of ≥ 2% in women
receiving MENOPUR® are shown in Table 1.
7
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1: MENOPUR® Administered subcutaneously in Women Undergoing IVF and ICSI.
Adverse Reactions with Incidence of 2% or Greater Occurring on or After GnRH Administration.
Body System/Preferred Term
IVF
n=434
N
%
Body as a whole
Abdominal cramps
13
3.0
Abdomen enlarged
10
2.3
Abdominal pain
29
6.7
Headache
27
6.2
Injection site pain + reaction
17
3.9
Injection site inflammation
10
2.3
Urogenital
OHSS
27
6.2
In addition, thrombophlebitis was reported in less than 1% of subjects.
In a second open label, multinational, multicenter, comparative IVF and ICSI trial, MENOPUR® and
BRAVELLE® were administered in the same syringe to 60 normal ovulatory infertile women. OHSS, post
retrieval cramping and nausea and spontaneous abortion were the most common adverse reactions
occurring at an incidence of ≥ 5% in women receiving the combination of MENOPUR® and BRAVELLE® .
In a third open label, US multicenter, comparative trial for ovulation induction in anovulatory or
oligovulatory infertile women, 76 subjects received subcutaneous or intramuscular injections of
MENOPUR® . The most common adverse reactions occurring at an incidence of ≥ 5% in women receiving
MENOPUR® were: headache; OHSS; injection site reaction, abdominal cramps, fullness and pain; and
nausea.
6.2
Postmarketing Experience
The following adverse reactions have been reported during postmarketing use of gonadotropins. Because
these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal
relationship to MENOPUR® cannot be reliably determined.
Gastrointestinal disorders: abdominal pain, abdominal pain lower, abdominal distension, nausea,
vomiting, abdominal discomfort
General disorders and administration site conditions: injection site reactions (most frequently reported
injection site reaction was injection site pain), fatigue
Nervous system disorders: headache, dizziness
Reproductive system disorders: OHSS [see Warnings and Precautions (5.2)], pelvic pain, ovarian cyst,
breast complaints (including breast pain, breast tenderness, breast discomfort and breast swelling)
Skin and subcutaneous tissue disorders: acne, rash
Vascular disorders: hot flush
7
DRUG INTERACTIONS
No drug/drug interaction studies in humans have been conducted for MENOPUR® .
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic effects
Pregnancy Category X [see Contraindications (4)].
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8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in the nursing infant from Menopur®, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.6
Renal and Hepatic Insufficiency
Safety, efficacy, and pharmacokinetics of MENOPUR® in women with renal or hepatic insufficiency have
not been established.
10 OVERDOSAGE
Aside from possible OHSS [see Warnings and Precautions (5.2)] and multiple gestations [see Warnings
and Precautions (5.5)], there is no additional information on the consequences of acute overdosage with
MENOPUR® .
11 DESCRIPTION
MENOPUR® is a preparation of gonadotropins (FSH and LH activity), extracted from the urine of
postmenopausal women, which has undergone additional steps for purification.
MENOPUR® is a sterile, lyophilized powder intended for subcutaneous (SC) injection after reconstitution
with sterile 0.9% Sodium Chloride Injection, USP. Each vial of MENOPUR® contains 75 International
Units of follicle-stimulating hormone (FSH) activity and 75 International Units of luteinizing hormone (LH)
activity, plus 21 mg lactose monohydrate and 0.005 mg Polysorbate 20 and Sodium Phosphate Buffer
(Sodium Phosphate Dibasic, Heptahydrate and Phosphoric Acid).
The biological activity of MENOPUR® is determined using the bioassays for FSH (ovarian weight gain
assay in female rats) and LH (seminal vesicle weight gain assay in male rats), modified to increase the
accuracy and reproducibility of these assays. The FSH and LH activity assays are standardized using the
Fourth International Standard for Urinary FSH and Urinary LH, November 2000, by the Expert Committee
on Biological Standardization of the W orld Health Organization (WHO ECBS). Both FSH and LH are
glycoproteins that are acidic and water soluble. Human Chorionic Gonadotropin (hCG) is detected in
MENOPUR® .
MENOPUR® has been mixed in vitro with Bravelle® with no evidence of aggregation.
Therapeutic class: Infertility
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
MENOPUR®, administered for 7 to 20 days, produces ovarian follicular growth and maturation in women
who do not have primary ovarian failure. Treatment with MENOPUR® in most instances results only in
follicular growth and maturation. When sufficient follicular maturation has occurred, hCG must be given to
induce ovulation.
12.3 Pharmacokinetics
Two open-label, randomized, controlled trials were conducted to assess the pharmacokinetics of
MENOPUR®. Study 2003-02 compared single doses of subcutaneous administration of the US and
European (EU) formulations of MENOPUR® in 57 healthy, pre-menopausal females who had undergone
pituitary suppression. The study established that the two formulations are bioequivalent. Study 2000-03
assessed single and multiple doses of MENOPUR® administered subcutaneously and intramuscularly in a
9
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3 phase cross-over design in 33 healthy, pre-menopausal females who had undergone pituitary
suppression. The primary pharmacokinetic endpoints were FSH AUC and C max values. The results are
summarized in Table 2.
Table 2: FSH Pharmacokinetic Parameters [Mean (SD)] Following MENOPUR® Administration
(Study 2000-03)
PK Parameters
Single Dose
(225 IU)
Multiple Dose
(225 IU x 1 day
then 150 IU x 6 days)
Subcutaneous
Intramuscular
Subcutaneous
Intramuscular
Cmax* (mIU/mL)
8.5 (2.5)
7.8 (2.4)
15.0 (3.6)
12.5 (2.3)
Tmax (hr)
17.9 (5.8)
27.5 (25.4)
8.0 (3.0)
9.0 (7.0)
AUC†
(hr-mlU/mL)
726.2 (243.0)
656.1 (233.7)
622.7 (153.0)
546.2 (91.2)
* Single dose Cmax , AUC 120 and multiple dose Cmaxss , AUC ss
Absorption
The subcutaneous route of administration trends toward greater bioavailability than the intramuscular
route for single and multiple doses of MENOPUR® .
Distribution
Human tissue or organ distribution of FSH and LH has not been studied for MENOPUR® .
Metabolism
Metabolism of FSH and LH has not been studied for MENOPUR® in humans.
Excretion
The elimination half-lives for FSH in the multiple-dose phase were similar (11-13 hours) for
subcutaneously administered MENOPUR® and intramuscularly administered MENOPUR® .
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic potential of
menotropins.
14
CLINICAL STUDIES
The efficacy of MENOPUR® was established in one randomized, open-label, multicenter, multinational (in
Europe and Israel), comparative clinical trial of women undergoing in vitro fertilization (IVF) or IVF plus
intracytoplasmic injection (ICSI) to achieve pregnancy.
All women began ovarian stimulation as part of an IVF cycle following pituitary suppression with a GnRH
agonist. A total of 373 patients were randomized to the MENOPUR® arm. Randomization was stratified by
insemination technique [conventional IVF vs. ICSI]. Efficacy was assessed based on the primary efficacy
parameter of continuing pregnancy. The initial daily dose of MENOPUR ® was 225 International Units
administered subcutaneously for five days. Thereafter, the dose was individualized according to each
patient's response, up to a maximum of 450 IU/day for a total maximum duration of stimulation of 20
days. Treatment outcomes are summarized in Table 3.
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Table 3: Efficacy Outcome in IVF Study (one cycle of treatment)
Parameter
Subcutaneously Administered MENOPUR®
n=373
Continuing Pregnancy (%)a
87 (23)b
Clinical Pregnancy (%)
98 (26)c
a Continuing pregnancy was defined as ultrasound visualization of gestational sac with fetal heartbeat at ≥10 weeks after ET
b Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis
c Secondary efficacy parameter. Study was not powered to demonstrate differences in this parameter
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
MENOPUR® (menotropins for injection) is supplied in sterile vials as a lyophilized, white to off-white
powder or pellet.
Each vial of MENOPUR® is accompanied by a vial of sterile diluent containing 2 mL of 0.9% Sodium
Chloride for Injection, USP:
75 International Units FSH and 75 International Units of LH activity, supplied as
NDC 55566-7501-1: Box of 5 vials + 5 vials diluent.
NDC 55566-7501-2: Box of 5 vials + 5 vials diluent + 5 Q•Cap® vial adapters
16.2
Storage and Handling
Lyophilized powder may be stored refrigerated or at room temperature (3° to 25° C/37° to 77°F) until
dispensed. Protect from light. Use immediately after reconstitution. Discard unused material.
17
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use).
17.1 Dosing and Use
Instruct women on the correct usage and dosing of MENOPUR® [see Dosage and Administration (2.2)].
Caution women not to change the dosage or the schedule of administration unless she is told to do so by
her healthcare provider.
17.2 Duration and Monitoring Required
Prior to beginning therapy with MENOPUR®, inform women about the time commitment and monitoring
procedures necessary for treatment [see Dosage and Administration (2.2) and Warnings and Precautions
(5.10)].
17.3 Instructions Regarding a Missed Dose
Inform the woman that if she misses or forgets to take a dose of MENOPUR®, the next dose should not
be doubled and she should call her healthcare provider for further dosing instructions.
17.4 Ovarian Hyperstimulation Syndrome
Inform women regarding the risks of OHSS [see Warnings and Precautions (5.2)] and OHSS-associated
symptoms including lung and blood vessel problems [see Warnings and Precautions (5.3)] and ovarian
torsion [see Warnings and Precautions (5.4)] with the use of MENOPUR® .
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17.5 Multi-fetal Gestation and Birth
Inform women regarding the risk of multi-fetal gestation and birth with the use of MENOPUR® [see
Warnings and Precautions (5.5)]
Vials of sterile diluent of 0.9% Sodium Chloride Injection, USP manufactured for Ferring
Pharmaceuticals Inc.
MANUFACTURED FOR:
company logo
Parsippany, NJ 07054
6314-02
Revised: February 2014
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Patient Information
MENOPUR® (Men-oh-pyoor)
(menotropins for injection)
for subcutaneous use
Read this Patient Information before you start using MENOPUR® and each time you
get a refill. There may be new information. This information does not take the place
of talking to your healthcare provider about your medical condition or your
treatment.
What is MENOPUR®?
MENOPUR® is a prescription medicine that contains follicle stimulating hormone
(FSH) and luteinizing hormone (LH). MENOPUR® causes your ovaries to make
multiple (more than 1) eggs as part of an Assisted Reproductive Technology (ART)
cycle.
Who should not use MENOPUR®?
Do not use MENOPUR® if you:
• are allergic to menotropins or any of the ingredients in MENOPUR®. See the end
of this leaflet for a complete list of ingredients in MENOPUR® .
• have ovaries that no longer make eggs (primary ovarian failure)
• are pregnant or think you may be pregnant. If MENOPUR® is taken while you are
pregnant, it may harm your baby.
• have problems with your thyroid gland, adrenal gland or pituitary gland that are
not controlled by taking medicine.
• have a tumor in your female organs, including your ovaries, breast, or uterus
that may get worse with high levels of estrogen
• have a tumor of your pituitary gland or hypothalamus
• have abnormal bleeding from your uterus or vagina and the cause is not known
• have ovarian cysts or enlarged ovaries, not due to a problem called polycystic
ovary syndrome (PCOS)
What should I tell my healthcare provider before using MENOPUR®?
Before you use MENOPUR®, tell your healthcare provider if you:
• have been told by a healthcare provider that you are at an increased risk for
blood clots (thrombosis)
• have ever had a blood clot (thrombosis), or anyone in your family has ever had
a blood clot
• had twisting of your ovary (ovarian torsion)
• had or have a cyst in your ovary
• have any other medical conditions
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• are breast feeding or plan to breast feed. It is not known if MENOPUR® passes
into your breast milk. You and your healthcare provider should decide if you will
use MENOPUR® or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider
and pharmacist when you get a new medicine.
How should I use MENOPUR®?
• Read the Instructions for Use at the end of this Patient Information about the
right way to use MENOPUR® or MENOPUR® mixed with BRAVELLE® .
• Use MENOPUR® exactly as your healthcare provider tells you to use it.
• Your healthcare provider will tell you how much MENOPUR® to use and when to
use it.
• Your healthcare provider may change your dose of MENOPUR® if needed.
• If you miss a dose of MENOPUR®, call your healthcare provider right away. Do
not double the amount of MENOPUR® you are using.
• You may need more than 1 vial of MENOPUR® for your dose.
• MENOPUR® may be mixed with BRAVELLE® in the same syringe.
What are possible side effects of MENOPUR®?
MENOPUR® may cause serious side effects, including:
• ovaries that are too large. MENOPUR® may cause your ovaries to be
abnormally large. Symptoms of large ovaries include bloating or pain in your
lower stomach (pelvic) area. If your ovaries become too large your healthcare
provider may tell you that you should not have intercourse (sex) so you do not
rupture an ovarian cyst.
• ovarian hyperstimulation syndrome (OHSS). Using MENOPUR® may cause
OHSS. OHSS is a serious medical condition that can happen when your ovaries
produce too many eggs (overstimulated). OHSS can cause fluid to suddenly
build up in the area of your stomach, chest, heart, and cause blood clots to
form. OHSS may also happen after you stop using MENOPUR®. Stop using
MENOPUR® and call your healthcare provider or go to the nearest hospital
emergency room right away if you have any of the following symptoms of
OHSS:
o severe pelvic or stomach pain
o swollen stomach
o nausea
o diarrhea
o vomiting
o trouble breathing
o sudden weight gain
o decreased or no urine
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• lung problems. MENOPUR® may cause serious lung problems that can
sometimes lead to death including fluid in the lungs, trouble breathing, and
worsening of asthma.
• blood clots. MENOPUR® may increase your chance of having blood clots in your
blood vessels. Blood clots can cause:
o blood vessel problems (thrombophlebitis)
o stroke
o loss of your arm or leg
o blood clot in your lung (pulmonary embolus)
• twisted (torsion) of your ovary. MENOPUR® may increase the chance of your
ovary twisting, if you already have certain conditions such as OHSS, pregnancy
and previous abdominal surgery. Twisting of your ovary may lead to blood flow
being cut off to your ovary.
• pregnancy with and birth of multiple babies. MENOPUR® may increase your
chance of having a pregnancy with more than 1 baby. Having a pregnancy and
giving birth to more than 1 baby at a time increases the health risk for you and
your babies. Your healthcare provider should talk to you about your chances of
multiple births before you start using MENOPUR® .
• birth defects. Babies born after ART may have an increased chance of birth
defects. Your age, certain sperm problems, your genetic background and that of
your partner, and a pregnancy with more than 1 baby at a time may increase
the chance that your baby may have birth defects.
• ectopic pregnancy (pregnancy outside your womb). MENOPUR® may
increase your chance of having a pregnancy that is abnormally outside of your
womb. Your chance of having a pregnancy outside of your womb is increased if
you also have fallopian tube problems.
• miscarriage. Your chance of loss of an early pregnancy may be increased if you
had difficulty becoming pregnant.
• tumors of the ovary. If you have used medicines like MENOPUR® more than 1
time to get pregnant, you may have an increased chance of having tumors in
your ovaries, including cancer.
The most common side effects of MENOPUR® include:
• stomach cramps, fullness or pain
• headache
• injection site swelling, heat, redness and pain
These are not all the possible side effects of MENOPUR®. For more information, ask your
healthcare provider or pharmacist.
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Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
How should I store MENOPUR®?
• Before mixing, store MENOPUR® powder in the refrigerator at room temperature between
37ºF to 77ºF (3ºC to 25ºC).
• Protect MENOPUR® from light.
• MENOPUR® should be used right after mixing.
• Throw away any unused MENOPUR® .
Keep MENOPUR® and all medicines out of the reach of children.
General Information about the safe and effective use of MENOPUR® .
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use MENOPUR® for a condition for which it was not prescribed. Do not give
MENOPUR® to other people, even if they have the same condition you have. It may harm them.
This Patient Information summarizes the most important information about MENOPUR®. If you
would like more information, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about MENOPUR® that is written for health professionals.
For more information go to www.menopur.com, or call 1-888-FERRING (1-888-337-7464).
What are the ingredients in MENOPUR®?
Active ingredient: menotropins
Inactive ingredients: lactose monohydrate, polysorbate, sodium phosphate buffer (sodium
phosphate dibasic, heptahydrate and phosphoric acid)
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Instructions for Use
MENOPUR® (Men-oh-pyoor)
(menotropins for injection)
for subcutaneous use
Your healthcare provider should show you how to mix and inject MENOPUR® or MENOPUR®
mixed with BRAVELLE® before you do it for the first time. Before using MENOPUR® or
MENOPUR® mixed with BRAVELLE® for the first time, read this Instructions for Use carefully.
Keep this leaflet in a safe place and read it when you have questions.
Supplies you will need to give your injection of MENOPUR® or MENOPUR® mixed with
BRAVELLE®. See Figure A.
• a clean, flat surface to work on, like a table
• vials of MENOPUR® powder (and BRAVELLE® powder if you are going to mix the 2 medicines)
• vials of 0.9% Sodium Chloride, USP used for mixing the medicine
• alcohol pads
• rubbing alcohol
• gauze pads
• a sterile syringe and needle. Your healthcare provider should tell you which syringe and
needle to use.
• the Q•Cap® that comes with your medicine
• a sharps disposal container for throwing away your used needles and syringes. See
“Disposing of your used needles and syringes” at the end of these instructions. usage illustration
Figure A
Step 1. Preparing your MENOPUR® or MENOPUR® mixed with BRAVELLE® .
•
Wash your hands well with soap and water. Dry your hands with a clean towel.
• Place all the supplies you need on the clean surface you already prepared.
• Open the Q•Cap® by peeling back the label. See Figure B.
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usage illustration
Figure B
• Set aside the blister pouch with the Q•Cap®. Do not take the Q•Cap® out of the pouch at
this time. Do not touch the ends of the Q•Cap® .
• Remove the plastic caps from the vials of MENOPUR® (and BRAVELLE® if needed) and 0.9%
Sodium Chloride, USP. See Figure C. usage illustration
Figure C
• Check the vial of MENOPUR® (and BRAVELLE® if needed) to make sure there is powder or a
pellet in the vial. Check the 0.9% Sodium Chloride, USP vial to make sure that there are no
particles in the liquid and the liquid in the vial is clear. If you do not see powder or see
particles or the liquid is discolored, do not use the vial and call your pharmacist or
healthcare provider.
• Wipe the tops of the vials with alcohol and allow them to dry. Do not touch the tops of the
vials after you have wiped them. See Figure D. usage illustration
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Figure D
• Place the vial of 0.9% Sodium Chloride, USP on the table. Remove the Q•Cap® from the
blister pouch by holding the sides with your fingers. See Figure E. Carefully twist the
syringe onto the connector end (luer) of the Q•Cap® until it is tight. Do not touch the spike
at the end of the Q•Cap® . See Figure E. usage illustration
Figure E
• Pull down on the syringe plunger until you have withdrawn the amount of 0.9% Sodium
Chloride, USP from the vial that your healthcare provider told you to use.
o The usual amount of 0.9% Sodium Chloride, USP used to mix your MENOPUR® is 1 mL,
but you should use the amount that your healthcare provider tells you to use. See
Figure F. usage illustration
Figure F
• Hold the syringe and place the spike end of the Q•Cap® over the top of the 0.9% Sodium
Chloride, USP vial. Push the tip of the Q•Cap® into the rubber stopper of the vial until it
stops. Be careful not to push down on the syringe plunger during this step. See Figure G. usage illustration
Figure G
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Reference ID: 3456572
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• Slowly push down on the syringe plunger to push the air from the syringe into the vial.
Keeping the syringe and Q•Cap® together, turn the vial upside down and pull down on the
syringe plunger to withdraw the right amount of 0.9% Sodium Chloride, USP from the vial.
Your healthcare provider should tell you the right amount of 0.9% Sodium Chloride, USP to
use. See Figure H. usage illustration
Figure H
• Place the 0.9% Sodium Chloride, USP vial on the table. Remove the Q•Cap® and syringe
from the vial by pulling up on the syringe barrel. Throw away the 0.9% Sodium Chloride,
USP vial in your household trash. See Figure I. usage illustration
Figure I
• Hold the vial of MENOPUR® powder in 1 hand. Hold the sides of the syringe with your other
hand and place the tip of the Q•Cap® over the top of the vial. Push the tip of the Q•Cap®
into the rubber stopper of the vial until it stops. Be very careful not to push down on the
syringe plunger during this step. See Figure J. usage illustration
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Figure J
•
Slowly push down on the syringe plunger to push the 0.9% Sodium Chloride, USP into the
vial with the MENOPUR® powder in it. Gently swirl the vial until the MENOPUR® powder is
completely dissolved. Do not shake the vial as this will cause bubbles. See Figure K. usage illustration
Figure K
• As soon as the powdered medicine has completely dissolved, turn the vial upside down and
pull down on the plunger to withdraw all of the MENOPUR® into the syringe. See Figure L. usage illustration
Figure L
If your healthcare provider tells you to use more than 1 vial of MENOPUR® or tells you
to mix your MENOPUR® with BRAVELLE® in the same syringe:
• Mix your first vial of MENOPUR® powder or BRAVELLE® powder with 0.9% Sodium Chloride,
USP. Do not inject your dose yet.
• Use the liquid in the syringe you have just mixed to mix the next vial of MENOPUR® or
BRAVELLE® . See Figure J through Figure L.
• You can use the liquid in the syringe to mix up to 5 more vials of medicine.
• Your healthcare provider will tell you how many vials of MENOPUR® and BRAVELLE® to use.
Step 2. Removing the Q•Cap® and adding your needle for injection.
• When you have finished mixing the last vial needed for your injection and have withdrawn
all the medicine into the syringe, remove the syringe from the Q•Cap® .
• Twist the syringe counter-clockwise while holding the Q•Cap® steady. Carefully remove the
syringe from the Q•Cap® . See Figure M. Throw away the Q•Cap® with the attached
medicine vial into your household trash. Carefully set the syringe with the medicine down
on the table, being careful not to touch the tip of the syringe.
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usage illustration
Figure M
• You are now ready to attach the needle to the syringe for your injection.
Your healthcare provider will tell you what needle you should use for your
injection.
• While holding the syringe with the syringe tip pointing up, place the needle on the top of
the syringe. Gently push down on the needle and twist the needle onto the syringe in a
clockwise direction until it is tight. See Figure N. usage illustration
Figure N
• Hold the syringe with the needle pointing straight up. Pull down slightly on the plunger and
tap the barrel of the syringe so that any air bubbles rise to the top. Slowly press the
plunger up until all the air is out of the syringe and a small drop of liquid is seen at the tip
of the needle. See Figure O. usage illustration
Figure O
•
Tap the syringe to remove the small drop of liquid at the tip of the needle. See Figure P.
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usage illustration
Figure P
• Carefully set the syringe with needle down on the table. Do not let the needle touch
anything to keep it sterile. The medicine is now ready for you to inject. See Figure Q. usage illustration
Figure Q
Step 3. Injecting MENOPUR® or MENOPUR® mixed with BRAVELLE® .
• Select a site to inject MENOPUR® or MENOPUR® mixed with BRAVELLE® on your stomach
area (abdomen).
o Pick a site a site on your lower abdomen, 1-2 inches below the navel, alternating
between left and right sides.
o Each day, inject in a different site to help reduce soreness and skin problems. For
example, on day 1, inject yourself on the right side of your abdomen. The next day,
inject yourself on the left side of your abdomen. Changing your injection sites every
day will help reduce soreness and skin problems. See Figure R. usage illustration
Figure R
•
Clean your injection site with an alcohol pad. Let the alcohol dry. See Figure S.
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usage illustration
Figure S
•
Carefully remove the needle cap from the syringe. See Figure T. usage illustration
Figure T
•
Hold the syringe in 1 hand. Use your other hand to gently hold a fold of skin where you will
insert your needle. Hold the skin between your thumb and index finger. See Figure U. usage illustration
Figure U
• Hold your syringe at a right angle to your skin, like a dart. Quickly insert the needle all the
way into your skin fold. See Figure V. usage illustration
Figure V
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•
Push down the plunger of the syringe with a steady motion. Keep pushing until all the
fluid is injected into your skin. See Figure W. usage illustration
Figure W
•
Let go of your skin fold and pull the needle straight out of your skin. See Figure X. usage illustration
Figure X
Step 4. After your injection.
• If there is any bleeding at your injection site, place a gauze pad over your injection site.
Apply gentle pressure to stop the bleeding. Do not rub the site. See Figure Y. usage illustration
Figure Y
• If your injection site becomes sore or red, you may put ice on your injection site for 1
minute and then take it off for 3 minutes. If needed, you may repeat this 3 or 4 times.
Step 5. Disposing of your used needles and syringes.
• Put your used needles and syringes in a FDA-cleared sharps disposal container right away
after use. Do not throw away (dispose of) loose needles and syringes in your
household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household
container that is:
o made of a heavy-duty plastic,
o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able
to come out,
o upright and stable during use,
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o leak-resistant, and
o properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be
state or local laws about how you should throw away used needles and syringes. For more
information about safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website
at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug
Administration.
MANUFACTURED FOR: company logo
FERRING PHARMACEUTICALS INC.
Parsippany, NJ 07054
6314-02
Rev 02/2014
26
Reference ID: 3456572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:32.300697 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021663s014lbl.pdf', 'application_number': 21663, 'submission_type': 'SUPPL ', 'submission_number': 14} |
5,880 |
_______________________________________________________________________________________________________________________________________
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
APIDRA safely and effectively. See full prescribing information for
APIDRA.
APIDRA (insulin glulisine [rDNA origin] injection) solution for injection
Initial U.S. Approval: 2004
----------------------------RECENT MAJOR CHANGES-------------------------
Dosage and administration (2.3)
09/2013
Warnings and Precautions (5.7)
09/2013
Warnings and Precautions (5.10)
05/2014
----------------------------INDICATIONS AND USAGE--------------------------
APIDRA is a rapid acting human insulin analog indicated to improve
glycemic control in adults and children with diabetes mellitus. (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
The dosage of APIDRA must be individualized (2.1)
Subcutaneous
Injection
Administer within 15 minutes before a meal or within 20
minutes after starting a meal. Use in a regimen with an
intermediate or long-acting insulin. (2.1, 2.2)
Continuous
Subcutaneous
Infusion Pump
APIDRA must not be mixed or diluted when used in an
external insulin infusion pump. (2.3)
Intravenous
Infusion
Infuse intravenously (0.05 Units/mL to 1 Units/mL APIDRA
in 0.9% sodium chloride using polyvinyl chloride infusion
bags) only under strict medical supervision with close
monitoring of blood glucose and potassium. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
APIDRA 100 units/mL (U-100) is available as: (3)
• 10 mL vials
• 3 mL SoloStar® prefilled pen
-------------------------------CONTRAINDICATIONS-----------------------------
• Do not use during episodes of hypoglycemia (4)
• Do not use in patients with hypersensitivity to APIDRA or any of its
excipients (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
• Dose adjustment and monitoring: Closely monitor blood glucose in all
patients treated with insulin. Change insulin regimens cautiously and only
under medical supervision.(5.1)
• Hypoglycemia: Most common adverse reaction of insulin therapy and may
be life-threatening (5.2)
• Allergic reactions: Severe, life-threatening, generalized allergy, including
anaphylaxis, can occur with any insulin, including APIDRA (5.3)
• Hypokalemia: All insulins, including APIDRA can cause hypokalemia,
which if untreated, may result in respiratory paralysis, ventricular
arrhythmia, and death (5.4)
• Renal or hepatic impairment: Like all insulins, may require a reduction in
the APIDRA dose (5.5)
• Mixing: APIDRA for subcutaneous injection should not be mixed with insulins
other than NPH insulin. Do not mix APIDRA with any insulin for intravenous
administration or for use in a continuous infusion pump (5.6)
• Pump use: Change the APIDRA in the pump reservoir every 48 hours (5.7)
• Intravenous use: Frequently monitor for hypoglycemia and hypokalemia. (5.8)
• Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure;
consider dosage reduction or discontinuation of TZD if heart failure occurs
(5.10)
------------------------------ADVERSE REACTIONS------------------------------
Adverse reactions commonly associated with APIDRA include hypoglycemia,
allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
• Certain drugs affect glucose metabolism and may necessitate insulin dose
adjustment (7)
• The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine). (7)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• APIDRA has not been studied in children under 4 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: May 2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosage considerations
2.2 Subcutaneous administration
2.3 Continuous subcutaneous infusion (insulin pump)
2.4 Intravenous administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
5.2 Hypoglycemia
5.3 Hypersensitivity and allergic reactions
5.4 Hypokalemia
5.5 Renal or hepatic impairment
5.6 Mixing of insulins
5.7 Subcutaneous insulin infusion pumps
5.8 Intravenous administration
5.9 Drug interactions
5.10 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6 ADVERSE REACTIONS
6.1 Clinical trial experience
6.2 Postmarketing experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing mothers
8.4 Pediatric use
8.5 Geriatric use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Clinical pharmacology in specific populations
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
14 CLINICAL STUDIES
14.1
Type 1 Diabetes-Adults
14.2
Type 2 Diabetes-Adults
14.3
Type 1 Diabetes-Adults: Pre-and post-meal administration
14.4
Type 1 Diabetes-Pediatric patients
14.5
Type 1 Diabetes-Adults: Continuous subcutaneous insulin infusion
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How supplied
16.2
Storage
16.3
Preparation and handling
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for all patients
17.2 For patients using continuous subcutaneous insulin pumps
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3506714
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
APIDRA is indicated to improve glycemic control in adults and children with diabetes mellitus.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage considerations
APIDRA is a recombinant insulin analog that is equipotent to human insulin (i.e. one unit of
APIDRA has the same glucose-lowering effect as one unit of regular human insulin) when given
intravenously. When given subcutaneously, APIDRA has a more rapid onset of action and a
shorter duration of action than regular human insulin.
The dosage of APIDRA must be individualized. Blood glucose monitoring is essential in all
patients receiving insulin therapy.
The total daily insulin requirement may vary and is usually between 0.5 to 1 Unit/kg/day. Insulin
requirements may be altered during stress, major illness, or with changes in exercise, meal
patterns, or coadministered drugs.
2.2 Subcutaneous administration
APIDRA should be given within 15 minutes before a meal or within 20 minutes after starting a
meal.
APIDRA given by subcutaneous injection should generally be used in regimens with an
intermediate or long-acting insulin.
APIDRA should be administered by subcutaneous injection in the abdominal wall, thigh, or
upper arm. Injection sites should be rotated within the same region (abdomen, thigh or upper
arm) from one injection to the next to reduce the risk of lipodystrophy [See Adverse Reactions
(6.1)].
2.3 Continuous subcutaneous infusion (insulin pump)
APIDRA may be administered by continuous subcutaneous infusion in the abdominal wall. Do
not use diluted or mixed insulins in external insulin pumps. Infusion sites should be rotated
within the same region to reduce the risk of lipodystrophy [See Adverse Reactions (6.1)]. The
initial programming of the external insulin infusion pump should be based on the total daily
insulin dose of the previous regimen.
The following insulin pumps† have been used in APIDRA clinical trials conducted by sanofi
aventis, the manufacturer of APIDRA:
• Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™,
Rapid C™, Rapid D™, and Tender™)
• MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate
QR™, and Quick-set™).
Reference ID: 3506714
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Before using a different insulin pump with APIDRA, read the pump label to make sure the pump
has been evaluated with APIDRA.
Physicians and patients should carefully evaluate information on pump use in the APIDRA
prescribing information, Patient Information Leaflet, and the pump manufacturer’s manual.
APIDRA-specific information should be followed for in-use time, frequency of changing
infusion sets, or other details specific to APIDRA usage, because APIDRA-specific information
may differ from general pump manual instructions. Failure to follow APIDRA-specific
instructions may lead to serious adverse events.
Patients administering APIDRA by continuous subcutaneous infusion must have an alternative
insulin delivery system in case of pump system failure.
Based on in vitro studies which have shown loss of the preservative, metacresol and insulin
degradation, APIDRA in the reservoir should be changed at least every 48 hours. APIDRA
should not be exposed to temperatures greater than 98.6°F (37°C).
In clinical use, the infusion sets and the APIDRA in the reservoir must be changed at least every
48 hours [See Warnings and Precautions (5.7) and How Supplied/Storage and Handling (16.2)].
2.4 Intravenous administration
APIDRA can be administered intravenously under medical supervision for glycemic control with
close monitoring of blood glucose and serum potassium to avoid hypoglycemia and
hypokalemia. For intravenous use, APIDRA should be used at concentrations of 0.05 Units/mL
to 1 Unit/mL insulin glulisine in infusion systems using polyvinyl chloride (PVC) bags.
APIDRA has been shown to be stable only in normal saline solution (0.9% sodium chloride).
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Do not administer insulin
mixtures intravenously.
3 DOSAGE FORMS AND STRENGTHS
APIDRA 100 units per mL (U-100) is available as:
• 10 mL vials
• 3 mL SoloStar prefilled pen
4 CONTRAINDICATIONS
APIDRA is contraindicated:
• during episodes of hypoglycemia
• in patients who are hypersensitive to APIDRA or to any of its excipients
When used in patients with known hypersensitivity to APIDRA or its excipients, patients
may develop localized or generalized hypersensitivity reactions [See Adverse Reactions
(6.1)].
Reference ID: 3506714
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin
regimen should be made cautiously and only under medical supervision. Changes in insulin
strength, manufacturer, type, or method of administration may result in the need for a change in
insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.
As with all insulin preparations, the time course of action for APIDRA may vary in different
individuals or at different times in the same individual and is dependent on many conditions,
including the site of injection, local blood supply, or local temperature. Patients who change their
level of physical activity or meal plan may require adjustment of insulin dosages.
5.2 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin therapy, including APIDRA. The
risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to
recognize and manage hypoglycemia. Severe hypoglycemia may lead to unconsciousness and/or
convulsions and may result in temporary or permanent impairment of brain function or death.
Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose
infusion or glucagon administration has been observed in clinical trials with insulin, including
trials with APIDRA.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of
meals), injection site, exercise, and concomitant medications may also alter the risk of
hypoglycemia [See Drug Interactions (7)].
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who
may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have
erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of
hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery.
Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia
may be different or less pronounced under certain conditions, such as longstanding diabetes,
diabetic nerve disease, use of medications such as beta-blockers [See Drug Interactions (7)], or
intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly,
loss of consciousness) prior to the patient’s awareness of hypoglycemia.
Intravenously administered insulin has a more rapid onset of action than subcutaneously
administered insulin, requiring closer monitoring for hypoglycemia.
5.3 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including APIDRA [See Adverse reactions (6.1)].
Reference ID: 3506714
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.4 Hypokalemia
All insulin products, including APIDRA, cause a shift in potassium from the extracellular to
intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause
respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at
risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations). Monitor glucose and potassium
frequently when APIDRA is administered intravenously.
5.5 Renal or hepatic impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or
hepatic impairment [See Clinical Pharmacology (12.4)].
5.6 Mixing of insulins
APIDRA for subcutaneous injection should not be mixed with insulin preparations other than
NPH insulin. If APIDRA is mixed with NPH insulin, APIDRA should be drawn into the syringe
first. Injection should occur immediately after mixing.
Do not mix APIDRA with other insulins for intravenous administration or for use in a
continuous subcutaneous infusion pump.
APIDRA for intravenous administration should not be diluted with solutions other than 0.9%
sodium chloride (normal saline). The efficacy and safety of mixing APIDRA with diluents or
other insulins for use in external subcutaneous infusion pumps have not been established.
5.7 Subcutaneous insulin infusion pumps
When used in an external insulin pump for subcutaneous infusion, APIDRA should not be
diluted or mixed with any other insulin. APIDRA in the reservoir must be changed at least every
48 hours. APIDRA should not be exposed to temperatures greater than 98.6°F (37°C).
Malfunction of the insulin pump or infusion set or handling errors or insulin degradation can
rapidly lead to hyperglycemia, ketosis and diabetic ketoacidosis. Prompt identification and
correction of the cause of hyperglycemia or ketosis or diabetic ketoacidosis is necessary. Interim
subcutaneous injections with APIDRA may be required. Patients using continuous subcutaneous
insulin infusion pump therapy must be trained to administer insulin by injection and have
alternate insulin therapy available. [See Dosage and Administration (2.3), How Supplied/Storage
and Handling (16), and Patient Counseling Information (17.2)].
5.8 Intravenous administration
When APIDRA is administered intravenously, glucose and potassium levels must be closely
monitored to avoid potentially fatal hypoglycemia and hypokalemia.
Do not mix APIDRA with other insulins for intravenous administration. APIDRA may be diluted
only in normal saline solution.
Reference ID: 3506714
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9 Drug interactions
Some medications may alter insulin requirements and the risk for hypoglycemia or
hyperglycemia [See Drug Interactions (7)].
5.10 Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)
gamma agonists, can cause dose-related fluid retention, particularly when used in combination
with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin,
including APIDRA and a PPAR-gamma agonist should be observed for signs and symptoms of
heart failure. If heart failure develops, it should be managed according to current standards of
care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [See Warnings and Precautions (5.2)]
• Hypokalemia [See Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates
reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
The frequencies of adverse drug reactions during APIDRA clinical trials in patients with type 1
diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Treatment –emergent adverse events in pooled studies of adults with type 1
diabetes (adverse events with frequency ≥ 5%)
APIDRA, %
All comparatorsa, %
(n=950)
(n=641)
Nasopharyngitis
10.6
12.9
Hypoglycemiab
6.8
6.7
Upper respiratory tract
6.6
5.6
i f
ti
Influenza
4.0
5.0
a Insulin lispro, regular human insulin, insulin aspart
b Only severe symptomatic hypoglycemia
Reference ID: 3506714
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2: Treatment –emergent adverse events in pooled studies of adults with type 2
diabetes (adverse events with frequency ≥ 5%)
APIDRA, %
Regular human
insulin, %
(n=883)
(n=883)
Upper respiratory tract
10.5
7.7
infection
Nasopharyngitis
7.6
8.2
Edema peripheral
7.5
7.8
Influenza
6.2
4.2
Arthralgia
5.9
6.3
Hypertension
3.9
5.3
•
Pediatrics
Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical
study in children and adolescents with type 1 diabetes treated with APIDRA (n=277) or insulin
lispro (n=295).
Table 3: Treatment –emergent adverse events in children and adolescents with type 1
diabetes (adverse reactions with frequency ≥ 5%)
APIDRA, %
Lispro, %
(n=295)
(n=277)
Nasopharyngitis
9.0
9.5
Upper respiratory tract
8.3
10.8
infection
Headache
6.9
11.2
Hypoglycemic seizure
6.1
4.7
•
Severe symptomatic hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including APIDRA [See Warnings and Precautions (5.2)]. The rates and incidence of severe
symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party,
were comparable for all treatment regimens (see Table 4). In the phase 3 clinical trial, children
and adolescents with type 1 diabetes had a higher incidence of severe symptomatic
hypoglycemia in the two treatment groups compared to adults with type 1 diabetes. (see Table 4)
[See Clinical Studies (14)].
Reference ID: 3506714
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4: Severe Symptomatic Hypoglycemia*
Type 1 Diabetes
Adults
12 weeks
with insulin glargine
Type 1 Diabetes
Adults
26 weeks
with insulin glargine
Type 2 Diabetes
Adults
26 weeks
with NPH human insulin
Type 1 Diabetes
Pediatrics
26 weeks
APIDRA
Pre-meal
APIDRA
Post-meal
Regular
Human
Insulin
APIDRA
Insulin
Lispro
APIDRA
Regular
Human
Insulin
APIDRA
Insulin
Lispro
Events per
month per
patient
0.05
0.05
0.13
0.02
0.02
0.00
0.00
0.09
0.08
Percent of
patients
(n/total N)
8.4%
(24/286)
8.4%
(25/296)
10.1%
(28/278)
4.8%
(16/339)
4.0%
(13/333)
1.4%
(6/416)
1.2%
(5/420)
16.2%
(45/277)
19.3%
(57/295)
* Severe symptomatic hypoglycemia defined as a hypoglycemic event requiring the assistance of another person
that met one of the following criteria:
the event was associated with a whole blood referenced blood glucose <36mg/dL or the event was associated
with prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.
• Insulin initiation and intensification of glucose control
Intensification or rapid improvement in glucose control has been associated with
a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy,
and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk
of diabetic retinopathy and neuropathy.
• Lipodystrophy
Long-term use of insulin, including APIDRA, can cause lipodystrophy at the site of repeated
insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose
tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate
insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See
Dosage and Administration (2.2, 2.3)].
• Weight gain
Weight gain can occur with insulin therapy, including APIDRA, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
• Peripheral Edema
Insulin, including APIDRA, may cause sodium retention and edema, particularly if previously
poor metabolic control is improved by intensified insulin therapy.
• Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)
In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter
occlusions and infusion site reactions were similar for APIDRA and insulin aspart treated
patients (Table 5).
8
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5: Catheter Occlusions and Infusion Site Reactions.
APIDRA
(n=29)
insulin aspart
(n=30)
Catheter occlusions/month
0.08
0.15
Infusion site reactions
10.3% (3/29)
13.3% (4/30)
• Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking APIDRA may experience redness, swelling, or
itching at the site of injection. These minor reactions usually resolve in a few days to a few
weeks, but in some occasions may require discontinuation of APIDRA. In some instances, these
reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or
poor injection technique.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin,
including APIDRA. Generalized allergy to insulin may cause whole body rash (including
pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
In controlled clinical trials up to 12 months duration, potential systemic allergic reactions were
reported in 79 of 1833 patients (4.3%) who received APIDRA and 58 of 1524 patients (3.8%)
who received the comparator short-acting insulins. During these trials treatment with APIDRA
was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.
Localized reactions and generalized myalgias have been reported with the use of metacresol,
which is an excipient of APIDRA.
Antibody Production
In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that
react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained
near baseline during the first 6 months of the study in the patients treated with APIDRA. A
decrease in antibody concentration was observed during the following 6 months of the study. In a
study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin
antibody concentration was observed in the patients treated with APIDRA and in the patients
treated with human insulin during the first 9 months of the study. Thereafter the concentration of
antibodies decreased in the APIDRA patients and remained stable in the human insulin patients.
There was no correlation between cross-reactive insulin antibody concentration and changes in
HbA1c, insulin doses, or incidence of hypoglycemia. The clinical significance of these
antibodies is not known.
APIDRA did not elicit a significant antibody response in a study of children and adolescents
with type 1 diabetes.
6.2 Postmarketing experience
The following adverse reactions have been identified during post-approval use of APIDRA.
Reference ID: 3506714
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to estimate reliably their frequency or establish a causal relationship to drug
exposure.
Medication errors have been reported in which other insulins, particularly long-acting insulins,
have been accidentally administered instead of APIDRA [See Patient Counseling Information
(17)].
7 DRUG INTERACTIONS
A number of drugs affect glucose metabolism and may necessitate insulin dose adjustment and
particularly close monitoring.
Drugs that may increase the blood glucose-lowering effect of insulins including APIDRA, and
therefore increase the risk of hypoglycemia, include oral antidiabetic products, pramlintide, ACE
inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene,
pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.
Drugs that may reduce the blood-glucose-lowering effect of APIDRA include corticosteroids,
niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline),
glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens,
progestogens (e.g., in oral contraceptives), protease inhibitors, and atypical antipsychotics.
Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood
glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs
such as beta-blockers, clonidine, guanethidine, and reserpine.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: Reproduction and teratology studies have been performed with insulin
glulisine in rats and rabbits using regular human insulin as a comparator. Insulin glulisine was
given to female rats throughout pregnancy at subcutaneous doses up to 10 Units/kg once daily
(dose resulting in an exposure 2 times the average human dose, based on body surface area
comparison) and did not have any remarkable toxic effects on embryo-fetal development.
Insulin glulisine was given to female rabbits throughout pregnancy at subcutaneous doses up to
1.5 Units/kg/day (dose resulting in an exposure 0.5 times the average human dose, based on body
surface area comparison). Adverse effects on embryo-fetal development were only seen at
maternal toxic dose levels inducing hypoglycemia. Increased incidence of post-implantation
Reference ID: 3506714
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
losses and skeletal defects were observed at a dose level of 1.5 Units/kg once daily (dose
resulting in an exposure 0.5 times the average human dose, based on body surface area
comparison) that also caused mortality in dams. A slight increased incidence of post-
implantation losses was seen at the next lower dose level of 0.5 Units/kg once daily (dose
resulting in an exposure 0.2 times the average human dose, based on body surface area
comparison) which was also associated with severe hypoglycemia but there were no defects at
that dose. No effects were observed in rabbits at a dose of 0.25 Units/kg once daily (dose
resulting in an exposure 0.1 times the average human dose, based on body surface area
comparison). The effects of insulin glulisine did not differ from those observed with
subcutaneous regular human insulin at the same doses and were attributed to secondary effects of
maternal hypoglycemia.
There are no well-controlled clinical studies of the use of APIDRA in pregnant women. Because
animal reproduction studies are not always predictive of human response, this drug should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is
essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic
control before conception and throughout pregnancy. Insulin requirements may decrease during
the first trimester, generally increase during the second and third trimesters, and rapidly decline
after delivery. Careful monitoring of glucose control is essential in these patients.
8.3 Nursing mothers
It is unknown whether insulin glulisine is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when APIDRA is administered to a nursing
woman. Use of APIDRA is compatible with breastfeeding, but women with diabetes who are
lactating may require adjustments of their insulin doses.
8.4 Pediatric use
The safety and effectiveness of subcutaneous injections of APIDRA have been established in
pediatric patients (age 4 to 17 years) with type 1 diabetes [See Clinical Studies (14.4)]. APIDRA
has not been studied in pediatric patients with type 1 diabetes younger than 4 years of age and in
pediatric patients with type 2 diabetes.
As in adults, the dosage of APIDRA must be individualized in pediatric patients based on
metabolic needs and frequent monitoring of blood glucose.
8.5 Geriatric use
In clinical trials (n=2408), APIDRA was administered to 147 patients ≥65 years of age and 27
patients ≥75 years of age. The majority of this small subset of elderly patients had type 2
diabetes. The change in HbA1c values and hypoglycemia frequencies did not differ by age.
Nevertheless, caution should be exercised when APIDRA is administered to geriatric patients.
10 OVERDOSAGE
Excess insulin may cause hypoglycemia and, particularly when given intravenously,
hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose.
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Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes of
hypoglycemia with coma, seizure, or neurologic impairment may be treated with
intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained
carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery. Hypokalemia must be corrected appropriately.
11 DESCRIPTION
APIDRA (insulin glulisine [rDNA origin] injection) is a rapid-acting human insulin analog
used to lower blood glucose. Insulin glulisine is produced by recombinant DNA technology
utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine differs
from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the
lysine in position B29 is replaced by glutamic acid. Chemically, insulin glulisine is 3B-lysine
29B-glutamic acid-human insulin, has the empirical formula C258H384N64O78S6 and a molecular
weight of 5823 and has the following structural formula:
A-chain
stru
ctur
al
fo
rmu
la
B-chain
APIDRA is a sterile, aqueous, clear, and colorless solution. Each milliliter of APIDRA contains
100 units (3.49 mg) insulin glulisine, 3.15 mg metacresol, 6 mg tromethamine, 5 mg sodium
chloride, 0.01 mg polysorbate 20, and water for injection. APIDRA has a pH of approximately
7.3. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium
hydroxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Regulation of glucose metabolism is the primary activity of insulins and insulin analogs,
including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake
by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis
and proteolysis, and enhance protein synthesis.
The glucose lowering activities of APIDRA and of regular human insulin are equipotent when
administered by the intravenous route. After subcutaneous administration, the effect of APIDRA
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is more rapid in onset and of shorter duration compared to regular human insulin. [See
Pharmacodynamics (12.2)].
12.2 Pharmacodynamics
Studies in healthy volunteers and patients with diabetes demonstrated that APIDRA has a more
rapid onset of action and a shorter duration of activity than regular human insulin when given
subcutaneously.
In a study in patients with type 1 diabetes (n= 20), the glucose-lowering profiles of APIDRA and
regular human insulin were assessed at various times in relation to a standard meal at a dose of
0.15 Units/kg. (Figure 1.)
The maximum blood glucose excursion (ΔGLUmax; baseline subtracted glucose concentration)
for APIDRA injected 2 minutes before a meal was 65 mg/dL compared to 64 mg/dL for regular
human insulin injected 30 minutes before a meal (see Figure 1A), and 84 mg/dL for regular
human insulin injected 2 minutes before a meal (see Figure 1B). The maximum blood glucose
excursion for APIDRA injected 15 minutes after the start of a meal was 85 mg/dL compared to
84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1C).
Figure 1. Serial mean blood glucose collected up to 6 hours following a single dose of APIDRA
and regular human insulin. APIDRA given 2 minutes (APIDRA - pre) before the start of a meal
compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal
(Figure 1A) and compared to regular human insulin (Regular - pre) given 2 minutes before a
meal (Figure 1B). APIDRA given 15 minutes (APIDRA - post) after start of a meal compared to
regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 1C). On the x-axis
zero (0) is the start of a 15-minute meal.
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g
raph
In a randomized, open-label, two-way crossover study, 16 healthy male subjects received an
intravenous infusion of APIDRA or regular human insulin with saline diluent at a rate of 0.8
milliUnits/kg/min for two hours. Infusion of the same dose of APIDRA or regular human insulin
produced equivalent glucose disposal at steady state.
12.3 Pharmacokinetics
Absorption and bioavailability
Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2)
demonstrated that absorption of insulin glulisine was faster than that of regular human insulin.
In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15
Units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120
minutes) and the peak concentration (Cmax) was 83 microUnits/mL (range 40 to 131
microUnits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239
minutes) and a Cmax of 50 microUnits/mL (range 35 to 71 microUnits/mL) for regular human
insulin. (Figure 2)
Figure 2. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with
type 1 diabetes after a dose of 0.15 Units/kg.
Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.2
Units/kg in an euglycemic clamp study in patients with type 2 diabetes (n=24) and a body mass
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index (BMI) between 20 and 36 kg/m2. The median time to maximum concentration (Tmax) was
100 minutes (range 40 to 120 minutes) and the median peak concentration (Cmax) was 84
microUnits/mL (range 53 to 165 microUnits/mL) for insulin glulisine compared to a median Tmax
of 240 minutes (range 80 to 360 minutes) and a median Cmax of 41 microUnits/mL (range 33 to
61 microUnits/mL) for regular human insulin. (Figure 3.)
Figure 3. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with
type 2 diabetes after a subcutaneous dose of 0.2 Units/kg.
When APIDRA was injected subcutaneously into different areas of the body, the time-
concentration profiles were similar. The absolute bioavailability of insulin glulisine after
subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%,
deltoid 71%, thigh 68%).
In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was
similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the
syringe) and following separate simultaneous subcutaneous injections. There was 27%
attenuation of the maximum concentration (Cmax) of APIDRA after premixing; however, the time
to maximum concentration (Tmax) was not affected. No data are available on mixing APIDRA
with insulin preparations other than NPH insulin. [See Clinical Studies (14)].
Distribution and elimination
The distribution and elimination of insulin glulisine and regular human insulin after intravenous
administration are similar with volumes of distribution of 13 and 21 L and half-lives of 13 and
17 minutes, respectively. After subcutaneous administration, insulin glulisine is eliminated more
rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86
minutes.
12.4
Clinical pharmacology in specific populations
Pediatric patients
The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin
were assessed in a study conducted in children 7 to 11 years old (n=10) and adolescents 12 to 16
years old (n=10) with type 1 diabetes. The relative differences in pharmacokinetics and
pharmacodynamics between APIDRA and regular human insulin in these patients with type 1
diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.
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Race
A study in 24 healthy Caucasians and Japanese subjects compared the pharmacokinetics and
pharmacodynamics after subcutaneous injection of insulin glulisine, insulin lispro, and regular
human insulin. With subcutaneous injection of insulin glulisine, Japanese subjects had a greater
initial exposure (33%) for the ratio of AUC(0-1h) to AUC(0-clamp end) than Caucasians (21%)
although the total exposures were similar. There were similar findings with insulin lispro and
regular human insulin.
Obesity
Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.3
Units/kg in a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass
index (BMI) between 30 and 40 kg/m2. The median time to maximum concentration (Tmax) was
85 minutes (range 49 to 150 minutes) and the median peak concentration (Cmax) was 192
microUnits/mL (range 98 to 380 microUnits/mL) for insulin glulisine compared to a median Tmax
of 150 minutes (range 90 to 240 minutes) and a median Cmax of 86 microUnits/mL (range 43 to
175 microUnits/mL) for regular human insulin.
The more rapid onset of action and shorter duration of activity of APIDRA and insulin lispro
compared to regular human insulin were maintained in an obese non-diabetic population (n= 18).
(Figure 4.)
Figure 4. Glucose infusion rates (GIR) in a euglycemic clamp study after subcutaneous injection
of 0.3 Units/kg of APIDRA, insulin lispro or regular human insulin in an obese population.
Renal impairment
Studies with human insulin have shown increased circulating levels of insulin in patients with
renal failure. In a study performed in 24 non-diabetic subjects with normal renal function
(ClCr >80 mL/min), moderate renal impairment (30-50 mL/min) and severe renal impairment
(<30 mL/min), the subjects with moderate and severe renal impairment had increased exposure
to insulin glulisine by 29% to 40% and reduced clearance of insulin glulisine by 20% to 25%
compared to subjects with normal renal function. [See Warnings and Precautions (5.4)].
Hepatic impairment
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The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of APIDRA
has not been studied. Some studies with human insulin have shown increased circulating levels
of insulin in patients with liver failure. [See Warnings and Precautions (5.4)].
Gender
The effect of gender on the pharmacokinetics and pharmacodynamics of APIDRA has not been
studied.
Pregnancy
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of APIDRA has not
been studied.
Smoking
The effect of smoking on the pharmacokinetics and pharmacodynamics of APIDRA has not been
studied.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
Standard 2-year carcinogenicity studies in animals have not been performed. In Sprague Dawley
rats, a 12-month repeat dose toxicity study was conducted with insulin glulisine at subcutaneous
doses of 2.5, 5, 20 or 50 Units/kg twice daily (dose resulting in an exposure 1, 2, 8, and 20 times
the average human dose, based on body surface area comparison).
There was a non-dose dependent higher incidence of mammary gland tumors in female rats
administered insulin glulisine compared to untreated controls. The incidence of mammary
tumors for insulin glulisine and regular human insulin was similar. The relevance of these
findings to humans is not known. Insulin glulisine was not mutagenic in the following tests:
Ames test, in vitro mammalian chromosome aberration test in V79 Chinese hamster cells, and in
vivo mammalian erythrocyte micronucleus test in rats.
In fertility studies in male and female rats at subcutaneous doses up to 10 Units/kg once daily
(dose resulting in an exposure 2 times the average human dose, based on body surface area
comparison), no clear adverse effects on male and female fertility, or general reproductive
performance of animals were observed.
14 CLINICAL STUDIES
The safety and efficacy of APIDRA was studied in adult patients with type 1 and type 2 diabetes
(n =1833) and in children and adolescent patients (4 to 17 years) with type 1 diabetes (n=572).
The primary efficacy parameter in these trials was glycemic control, assessed using glycated
hemoglobin (GHb reported as HbA1c equivalent).
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14.1 Type 1 Diabetes-Adults
A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
patients with type 1 diabetes to assess the safety and efficacy of APIDRA (n= 339) compared to
insulin lispro (n= 333) when administered subcutaneously within 15 minutes before a meal.
Insulin glargine was administered once daily in the evening as the basal insulin. There was a 4
week run-in period with insulin lispro and insulin glargine prior to randomization. Most patients
were Caucasian (97%). Fifty eight percent of the patients were men. The mean age was 39 years
(range 18 to 74 years). Glycemic control, the number of daily short-acting insulin injections and
the total daily doses of APIDRA and insulin lispro were similar in the two treatment groups
(Table 6).
Table 6: Type 1 Diabetes Mellitus–Adult
Treatment duration
26 weeks
Treatment in combination with:
Insulin glargine
APIDRA
Insulin Lispro
Glycated hemoglobin (GHb)* (%)
Number of patients
331
322
Baseline mean
7.6
7.6
Adjusted mean change from baseline
-0.1
-0.1
Treatment difference: APIDRA – Insulin Lispro
0.0
95% CI for treatment difference
(-0.1; 0.1)
Basal insulin dose (Units/day)
Baseline mean
24
24
Adjusted mean change from baseline
0
2
Short-acting insulin dose (Units/day)
Baseline mean
30
31
Adjusted mean change from baseline
-1
-1
Mean number of short-acting insulin injections per day
3
3
Body weight (kg)
Baseline mean
73.9
74.1
Mean change from baseline
0.6
0.3
*GHb reported as HbA1c equivalent
14.2 Type 2 Diabetes-Adults
A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
insulin-treated patients with type 2 diabetes to assess the safety and efficacy of APIDRA (n=
435) given within 15 minutes before a meal compared to regular human insulin (n=441)
administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the
basal insulin. All patients participated in a 4-week run-in period with regular human insulin and
NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The
mean age was 58 years (range 26 to 84 years). The average body mass index (BMI) was 34.6
kg/m2. At randomization, 58% of the patients were taking an oral antidiabetic agent. These
patients were instructed to continue use of their oral antidiabetic agent at the same dose
throughout the trial. The majority of patients (79%) mixed their short-acting insulin with NPH
human insulin immediately prior to injection. The reductions from baseline in GHb were similar
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between the 2 treatment groups (see Table 7). No differences between APIDRA and regular
human insulin groups were seen in the number of daily short-acting insulin injections or basal or
short-acting insulin doses. (See Table 7.)
Table 7: Type 2 Diabetes Mellitus–Adult
Treatment duration
26 weeks
Treatment in combination with:
NPH human insulin
APIDRA
Regular Human
Insulin
Glycated hemoglobin (GHb)* (%)
Number of patients
404
403
Baseline mean
7.6
7.5
Adjusted mean change from baseline
-0.5
-0.3
Treatment difference: APIDRA – Regular Human Insulin
-0.2
95% CI for treatment difference
(-0.3; -0.1)
Basal insulin dose (Units/day)
Baseline mean
59
57
Adjusted mean change from baseline
6
6
Short-acting insulin dose (Units/day)
Baseline mean
32
31
Adjusted mean change from baseline
4
5
Mean number of short-acting insulin injections per day
2
2
Body weight (kg)
Baseline mean
100.5
99.2
Mean change from baseline
1.8
2.0
*GHb reported as HbA1c equivalent
14.3 Type 1 Diabetes-Adults: Pre- and post-meal administration
A 12-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
patients with type 1 diabetes to assess the safety and efficacy of APIDRA administered at
different times with respect to a meal. APIDRA was administered subcutaneously either within
15 minutes before a meal (n=286) or immediately after a meal (n=296) and regular human
insulin (n= 278) was administered subcutaneously 30 to 45 minutes prior to a meal. Insulin
glargine was administered once daily at bedtime as the basal insulin. There was a 4-week run-in
period with regular human insulin and insulin glargine followed by randomization. Most patients
were Caucasian (94%). The mean age was 40 years (range 18 to 73 years). Glycemic control
(see Table 8) was comparable for the 3 treatment regimens. No changes from baseline between
the treatments were seen in the total daily number of short-acting insulin injections. (See Table
8.)
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Table 8: Pre- and Post-Meal Administration in Type 1 Diabetes Mellitus–Adult
Treatment duration
Treatment in combination with:
Glycated hemoglobin (GHb)* (%)
Number of patients
Baseline mean
Adjusted mean change from baseline**
Basal insulin dose (Units/day)
Baseline mean
Adjusted mean change from baseline
Short-acting insulin dose (Units/day)
Baseline mean
Adjusted mean change from baseline
Mean number of short-acting insulin injections per day
Body weight (kg)
Baseline mean
Mean change from baseline
12 weeks
insulin glargine
12 weeks
insulin glargine
12 weeks
insulin glargine
APIDRA
pre meal
APIDRA
post meal
Regular Human
Insulin
268
276
257
7.7
7.7
7.6
-0.3
-0.1
-0.1
29
29
28
1
0
1
29
29
27
-1
-1
2
3
3
3
79.2
80.3
78.9
0.3
-0.3
0.3
*GHb reported as HbA1c equivalent
**Adjusted mean change from baseline treatment difference (98.33% CI for treatment difference):
APIDRA pre meal vs. Regular Human Insulin - 0.1 (-0.3; 0.0)
APIDRA post meal vs. Regular Human Insulin 0.0 (-0.1; 0.2)
APIDRA post meal vs. pre meal 0.2 (0.0; 0.3)
14.4 Type 1 Diabetes-Pediatric patients
A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in
children and adolescents older than 4 years of age with type 1 diabetes mellitus to assess the
safety and efficacy of APIDRA (n= 277) compared to insulin lispro (n= 295) when administered
subcutaneously within 15 minutes before a meal. Patients also received insulin glargine
(administered once daily in the evening) or NPH insulin (administered once in the morning and
once in the evening). There was a 4-week run-in period with insulin lispro and insulin glargine or
NPH prior to randomization. Most patients were Caucasian (91%). Fifty percent of the patients
were male. The mean age was 12.5 years (range 4 to 17 years). Mean BMI was 20.6 kg/m2 .
Glycemic control (see Table 9) was comparable for the two treatment regimens.
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Table 9: Results from a 26-week study in pediatric patients with type 1 diabetes mellitus
Number of patients
Basal Insulin
Glycated hemoglobin (GHb)* (%)
Baseline mean
Adjusted mean change from baseline
Treatment Difference: Mean (95% confidence interval)
Basal insulin dose (Units/kg/day)
Baseline mean
Mean change from baseline
Short-acting insulin dose (Units/kg/day)
Baseline mean
Mean change from baseline
Mean number of short-acting insulin injections per day
Baseline mean body weight (kg)
Mean weight change from baseline (kg)
APIDRA
Lispro
271
291
NPH or insulin glargine
NPH or insulin glargine
8.2
8.2
0.1
0.2
-0.1 (-0.2, 0.1)
0.5
0.5
0.0
0.0
0.5
0.5
0.0
0.0
3
3
51.5
2.2
50.8
2.2
*GHb reported as HbA1c equivalent
14.5 Type 1 Diabetes-Adults: Continuous subcutaneous insulin infusion
A 12-week randomized, active control study (APIDRA versus insulin aspart) conducted in adults
with type 1 diabetes (APIDRA n= 29, insulin aspart n=30) evaluated the use of APIDRA in an
external continuous subcutaneous insulin pump. All patients were Caucasian. The mean age was
46 years (range 21 to 73 years). The mean GHb increased from baseline to endpoint in both
treatment groups (from 6.8% to 7.0% for APIDRA; from 7.1% to 7.2% for insulin aspart).
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How supplied
APIDRA 100 units per mL (U-100) is available as:
10 mL vials
NDC 0088-2500-33
3 mL SoloStar prefilled pen, package of 5
NDC 0088-2502-05
Pen needles are not included in the packs.
Solostar is compatible with all pen needles from Becton Dickinson and Company, Ypsomed and
Owen Mumford.
16.2 Storage
Do not use after the expiration date (see carton and container).
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Unopened Vial/SoloStar
Unopened APIDRA vials and SoloStar should be stored in a refrigerator, 36°F-46°F (2°C-8°C).
Protect from light. APIDRA should not be stored in the freezer and it should not be allowed to
freeze. Discard if it has been frozen.
Unopened vials/SoloStar not stored in a refrigerator must be used within 28 days.
Open (In-Use) Vial:
Opened vials, whether or not refrigerated, must be used within 28 days. If refrigeration is not
possible, the open vial in use can be kept unrefrigerated for up to 28 days away from direct heat
and light, as long as the temperature is not greater than 77°F (25°C).
Open (In-Use) SoloStar prefilled pen:
The opened (in-use) SoloStar should NOT be refrigerated but should be kept below 77◦F (25◦C)
away from direct heat and light. The opened (in-use) SoloStar kept at room temperature must be
discarded after 28 days.
Infusion sets:
Infusion sets (reservoirs, tubing, and catheters) and the APIDRA in the reservoir must be
discarded after 48 hours of use or after exposure to temperatures that exceed 98.6°F (37°C).
Intravenous use:
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION (2.4) are stable
at room temperature for 48 hours.
16.3 Preparation and handling
After dilution for intravenous use, the solution should be inspected visually for particulate matter
and discoloration prior to administration. Do not use the solution if it has become cloudy or
contains particles; use only if it is clear and colorless. APIDRA is not compatible with Dextrose
solution and Ringers solution and, therefore, cannot be used with these solution fluids. The use
of APIDRA with other solutions has not been studied and is, therefore, not recommended.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
17.1 Instructions for all patients
Patients should be instructed on self-management procedures including glucose monitoring,
proper injection technique, and management of hypoglycemia and hyperglycemia.
Patients must be instructed on handling of special situations such as intercurrent conditions
(illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent
administration of an increased insulin dose, inadequate food intake, and skipped meals.
Refer patients to the APIDRA Patient Information Leaflet for additional information.
Women with diabetes should be advised to inform their doctor if they are pregnant or are
contemplating pregnancy.
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Accidental mix-ups between APIDRA and other insulins, particularly long-acting insulins, have
been reported. To avoid medication errors between APIDRA and other insulins, patients should
be instructed to always check the insulin label before each injection.
17.2 For patients using continuous subcutaneous insulin pumps
Patients using external pump infusion therapy should be trained appropriately.
The following insulin pumps† have been used in APIDRA clinical trials conducted by sanofi
aventis, the manufacturer of APIDRA:
• Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™,
Rapid C™, Rapid D™, and Tender™)
• MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate
QR™, and Quick-set™).
Before using a different insulin pump with APIDRA, read the pump label to make sure the pump
has been evaluated with APIDRA.
To minimize insulin degradation, infusion set occlusion, and loss of the preservative
(metacresol), the infusion sets (reservoir, tubing, and catheter) and the APIDRA in the reservoir
must be replaced at least every 48 hours and a new infusion site should be selected. The
temperature of the insulin may exceed ambient temperature when the pump housing, cover,
tubing or sport case is exposed to sunlight or radiant heat. Insulin exposed to temperatures higher
than 98.6°F (37°C) should be discarded. Infusion sites that are erythematous, pruritic, or
thickened should be reported to the healthcare professional, and a new site selected because
continued infusion may increase the skin reaction or alter the absorption of APIDRA.
Pump or infusion set malfunctions or handling errors or insulin degradation can lead to rapid
hyperglycemia, and ketosis and diabetic ketoacidosis. This is especially pertinent for rapid-acting
insulin analogs that are more rapidly absorbed through skin and have a shorter duration of action.
Prompt identification and correction of the cause of hyperglycemia or ketosis or diabetic
ketoacidosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage,
disconnection or kinking, handling errors and degraded insulin. Less commonly, hypoglycemia
from pump malfunction may occur. If these problems cannot be promptly corrected, patients
should resume therapy with subcutaneous insulin injection and contact their healthcare
professional. Patients administering APIDRA by continuous subcutaneous infusion must have an
alternative insulin delivery system in case of pump system failure. [See Dosage and
Administration (2.3), Warnings and Precautions (5.7), and How Supplied/Storage and Handling
(16)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
©2014 sanofi-aventis U.S. LLC
†The brands listed are the registered trademarks of their respective owners and are not trademarks
of sanofi-aventis U.S. LLC
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Patient Information
APIDRA (uh PEE druh)
(insulin glulisine [recombinant DNA origin] injection)
solution for injection
Read the Patient Information that comes with APIDRA before you start taking it and each time
you get a refill. There may be new information. This leaflet does not take the place of talking
with your healthcare provider about your diabetes or treatment. If you have questions about
APIDRA or about diabetes, talk with your healthcare provider.
What is APIDRA?
APIDRA is a man-made insulin used to control high blood sugar in adults and children with
diabetes mellitus.
It is not known if APIDRA is safe or effective in:
• children under age 4 with type 1 diabetes
• children with type 2 diabetes
Who should NOT take APIDRA?
Do not take APIDRA:
• when your blood sugar is too low (hypoglycemia). See the section, “What are the
possible side effects of APIDRA?”
• if you are allergic to any of the ingredients in APIDRA. See the end of this leaflet for a
complete list of ingredients. Ask your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking APIDRA?
Medical conditions can affect your insulin needs. Tell your healthcare provider about all of
your medical conditions, including if you:
• have liver or kidney problems.
• are pregnant, plan to become pregnant, or are breast-feeding. It is not known if
APIDRA will harm your unborn baby or nursing child. You and your healthcare
provider should talk about the best way to manage your diabetes while you are pregnant
or breast-feeding. It is especially important to keep good control of your blood sugar
during pregnancy.
• have heart failure or other heart problems. If you have heart failure, it may get worse
while you take TZDs with APIDRA
Reference ID: 3506714
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements especially ones commonly called
TZDs (thiazolidinediones).
Know the medicines you take. Keep a list of your medicines with you and show it to your
healthcare provider and pharmacist when you get a new medicine.
How should I take APIDRA?
• Take APIDRA exactly as prescribed.
• Do not make any changes to your dose or type of insulin unless told to do so by your
healthcare provider.
• Know your insulin. Make sure you know:
• the type and strength of insulin prescribed for you
• the amount of insulin you take
• the best time for you to take your insulin. This may change if you take a different
type of insulin or if the way you give your insulin changes for example, using an
insulin pump instead of giving injections under the skin (subcutaneous injections).
• APIDRA starts working faster than regular insulin, but does not work as long.
• APIDRA is usually used with a longer-acting insulin when given by injection under the
skin (subcutaneous), or by itself when using an insulin pump.
• Read the instructions for use that come with your APIDRA. Talk to your healthcare
provider if you have any questions. Your healthcare provider should show you how to
inject APIDRA before you start taking it.
• Your healthcare provider will prescribe the best type of APIDRA for you. APIDRA is
available in:
• 3 mL SoloStar® prefilled pen
• 10 mL vials
•
You need a prescription to get APIDRA. Always be sure you receive the right insulin
from the pharmacy.
• Check your blood sugar level before each use of APIDRA. Ask your healthcare provider
what your blood sugars should be and when you should check your blood sugar levels.
• Check the label to make sure you have the correct insulin type. This is especially
important if you also take long-acting insulin.
• APIDRA should look clear and colorless. Do not use APIDRA if it looks cloudy,
colored, or has particles in it. Talk with your pharmacist or healthcare provider if you
have any questions.
• If you take too much APIDRA, your blood sugar may fall low (hypoglycemia). You can
treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary right
away.
• Do not share needles, insulin pens or syringes with others.
Reference ID: 3506714
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Your dose of APIDRA may need to be changed because of:
•
illness
• change in diet
•
stress
• change in physical activity or exercise
•
other medicines you take
• travel
Check your blood sugar and stay on the diet and exercise plan as prescribed by your healthcare
provider.
What should I consider while taking APIDRA?
• Alcohol may affect your blood sugar when you take APIDRA
• Driving and operating machinery. You may have trouble paying attention or
reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a
car or operate machinery. Ask your healthcare provider if it is alright for you to drive
if you have:
o low blood sugar (hypoglycemia)
o decreased or no warning signs of low blood sugar
What are the possible side effects of APIDRA?
APIDRA can cause serious side effects, including:
• Low blood sugar (hypoglycemia). Symptoms of low blood sugar may include:
o feeling anxious, or irritable, mood changes
o trouble concentrating or feeling confused
o tingling in your hands, feet, lips, or tongue
o feeling dizzy, light-headed, or drowsy
o nightmares or trouble sleeping
o headache
o blurred vision
o slurred speech
o a fast heart beat
o sweating
o shakiness
o walking unsteady
Very low blood sugar (hypoglycemia) can cause unconsciousness (passing out), seizures, and
death. Talk to your healthcare provider about how to tell if you have low blood sugar and what
to do if this happens while taking APIDRA. Know your symptoms of low blood sugar. Follow
your healthcare provider’s instructions for treating your low blood sugar.
Reference ID: 3506714
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Talk to your healthcare provider if low blood sugar is a problem for you. Your dose of APIDRA
may need to be changed.
• Serious allergic reactions.
Get medical help right away if you have any of these symptoms of a severe allergic reaction:
• a rash all over your body
• shortness of breath
• trouble breathing (wheezing)
• fast pulse
• sweating
• feel faint (due to low blood pressure)
• Low potassium in your blood. Your doctor will check you for this.
Common side effects include:
• Reactions at the injection site (local allergic reaction). You may get redness, swelling
and itching at the injection site. If you keep having skin reactions or they are serious talk
to your healthcare provider.
• Skin thickening or pits at the injection site. Do not inject insulin into skin where this
has happened. Choose an injection area (upper arm, thigh, or stomach area). Change
injection sites within the area you choose with each dose. Do not inject into the exact
same spot for each injection.
• Weight gain
Heart Failure. Taking certain diabetes pills called thiazolidinediones or "TZDs" with APIDRA
may cause heart failure in some people. This can happen even if you have never had heart failure
or heart problems before. If you already have heart failure it may get worse while you take TZDs
with APIDRA. Your healthcare provider should monitor you closely while you are taking TZDs
with APIDRA. Tell your healthcare provider if you have any new or worse symptoms of heart
failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
During treatment with TZDs and APIDRA, the TZD dose may need to be adjusted or stopped by
your healthcare provider if you have new or worse heart failure.
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all of the possible side effects of APIDRA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1
800-332-1088.
Reference ID: 3506714
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store APIDRA?
• See the Patient Instructions for Use that come with your APIDRA for specific storage
instructions.
Unopened APIDRA:
• Do not use APIDRA after the expiration date stamped on the label.
• Keep all unopened APIDRA in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Do not freeze. Do not use APIDRA if it has been frozen.
• Keep APIDRA away from direct heat and light.
• Unopened vials and SoloStar that were not kept in a refrigerator must be used within 28
days after opening.
General Information about APIDRA
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not use APIDRA for a condition for which it was not prescribed. Do not give
APIDRA to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about APIDRA. If you would like more
information, talk with your healthcare provider. You can ask your healthcare provider for
information about APIDRA that is written for healthcare providers. For more information about
APIDRA call 1-800-633-1610 or go to www.apidra.com.
What are the ingredients in APIDRA?
Active ingredient: insulin glulisine
Inactive ingredients: metacresol, tromethamine, sodium chloride, polysorbate 20, water for
injection, hydrochloric acid or sodium hydroxide
ADDITIONAL INFORMATION
DIABETES FORECAST is a national magazine designed especially for patients with diabetes
and their families and is available by subscription from the American Diabetes Association,
(ADA), P.O. Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). You
may also visit the ADA website at www.diabetes.org.
Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research
Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1
800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdf.org.
To get more information about diabetes, check with your healthcare provider or diabetes
educator or visit www.DiabetesWatch.com.
Reference ID: 3506714
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For more information about APIDRA call 1-800-633-1610 or visit www.apidra.com.
Rev. May 2014
sanofi-aventis U.S. LLC
Bridgewater NJ 08807
A SANOFI COMPANY
©2014 sanofi-aventis U.S. LLC
Reference ID: 3506714
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
APIDRA® SoloStar®
(insulin glulisine [rDNA origin] injection)
3 mL prefilled pen
Patient Instructions for Use
Be sure that you read, understand and follow these instructions before you use your APIDRA
SoloStar® . Talk with your healthcare provider about the right way to use your APIDRA
SoloStar before you use it for the first time. Keep this leaflet in case you need to look at it
again later.
APIDRA SoloStar should not be used by people who are blind or have severe vision
problems, without the help of a person who has good eyesight and who is trained to use the
APIDRA SoloStar the right way.
APIDRA SoloStar is a disposable prefilled pen used to inject APIDRA. Each APIDRA
SoloStar has 300 units of insulin which can be used for many doses. You can select a dose
from 1 to 80 units. The pen plunger moves with each dose. The plunger will only move to
the end of the cartridge when 300 units of insulin have been given. usage illustration
If you will give yourself subcutaneous injections of APIDRA:
• You should take APIDRA within 15 minutes before a meal or within 20 minutes after
starting a meal.
• Do not inject APIDRA if you are not going to eat within 15 minutes.
• Inject APIDRA into the skin of your upper arm, thigh, or stomach area. Do not inject
APIDRA into a vein or into a muscle.
• Choose an injection area (upper arm, thigh, or stomach area). Change injection sites
within the area you choose with each dose. Do not inject into the exact same spot
for each injection.
Important information for use of APIDRA SoloStar:
•
Use a new needle for each injection.
APIDRA Solostar may be used with pen needles from Becton Dickinson and Company,
Ypsomed and Owen Mumford. Contact your healthcare provider for further
information.
•
Do a safety test before each injection. (See step 3.)
•
Do not select a dose or press the injection button without a needle attached.
•
Do not share your APIDRA SoloStar with others even if they have diabetes.
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If your injection is given by another person, this person must be careful to avoid
accidental needle stick injury and prevent passing (transmission of) infection.
•
Do not use APIDRA SoloStar if it is damaged or if you are not sure that it is working
correctly.
•
Always carry an extra APIDRA SoloStar prefilled pen in case your APIDRA SoloStar
is lost or damaged.
Step 1. Preparing for an injection
Make sure you have the following items:
• Apidra SoloStar
• Pen needles
• Alcohol swab
• Puncture resistant container. See “How do I dispose of used needles and APIDRA
SoloStar?”.
A. Check the label on your APIDRA SoloStar to make sure you have the right insulin. The
APIDRA Solostar is blue. It has a dark blue injection button with a raised ring on the
top.
B. Check the expiration date, located on the carton or the label of your APIDRA SoloStar,
to make sure the date has not passed. Do not use an APIDRA SoloStar if the date has
passed.
C. Take off the pen cap.
D. Look at the insulin in your APIDRA SoloStar. Check to make sure that the insulin looks
clear. Do not use this APIDRA SoloStar if the insulin is cloudy, colored, or has particles
in it.
Step 2. Attaching the needle
Always use a new sterile needle for each injection to help prevent contamination, and
potential needle blocks.
Read the pen needle “Instructions for Use” before you use them.
Please note: Pen needles may look different. The pen needles shown are for illustrative
purposes only.
A. Wipe the Rubber Seal with alcohol.
B. Remove the protective seal from the new pen needle.
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C. Line up the needle with the pen, and keep it straight as you attach it (screw or push on,
depending on the needle type). usage illustration
• If you do not keep the needle straight while you attach it this can damage the rubber seal,
and cause leakage of insulin, or break the needle. usage illustration
Step 3. Doing a Safety test
Do a safety test before each injection to make sure that you get the correct dose of APIDRA.
The safety test:
• makes sure that the pen and needle work properly
• removes air bubbles
A. Select a dose of 2 units by turning the dosage selector. usage illustration
B. Take off the outer needle cap and keep it to remove the used needle after injection. Take
off the inner needle cap and dispose of it. usage illustration
C. Hold the pen with the needle pointing upwards.
D. Tap the insulin reservoir so that any air bubbles rise up towards the needle.
E. Press the injection button all the way in. Check if insulin comes out of the needle tip.
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
You may have to do the safety test more than once before you see the insulin.
•
If no insulin comes out, check for air bubbles and repeat the safety test two more times
to remove them.
•
If still no insulin comes out, the needle may be blocked. Change the needle and try
again.
•
If no insulin comes out after changing the needle, your APIDRA SoloStar may be
damaged. Do not use this APIDRA SoloStar.
Step 4. Selecting your dose
Select the APIDRA dose prescribed by your healthcare provider. You can select the insulin
dose in steps of 1 unit, from a minimum of 1 unit to a maximum of 80 units. If you need a
dose larger than 80 units, you should give it as two or more injections.
A. Check that the dose window shows “0” after the safety test.
B. Select your needed dose (in the example below, the selected dose is 30 units). If you turn
past your dose, you can turn back down. usage illustration
•
Do not push the injection button while turning, insulin will come out.
•
You cannot turn the dosage selector passed the number of units left in the pen. Do not
force the dosage selector to turn. In this case, either you can inject the amount of
insulin that is still in the pen and finish your dose with a new APIDRA SoloStar or you
can use a new APIDRA SoloStar for your full dose.
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Step 5. Giving the injection
A. Give the injection exactly as shown to you by your healthcare provider.
B. Insert the needle into your skin. usage illustration
C. Inject the dose by pressing the injection button in all the way. Only push the injection
button when you are ready to inject. The number in the dose window will return to “0”
as you inject. usage illustration
D. Keep the injection button pressed all the way in. Slowly count to 10 before you take the
needle out of your skin. This will make sure that the full dose has been given.
Step 6. Removing and disposing of the pen needle
Always remove the pen needle after each injection and store your APIDRA SoloStar without
a needle attached. This helps prevent:
• Contamination and infection
• Air from getting into the insulin reservoir and leakage of insulin. This will help to make
sure you inject the right dose of insulin.
A. Follow the instructions from your healthcare provider when removing and disposing of
the needle. For example “scoop” the outer needle cap back on the needle and use it to
unscrew the used needle from the pen. To lessen the risk of accidental needle stick
injury and passing infection:
• do not recap needles with your fingers
• never replace the inner needle cap.
If your injection is given by another person, this person must also be careful when
removing and disposing of the needles to prevent accidental needle stick injury and
passing infection.
B. Dispose of the needle the right way into your special puncture resistant container (See
“How Do I Dispose of used needles and APIDRA SoloStar?”).
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C. Always put the pen cap back on the pen, then store the APIDRA SoloStar until your next
injection.
How do I dispose of used needles and APIDRA SoloStar?
• Check with your healthcare provider for instructions about the right way to dispose of
used needles and APIDRA SoloStar. There may be local or state laws about how to
throw away used needles and APIDRA SoloStar. Do not dispose of used needles or
APIDRA SoloStar in household trash and do not recycle them.
• Put used needles and used empty APIDRA SoloStar in a container made specially for
disposing of used syringes and needles (called a “sharps” container) or a hard plastic
container (such as empty detergent bottles),with a screw-on cap, or metal container with
a plastic lid labeled “Used Syringes”. These containers should be sealed and disposed
of the right way.
How should I Store APIDRA SoloStar?
•
Do not refrigerate APIDRA SoloStar after first use.
•
Keep at room temperature below 77ºF (25ºC).
•
Dispose of any opened APIDRA SoloStar 28 days after first use.
Maintenance
• Protect your APIDRA SoloStar from dust and dirt.
• You can clean the outside of your APIDRA SoloStar by wiping it with a damp cloth.
• Do not soak, wash or lubricate the pen as this may damage it.
• Handle your APIDRA SoloStar with care. Avoid situations where your APIDRA
SoloStar might be damaged. If you are concerned that your APIDRA SoloStar may be
damaged, use a new one.
If you have any questions about APIDRA SoloStar or about diabetes, ask your healthcare
provider, go to www.apidra.com or call sanofi-aventis U.S. at 1-800-633-1610.
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Date of revision:
05/2014
©2013 sanofi-aventis U.S. LLC
Reference ID: 3506714
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:32.320525 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021629s029lbl.pdf', 'application_number': 21629, 'submission_type': 'SUPPL ', 'submission_number': 29} |
6,232 | NovoLog® Mix 50/50
50% insulin aspart protamine suspension and 50% insulin aspart injection, (rDNA origin)
DESCRIPTION
NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injec-
tion, [rDNA origin]) is an insulin analog suspension containing 50% insulin aspart protamine
crystals and 50% soluble insulin aspart. NovoLog® Mix 50/50 is a blood glucose-lowering agent
with a rapid onset and an intermediate duration of action. Insulin aspart is homologous with reg-
ular human insulin with the exception of a single substitution of the amino acid proline by aspar-
tic acid in position B28, and is produced by recombinant DNA technology utilizing
Saccharomyces cerevisiae (baker’s yeast) as the production organism. Insulin aspart
(NovoLog®) has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
Structural formula:
NovoLog® Mix 50/50 is a uniform, white, sterile suspension that contains insulin aspart (B28 asp
regular human insulin analog) 100 Units/ml, 16 mg glycerol, 1.50 mg phenol, 1.72 mg metacre-
sol, 19.6 μg zinc, 1.25 mg disodium hydrogen phosphate dihydrate, 1.17 mg sodium chloride,
and 0.23 mg protamine sulfate. NovoLog® Mix 50/50 has a pH of 7.10 – 7.44. Hydrochloric
acid or sodium hydroxide may be added to adjust pH.
CLINICAL PHARMACOLOGY
Mechanism of action
The primary activity of NovoLog® Mix 50/50 is the regulation of glucose metabolism. Insulin
products including the insulin in NovoLog® Mix 50/50, exert their specific action through bind-
ing to insulin receptors.
Insulin binding activates mechanisms to lower blood glucose by facilitating cellular uptake of
glucose into skeletal muscle and fat while simultaneously inhibiting the output of glucose from
the liver.
Reference ID: 3273545
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In standard biological assays in mice and rabbits, one unit of NovoLog® (insulin aspart) has the
same glucose-lowering effect as one unit of regular human insulin.
Pharmacokinetics
Bioavailability and Absorption
The single substitution of the amino acid proline with aspartic acid at position B28 in insulin
aspart (NovoLog®) reduces the molecule’s tendency to form hexamers as observed with regular
human insulin. This results in more rapid absorption from the subcutaneous spaces than seen
with regular human insulin. The rapid absorption characteristics of NovoLog® are maintained by
NovoLog® Mix 50/50, containing 50% insulin aspart in soluble form. The remaining 50% is in
crystalline form as insulin aspart protamine which has a prolonged absorption profile after sub-
cutaneous injection.
In an euglycemic clamp study in patients with type 1 diabetes (n=32) after dosing with 0.4 U/kg
of NovoLog® Mix 70/30, 50/50, and NovoLog® on three different study days, a Cmax of 98 ± 29
mU/L was reached after approximately 80 minutes for NovoLog® Mix 50/50 (See Table 1).
There was diminishing distinction in pharmacokinetics between the two NovoLog Mix formula-
tions at later time points (See Figure 2).
Table 1: Pharmacokinetic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix
70/30 and NovoLog® in patients with Type 1 diabetes mellitus
NovoLog® Mix 50/50 versus
NovoLog® Mix 70/30
NovoLog® versus
NovoLog® Mix 50/50
Cmax
AUC0-2h
1.49 [1.34; 1.65]
1.48 [1.35; 1.64]
2.04 [1.84; 2.26]
2.01 [1.82; 2.22]
Values are expressed as mean ratios [95% confidence intervals]
Reference ID: 3273545
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
x14/sum5070-us/current - 07SEP2007 - f_fda_sep_07_1746.sas/fda_sep_07/f_fda_sep_07_1746_iasp.cgm
Novolog
Novolog Mix 50/50
Novolog Mix 70/30
IAsp (mU/L)
0
20
40
60
80
100
120
140
160
180
200
Nominal time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Figure 2. Pharmacokinetic profiles of NovoLog® Mix 50/50, 70/30, and NovoLog® in
Patients with Type 1 diabetes mellitus
The bioavailability of insulin aspart is decreased with increasing protamine sulfate concentration
in any NovoLog® Mix formulation. Consequently, exposure of a subcutaneous dose of
NovoLog® Mix 50/50 may be reduced in comparison to the comparable dose of insulin aspart
(NovoLog®) and an intermediate insulin that are mixed by the patient prior to injection. No clin-
ical studies have been conducted comparing NovoLog® Mix 50/50 to proportionate doses of in-
sulin aspart (NovoLog®) and an intermediate-acting insulin that are mixed by the patient prior to
injection. Switching to a regimen that contains a NovoLog® Mix formulation will require careful
blood glucose monitoring to ensure adequacy of glycemic control and to avoid hypoglycemia.
The rate of insulin absorption and consequently the onset of activity are known to be affected by
the site of injection, exercise, and other variables (see PRECAUTIONS, General). The influence
of different injection sites on the absorption of NovoLog® Mix 50/50 has not been investigated.
Distribution and Elimination
NovoLog® Mix 50/50 is a biphasic insulin which contains 50% soluble insulin aspart.
NovoLog® has a low binding to plasma proteins, 0 – 9%, similar to regular human insulin. After
subcutaneous administration in normal male volunteers (n=24), NovoLog® was more rapidly
eliminated than regular human insulin with an average apparent half-life of 81 minutes compared
to 141 minutes for regular human insulin.
Pharmacodynamics
Reference ID: 3273545
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In an euglycemic clamp study in subjects with type 1 diabetes, a maximum glucose infusion rate
(GIRmax) of 6.0 ± 1.7 mg/kg/min was reached after approximately 2.5 hours for NovoLog® Mix
50/50 (See Table 2). There was diminishing distinction in pharmacodynamics between the two
NovoLog® Mix formulations at later time points (See Figure 3).
Table 2: Pharmacodynamic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix
70/30 and NovoLog® in patients with Type 1 diabetes mellitus
NovoLog® Mix 50/50 versus
NovoLog® Mix 70/30
NovoLog® versus
NovoLog® Mix 50/50
GIRmax
AUCGIR,0-2h
1.29 [1.17; 1.43]
1.52 [1.31; 1.78]
1.49 [1.35; 1.65]
1.44 [1.23; 1.67]
Values are expressed as mean ratios [95% confidence intervals]
x14/sum5070-us/current - 07SEP2007 - f_fda_sep_07_1746.sas/fda_sep_07/f_fda_sep_07_1746_gir.cgm
Novolog
Novolog Mix 50/50
Novolog Mix 70/30
GIR (mg/(kg*min))
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
Nominal time (hours)
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Figure 3. Pharmacodynamic profiles of NovoLog® Mix 50/50, 70/30, and NovoLog® in
patients with Type 1 diabetes mellitus
Special populations
Children and adolescents – The pharmacokinetic and pharmacodynamic properties of NovoLog®
Mix 50/50 have not been assessed in children and adolescents less than 18 years of age.
Geriatrics – The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog®
Mix 50/50 has not been studied.
Reference ID: 3273545
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gender – The effect of gender on the pharmacokinetics and pharmacodynamics of NovoLog®
Mix 50/50 has not been studied.
Obesity – The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and
pharmacodynamics of NovoLog® Mix 50/50 has not been studied but data on the rapid-acting
component (NovoLog®) show no significant effect.
Ethnic origin – The effect of ethnic origin on the pharmacokinetics and pharmacodynamics of
NovoLog® Mix 50/50 has not been studied.
Renal impairment – The effect of renal function on the pharmacokinetics and pharmacodynamics
of NovoLog® Mix 50/50 has not been studied but data on the rapid-acting component
(NovoLog®) show no significant effect. Some studies with human insulin have shown increased
circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose
adjustments of insulin, including NovoLog® Mix 50/50 may be necessary in patients with renal
dysfunction (see PRECAUTIONS, Renal Impairment).
Hepatic impairment – The effect of hepatic impairment on the pharmacokinetics and pharmaco-
dynamics of NovoLog® Mix 50/50 has not been studied but data on the rapid-acting component
(NovoLog®) show no significant effect. Some studies with human insulin have shown increased
circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose
adjustments of insulin, including NovoLog® Mix 50/50, may be necessary in patients with he-
patic dysfunction (see PRECAUTIONS, Hepatic Impairment).
Pregnancy – The effect of pregnancy on the pharmacokinetics and pharmacodynamics of
NovoLog® Mix 50/50 has not been studied (see PRECAUTIONS, Pregnancy).
Smoking – The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoLog®
Mix 50/50 has not been studied.
INDICATIONS AND USAGE
NovoLog® Mix 50/50 is indicated as an adjunct to diet and exercise to improve glycemic control
in patients with diabetes mellitus.
CONTRAINDICATIONS
NovoLog® Mix 50/50 is contraindicated during episodes of hypoglycemia and in patients hyper-
sensitive to NovoLog® Mix 50/50 or any of the excipients.
WARNINGS
Because NovoLog® Mix 50/50 has peak pharmacodynamic activity between 1 and 4 hours after
injection, it should be administered with meals.
NovoLog® Mix 50/50 should not be administered intravenously.
NovoLog® Mix 50/50 is not to be used in insulin infusion pumps.
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NovoLog® Mix 50/50 should not be mixed with any other insulin product.
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog® Mix
50/50. As with all insulins, the timing of hypoglycemia may differ among various insulin for-
mulations.
Glucose monitoring is recommended for all patients with diabetes.
Any change of insulin dose should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, premixed), species
(animal, human), or method of manufacture (rDNA versus animal-source insulin) may result in
the need for a change in dosage.
Fluid retention and heart failure with concomitant use of PPAR gamma agonists: Thia-
zolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma
agonists, can cause dose-related fluid retention, particularly when used in combination with in-
sulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, in-
cluding NovoLog® Mix 50/50, and a PPAR-gamma antagonist should be observed for signs and
symptoms of heart failure. If heart failure develops, it should be managed according to current
standards of care, and discontinuation or dose reductions of the PPAR-gamma agonist must be
considered.
PRECAUTIONS
General
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with
the use of all insulins. Because of differences in the action of NovoLog® Mix 50/50 and other
insulins, care should be taken in patients in whom such potential side effects might be clinically
relevant (e.g. patients who are fasting, have autonomic neuropathy, or are using potassium-
lowering drugs or patients taking drugs sensitive to serum potassium level). Because there is di-
urnal variation in insulin resistance and endogenous insulin secretion, variability in the time and
content of meals, and variability in the time and extent of exercise, fixed ratio insulin mixtures
may not provide optimal glycemic control for all patients. Adjustments in insulin dose or insulin
type may be needed during illness, emotional stress, and other physiologic stress in addition to
changes in meals and exercise.
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site
used for injection and the degree of vascularization of the site. Smoking, temperature, and exer-
cise contribute to variations in blood flow and insulin absorption. These and other factors con-
tribute to inter- and intra-patient variability.
Insulin may cause sodium retention and edema (swelling of hands and feet), particularly if previ-
ously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy at the
injection site and hypersensitivity are among other potential clinical adverse effects associated
with the use of all insulins.
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Hypoglycemia – As with all insulin preparations, hypoglycemic reactions may be associated
with the administration of NovoLog® Mix 50/50. Rapid changes in serum glucose concentra-
tions may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose
value. Early warning symptoms of hypoglycemia may be different or less pronounced under cer-
tain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such
as beta-blockers, or intensified diabetes control.
Renal Impairment - Clinical or pharmacology studies with NovoLog® Mix 50/50 in patients
with diabetes with various degrees of renal impairment have not been conducted. As with other
insulins, the requirements for NovoLog® Mix 50/50 may be reduced in patients with renal im-
pairment.
Hepatic Impairment – Clinical or pharmacology studies with NovoLog® Mix 50/50 in patients
with diabetes with various degrees of hepatic impairment have not been conducted. As with
other insulins, the requirements for NovoLog® Mix 50/50 may be reduced in patients with he-
patic impairment.
Allergy - Local reactions: Erythema, swelling, and pruritus at the injection site have been ob-
served with insulin therapy. Reactions may be related to the insulin molecule, other compo-
nents in the insulin preparation including protamine and cresol, components in skin cleansing
agents, or injection techniques.
Systemic reactions: Less common, but potentially more serious, is generalized allergy to insulin,
which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing,
reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, in-
cluding anaphylactic reaction, may be life threatening. Localized reactions and generalized my-
algias have been reported with the use of cresol as an injectable excipient.
Antibody production – Antibodies have not been extensively investigated during the clinical
development of NovoLog® Mix 50/50. Antibodies specific to NovoLog® and cross-reactive
with both NovoLog® and human insulin have been evaluated previously in connection with the
clinical development of NovoLog®. In addition, specific anti-insulin antibodies as well as cross-
reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial
between NovoLog® Mix 70/30 and human pre-mixed insulin and NovoLog® as well as in a
long-term extension trial. Changes in cross-reactive antibodies were more common after
NovoLog® Mix 70/30 than with human pre-mixed insulin but these changes did not correlate
with change in HbA1c or increase in insulin dose. The clinical significance of these antibodies
has not been established. Antibodies did not increase further after long-term exposure (>6
months) to NovoLog® Mix 70/30.
Information for patients - Maintenance of normal or near-normal glucose control is a treat-
ment goal in diabetes mellitus and has been associated with a reduction in diabetes complica-
tions. Patients should consult with their healthcare provider before using NovoLog® Mix 50/50
as a mealtime insulin; the decision should be based on the patient’s insulin needs for that par-
ticular meal. Patients should be informed that alcohol, including beer and wine, may affect their
blood sugar when taking NovoLog® Mix 50/50. Patients should be informed about potential
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risks and advantages of NovoLog® Mix 50/50 therapy including the possible side effects. Pa-
tients should be informed that hypoglycemia may impair the ability to concentrate and react,
which may present a risk in situations where these abilities are especially important, such as
driving or operating other machinery.
Patients should also be offered continued education and advice on insulin therapies, injection
technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglo-
bin testing, recognition and management of hypo- and hyperglycemia, adherence to meal plan-
ning, complications of insulin therapy, timing of dosage, instruction for use of injection devices
and proper storage of insulin.
Female patients should be advised to discuss with their physician if they intend to, or if they be-
come, pregnant because information is not available on the use of NovoLog® Mix 50/50 during
pregnancy or lactation (see PRECAUTIONS, Pregnancy).
Laboratory Tests – The therapeutic response to NovoLog® Mix 50/50 should be assessed by
measurement of serum or blood glucose and glycosylated hemoglobin.
Drug Interactions – A number of substances affect glucose metabolism and may require insulin
dose adjustment and particularly close monitoring. The following are examples of substances
that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral
antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoam-
ine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide),
sulfonamide antibiotics.
The following are examples of substances that may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g. epinephrine, salbuta-
mol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens,
progestogens (e.g., in oral contraceptives).
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-
glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
In addition, under the influence of sympatholytic medical products such as beta-blockers, clo-
nidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent (see
CLINICAL PHARMACOLOGY).
Mixing of insulins
NovoLog® Mix 50/50 should not be mixed with any other insulin product.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the car-
cinogenic potential of NovoLog® Mix 50/50. In 52-week studies, Sprague-Dawley rats were
dosed subcutaneously with NovoLog®, the rapid-acting component of NovoLog® Mix 50/50, at
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10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0
U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog®
increased the incidence of mammary gland tumors in females when compared to untreated con-
trols. The incidence of mammary tumors for NovoLog® was not significantly different than for
regular human insulin. The relevance of these findings to humans is not known. NovoLog®
was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene muta-
tion test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus
test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and fe-
male rats, NovoLog® at subcutaneous doses up to 200 U/kg/day (approximately 32 times the
human subcutaneous dose, based on U/body surface area) had no direct adverse effects on male
and female fertility, or on general reproductive performance of animals.
Pregnancy: Teratogenic Effects: Pregnancy Category C:
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. This background risk is increased in pregnancies complicated by
hyperglycemia and may be decreased with good metabolic control. It is essential for patients
with diabetes or history of gestational diabetes to maintain good metabolic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first
trimester, generally increase during the second and third trimesters, and rapidly decline after
delivery. Insulin mixtures, including NovoLog Mix 50/50, may be limited in their ability to pro-
vide near-normal glycemic control, as recommended during pregnancy. Careful monitoring of
glucose control is essential in patients with diabetes during pregnancy.
It is not known whether NovoLog® Mix 50/50 can cause fetal harm when administered to a
pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled
studies of the use of NovoLog® Mix 50/50 in pregnant women.
Animal reproduction studies have not been conducted with NovoLog® Mix 50/50. However,
reproductive toxicology and teratology studies have been performed with NovoLog® (the rapid-
acting component of NovoLog® Mix 50/50) and regular human insulin in rats and rabbits. In
these studies, NovoLog® was given to female rats before mating, during mating, and throughout
pregnancy, and to rabbits during organogenesis. The effects of NovoLog® did not differ from
those observed with subcutaneous regular human insulin. NovoLog®, like human insulin,
caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of
200 U/kg/day (approximately 32-times the human subcutaneous dose of 1.0 U/kg/day, based on
U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are
probably secondary to maternal hypoglycemia at high doses. No significant effects were ob-
served in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day.
These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats
and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface
area.
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Nursing mothers - It is unknown whether NovoLog® Mix 50/50 is excreted in human milk as is
human insulin. There are no adequate and well-controlled studies of the use of NovoLog® Mix
50/50 or NovoLog® in lactating women.
Pediatric Use - Safety and effectiveness of NovoLog® Mix 50/50 in children have not been es-
tablished.
Geriatric Use - Safety and effectiveness of NovoLog® Mix 50/50 in geriatric population have
not been studied. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy in this population.
ADVERSE REACTIONS
During clinical trials the overall adverse event profile of NovoLog® Mix 50/50 was comparable
to Novolin® 70/30. Adverse events commonly associated with human insulin therapy include the
following:
Body as whole: allergic reactions (see PRECAUTIONS, Allergy).
Skin and Appendages: Injection site reaction, lipodystrophy, pruritus, rash (see PRECAU-
TIONS, Allergy).
Hypoglycemia: see WARNINGS and PRECAUTIONS.
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy ex-
penditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Ad-
justments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with
coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous gluca-
gon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be
necessary because hypoglycemia may recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION
The written prescription for NovoLog® Mix 50/50 should include the full name, to avoid
confusion with NovoLog® (insulin aspart) and NovoLog® Mix 70/30 (70% insulin aspart
protamine suspension and 30% insulin aspart injection, (rDNA origin).
NovoLog® Mix 50/50 should be administered within 15 minutes of meal initiation up to three
times daily. It is intended only for subcutaneous injection into the abdominal wall, thigh, or
upper arm. NovoLog® Mix 50/50 should not be administered intravenously.
No clinical studies have been conducted comparing NovoLog® Mix 50/50 to proportionate doses
of insulin aspart (NovoLog®) and an intermediate-acting insulin that are mixed by the patient
prior to injection. Initiating or switching to a regimen that contains a NovoLog® Mix formula-
tion, as with any change in an insulin regimen, will require careful blood glucose monitoring to
ensure adequacy of glycemic control and to avoid hypoglycemia.
Dose regimens of NovoLog® Mix 50/50 will vary among patients and should be determined by
the health care professional familiar with the patient’s metabolic needs, eating habits, and other
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lifestyle variables. As with all insulins, the duration of action may vary according to the dose,
injection site, blood flow, temperature, and level of physical activity and conditioning.
Administration using PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery
devices and NovoLog® Mix 50/50 FlexPen® Prefilled syringes:
PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery devices*:
NovoLog® Mix 50/50 PenFill® suspension should be visually inspected and resuspended imme-
diately before use. The resuspended NovoLog® Mix 50/50 must appear uniformly white and
cloudy. Before inserting the cartridge into the insulin delivery system, roll the cartridge be-
tween your palms 10 times.
The cartridge should be kept horizontal while rolling. Thereafter, turn the cartridge upside
down so that the glass ball moves from one end of the cartridge to the other. Do this at least 10
times. The rolling and turning procedure must be repeated until the suspension appears uni-
formly white and cloudy. Mixing is easier when the insulin has reached room temperature. In-
ject immediately. Before each subsequent injection, turn the 3 mL PenFill® cartridge compati-
ble delivery devices* upside down so that the glass ball moves from one end of the cartridge to
the other. Repeat this at least 10 times until the suspension appears uniformly white and cloudy.
Inject immediately.
Always remove the needle after each injection and store the 3 mL PenFill® cartridge com-
patible delivery device without a needle attached. This prevents contamination and/or in-
fection, entry of air into the insulin reservoir, or leakage of insulin and will ensure accu-
rate dosing. Always use a new needle for each injection to prevent contamination. Used
needles or lancets should be placed in sharps containers (such as red biohazard contain-
ers), hard plastic containers (such as detergent bottles), or metal containers (such as an
empty coffee can). Such containers should be sealed and disposed of properly.
*NovoLog® Mix 50/50 PenFill® cartridges are designed for use with Novo Nordisk 3 mL
PenFill® cartridge compatible insulin delivery devices, with or without the addition of a
NovoPen® 3 PenMate®, and NovoFine® disposable needles.
Disposable NovoLog® Mix 50/50 FlexPen® Prefilled Syringes:
NovoLog® Mix 50/50 suspension should be visually inspected and resuspended immediately
before use. The resuspended NovoLog® Mix 50/50 must appear uniformly white and cloudy.
Before use, roll the disposable NovoLog® Mix 50/50 FlexPen® Prefilled syringe between your
palms 10 times. This procedure should be carried out with the NovoLog® Mix 50/50 FlexPen®
Prefilled syringe in a horizontal position. Thereafter, turn the disposable NovoLog® Mix 50/50
FlexPen® Prefilled syringe upside down so that the glass ball moves from one end of the reser-
voir to the other. Do this at least 10 times. The rolling and turning procedure must be repeated
until the suspension appears uniformly white and cloudy. Mixing is easier when the insulin has
reached room temperature. Inject immediately. Before each subsequent injection, turn the dis-
posable NovoLog® Mix 50/50 FlexPen® Prefilled syringe upside down so that the glass ball
moves from one end of the reservoir to the other at least 10 times and until the suspension ap-
pears uniformly white and cloudy. Inject immediately.
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Always remove the needle after each injection and store the NovoLog® Mix 50/50
FlexPen® Prefilled Syringe without a needle attached. This prevents contamination and/or
infection, entry of air into the insulin reservoir, or leakage of insulin and will ensure accu-
rate dosing. Always use a new needle for each injection to prevent contamination. Used
needles, or lancets should be placed in sharps containers (such as red biohazard contain-
ers), hard plastic containers (such as detergent bottles), or metal containers (such as an
empty coffee can). Such containers should be sealed and disposed of properly.
HOW SUPPLIED
NovoLog® Mix 50/50 is available in the following package sizes: each presentation containing
100 Units of insulin aspart per mL (U-100).
3 mL PenFill® cartridges*
NDC 0169-3672-12
3 mL NovoLog® Mix 50/50 FlexPen® Prefilled Syringe
NDC 0169-3676-19
* NovoLog® Mix 50/50 PenFill® cartridges are designed for use with Novo Nordisk 3 mL
PenFill® cartridge compatible insulin delivery devices, with or without the addition of a
NovoPen® 3 PenMate®, and NovoFine® disposable needles.
RECOMMENDED STORAGE
Unused NovoLog® Mix 50/50 should be stored in a refrigerator between 2o and 8oC (36o to
46oF). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do
not freeze or use NovoLog® Mix 50/50 if it has been frozen.
PenFill® cartridges or NovoLog® Mix 50/50 FlexPen® Prefilled syringes:
Once a cartridge or a NovoLog® Mix 50/50 FlexPen® Prefilled syringe is punctured, it may be
used for up to 14 days if it is kept at room temperature below 30°C (86°F). Cartridges or
NovoLog® Mix 50/50 FlexPen® Prefilled syringes in use should not be stored in the refrigerator.
Keep all PenFill® cartridges and NovoLog® Mix 50/50 FlexPen® Prefilled syringes away from
direct heat and light.
Unpunctured PenFill® cartridges and NovoLog® Mix 50/50 FlexPen® Prefilled syringes can be
used until the expiration date printed on the label if they are stored in a refrigerator. After re-
moving NovoLog® Mix 50/50 PenFill® cartridges or NovoLog® Mix 50/50 FlexPen® Prefilled
syringes from the refrigerator it is recommended to let the PenFill® cartridges or NovoLog® Mix
50/50 FlexPen® Prefilled syringe reach room temperature before resuspending the insulin as
recommended for first time use. Keep unused PenFill® cartridges and NovoLog® Mix 50/50
FlexPen® Prefilled syringes in the carton so they will stay clean and protected from light.
These storage conditions are summarized in the following table:
Not in-use (unopened)
Room Temperature
(below 30°C [86°F])
Not in-use (unopened)
Refrigerated
(2 o-8o C [36o to 46oF])
In-use (opened)
Room Temperature
(at or below 30°C [86°F])
3 mL PenFill® cartridges
14 days
Until expiration date
14 days (Do not refrigerate)
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3 mL NovoLog® Mix
50/50 FlexPen®
14 days
Until expiration date
14 days (Do not refrigerate)
Rx Only
Date of issue: XXX xx, XXXX
Version: X
NovoLog®, FlexPen®, Novolin® and NovoFine® are registered trademarks of Novo Nordisk A/S.
20xx Novo Nordisk
NovoLog® Mix 50/50 is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422, 5,840,680
and 5,866,538 and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
FlexPen® is covered by US Patent Nos. 6,235,004, 6,004,297, 6,582,404 and other patents pend-
ing.
Manufactured by:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Manufactured for:
Novo Nordisk Inc.
Princeton, NJ 08540
www.novonordisk-us.com
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Patient Information for NovoLog® Mix 50/50
NovoLog® Mix 50/50 (NO-vo-log-MIX-FIF-tee-FIF-tee)
(50% insulin aspart protamine suspension and 50% insulin aspart injection, [rDNA origin])
Important:
Know your insulin. Do not change the type of insulin you take unless told to do
so by your healthcare provider. The amount of insulin you take as well as the
best time for you to take your insulin may need to change if you take a different
type of insulin.
Make sure you have the type and strength of insulin prescribed for you.
Read this Patient Information that comes with NovoLog® Mix 50/50 before you
start taking it and each time you get a refill. There may be new information since
your last refill. This leaflet does not take the place of talking with your healthcare
provider about your diabetes or your treatment. Make sure that you know how to
manage your diabetes. Ask your healthcare provider if you have any questions
about managing your diabetes.
What is NovoLog® Mix 50/50?
NovoLog® Mix 50/50 is both a rapid-acting and long-acting man-made insulin.
NovoLog® Mix 50/50 comes in:
3 mL PenFill® cartridges.
3 mL NovoLog® Mix 50/50 FlexPen® Prefilled syringe.
Only use NovoLog® Mix 50/50 if all of the medicine looks white and cloudy after
you mix it (resuspension) (see “Patient Instructions for Use”). If your NovoLog®
Mix 50/50 looks clear, do not use it and call Novo Nordisk at 1-800-727-6500.
Who should not take NovoLog® Mix 50/50?
Do not use NovoLog® Mix 50/50 if:
Your blood sugar is too low (hypoglycemia). After treating your low blood
sugar, follow your healthcare provider's instructions on the use of
NovoLog® Mix 50/50.
You are allergic to anything in NovoLog® Mix 50/50. See the end of this
leaflet for a complete list of ingredients in NovoLog® Mix 50/50. Check
with your healthcare provider if you are not sure.
Tell your healthcare provider:
about all of your medical conditions. Medical conditions can affect
your insulin needs and your dose of NovoLog® Mix 50/50.
if you are pregnant or breast feeding. You and your healthcare provider
should talk about the best way to manage your diabetes while you are
pregnant or breastfeeding. NovoLog® Mix 50/50 has not been studied in
pregnant or nursing women.
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about all of the medicines you take, including prescription and non-
prescription medicines, vitamins and herbal supplements. Many
medicines can affect your blood sugar levels and your insulin needs. Your
NovoLog® Mix 50/50 dose may need to change if you take other
medicines.
if you take any other medicines, especially ones commonly called
TZDs (thiazolidinediones).
if you have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with NovoLog® Mix 50/50.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers.
How should I take NovoLog® Mix 50/50?
Read the instructions for use that come with your NovoLog® Mix 50/50
product. Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject NovoLog® Mix 50/50 before
you start taking it.
Take NovoLog® Mix 50/50 exactly as prescribed. NovoLog® Mix 50/50
is injected right before a meal, up to three (3) times each day.
NovoLog® Mix 50/50 starts acting fast, so inject it up to 15 minutes
before you eat a meal. Do not inject NovoLog® Mix 50/50 if you are not
planning to eat within 15 minutes.
Inject NovoLog® Mix 50/50 under the skin of your stomach area,
upper arms, or upper legs. NovoLog® Mix 50/50 may affect your blood
sugar levels sooner if you inject it into the skin of your stomach area.
Change (rotate) sites with each dose. Although you can inject insulin
in the same area, do not inject into the exact same spot for each
injection.
Check your blood sugar levels. Ask your healthcare provider how often
you should check your blood sugar levels for hypoglycemia (too low blood
sugar) and hyperglycemia (too high blood sugar).
If you take too much NovoLog® Mix 50/50, your blood sugar may fall
low (hypoglycemia). You can treat mild low blood sugar (hypoglycemia)
by drinking or eating something sugary right away (fruit juice, sugar
candies, or glucose tablets). It is important to treat low blood sugar
(hypoglycemia) right away because it could get worse and you could pass
out (become unconscious). If you pass out you will need help from
another person or emergency medical services right away, and will need
treatment with a glucagon injection or treatment at a hospital. See “What
are the most common side effects of NovoLog® Mix 50/50?” for more
information on low blood sugar (hypoglycemia).
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If you forget to take your dose of NovoLog® Mix 50/50, your blood
sugar may go too high (hyperglycemia). High blood sugar
(hyperglycemia) if not treated can lead to loss of consciousness (passing
out), coma or even death. Symptoms of high blood sugar may include:
increased thirst
frequent urination
drowsiness
loss of appetite
fruity odor on the breath
high amounts of sugar and ketones in your
urine
nausea, vomiting (throwing up), or
abdominal pain
a hard time breathing
Follow your healthcare provider’s instructions for treating high blood sugar, and talk to
your healthcare provider if high blood sugar is a problem for you.
Your insulin dosage may need to change because of:
illness
stress
other medicines you take
change in food intake
change in physical activity or
exercise
surgery
Follow your healthcare provider’s instructions to make changes in your insulin
dose.
Never mix NovoLog® Mix 50/50 with other insulin products.
Never use NovoLog® Mix 50/50 in an insulin pump.
Never inject NovoLog® Mix 50/50 into a vein.
See the end of this patient information for instructions about preparing and giving
the injection.
What are the most common side effects of NovoLog® Mix 50/50?
Low blood sugar (hypoglycemia). Symptoms of low blood sugar may
include:
sweating
dizziness or
lightheadedness
shakiness
hunger
fast heart beat
tingling of lips or tongue
trouble concentrating or confusion
blurred vision
slurred speech
anxiety, irritability or mood changes
headache
Alcohol, including beer and wine, may affect your blood sugar when you take
NovoLog® Mix 50/50.
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Your ability to concentrate or react may be reduced if you have hypoglycemia. Be
careful when you drive a car or operate machinery. Ask your healthcare provider
if you should drive if you have:
frequent hypoglycemia
reduced or absent warning signs of hypoglycemia
Severe low blood sugar can cause unconsciousness (passing out), seizures, and
death. Know your symptoms of low blood sugar. Follow your healthcare
provider’s instructions for treating low blood sugar. Talk to your healthcare
provider if low blood sugar is a problem for you.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
Other possible side effects include:
Serious allergic reaction (whole body allergic reaction). Get medical
help right away if you develop a rash over your whole body, have trouble
breathing, a fast heartbeat, or sweating.
Reactions at the injection site (local allergic reaction). You may get
redness, swelling and itching at the injection site. If you keep having skin
reactions or they are serious, you may need to stop taking NovoLog® Mix
50/50 and take a different insulin. Do not inject insulin into a skin area that
is red, swollen, or itchy.
Skin thickens or pits at the injection site (lipodystrophy). Change
(rotate) where you inject your insulin to help prevent these skin changes
from happening. Do not inject insulin into this type of skin.
Swelling of your hands and feet.
Heart Failure. Taking certain diabetes pills called thiazolidinediones or
“TZDs” with NovoLog® Mix 50/50 may cause heart failure in some people.
This can happen even if you have never had heart failure or heart
problems before. If you already have heart failure it may get worse while
you take TZDs with NovoLog® Mix 50/50. Your healthcare provider should
monitor you closely while you are taking TZDs with NovoLog® Mix 50/50.
Tell your healthcare provider if you have any new or worse symptoms of
heart failure including:
shortness of breath
swelling of your ankles or feet
sudden weight gain
Treatment with TZDs and NovoLog® Mix 50/50 may need to be adjusted or
stopped by your healthcare provider if you have new or worse heart failure.
Low potassium in your blood (hypokalemia).
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These are not all of the possible side effects from NovoLog® Mix 50/50. Ask
your healthcare provider or pharmacist for more information.
How should I store NovoLog® Mix 50/50?
Unopened NovoLog® Mix 50/50:
Keep all unopened NovoLog® Mix 50/50 in the refrigerator between 36° to
46° F (2° to 8° C). Do not store in the freezer or next to the refrigerator
cooling element. Do not freeze.
Keep unopened NovoLog® Mix 50/50 in the carton to protect from light.
After the package has been opened:
Do not put NovoLog® Mix 50/50 that you are using in the refrigerator.
Keep at room temperature at or below 86°F (30°C) for up to 14 days.
Keep NovoLog® Mix 50/50 away from direct heat or light.
Throw away used NovoLog® Mix 50/50 after 14 days of use, even if there
is insulin left in the cartridge or syringe.
General information about NovoLog® Mix 50/50
Medicines are sometimes prescribed for conditions that are not mentioned in the
patient leaflet. Do not use NovoLog® Mix 50/50 for a condition for which it was
not prescribed. Do not give NovoLog® Mix 50/50 to other people, even if they
have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog® Mix
50/50. If you would like more information about NovoLog® Mix 50/50 or diabetes,
talk with your healthcare provider. You can ask your healthcare provider or
pharmacist for information about NovoLog® Mix 50/50 which is written for
healthcare professionals. For more information, call 1-800-727-6500 or visit
www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1660 Duke Street, Alexandria, VA 22314 and on
www.diabetes.org.
What are the ingredients in NovoLog® Mix 50/50?
insulin aspart
glycerol
phenol
metacresol
protamine sulfate
zinc
disodium hydrogen phosphate
dihydrate
sodium chloride
hydrochloric acid and/or sodium
hydroxide may be added
Date of Issue: XXXX xx, XXXX
Version: X
Reference ID: 3273545
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NovoLog®, PenFill®, FlexPen®, NovoPen®, NovoFine®, PenMate®, are registered
trademarks of Novo Nordisk A/S.
NovoLog® Mix 50/50 is covered by US Patent Nos. 5,547,930,
5,618,913, 5,834,422, 5,840,680 and 5,866,538 and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
FlexPen® is covered by US Patent Nos. 6,235,004, 6,004,297, 6,582,404 and
other patents pending.
© 200X Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® Mix 50/50 contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
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Page 1 of 5
Patient Instructions for Use
NovoLog® Mix 50/50 cartridge
Before using the NovoLog® Mix 50/50 cartridge
1. Talk with your healthcare provider to find out where to inject NovoLog® Mix
50/50 (injection sites) and how to give an injection with your insulin delivery
device.
2. Read the instruction manual that comes with your insulin delivery device for
complete instructions on how to use the PenFill® cartridge with the device.
How to use the NovoLog® Mix 50/50 cartridge
1. Check your insulin. Just before using your NovoLog® Mix 50/50 cartridge,
check to make sure that you have the right type of insulin. This is especially
important if you use different types of insulin.
2. Carefully look at the cartridge and the insulin inside it. The insulin should
be white and cloudy (after being mixed). The tamper-resistant foil should be in
place before the first use. If the foil has been broken or removed before your
first use of the cartridge, or if the insulin is clear, do not use it. Call Novo
Nordisk at 1-800-727-6500.
3. Gather your supplies for injecting NovoLog® Mix 50/50. You will need your
NovoLog® Mix 50/50 PenFill® cartridge, your insulin delivery device,
NovoFine® single use needles and an alcohol swab. Be sure to use an
insulin delivery device that is made to work with NovoLog® Mix 50/50 PenFill®
cartridges. These insulin delivery devices can be used with a NovoPen® 3
PenMate® if you would like to hide the needle from view during injection.
4. Wash your hands well with soap and water.
5. Clean your injection site with an alcohol swab and let the injection site dry
before you inject.
6. Before inserting a 3 mL cartridge into your insulin delivery device for the first
time, roll the cartridge between your palms 10 times. These steps should be
done with the 3 mL PenFill® cartridge in a horizontal (flat) position (see
Diagram 1 below). Then turn the PenFill® cartridge up and down between
positions a and b (see Diagram 2 below) so the glass ball moves from one
end of the cartridge to the other. Do this at least 10 times. Repeat the rolling
and turning steps until the insulin looks white and cloudy. Mixing is easier
when the insulin is at room temperature.
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Page 2 of 5
7. Insert the PenFill® cartridge into the insulin delivery device. Wipe the front
rubber stopper of the 3 mL PenFill® cartridge with an alcohol swab, then
screw on a new needle (see Diagram 3 below).
For NovoFine® needles, remove the big outer needle cap and the
inner needle cap (see Diagram 4 above). Always use a new needle for each
injection to prevent infection.
Giving the airshot before each injection:
To prevent the injection of air and make sure insulin is delivered; you must do an
air shot before each injection. Hold the device with the needle pointing up and
gently tap the PenFill® cartridge holder with your finger a few times to raise any
air bubbles to the top of the cartridge (see Diagram 5 below). Do the airshot as
described in the device instruction manual.
2
1
3
4
5
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Page 3 of 5
Giving the injection
8. Dial the number of units you need to inject on the device (see Diagram 6
below). Inject right away as you were shown by your healthcare provider. If
there is a delay between mixing of the insulin and the injection, the insulin will
need to be mixed again.
9. Pinch a fold of skin between 2 fingers, then push the needle into the pinched
up skin (see Diagram 7 below). Inject the dose by pressing the push button
all the way in. Keep the needle in the skin for at least 6 seconds, and keep
the push button pressed all the way in until the needle has been pulled out
from the skin. This will make sure that the full dose has been given. If blood
appears after you take the needle out of your skin, press the injection site
lightly with a finger. Do not rub the area.
After the injection
10. Remove the needle from the insulin delivery device after each injection. Keep
the 3 mL PenFill® cartridge in the insulin delivery device. The needle should
not be attached to the insulin delivery device during storage. This will prevent
6
7
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Page 4 of 5
infection or leakage of insulin, and will help ensure that you receive the right
dose of NovoLog® Mix 50/50.
11. Put the used needle in a sharps container, or some type of hard plastic or
metal container that can be sealed, such as a detergent bottle or coffee can.
Ask your healthcare provider how to seal and throw away these containers
safely. There may be local or state laws about how to throw away used
needles and syringes.
12. Put the pen cap back on the insulin delivery device.
After the first use of the 3 mL PenFill® cartridge
1. If the 3 mL PenFill® cartridge is already in the insulin delivery device, turn it
upside down between positions a and b (see Diagram 2 above), so that the
glass ball moves from one end of the 3 mL PenFill® cartridge to the other. Do
this until all of the insulin looks white and cloudy.
2. Before you inject, there must be at least 12 units of insulin left in the cartridge
to make sure the remaining insulin is evenly mixed. If there are less than 12
units left, use a new 3 mL PenFill® cartridge.
3. An airshot should be done before each injection. Do the airshot as described
in the device instruction manual.
4. Do not remove the 3 mL cartridge from the insulin delivery device.
5. Put the pen cap back on the insulin delivery device.
IMPORTANT NOTES
• Do not use if you need to do more than 6 airshots before the first use of each
NovoLog® Mix 50/50 cartridge to get a drop of insulin at the needle tip. Contact
Novo Nordisk at 1-800-727-6500.
• Remember to do an airshot before each injection. See the device instruction
manual.
• Do not drop the NovoLog® Mix 50/50 cartridge and insulin delivery device.
• Keep the NovoLog® Mix 50/50 cartridge and insulin delivery device with you.
Do not leave it in a car or other places where it can get too hot or too cold.
• NovoLog® Mix 50/50 cartridges are designed for use with NovoFine®
disposable needles.
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Page 5 of 5
• Do not put a disposable needle on the NovoLog® Mix 50/50 cartridge and
insulin delivery device until you are ready to use it. Remove the needle right
after use. Do not recap the needle.
• Throw away used needles safely, so other people will not be harmed.
Talk to your healthcare provider about how to safely throw away your used
needles.
• Throw away the used NovoLog® Mix 50/50 cartridges without the needle
attached.
• Always carry an extra NovoLog® Mix 50/50 cartridge with you in case the
NovoLog® Mix 50/50 cartridge is damaged or lost. Always keep the
NovoLog® Mix 50/50 cartridge in the outer carton when you are not using it in
order to protect it from light.
• Keep your NovoLog® Mix 50/50 cartridge out of the reach of children. Use
NovoLog® Mix 50/50 cartridges as directed to treat your diabetes. Do not
share it with anyone else even if he or she also has diabetes.
Reference ID: 3273545
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Page 1 of 7
Patient Instructions for Use
NovoLog® Mix 50/50 FlexPen® Prefilled syringe
How to use the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
NovoLog® Mix 50/50 FlexPen® Prefilled syringe is a disposable insulin delivery
system. NovoLog® Mix 50/50 FlexPen® Prefilled syringe is to be used with
NovoFine® single use needles. People who are blind or have severe vision
problems should only use the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
with the help of a sighted person who is trained to use the NovoLog® Mix 50/50
FlexPen® Prefilled syringe the right way.
Please read these instructions completely before using this device.
Figure 1
Diagram of a NovoLog® Mix 50/50 FlexPen® Prefilled syringe
Figure 2
Diagram of a NovoFine® needle
NovoFine® needle
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Page 2 of 7
1. PREPARING THE NOVOLOG® MIX 50/50 FLEXPEN® PREFILLED
SYRINGE
Before you start to prepare your injection, check the label to make sure
that you are taking the right type of insulin. NovoLog® Mix 50/50 should look
white and cloudy (after being mixed). This is especially important if you use 2
types of insulin.
• Pull off the pen cap.
• Wipe the rubber stopper with an alcohol swab.
• Before using a new NovoLog® Mix 50/50 FlexPen® Prefilled syringe for the
first time, do the following to mix (resuspend) the insulin:
• Hold the NovoLog® Mix 50/50 FlexPen® Prefilled syringe in a
horizontal (flat) position between your palms (see diagram A
above). Roll the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe between your palms 10 times.
• Then, turn the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
up and down. Move the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe between position 1 and 2 so that the glass ball moves
from one end of the insulin cartridge to the other (see diagram B
above). Do this at least 10 times. Repeat the rolling and
turning steps until all of the insulin looks white and cloudy.
Mixing (resuspension) is easier when the insulin is at room
temperature.
• After mixing, continue to do the following steps right away. If
there is a delay, the insulin will need to be mixed again.
• Remove the protective tab from the disposable needle and screw the
needle tightly onto the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
B
C
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Page 3 of 7
(see diagram C above). Do not place a disposable needle on your
NovoLog® Mix 50/50 FlexPen® Prefilled syringe until you are ready to take
your injection.
• Pull off the outer and inner needle caps (see diagram D above). Do not
throw away the big outer needle cap.
• Giving the airshot before each injection:
Small amounts of air may collect in the needle and insulin cartridge during
normal use. To avoid injecting air and to make sure you take the right
dose of insulin, do the following:
• Dial 2 units by turning the dose selector so that the arrow
lines up with the “2” in the dosage indicator window (see
diagram E below).
• Hold the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
with the needle pointing up. Tap the insulin cartridge gently
with your finger a few times (see diagram F below). A small
air bubble may remain but it will not be injected. The NovoLog®
Mix 50/50 FlexPen® Prefilled syringe prevents the insulin
cartridge from being completely emptied.
• Keep the needle pointing up and press the push button (on the
end of the NovoLog® Mix 50/50 FlexPen® Prefilled syringe) all
the way in (see diagram G below). You should see a drop of
D
E
F
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Page 4 of 7
insulin at the needle tip. If you don’t see a drop of insulin,
repeat the procedure (dial 2 units, tap the insulin cartridge and
press the push button) until insulin appears. You may need to
do this up to 6 times. If you don’t see a drop of insulin after 6
times, do not use the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe and contact Novo Nordisk at 1-800-727-6500.
2. SETTING THE DOSE
• Check and make sure that the dose selector is set at zero (0) (see
diagram H above).
• Dial the number of units you need to inject by turning the dose selector so
the arrow lines up with your dose.
• The dose can be corrected by turning the dose selector in either direction.
When dialing back, be careful not to press the push button. Pressing the
button will cause the insulin to come out. You cannot set a dose larger
than the number of units left in the cartridge. You will hear a click for
every single unit dialed. Do not set the dose by counting the number of
clicks you hear.
3. GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider.
H
G
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Page 5 of 7
• Wipe the injection site with an alcohol swab and let the area dry.
• Pinch a fold of skin between 2 fingers, then push the needle into the
pinched up skin (see diagram I above).
• Give the dose by pressing the push button all the way in (see diagram J
below). Be careful to only press the push button when injecting.
• Keep the needle in the skin for at least 6 seconds, and keep the push
button pressed all the way in until the needle has been pulled out from the
skin. This will make sure that the full dose has been given. If blood
appears after you take the needle out of your skin, press the injection site
lightly with a finger. Do not rub the area.
After the injection
• Remove the needle from the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe after each injection. This helps to prevent contamination,
infection, and leakage of insulin, and will help to make sure you inject the
right dose of insulin. Put the needle in a sharps container, or some type of
hard plastic or metal container that can be sealed such as a detergent
bottle or coffee can. These containers should be sealed and thrown away
safely. Ask your healthcare provider how to throw away a used sharps
container. There may be local or state laws about how to throw away
used needles and syringe.
• Put the pen cap back on the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe.
I
J
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Page 6 of 7
Healthcare providers, relatives, and other caregivers should follow general
precautions for removing and disposing of needles to lessen the possible
chance of needle stick injury.
4. FUTURE INJECTIONS
It is important that you use a new needle for each injection. Follow the
directions in steps 1, 2, and 3 above.
Before you inject, there must be at least 12 units of insulin left in the cartridge to
make sure the remaining insulin is evenly mixed. If there are less than 12 units
left, use a new NovoLog® Mix 50/50 FlexPen® Prefilled syringe.
The numbers on the insulin cartridge can be used to estimate the amount of
insulin left in the NovoLog® Mix 50/50 FlexPen® Prefilled syringe. Do not use
these numbers to measure the insulin dose. You cannot set a dose more than
the number of units remaining in the cartridge.
Mix (resuspend) the insulin before each injection:
• Turn the NovoLog® Mix 50/50 FlexPen® Prefilled syringe up and down
between position 1 and 2 so that the glass ball moves from one end of the
insulin cartridge to the other (see diagram B above). Do this at least 10
times. Repeat the procedure until all of the insulin looks white and cloudy.
• Continue to follow the directions as described in steps 1, 2, and 3 above.
If there is a delay in any step, the insulin will need to be mixed
(resuspended) again.
5. FUNCTION CHECK
If your NovoLog® Mix 50/50 FlexPen® Prefilled syringe is not working the right
way, follow this procedure:
• Screw on a new NovoFine® needle.
• Do an airshot as described in step 1.
• Put the big outer needle cap onto the needle. Do not put on the inner
needle cap.
• Turn the dose selector so that the arrow lines up with the 20 units in the
dose indicator window.
K
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Page 7 of 7
• Hold the NovoLog® Mix 50/50 FlexPen® Prefilled syringe so the needle is
pointing down.
• Press the push button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram K
above). If the NovoLog® Mix 50/50 FlexPen® Prefilled syringe has released too
much or too little insulin, do the function check again. If it happens again, do not
use your NovoLog® Mix 50/50 FlexPen® Prefilled syringe and contact Novo
Nordisk at 1-800-727-6500.
6. IMPORTANT NOTES
• If you need to do more than 6 airshots before the first use of each NovoLog®
Mix 50/50 FlexPen® Prefilled syringe to get a drop of insulin at the needle tip,
do not use the NovoLog® Mix 50/50 FlexPen® Prefilled syringe. Contact Novo
Nordisk at 1-800-727-6500.
• Remember to perform an airshot before each injection. See diagrams E and F.
• Do not drop the NovoLog® Mix 50/50 FlexPen® Prefilled syringe.
• Keep the NovoLog® Mix 50/50 FlexPen® Prefilled syringe with you. Do not
leave it in a car or other place where it can get too hot or too cold.
• NovoLog® Mix 50/50 FlexPen® Prefilled syringe should be used with NovoFine®
disposable needles.
• Do not put a disposable needle on the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe until you are ready to use it. Remove the needle right after use. Do not
recap the needle.
• Throw away used needles safely, so other people will not be harmed.
Talk to your healthcare provider about how to safely throw away your used
needles.
• Throw away the used NovoLog® Mix 50/50 FlexPen® Prefilled syringe without
the needle attached.
• Always carry an extra NovoLog® Mix 50/50 FlexPen® Prefilled syringe with
you in case the NovoLog® Mix 50/50 FlexPen® Prefilled syringe is damaged
or lost.
• Keep your NovoLog® Mix 50/50 FlexPen® Prefilled syringe out of the reach of
children. Use NovoLog® Mix 50/50 FlexPen® Prefilled syringe as directed to
treat your diabetes. Do not share it with anyone else even if he or she also
has diabetes.
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| custom-source | 2025-02-12T13:43:32.433794 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021810s004lbl.pdf', 'application_number': 21810, 'submission_type': 'SUPPL ', 'submission_number': 4} |
6,233 |
NovoLog® Mix 50/50
50% insulin aspart protamine suspension and 50% insulin aspart injection, (rDNA origin)
DESCRIPTION
NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injec
tion, [rDNA origin]) is an insulin analog suspension containing 50% insulin aspart protamine
crystals and 50% soluble insulin aspart. NovoLog® Mix 50/50 is a blood glucose-lowering agent
with a rapid onset and an intermediate duration of action. Insulin aspart is homologous with reg
ular human insulin with the exception of a single substitution of the amino acid proline by aspar
tic acid in position B28, and is produced by recombinant DNA technology utilizing
Saccharomyces cerevisiae (baker’s yeast) as the production organism. Insulin aspart
(NovoLog®) has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
Structural formula: structural formula
NovoLog® Mix 50/50 is a uniform, white, sterile suspension that contains insulin aspart (B28 asp
regular human insulin analog) 100 Units/ml, 16 mg glycerol, 1.50 mg phenol, 1.72 mg metacre
sol, 19.6 μg zinc, 1.25 mg disodium hydrogen phosphate dihydrate, 1.17 mg sodium chloride,
and 0.23 mg protamine sulfate. NovoLog® Mix 50/50 has a pH of 7.10 – 7.44. Hydrochloric
acid or sodium hydroxide may be added to adjust pH.
CLINICAL PHARMACOLOGY
Mechanism of action
The primary activity of NovoLog® Mix 50/50 is the regulation of glucose metabolism. Insulin
products including the insulin in NovoLog® Mix 50/50, exert their specific action through bind
ing to insulin receptors.
Insulin binding activates mechanisms to lower blood glucose by facilitating cellular uptake of
glucose into skeletal muscle and fat while simultaneously inhibiting the output of glucose from
the liver.
Reference ID: 3706666
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In standard biological assays in mice and rabbits, one unit of NovoLog® (insulin aspart) has the
same glucose-lowering effect as one unit of regular human insulin.
Pharmacokinetics
Bioavailability and Absorption
The single substitution of the amino acid proline with aspartic acid at position B28 in insulin
aspart (NovoLog®) reduces the molecule’s tendency to form hexamers as observed with regular
human insulin. This results in more rapid absorption from the subcutaneous spaces than seen
with regular human insulin. The rapid absorption characteristics of NovoLog® are maintained by
NovoLog® Mix 50/50, containing 50% insulin aspart in soluble form. The remaining 50% is in
crystalline form as insulin aspart protamine which has a prolonged absorption profile after sub
cutaneous injection.
In an euglycemic clamp study in patients with type 1 diabetes (n=32) after dosing with 0.4 U/kg
of NovoLog® Mix 70/30, 50/50, and NovoLog® on three different study days, a Cmax of 98 ± 29
mU/L was reached after approximately 80 minutes for NovoLog® Mix 50/50 (See Table 1).
There was diminishing distinction in pharmacokinetics between the two NovoLog Mix formula
tions at later time points (See Figure 2).
Table 1: Pharmacokinetic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix
70/30 and NovoLog® in patients with Type 1 diabetes mellitus
NovoLog® Mix 50/50 versus
NovoLog® Mix 70/30
NovoLog® versus
NovoLog® Mix 50/50
Cmax
AUC0-2h
1.49 [1.34; 1.65]
1.48 [1.35; 1.64]
2.04 [1.84; 2.26]
2.01 [1.82; 2.22]
Values are expressed as mean ratios [95% confidence intervals]
Reference ID: 3706666
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200
180
160
140
120
IAsp (mU/L)
100 graph
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
80
60
40
20
0
Nominal time (hours)
Novolog
Novolog Mix 50/50
Novolog Mix 70/30
x14/sum5070-us/current - 07SEP2007 - f_fda_sep_07_1746.sas/fda_sep_07/f_fda_sep_07_1746_iasp.cgm
Figure 2. Pharmacokinetic profiles of NovoLog® Mix 50/50, 70/30, and NovoLog® in
Patients with Type 1 diabetes mellitus
The bioavailability of insulin aspart is decreased with increasing protamine sulfate concentration
in any NovoLog® Mix formulation. Consequently, exposure of a subcutaneous dose of
NovoLog® Mix 50/50 may be reduced in comparison to the comparable dose of insulin aspart
(NovoLog®) and an intermediate insulin that are mixed by the patient prior to injection. No clin
ical studies have been conducted comparing NovoLog® Mix 50/50 to proportionate doses of in
sulin aspart (NovoLog®) and an intermediate-acting insulin that are mixed by the patient prior to
injection. Switching to a regimen that contains a NovoLog® Mix formulation will require careful
blood glucose monitoring to ensure adequacy of glycemic control and to avoid hypoglycemia.
The rate of insulin absorption and consequently the onset of activity are known to be affected by
the site of injection, exercise, and other variables (see PRECAUTIONS, General). The influence
of different injection sites on the absorption of NovoLog® Mix 50/50 has not been investigated.
Distribution and Elimination
NovoLog® Mix 50/50 is a biphasic insulin which contains 50% soluble insulin aspart.
NovoLog® has a low binding to plasma proteins, 0 – 9%, similar to regular human insulin. After
subcutaneous administration in normal male volunteers (n=24), NovoLog® was more rapidly
eliminated than regular human insulin with an average apparent half-life of 81 minutes compared
to 141 minutes for regular human insulin.
Pharmacodynamics
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In an euglycemic clamp study in subjects with type 1 diabetes, a maximum glucose infusion rate
(GIRmax) of 6.0 ± 1.7 mg/kg/min was reached after approximately 2.5 hours for NovoLog® Mix
50/50 (See Table 2). There was diminishing distinction in pharmacodynamics between the two
NovoLog® Mix formulations at later time points (See Figure 3).
Table 2: Pharmacodynamic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix
70/30 and NovoLog® in patients with Type 1 diabetes mellitus
NovoLog® Mix 50/50 versus
NovoLog® Mix 70/30
NovoLog® versus
NovoLog® Mix 50/50
GIRmax
1.29 [1.17; 1.43]
1.49 [1.35; 1.65]
AUCGIR,0-2h
1.52 [1.31; 1.78]
1.44 [1.23; 1.67]
Values are expressed as mean ratios [95% confidence intervals]
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
kg*min))
(mg/(
4.0
GIR
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Nominal time (hours)
Novolog
Novolog Mix 50/50
Novolog Mix 70/30
x14/sum5070-us/current - 07SEP2007 - f_fda_sep_07_1746.sas/fda_sep_07/f_fda_sep_07_1746_gir.cgm
Figure 3. Pharmacodynamic profiles of NovoLog® Mix 50/50, 70/30, and NovoLog® in
patients with Type 1 diabetes mellitus
Special populations
Children and adolescents – The pharmacokinetic and pharmacodynamic properties of NovoLog®
Mix 50/50 have not been assessed in children and adolescents less than 18 years of age.
Geriatrics – The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog®
Mix 50/50 has not been studied.
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Gender – The effect of gender on the pharmacokinetics and pharmacodynamics of NovoLog®
Mix 50/50 has not been studied.
Obesity – The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and
pharmacodynamics of NovoLog® Mix 50/50 has not been studied but data on the rapid-acting
component (NovoLog®) show no significant effect.
Ethnic origin – The effect of ethnic origin on the pharmacokinetics and pharmacodynamics of
NovoLog® Mix 50/50 has not been studied.
Renal impairment – The effect of renal function on the pharmacokinetics and pharmacodynamics
of NovoLog® Mix 50/50 has not been studied but data on the rapid-acting component
(NovoLog®) show no significant effect. Some studies with human insulin have shown increased
circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose
adjustments of insulin, including NovoLog® Mix 50/50 may be necessary in patients with renal
dysfunction (see PRECAUTIONS, Renal Impairment).
Hepatic impairment – The effect of hepatic impairment on the pharmacokinetics and pharmaco
dynamics of NovoLog® Mix 50/50 has not been studied but data on the rapid-acting component
(NovoLog®) show no significant effect. Some studies with human insulin have shown increased
circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose
adjustments of insulin, including NovoLog® Mix 50/50, may be necessary in patients with hepat
ic dysfunction (see PRECAUTIONS, Hepatic Impairment).
Pregnancy – The effect of pregnancy on the pharmacokinetics and pharmacodynamics of
NovoLog® Mix 50/50 has not been studied (see PRECAUTIONS, Pregnancy).
Smoking – The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoLog®
Mix 50/50 has not been studied.
INDICATIONS AND USAGE
NovoLog® Mix 50/50 is indicated as an adjunct to diet and exercise to improve glycemic control
in patients with diabetes mellitus.
CONTRAINDICATIONS
NovoLog® Mix 50/50 is contraindicated during episodes of hypoglycemia and in patients hyper
sensitive to NovoLog® Mix 50/50 or any of the excipients.
WARNINGS
NovoLog Mix 50/50 PenFill cartridges, PenFill cartridge compatible insulin delivery devices,
and NovoLog Mix 50/50 PenFill Prefilled syringes must never be shared between patients, even
if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.
Because NovoLog® Mix 50/50 has peak pharmacodynamic activity between 1 and 4 hours after
injection, it should be administered with meals.
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NovoLog® Mix 50/50 should not be administered intravenously.
NovoLog® Mix 50/50 is not to be used in insulin infusion pumps.
NovoLog® Mix 50/50 should not be mixed with any other insulin product.
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog® Mix
50/50. As with all insulins, the timing of hypoglycemia may differ among various insulin for
mulations.
Glucose monitoring is recommended for all patients with diabetes.
Any change of insulin dose should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, premixed), species
(animal, human), or method of manufacture (rDNA versus animal-source insulin) may result in
the need for a change in dosage.
Fluid retention and heart failure with concomitant use of PPAR gamma agonists: Thiazoli
dinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma ago
nists, can cause dose-related fluid retention, particularly when used in combination with insulin.
Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including
NovoLog® Mix 50/50, and a PPAR-gamma antagonist should be observed for signs and symp
toms of heart failure. If heart failure develops, it should be managed according to current stand
ards of care, and discontinuation or dose reductions of the PPAR-gamma agonist must be con
sidered.
PRECAUTIONS
General
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with
the use of all insulins. Because of differences in the action of NovoLog® Mix 50/50 and other
insulins, care should be taken in patients in whom such potential side effects might be clinically
relevant (e.g. patients who are fasting, have autonomic neuropathy, or are using potassium-
lowering drugs or patients taking drugs sensitive to serum potassium level). Because there is di
urnal variation in insulin resistance and endogenous insulin secretion, variability in the time and
content of meals, and variability in the time and extent of exercise, fixed ratio insulin mixtures
may not provide optimal glycemic control for all patients. Adjustments in insulin dose or insulin
type may be needed during illness, emotional stress, and other physiologic stress in addition to
changes in meals and exercise.
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site
used for injection and the degree of vascularization of the site. Smoking, temperature, and exer
cise contribute to variations in blood flow and insulin absorption. These and other factors con
tribute to inter- and intra-patient variability.
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Insulin may cause sodium retention and edema (swelling of hands and feet), particularly if previ
ously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy at the
injection site and hypersensitivity are among other potential clinical adverse effects associated
with the use of all insulins.
Hypoglycemia – As with all insulin preparations, hypoglycemic reactions may be associated
with the administration of NovoLog® Mix 50/50. Rapid changes in serum glucose concentra
tions may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose
value. Early warning symptoms of hypoglycemia may be different or less pronounced under cer
tain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such
as beta-blockers, or intensified diabetes control.
Renal Impairment - Clinical or pharmacology studies with NovoLog® Mix 50/50 in patients
with diabetes with various degrees of renal impairment have not been conducted. As with other
insulins, the requirements for NovoLog® Mix 50/50 may be reduced in patients with renal im
pairment.
Hepatic Impairment – Clinical or pharmacology studies with NovoLog® Mix 50/50 in patients
with diabetes with various degrees of hepatic impairment have not been conducted. As with
other insulins, the requirements for NovoLog® Mix 50/50 may be reduced in patients with he
patic impairment.
Allergy - Local reactions: Erythema, swelling, and pruritus at the injection site have been ob
served with insulin therapy. Reactions may be related to the insulin molecule, other compo
nents in the insulin preparation including protamine and cresol, components in skin cleansing
agents, or injection techniques.
Systemic reactions: Less common, but potentially more serious, is generalized allergy to insulin,
which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing,
reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, in
cluding anaphylactic reaction, may be life threatening. Localized reactions and generalized my
algias have been reported with the use of cresol as an injectable excipient.
Antibody production – Antibodies have not been extensively investigated during the clinical
development of NovoLog® Mix 50/50. Antibodies specific to NovoLog® and cross-reactive
with both NovoLog® and human insulin have been evaluated previously in connection with the
clinical development of NovoLog®. In addition, specific anti-insulin antibodies as well as cross-
reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial be
tween NovoLog® Mix 70/30 and human pre-mixed insulin and NovoLog® as well as in a long-
term extension trial. Changes in cross-reactive antibodies were more common after NovoLog®
Mix 70/30 than with human pre-mixed insulin but these changes did not correlate with change
in HbA1c or increase in insulin dose. The clinical significance of these antibodies has not been
established. Antibodies did not increase further after long-term exposure (>6 months) to Novo-
Log® Mix 70/30.
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Information for patients - Maintenance of normal or near-normal glucose control is a treat
ment goal in diabetes mellitus and has been associated with a reduction in diabetes complica
tions. Patients should consult with their healthcare provider before using NovoLog® Mix 50/50
as a mealtime insulin; the decision should be based on the patient’s insulin needs for that partic
ular meal. Patients should be informed that alcohol, including beer and wine, may affect their
blood sugar when taking NovoLog® Mix 50/50. Patients should be informed about potential
risks and advantages of NovoLog® Mix 50/50 therapy including the possible side effects. Pa
tients should be informed that hypoglycemia may impair the ability to concentrate and react,
which may present a risk in situations where these abilities are especially important, such as
driving or operating other machinery.
Patients should also be offered continued education and advice on insulin therapies, injection
technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglo
bin testing, recognition and management of hypo- and hyperglycemia, adherence to meal plan
ning, complications of insulin therapy, timing of dosage, instruction for use of injection devices
and proper storage of insulin.
Female patients should be advised to discuss with their physician if they intend to, or if they be
come, pregnant because information is not available on the use of NovoLog® Mix 50/50 during
pregnancy or lactation (see PRECAUTIONS, Pregnancy).
Laboratory Tests – The therapeutic response to NovoLog® Mix 50/50 should be assessed by
measurement of serum or blood glucose and glycosylated hemoglobin.
Drug Interactions – A number of substances affect glucose metabolism and may require insulin
dose adjustment and particularly close monitoring. The following are examples of substances
that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral
antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoam
ine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide),
sulfonamide antibiotics.
The following are examples of substances that may reduce the blood-glucose-lowering effect:
corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g. epinephrine, salbuta
mol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens,
progestogens (e.g., in oral contraceptives).
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood
glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
In addition, under the influence of sympatholytic medical products such as beta-blockers,
clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent (see
CLINICAL PHARMACOLOGY).
Mixing of insulins
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NovoLog® Mix 50/50 should not be mixed with any other insulin product.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the car
cinogenic potential of NovoLog® Mix 50/50. In 52-week studies, Sprague-Dawley rats were
dosed subcutaneously with NovoLog®, the rapid-acting component of NovoLog® Mix 50/50, at
10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0
U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog®
increased the incidence of mammary gland tumors in females when compared to untreated con
trols. The incidence of mammary tumors for NovoLog® was not significantly different than for
regular human insulin. The relevance of these findings to humans is not known. NovoLog®
was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene muta
tion test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus
test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and fe
male rats, NovoLog® at subcutaneous doses up to 200 U/kg/day (approximately 32 times the
human subcutaneous dose, based on U/body surface area) had no direct adverse effects on male
and female fertility, or on general reproductive performance of animals.
Pregnancy: Teratogenic Effects: Pregnancy Category C:
All pregnancies have a background risk of birth defects, loss, or other adverse outcome
regardless of drug exposure. This background risk is increased in pregnancies complicated by
hyperglycemia and may be decreased with good metabolic control. It is essential for patients
with diabetes or history of gestational diabetes to maintain good metabolic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first
trimester, generally increase during the second and third trimesters, and rapidly decline after
delivery. Insulin mixtures, including NovoLog Mix 50/50, may be limited in their ability to pro
vide near-normal glycemic control, as recommended during pregnancy. Careful monitoring of
glucose control is essential in patients with diabetes during pregnancy.
It is not known whether NovoLog® Mix 50/50 can cause fetal harm when administered to a
pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled
studies of the use of NovoLog® Mix 50/50 in pregnant women.
Animal reproduction studies have not been conducted with NovoLog® Mix 50/50. However,
reproductive toxicology and teratology studies have been performed with NovoLog® (the rapid-
acting component of NovoLog® Mix 50/50) and regular human insulin in rats and rabbits. In
these studies, NovoLog® was given to female rats before mating, during mating, and throughout
pregnancy, and to rabbits during organogenesis. The effects of NovoLog® did not differ from
those observed with subcutaneous regular human insulin. NovoLog®, like human insulin,
caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of
200 U/kg/day (approximately 32-times the human subcutaneous dose of 1.0 U/kg/day, based on
U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three times the
human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are
probably secondary to maternal hypoglycemia at high doses. No significant effects were ob
served in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day.
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These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats
and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface
area.
Nursing mothers - It is unknown whether NovoLog® Mix 50/50 is excreted in human milk as is
human insulin. There are no adequate and well-controlled studies of the use of NovoLog® Mix
50/50 or NovoLog® in lactating women.
Pediatric Use - Safety and effectiveness of NovoLog® Mix 50/50 in children have not been es
tablished.
Geriatric Use - Safety and effectiveness of NovoLog® Mix 50/50 in geriatric population have
not been studied. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy in this population.
ADVERSE REACTIONS
During clinical trials the overall adverse event profile of NovoLog® Mix 50/50 was comparable
to Novolin® 70/30. Adverse events commonly associated with human insulin therapy include the
following:
Body as whole: allergic reactions (see PRECAUTIONS, Allergy).
Skin and Appendages: Injection site reaction, lipodystrophy, pruritus, rash (see PRECAU
TIONS, Allergy).
Hypoglycemia: see WARNINGS and PRECAUTIONS.
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy ex
penditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Ad
justments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with
coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous gluca
gon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be
necessary because hypoglycemia may recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION
The written prescription for NovoLog® Mix 50/50 should include the full name, to avoid
confusion with NovoLog® (insulin aspart) and NovoLog® Mix 70/30 (70% insulin aspart
protamine suspension and 30% insulin aspart injection, (rDNA origin).
NovoLog® Mix 50/50 should be administered within 15 minutes of meal initiation up to three
times daily. It is intended only for subcutaneous injection into the abdominal wall, thigh, or
upper arm. NovoLog® Mix 50/50 should not be administered intravenously.
No clinical studies have been conducted comparing NovoLog® Mix 50/50 to proportionate doses
of insulin aspart (NovoLog®) and an intermediate-acting insulin that are mixed by the patient
prior to injection. Initiating or switching to a regimen that contains a NovoLog® Mix formula-
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tion, as with any change in an insulin regimen, will require careful blood glucose monitoring to
ensure adequacy of glycemic control and to avoid hypoglycemia.
Dose regimens of NovoLog® Mix 50/50 will vary among patients and should be determined by
the health care professional familiar with the patient’s metabolic needs, eating habits, and other
lifestyle variables. As with all insulins, the duration of action may vary according to the dose,
injection site, blood flow, temperature, and level of physical activity and conditioning.
Administration using PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery
devices and NovoLog® Mix 50/50 FlexPen® Prefilled syringes:
PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery devices*:
NovoLog® Mix 50/50 PenFill® suspension should be visually inspected and resuspended imme
diately before use. The resuspended NovoLog® Mix 50/50 must appear uniformly white and
cloudy. Before inserting the cartridge into the insulin delivery system, roll the cartridge be
tween your palms 10 times.
The cartridge should be kept horizontal while rolling. Thereafter, turn the cartridge upside
down so that the glass ball moves from one end of the cartridge to the other. Do this at least 10
times. The rolling and turning procedure must be repeated until the suspension appears uni
formly white and cloudy. Mixing is easier when the insulin has reached room temperature. In
ject immediately. Before each subsequent injection, turn the 3 mL PenFill® cartridge compati
ble delivery devices* upside down so that the glass ball moves from one end of the cartridge to
the other. Repeat this at least 10 times until the suspension appears uniformly white and cloudy.
Inject immediately.
Always remove the needle after each injection and store the 3 mL PenFill® cartridge com
patible delivery device without a needle attached. This prevents contamination and/or in
fection, entry of air into the insulin reservoir, or leakage of insulin and will ensure accu
rate dosing. Always use a new needle for each injection to prevent contamination. Used
needles or lancets should be placed in sharps containers (such as red biohazard contain
ers), hard plastic containers (such as detergent bottles), or metal containers (such as an
empty coffee can). Such containers should be sealed and disposed of properly.
*NovoLog® Mix 50/50 PenFill® cartridges are designed for use with Novo Nordisk 3 mL
PenFill® cartridge compatible insulin delivery devices, with or without the addition of a
NovoPen® 3 PenMate®, and NovoFine® disposable needles.
Disposable NovoLog® Mix 50/50 FlexPen® Prefilled Syringes:
NovoLog® Mix 50/50 suspension should be visually inspected and resuspended immediately
before use. The resuspended NovoLog® Mix 50/50 must appear uniformly white and cloudy.
Before use, roll the disposable NovoLog® Mix 50/50 FlexPen® Prefilled syringe between your
palms 10 times. This procedure should be carried out with the NovoLog® Mix 50/50 FlexPen®
Prefilled syringe in a horizontal position. Thereafter, turn the disposable NovoLog® Mix 50/50
FlexPen® Prefilled syringe upside down so that the glass ball moves from one end of the reser
voir to the other. Do this at least 10 times. The rolling and turning procedure must be repeated
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until the suspension appears uniformly white and cloudy. Mixing is easier when the insulin has
reached room temperature. Inject immediately. Before each subsequent injection, turn the dis
posable NovoLog® Mix 50/50 FlexPen® Prefilled syringe upside down so that the glass ball
moves from one end of the reservoir to the other at least 10 times and until the suspension ap
pears uniformly white and cloudy. Inject immediately.
Always remove the needle after each injection and store the NovoLog® Mix 50/50
FlexPen® Prefilled Syringe without a needle attached. This prevents contamination and/or
infection, entry of air into the insulin reservoir, or leakage of insulin and will ensure accu
rate dosing. Always use a new needle for each injection to prevent contamination. Used
needles, or lancets should be placed in sharps containers (such as red biohazard contain
ers), hard plastic containers (such as detergent bottles), or metal containers (such as an
empty coffee can). Such containers should be sealed and disposed of properly.
HOW SUPPLIED
NovoLog® Mix 50/50 is available in the following package sizes: each presentation containing
100 Units of insulin aspart per mL (U-100).
3 mL PenFill® cartridges*
NDC 0169-3672-12
3 mL NovoLog® Mix 50/50 FlexPen® Prefilled Syringe
NDC 0169-3676-19
* NovoLog® Mix 50/50 PenFill® cartridges are designed for use with Novo Nordisk 3 mL
PenFill® cartridge compatible insulin delivery devices, with or without the addition of a
NovoPen® 3 PenMate®, and NovoFine® disposable needles. NovoLog Mix 50/50 PenFill
cartridges, PenFill cartridge compatible insulin delivery devices, and NovoLog Mix 50/50
FlexPen® Prefilled syringes must never be shared between patients, even if the needle is
changed.
RECOMMENDED STORAGE
Unused NovoLog® Mix 50/50 should be stored in a refrigerator between 2o and 8oC (36o to
46oF). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do
not freeze or use NovoLog® Mix 50/50 if it has been frozen.
PenFill® cartridges or NovoLog® Mix 50/50 FlexPen® Prefilled syringes:
Once a cartridge or a NovoLog® Mix 50/50 FlexPen® Prefilled syringe is punctured, it may be
used for up to 14 days if it is kept at room temperature below 30°C (86°F). Cartridges or
NovoLog® Mix 50/50 FlexPen® Prefilled syringes in use should not be stored in the refrigerator.
Keep all PenFill® cartridges and NovoLog® Mix 50/50 FlexPen® Prefilled syringes away from
direct heat and light.
Unpunctured PenFill® cartridges and NovoLog® Mix 50/50 FlexPen® Prefilled syringes can be
used until the expiration date printed on the label if they are stored in a refrigerator. After re
moving NovoLog® Mix 50/50 PenFill® cartridges or NovoLog® Mix 50/50 FlexPen® Prefilled
syringes from the refrigerator it is recommended to let the PenFill® cartridges or NovoLog® Mix
50/50 FlexPen® Prefilled syringe reach room temperature before resuspending the insulin as
Reference ID: 3706666
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recommended for first time use. Keep unused PenFill® cartridges and NovoLog® Mix 50/50
FlexPen® Prefilled syringes in the carton so they will stay clean and protected from light.
Always remove the needle after each injection and store the 3 mL PenFill® cartridge de
livery device or NovoLog® Mix 50/50 FlexPen® Prefilled syringes without a needle at
tached. This prevents contamination and/or infection, or leakage of insulin, and will en
sure accurate dosing. Always use a new needle for each injection to prevent contamina
tion.
These storage conditions are summarized in the following table:
Not in-use (unopened)
Room Temperature
(below 30°C [86°F])
Not in-use (unopened)
Refrigerated
(2 o-8o C [36o to 46oF])
In-use (opened)
Room Temperature
(at or below 30°C [86°F])
3 mL PenFill® cartridges
14 days
Until expiration date
14 days (Do not refrigerate)
3 mL NovoLog® Mix
50/50 FlexPen®
14 days
Until expiration date
14 days (Do not refrigerate)
Rx Only
Date of issue: February 2015
Version: X
NovoLog®, FlexPen®, Novolin® and NovoFine® are registered trademarks of Novo Nordisk A/S.
2015 Novo Nordisk
NovoLog® Mix 50/50 is covered by US Patent Nos. 5,547,930, 5,618,913, 5,834,422, 5,840,680
and 5,866,538 and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
FlexPen® is covered by US Patent Nos. 6,004,297, RE 43,834, RE 41,956 and other patents
pending.
Manufactured by:
Novo Nordisk A/S
2880 Bagsvaerd, Denmark
Manufactured for:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
www.novonordisk-us.com
Reference ID: 3706666
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Patient Information for NovoLog® Mix 50/50
NovoLog® Mix 50/50 (NO-vo-log-MIX-FIF-tee-FIF-tee)
(50% insulin aspart protamine suspension and 50% insulin aspart injection, [rDNA origin])
Important:
Know your insulin. Do not change the type of insulin you take unless told to do
so by your healthcare provider. The amount of insulin you take as well as the
best time for you to take your insulin may need to change if you take a different
type of insulin.
Make sure you have the type and strength of insulin prescribed for you.
Read this Patient Information that comes with NovoLog® Mix 50/50 before you
start taking it and each time you get a refill. There may be new information since
your last refill. This leaflet does not take the place of talking with your healthcare
provider about your diabetes or your treatment. Make sure that you know how to
manage your diabetes. Ask your healthcare provider if you have any questions
about managing your diabetes.
Do not share your NovoLog Mix 50/50 PenFill cartridges, PenFill cartridge
compatible insulin delivery devices, and NovoLog Mix 50/50 PenFill
Prefilled syringes with other people, even if the needle has been changed.
You may give other people a serious infection, or get a serious infection
from them.
What is NovoLog® Mix 50/50?
NovoLog® Mix 50/50 is both a rapid-acting and long-acting man-made insulin.
NovoLog® Mix 50/50 comes in:
•
3 mL PenFill® cartridges.
•
3 mL NovoLog® Mix 50/50 FlexPen® Prefilled syringe.
Only use NovoLog® Mix 50/50 if all of the medicine looks white and cloudy after
you mix it (resuspension) (see “Patient Instructions for Use”). If your NovoLog®
Mix 50/50 looks clear, do not use it and call Novo Nordisk at 1-800-727-6500.
Who should not take NovoLog® Mix 50/50?
Do not use NovoLog® Mix 50/50 if:
•
Your blood sugar is too low (hypoglycemia). After treating your low blood
sugar, follow your healthcare provider's instructions on the use of
NovoLog® Mix 50/50.
•
You are allergic to anything in NovoLog® Mix 50/50. See the end of this
leaflet for a complete list of ingredients in NovoLog® Mix 50/50. Check
with your healthcare provider if you are not sure.
Reference ID: 3706666
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Tell your healthcare provider:
•
about all of your medical conditions. Medical conditions can affect
your insulin needs and your dose of NovoLog® Mix 50/50.
•
if you are pregnant or breast feeding. You and your healthcare provider
should talk about the best way to manage your diabetes while you are
pregnant or breastfeeding. NovoLog® Mix 50/50 has not been studied in
pregnant or nursing women.
•
about all of the medicines you take, including prescription and non
prescription medicines, vitamins and herbal supplements. Many
medicines can affect your blood sugar levels and your insulin needs. Your
NovoLog® Mix 50/50 dose may need to change if you take other
medicines.
•
if you take any other medicines, especially ones commonly called
TZDs (thiazolidinediones).
•
if you have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with NovoLog® Mix 50/50.
Know the medicines you take. Keep a list of your medicines with you to show all
your healthcare providers.
How should I take NovoLog® Mix 50/50?
Read the instructions for use that come with your NovoLog® Mix 50/50
product. Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject NovoLog® Mix 50/50 before
you start taking it.
•
Take NovoLog® Mix 50/50 exactly as prescribed. NovoLog® Mix 50/50
is injected right before a meal, up to three (3) times each day.
•
NovoLog® Mix 50/50 starts acting fast, so inject it up to 15 minutes
before you eat a meal. Do not inject NovoLog® Mix 50/50 if you are not
planning to eat within 15 minutes.
•
Inject NovoLog® Mix 50/50 under the skin of your stomach area,
upper arms, or upper legs. NovoLog® Mix 50/50 may affect your blood
sugar levels sooner if you inject it into the skin of your stomach area.
•
Change (rotate) sites with each dose. Although you can inject insulin
in the same area, do not inject into the exact same spot for each
injection.
•
Check your blood sugar levels. Ask your healthcare provider how often
you should check your blood sugar levels for hypoglycemia (too low blood
sugar) and hyperglycemia (too high blood sugar).
•
If you take too much NovoLog® Mix 50/50, your blood sugar may fall
low (hypoglycemia). You can treat mild low blood sugar (hypoglycemia)
Reference ID: 3706666
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
by drinking or eating something sugary right away (fruit juice, sugar
candies, or glucose tablets). It is important to treat low blood sugar
(hypoglycemia) right away because it could get worse and you could pass
out (become unconscious). If you pass out you will need help from
another person or emergency medical services right away, and will need
treatment with a glucagon injection or treatment at a hospital. See “What
are the most common side effects of NovoLog® Mix 50/50?” for more
information on low blood sugar (hypoglycemia).
•
If you forget to take your dose of NovoLog® Mix 50/50, your blood
sugar may go too high (hyperglycemia). High blood sugar
(hyperglycemia) if not treated can lead to loss of consciousness (passing
out), coma or even death. Symptoms of high blood sugar may include:
• increased thirst
• fruity odor on the breath
• frequent urination
• high amounts of sugar and ketones in your
• drowsiness
urine
• loss of appetite
• nausea, vomiting (throwing up), or
abdominal pain
• a hard time breathing
Follow your healthcare provider’s instructions for treating high blood sugar, and talk to
your healthcare provider if high blood sugar is a problem for you.
• Do not share your NovoLog Mix 50/50 PenFill cartridges, PenFill
cartridge compatible insulin delivery devices, and NovoLog Mix
50/50 PenFill Prefilled syringes with other people, even if the needle
has been changed. You may give other people a serious infection, or
get a serious infection from them.
• Do not reuse or share your needles with other people. You may give other
people a serious infection, or get a serious infection from them.
Your insulin dosage may need to change because of:
• illness
• change in food intake
• stress
• change in physical activity or
• other medicines you take
exercise
• surgery
Follow your healthcare provider’s instructions to make changes in your insulin
dose.
• Never mix NovoLog® Mix 50/50 with other insulin products.
• Never use NovoLog® Mix 50/50 in an insulin pump.
• Never inject NovoLog® Mix 50/50 into a vein.
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See the end of this patient information for instructions about preparing and giving
the injection.
What are the most common side effects of NovoLog® Mix 50/50?
• Low blood sugar (hypoglycemia). Symptoms of low blood sugar may
include:
• sweating
• trouble concentrating or confusion
• dizziness or
• blurred vision
lightheadedness
• slurred speech
• shakiness
• anxiety, irritability or mood changes
• hunger
• headache
• fast heart beat
• tingling of lips or tongue
Alcohol, including beer and wine, may affect your blood sugar when you take
NovoLog® Mix 50/50.
Your ability to concentrate or react may be reduced if you have hypoglycemia. Be
careful when you drive a car or operate machinery. Ask your healthcare provider
if you should drive if you have:
• frequent hypoglycemia
• reduced or absent warning signs of hypoglycemia
Severe low blood sugar can cause unconsciousness (passing out), seizures, and
death. Know your symptoms of low blood sugar. Follow your healthcare
provider’s instructions for treating low blood sugar. Talk to your healthcare
provider if low blood sugar is a problem for you.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
Other possible side effects include:
•
Serious allergic reaction (whole body allergic reaction). Get medical
help right away if you develop a rash over your whole body, have trouble
breathing, a fast heartbeat, or sweating.
•
Reactions at the injection site (local allergic reaction). You may get
redness, swelling and itching at the injection site. If you keep having skin
reactions or they are serious, you may need to stop taking NovoLog® Mix
50/50 and take a different insulin. Do not inject insulin into a skin area that
is red, swollen, or itchy.
•
Skin thickens or pits at the injection site (lipodystrophy). Change
(rotate) where you inject your insulin to help prevent these skin changes
from happening. Do not inject insulin into this type of skin.
•
Swelling of your hands and feet.
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Heart Failure. Taking certain diabetes pills called thiazolidinediones or
“TZDs” with NovoLog® Mix 50/50 may cause heart failure in some people.
This can happen even if you have never had heart failure or heart
problems before. If you already have heart failure it may get worse while
you take TZDs with NovoLog® Mix 50/50. Your healthcare provider
should monitor you closely while you are taking TZDs with NovoLog® Mix
50/50. Tell your healthcare provider if you have any new or worse
symptoms of heart failure including:
•
shortness of breath
•
swelling of your ankles or feet
•
sudden weight gain
Treatment with TZDs and NovoLog® Mix 50/50 may need to be adjusted or
stopped by your healthcare provider if you have new or worse heart failure.
•
Low potassium in your blood (hypokalemia).
These are not all of the possible side effects from NovoLog® Mix 50/50. Ask
your healthcare provider or pharmacist for more information.
How should I store NovoLog® Mix 50/50?
Unopened NovoLog® Mix 50/50:
•
Keep all unopened NovoLog® Mix 50/50 in the refrigerator between 36° to
46° F (2° to 8° C). Do not store in the freezer or next to the refrigerator
cooling element. Do not freeze.
•
Keep unopened NovoLog® Mix 50/50 in the carton to protect from light.
After the package has been opened:
•
Do not put NovoLog® Mix 50/50 that you are using in the refrigerator.
Keep at room temperature at or below 86°F (30°C) for up to 14 days.
•
Keep NovoLog® Mix 50/50 away from direct heat or light.
•
Throw away used NovoLog® Mix 50/50 after 14 days of use, even if there
is insulin left in the cartridge or syringe.
General information about NovoLog® Mix 50/50
Medicines are sometimes prescribed for conditions that are not mentioned in the
patient leaflet. Do not use NovoLog® Mix 50/50 for a condition for which it was
not prescribed. Do not give NovoLog® Mix 50/50 to other people, even if they
have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about NovoLog® Mix
50/50. If you would like more information about NovoLog® Mix 50/50 or diabetes,
talk with your healthcare provider. You can ask your healthcare provider or
pharmacist for information about NovoLog® Mix 50/50 which is written for
Reference ID: 3706666
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healthcare professionals. For more information, call 1-800-727-6500 or visit
www.novonordisk-us.com.
Helpful information for people with diabetes is published by the American
Diabetes Association, 1660 Duke Street, Alexandria, VA 22314 and on
www.diabetes.org.
What are the ingredients in NovoLog® Mix 50/50?
•
insulin aspart
•
zinc
•
glycerol
•
disodium hydrogen phosphate
•
phenol
dihydrate
•
metacresol
•
sodium chloride
•
protamine sulfate
•
hydrochloric acid and/or sodium
hydroxide may be added
Date of Issue: February 2015
Version: X
NovoLog®, PenFill®, FlexPen®, NovoPen®, NovoFine®, PenMate®, are registered
trademarks of Novo Nordisk A/S.
NovoLog® Mix 50/50 is covered by US Patent Nos. 5,547,930,
5,618,913, 5,834,422, 5,840,680 and 5,866,538 and other patents pending.
PenFill® is covered by US Patent No. 5,693,027.
FlexPen® is covered by US Patent Nos. 6,235,004, 6,004,297, 6,582,404 and
other patents pending.
© 2015 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NovoLog® Mix 50/50 contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
Reference ID: 3706666
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Instructions for Use
NovoLog® Mix 50/50 FlexPen® Prefilled syringe
How to use the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
Do not share your NovoLog Mix 50/50 Prefilled syringe with other people,
even if the needle has been changed. You may give other people a serious
infection, or get a serious infection from them.
NovoLog® Mix 50/50 FlexPen® Prefilled syringe is a disposable insulin delivery
system. NovoLog® Mix 50/50 FlexPen® Prefilled syringe is to be used with
NovoFine® single use needles.
People who are blind or have severe vision problems should only use the
NovoLog® Mix 50/50 FlexPen® Prefilled syringe with the help of a sighted person
who is trained to use the NovoLog® Mix 50/50 FlexPen® Prefilled syringe the right
way.
Please read these instructions completely before using this device. usage illustration
Figure 1
Diagram of a NovoLog® Mix 50/50 FlexPen® Prefilled syringe
NovoFine® needle usage illustration
Figure 2
Diagram of a NovoFine® needle
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1. PREPARING THE NOVOLOG® MIX 50/50 FLEXPEN® PREFILLED
SYRINGE
Before you start to prepare your injection, check the label to make sure
that you are taking the right type of insulin. NovoLog® Mix 50/50 should look
white and cloudy (after being mixed). This is especially important if you use 2
types of insulin.
• Pull off the pen cap.
• Wipe the rubber stopper with an alcohol swab. usage illustration
• Before using a new NovoLog® Mix 50/50 FlexPen® Prefilled syringe for the
first time, do the following to mix (resuspend) the insulin:
• Hold the NovoLog® Mix 50/50 FlexPen® Prefilled syringe in a
horizontal (flat) position between your palms (see diagram A
above). Roll the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe between your palms 10 times.
• Then, turn the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
up and down. Move the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe between position 1 and 2 so that the glass ball moves
from one end of the insulin cartridge to the other (see diagram B
above). Do this at least 10 times. Repeat the rolling and
turning steps until all of the insulin looks white and cloudy.
Mixing (resuspension) is easier when the insulin is at room
temperature.
• After mixing, continue to do the following steps right away. If
there is a delay, the insulin will need to be mixed again. usage illustration
Reference ID: 3706666
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• Remove the protective tab from the disposable needle and screw the
needle tightly onto the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
(see diagram C above). Do not place a disposable needle on your
NovoLog® Mix 50/50 FlexPen® Prefilled syringe until you are ready to take
your injection. usage illustration
• Pull off the outer and inner needle caps (see diagram D above). Do not
throw away the big outer needle cap.
• Giving the airshot before each injection:
Small amounts of air may collect in the needle and insulin cartridge during
normal use. To avoid injecting air and to make sure you take the right
dose of insulin, do the following:
• Dial 2 units by turning the dose selector so that the arrow
lines up with the “2” in the dosage indicator window (see
diagram E below).
• Hold the NovoLog® Mix 50/50 FlexPen® Prefilled syringe
with the needle pointing up. Tap the insulin cartridge gently
with your finger a few times (see diagram F below). A small
air bubble may remain but it will not be injected. The NovoLog®
Mix 50/50 FlexPen® Prefilled syringe prevents the insulin
cartridge from being completely emptied. usage illustration
Reference ID: 3706666
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usage illustration
• Keep the needle pointing up and press the push button (on the
end of the NovoLog® Mix 50/50 FlexPen® Prefilled syringe) all
the way in (see diagram G below). You should see a drop of
insulin at the needle tip. If you don’t see a drop of insulin,
repeat the procedure (dial 2 units, tap the insulin cartridge and
press the push button) until insulin appears. You may need to
do this up to 6 times. If you don’t see a drop of insulin after 6
times, do not use the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe and contact Novo Nordisk at 1-800-727-6500. usage illustration
Reference ID: 3706666
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2. SETTING THE DOSE usage illustration
• Check and make sure that the dose selector is set at zero (0) (see
diagram H above).
• Dial the number of units you need to inject by turning the dose selector so
the arrow lines up with your dose.
• The dose can be corrected by turning the dose selector in either direction.
When dialing back, be careful not to press the push button. Pressing the
button will cause the insulin to come out. You cannot set a dose larger
than the number of units left in the cartridge. You will hear a click for
every single unit dialed. Do not set the dose by counting the number of
clicks you hear.
3. GIVING THE INJECTION
Do the injection exactly as shown to you by your healthcare provider. usage illustration
• Wipe the injection site with an alcohol swab and let the area dry.
Reference ID: 3706666
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• Pinch a fold of skin between 2 fingers, then push the needle into the
pinched up skin (see diagram I above).
• Give the dose by pressing the push button all the way in (see diagram J
below). Be careful to only press the push button when injecting. usage illustration
• Keep the needle in the skin for at least 6 seconds, and keep the push
button pressed all the way in until the needle has been pulled out from the
skin. This will make sure that the full dose has been given. If blood
appears after you take the needle out of your skin, press the injection site
lightly with a finger. Do not rub the area.
After the injection
• Put your used NovoLog® Mix 50/50 FlexPen® Prefilled syringe and needles
in a FDA-cleared sharps disposal container right away after use. Do not
throw away (dispose of) loose needles and Pens in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use
a household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of your sharps
disposal container. There may be state or local laws about how you should
throw away used needles and syringes. For more information about the
safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
Reference ID: 3706666
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your
used sharps disposal container.
• Put the pen cap back on the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe.
Healthcare providers, relatives, and other caregivers should follow general
precautions for removing and disposing of needles to lessen the possible
chance of needle stick injury.
4. FUTURE INJECTIONS
It is important that you use a new needle for each injection. Do not reuse
or share your needles with other people. You may give other people a serious
infection, or get a serious infection from them. Follow the directions in steps 1, 2,
and 3 above.
Before you inject, there must be at least 12 units of insulin left in the cartridge to
make sure the remaining insulin is evenly mixed. If there are less than 12 units
left, use a new NovoLog® Mix 50/50 FlexPen® Prefilled syringe.
The numbers on the insulin cartridge can be used to estimate the amount of
insulin left in the NovoLog® Mix 50/50 FlexPen® Prefilled syringe. Do not use
these numbers to measure the insulin dose. You cannot set a dose more than
the number of units remaining in the cartridge.
Mix (resuspend) the insulin before each injection:
• Turn the NovoLog® Mix 50/50 FlexPen® Prefilled syringe up and down
between position 1 and 2 so that the glass ball moves from one end of the
insulin cartridge to the other (see diagram B above). Do this at least 10
times. Repeat the procedure until all of the insulin looks white and cloudy.
• Continue to follow the directions as described in steps 1, 2, and 3 above.
If there is a delay in any step, the insulin will need to be mixed
(resuspended) again.
5. FUNCTION CHECK
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usage illustration
If your NovoLog® Mix 50/50 FlexPen® Prefilled syringe is not working the right
way, follow this procedure:
• Screw on a new NovoFine® needle.
• Do an airshot as described in step 1.
• Put the big outer needle cap onto the needle. Do not put on the inner
needle cap.
• Turn the dose selector so that the arrow lines up with the 20 units in the
dose indicator window.
• Hold the NovoLog® Mix 50/50 FlexPen® Prefilled syringe so the needle is
pointing down.
• Press the push button all the way in.
The insulin should fill the lower part of the big outer needle cap (see diagram K
above). If the NovoLog® Mix 50/50 FlexPen® Prefilled syringe has released too
much or too little insulin, do the function check again. If it happens again, do not
use your NovoLog® Mix 50/50 FlexPen® Prefilled syringe and contact Novo
Nordisk at 1-800-727-6500.
6. IMPORTANT NOTES
• If you need to do more than 6 airshots before the first use of each NovoLog®
Mix 50/50 FlexPen® Prefilled syringe to get a drop of insulin at the needle tip,
do not use the NovoLog® Mix 50/50 FlexPen® Prefilled syringe. Contact Novo
Nordisk at 1-800-727-6500.
• Remember to perform an airshot before each injection. See diagrams E and F.
• Do not drop the NovoLog® Mix 50/50 FlexPen® Prefilled syringe.
• Keep the NovoLog® Mix 50/50 FlexPen® Prefilled syringe with you. Do not
leave it in a car or other place where it can get too hot or too cold.
• NovoLog® Mix 50/50 FlexPen® Prefilled syringe should be used with NovoFine®
disposable needles.
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• Do not share your NovoLog® Mix 50/50 FlexPen® Prefilled syringe or needles
with other people. You may give other people a serious infection, or get a
serious infection from them.
• Do not put a disposable needle on the NovoLog® Mix 50/50 FlexPen® Prefilled
syringe until you are ready to use it. Remove the needle right after use. Do not
recap the needle.
• Throw away the used NovoLog® Mix 50/50 FlexPen® Prefilled syringe without
the needle attached.
• Always carry an extra NovoLog® Mix 50/50 FlexPen® Prefilled syringe with
you in case the NovoLog® Mix 50/50 FlexPen® Prefilled syringe is damaged
or lost.
• Keep your NovoLog® Mix 50/50 FlexPen® Prefilled syringe out of the reach of
children. Use NovoLog® Mix 50/50 FlexPen® Prefilled syringe as directed to
treat your diabetes. Do not share it with other people even if he or she also
has diabetes.
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Instructions for Use
NovoLog® Mix 50/50 cartridge
Do not share your NovoLog Mix 50/50 PenFill Cartridge or Penfill cartridge
compatible insulin delivery device with other people, even if the needle has
been changed. You may give other people a serious infection, or get a
serious infection from them.
Before using the NovoLog® Mix 50/50 cartridge
1. Talk with your healthcare provider to find out where to inject NovoLog® Mix
50/50 (injection sites) and how to give an injection with your insulin delivery
device.
2. Read the instruction manual that comes with your insulin delivery device for
complete instructions on how to use the PenFill® cartridge with the device.
How to use the NovoLog® Mix 50/50 cartridge
1. Check your insulin. Just before using your NovoLog® Mix 50/50 cartridge,
check to make sure that you have the right type of insulin. This is especially
important if you use different types of insulin.
2. Carefully look at the cartridge and the insulin inside it. The insulin should
be white and cloudy (after being mixed). The tamper-resistant foil should be in
place before the first use. If the foil has been broken or removed before your
first use of the cartridge, or if the insulin is clear, do not use it. Call Novo
Nordisk at 1-800-727-6500.
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3. Gather your supplies for injecting NovoLog® Mix 50/50. You will need your
NovoLog® Mix 50/50 PenFill® cartridge, your insulin delivery device,
NovoFine® single use needles and an alcohol swab. Be sure to use an
insulin delivery device that is made to work with NovoLog® Mix 50/50 PenFill®
cartridges. These insulin delivery devices can be used with a NovoPen® 3
PenMate® if you would like to hide the needle from view during injection.
4. Wash your hands well with soap and water.
5. Clean your injection site with an alcohol swab and let the injection site dry
before you inject.
6. Before inserting a 3 mL cartridge into your insulin delivery device for the first
time, roll the cartridge between your palms 10 times. These steps should be
done with the 3 mL PenFill® cartridge in a horizontal (flat) position (see
Diagram 1 below). Then turn the PenFill® cartridge up and down between
positions a and b (see Diagram 2 below) so the glass ball moves from one
end of the cartridge to the other. Do this at least 10 times. Repeat the rolling
and turning steps until the insulin looks white and cloudy. Mixing is easier
when the insulin is at room temperature. usage illustration
7. Insert the PenFill® cartridge into the insulin delivery device. Wipe the front
rubber stopper of the 3 mL PenFill® cartridge with an alcohol swab, then
screw on a new needle (see Diagram 3 below).
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usage illustration
For NovoFine® needles, remove the big outer needle cap and the
inner needle cap (see Diagram 4 above). Always use a new needle for each
injection to prevent infection. Do not share your PenFill cartridge or Penfill
cartridge compatible insulin delivery device with other people, even if the
needle has been changed. You may give other people a serious infection, or
get a serious infection from them.
Giving the airshot before each injection:
To prevent the injection of air and make sure insulin is delivered; you must do an
air shot before each injection. Hold the device with the needle pointing up and
gently tap the PenFill® cartridge holder with your finger a few times to raise any
air bubbles to the top of the cartridge (see Diagram 5 below). Do the airshot as
described in the device instruction manual. usage illustration
Giving the injection
8. Dial the number of units you need to inject on the device (see Diagram 6
below). Inject right away as you were shown by your healthcare provider. If
there is a delay between mixing of the insulin and the injection, the insulin will
need to be mixed again.
Reference ID: 3706666
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usage illustration
9. Pinch a fold of skin between 2 fingers, then push the needle into the pinched
up skin (see Diagram 7 below). Inject the dose by pressing the push button
all the way in. Keep the needle in the skin for at least 6 seconds, and keep
the push button pressed all the way in until the needle has been pulled out
from the skin. This will make sure that the full dose has been given. If blood
appears after you take the needle out of your skin, press the injection site
lightly with a finger. Do not rub the area. usage illustration
After the injection
10.Remove the needle from the insulin delivery device after each injection. Keep
the 3 mL PenFill® cartridge in the insulin delivery device. The needle should
not be attached to the insulin delivery device during storage. This will prevent
infection or leakage of insulin, and will help ensure that you receive the right
dose of NovoLog® Mix 50/50.
Reference ID: 3706666
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• Put your used NovoLog Mix 50/50 PenFill Cartridge and needles in a FDA-
cleared sharps disposal container right away after use. Do not throw away
(dispose of) loose needles and Pens in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use
a household container that is:
o made of a heavy-duty plastic
o can be closed with a tight-fitting, puncture-resistant lid, without sharps
being able to come out
o upright and stable during use
o leak-resistant
o properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of your sharps
disposal container. There may be state or local laws about how you should
throw away used needles and syringes. For more information about the
safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website at:
http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your
used sharps disposal container.
11.Put the pen cap back on the insulin delivery device.
After the first use of the 3 mL PenFill® cartridge
1. If the 3 mL PenFill® cartridge is already in the insulin delivery device, turn it
upside down between positions a and b (see Diagram 2 above), so that the
glass ball moves from one end of the 3 mL PenFill® cartridge to the other. Do
this until all of the insulin looks white and cloudy.
2. Before you inject, there must be at least 12 units of insulin left in the cartridge
to make sure the remaining insulin is evenly mixed. If there are less than 12
units left, use a new 3 mL PenFill® cartridge.
3. An airshot should be done before each injection. Do the airshot as described
in the device instruction manual.
4. Do not remove the 3 mL cartridge from the insulin delivery device.
5. Put the pen cap back on the insulin delivery device.
IMPORTANT NOTES
Reference ID: 3706666
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• Do not use if you need to do more than 6 airshots before the first use of each
NovoLog® Mix 50/50 cartridge to get a drop of insulin at the needle tip. Contact
Novo Nordisk at 1-800-727-6500.
• Remember to do an airshot before each injection. See the device instruction
manual.
• Do not drop the NovoLog® Mix 50/50 cartridge and insulin delivery device.
• Keep the NovoLog® Mix 50/50 cartridge and insulin delivery device with you.
Do not leave it in a car or other places where it can get too hot or too cold.
• NovoLog® Mix 50/50 cartridges are designed for use with NovoFine®
disposable needles.
• Do not share your NovoLog® Mix 50/50 cartridges or needles with other
people. You may give other people a serious infection, or get a serious infection
from them.
• Do not put a disposable needle on the NovoLog® Mix 50/50 cartridge and
insulin delivery device until you are ready to use it. Remove the needle right
after use. Do not recap the needle.
• Throw away the used NovoLog® Mix 50/50 cartridges without the needle
attached.
• Always carry an extra NovoLog® Mix 50/50 cartridge with you in case the
NovoLog® Mix 50/50 cartridge is damaged or lost. Always keep the
NovoLog® Mix 50/50 cartridge in the outer carton when you are not using it in
order to protect it from light.
• Keep your NovoLog® Mix 50/50 cartridge out of the reach of children. Use
NovoLog® Mix 50/50 cartridges as directed to treat your diabetes. Do not
share it with other people even if he or she also has diabetes.
Reference ID: 3706666
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:32.704696 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021810s010lbl.pdf', 'application_number': 21810, 'submission_type': 'SUPPL ', 'submission_number': 10} |
6,279 | HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
INCRELEX® safely and effectively. See full prescribing information for
INCRELEX®.
INCRELEX® (mecasermin [rDNA origin] injection), for subcutaneous use
Initial U.S. Approval: 2005
----------------------------INDICATIONS AND USAGE---------------------------
INCRELEX® (mecasermin [rDNA origin] injection) is indicated for the
treatment of growth failure in children with severe primary IGF-1 deficiency
or with growth hormone (GH) gene deletion who have developed neutralizing
antibodies to GH. (1.1)
Limitations of use: INCRELEX® is not a substitute to GH for approved GH
indications.
----------------------DOSAGE AND ADMINISTRATION-----------------------
INCRELEX® should be administered subcutaneously. (2.2)
Injection sites should be rotated to avoid lipohypertrophy. (2.2)
Recommended starting dose: 0.04 to 0.08 mg/kg (40 to 80
micrograms/kg) twice daily. If well-tolerated for at least one week, the
dose may be increased by 0.04 mg/kg per dose, to the maximum dose of
0.12 mg/kg given twice daily. (2.1)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
INCRELEX® is a sterile solution supplied in a multiple dose glass vial at
a concentration of 10 mg per mL (40 mg per vial). (3)
-------------------------------CONTRAINDICATIONS------------------------------
Active or Suspected Neoplasia (4)
Known Hypersensitivity to mecasermin (4)
Intravenous Administration (4)
Closed Epiphyses (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
Hypoglycemia: INCRELEX® should be administered shortly before or
after a meal or snack, because it has insulin-like hypoglycemic effects.
(5.1)
Hypersensitivity and Allergic Reactions, including Anaphylaxis: A low
number of cases indicative of anaphylaxis requiring hospitalization have
been reported. Parents and patients should be informed that such
reactions are possible and that if a systemic allergic reaction occurs,
treatment should be interrupted and prompt medical attention should be
sought. (5.2)
Intracranial Hypertension: Funduscopic examination is recommended at
the initiation and periodically during the course of INCRELEX® therapy.
(5.3)
Lymphoid Tissue Hypertrophy (tonsillar/adenoidal hypertrophy):
Patients should have periodic examinations to rule out potential
complications and receive appropriate treatment if necessary. (5.4)
Slipped Capital Femoral Epiphysis (SCFE): Evaluate any child with
onset of a limp or hip/knee pain for possible SCFE. (5.5)
Progression of Scoliosis: Monitor any child with scoliosis for
progression of the spine curve. (5.6)
------------------------------ADVERSE REACTIONS-------------------------------
Common INCRELEX®-related adverse reactions in clinical trials include:
hypoglycemia (5.1, 6.1), local and systemic hypersensitivity (5.2, 6.1, 6.3),
tonsillar hypertrophy (5.4, 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen
Biopharmaceuticals, Inc. at 1-866-837-2422 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Pregnancy: Based on animal data, INCRELEX® may cause fetal harm.
(8.1)
Pediatric Use: Safety and effectiveness has not been established in
children less than 2 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: March 2016
_____________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Severe Primary IGF-1 Deficiency (Primary IGFD)
2
DOSAGE AND ADMINISTRATION
2.1 Dosage
2.2 Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hypoglycemia
5.2 Hypersensitivity and Allergic Reactions, including Anaphylaxis
5.3 Intracranial Hypertension
5.4 Lymphoid Tissue Hypertrophy
5.5 Slipped Capital Femoral Epiphysis
5.6 Progression of Preexisting Scoliosis
5.7 Benzyl Alcohol
6
ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Immunogenicity
6.3 Post-Marketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Effects of INCRELEX® Treatment of Children with Severe
Primary Insulin-like Growth Factor-1 Deficiency
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Severe Primary IGF-1 Deficiency (Primary IGFD)
INCRELEX® (mecasermin [rDNA origin] injection) is indicated for the treatment of:
growth failure in children with severe primary IGF-1 deficiency.
growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.
Severe Primary IGF-1 deficiency (IGFD) is defined by:
height standard deviation score –3.0 and
basal IGF-1 standard deviation score –3.0 and
normal or elevated growth hormone (GH).
Severe Primary IGFD includes classical and other forms of growth hormone insensitivity.
Patients with Primary IGFD may have mutations in the GH receptor (GHR), post-GHR signaling
pathway including the IGF-1 gene. They are not GH deficient, and therefore, they cannot be
expected to respond adequately to exogenous GH treatment.
INCRELEX® is not intended for use in subjects with secondary forms of IGF-1 deficiency, such
as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses
of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before
initiating INCRELEX® treatment.
Limitations of use: INCRELEX® is not a substitute to GH for approved GH indications.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated
dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur,
preprandial glucose monitoring should continue. The dosage of INCRELEX® should be
individualized for each patient. The recommended starting dose of INCRELEX® is 0.04 to
0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. If well-tolerated for
at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of
0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been
evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not
be used. If hypoglycemia occurs with recommended doses despite adequate food intake, the
dose should be reduced. INCRELEX® should be administered shortly before or after
(± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for
any reason, that dose of INCRELEX® should be withheld. Subsequent doses of INCRELEX®
should never be increased to make up for one or more omitted doses.
Treatment with INCRELEX should be supervised by a physician who is experienced in the
diagnosis and management of pediatric patients with short stature associated with severe primary
IGF-1 deficiency or with growth hormone gene deletion and who have developed neutralizing
antibodies to growth hormone.
2.2 Administration
INCRELEX® is administered by subcutaneous injection.
INCRELEX® injection sites should be rotated to a different site (upper arm, thigh, buttock or
abdomen) with each injection to help prevent lipohypertrophy.
INCRELEX® should be administered using sterile disposable syringes and needles. The syringes
should be of small enough volume so that the prescribed dose can be withdrawn from the vial
with accuracy.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
If using syringes that measure dose in units, doses in mg/kg must be converted to units using the
following formula: Weight (kg) x Dose (mg/kg) x 1 mL/10 mg x 100 units/1 mL =
units/injection.
3 DOSAGE FORMS AND STRENGTHS
INCRELEX® is a sterile solution available at a concentration of 10 mg per mL (40 mg per vial).
4 CONTRAINDICATIONS
Active or Suspected Neoplasia
INCRELEX® is contraindicated in the presence of active or suspected malignancy, and therapy
should be discontinued if evidence of malignancy develops.
Known Hypersensitivity
INCRELEX® should not be used by patients who are allergic to mecasermin (rhIGF-1) or any of
the inactive ingredients in INCRELEX®, or who have experienced a severe hypersensitivity to
INCRELEX® [see Warnings and Precautions (5.2) and Adverse Reactions (6.3)]
Intravenous Administration
Intravenous administration of INCRELEX® is contraindicated.
Closed Epiphyses
INCRELEX® should not be used for growth promotion in patients with closed epiphyses.
5 WARNINGS AND PRECAUTIONS
5.1 Hypoglycemia
Reference ID: 3902304
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Because INCRELEX® has insulin-like hypoglycemic effects it should be administered shortly
before or after (± 20 minutes) a meal or snack. Glucose monitoring and INCRELEX® dose
titration are recommended until a well tolerated dose is established [see Dosage and
Administration (2.1)] and subsequently as medically indicated. Special attention should be paid
to small children because their oral intake may not be consistent. Patients should avoid engaging
in any high-risk activities (e.g., driving, etc.) within 2 to 3 hours after dosing, particularly during
the initiation of INCRELEX® treatment until tolerability and a stable dose have been established
[see Adverse Reactions (6.1)]. INCRELEX® should not be administered when the meal or
snack is omitted. The dose of INCRELEX® should never be increased to make up for one or
more omitted doses.
5.2 Hypersensitivity and Allergic Reactions, including Anaphylaxis
Allergic reactions to INCRELEX® have been reported post-marketing. They range from
localized (injection site) reactions to systemic reactions, including anaphylaxis requiring
hospitalization. Parents and patients should be informed that such reactions are possible and that
if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical
attention should be sought. [see Contraindications (4) and Adverse Reactions (6.3)]
5.3 Intracranial Hypertension
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or
vomiting have occurred in patients treated with INCRELEX®. IH-associated signs and
symptoms resolved after interruption of dosing. Funduscopic examination is recommended at
the initiation and periodically during the course of INCRELEX® therapy. [see Adverse Reactions
(6.3)]
5.4 Lymphoid Tissue Hypertrophy
Lymphoid tissue (e.g., tonsillar and adenoidal) hypertrophy associated with complications, such
as snoring, sleep apnea, and chronic middle-ear effusions have been reported with the use of
INCRELEX®. Patients should have periodic examinations to rule out such potential
complications and receive appropriate treatment if necessary. [see Adverse Reactions (6.3)]
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.5 Slipped Capital Femoral Epiphysis
Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Any
pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX®
therapy should be carefully evaluated.
5.6 Progression of Preexisting Scoliosis
Progression of scoliosis may occur in patients who experience rapid growth. Because
INCRELEX® increases growth rate, patients with a history of scoliosis who are treated with
INCRELEX® should be monitored for progression of scoliosis.
5.7 Benzyl Alcohol
Benzyl alcohol, a component of this product, has been associated with serious adverse
events and death, particularly in pediatric patients. The “gasping syndrome,”
(characterized by central nervous system depression, metabolic acidosis, gasping
respirations, and high levels of benzyl alcohol and its metabolites found in the blood and
urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and
low-birth weight neonates. Additional symptoms may include gradual neurological
deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin
breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular
collapse. Practitioners administering this and other medications containing benzyl
alcohol should consider the combined daily metabolic load of benzyl alcohol from all
sources.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the
labeling:
Hypoglycemia [see Warnings and Precautions (5.1)]
Hypersensitivity and Allergic Reactions, including Anaphylaxis [see
Contraindications (4), Warnings and Precautions (5.2)]
Intracranial hypertension (IH) [see Warnings and Precautions (5.3)]
Tonsillar and Adenoidal Hypertrophy and related complications [see Warnings
and Precautions (5.4)]
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and
representing 274 subject-years, no subjects withdrew from any clinical study because of adverse
reactions. Adverse reactions to INCRELEX® treatment that occurred in 5% or more of these
study participants are listed below by organ class.
Metabolism and Nutrition Disorders: hypoglycemia
General Disorders and Administrative Site Conditions: lipohypertrophy, bruising
Infections and Infestations: otitis media, serous otitis media
Respiratory, Thoracic and Mediastinal Disorders: snoring, tonsillar hypertrophy
Nervous System Disorders: headache, dizziness, convulsions
Gastrointestinal Disorders: vomiting
Ear and Labyrinth Disorders: hypoacusis, fluid in middle ear, ear pain, abnormal
tympanometry
Cardiac Disorders: cardiac murmur
Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity
Blood and Lymphatic System Disorders: thymus hypertrophy
Surgical and Medical Procedures: ear tube insertion
Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy.
Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe
hypoglycemia (requiring assistance and treatment) on one or more occasions and 4 subjects
experienced hypoglycemic seizures/loss of consciousness on one or more occasions. Of the
30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment.
The frequency of hypoglycemia was highest in the first month of treatment, and episodes were
more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a
meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of
INCRELEX®.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with
lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was
performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the
procedure in all three cases.
Intracranial hypertension occurred in three subjects. In two subjects the events resolved without
interruption of INCRELEX® treatment. INCRELEX® treatment was discontinued in the third
subject and resumed later at a lower dose without recurrence.
Mild elevations in the serum AST and LDH were found in a significant proportion of patients
before and during treatment. Rise in levels of these serum enzymes did not lead to treatment
discontinuation. ALT elevations were occasionally noted during treatment.
Renal and splenic lengths (measured by ultrasound) increased rapidly on INCRELEX® treatment
during the first years of therapy. This lengthening slowed down subsequently; though in some
patients, renal and/or splenic length reached or surpassed the 95th percentile. Renal function (as
defined by serum creatinine and calculated creatinine clearance) was normal in all patients,
irrespective of renal growth.
Elevations in cholesterol and triglycerides to above the upper limit of normal were observed
before and during treatment.
Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals
without associated clinical symptoms. The relation of these cardiac changes to drug treatment
cannot be assessed due to underlying disease and the lack of a control group.
Thickening of the soft tissues of the face was observed in several patients and should be
monitored during INCRELEX® treatment.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of antibody (including neutralizing antibody) positivity in an assay may be
influenced by several factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons, comparison of
the incidence of antibodies to INCRELEX® with the incidence of antibodies to other products
may be misleading.
Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23
children with Primary IGFD treated for 2 years. However, no clinical consequences of these
antibodies were observed (e.g., attenuation of growth).
6.3 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of INCRELEX®.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Systemic hypersensitivity: anaphylaxis, generalized urticaria, angioedema, dyspnea
In the post-marketing setting, the frequency of cases indicative of anaphylaxis was
estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea, and some
patients required hospitalization. Upon re-administration, symptoms did not re-occur in
all patients.
Local allergic reactions at the injection site: pruritus, urticaria
Skin and Subcutaneous Tissue Disorders: alopecia, hair texture abnormal
General Disorders and Administrative Site Conditions: injection site reactions (e.g. erythema,
pain, haematoma, haemorrhage, induration, rash, swelling)
Reference ID: 3902304
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Musculoskeletal and Connective Tissue Disorders: osteonecrosis/avascular necrosis
(occasionally associated with slipped capital femoral epiphysis)
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C. Studies to assess embryo-fetal toxicity evaluated the effects of
INCRELEX® during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day
and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered
intravenously. There were no observed embryo-fetal developmental abnormalities in rats
given up to 16 mg/kg/day (20 times the maximum recommended human dose [MRHD]
based on body surface area [BSA] comparison). In the rabbit study, the NOAEL for fetal
toxicity was 0.5 mg/kg (2 times the MRHD based on BSA) due to an increase in fetal
death at 2 mg/kg. INCRELEX® displayed no teratogenicity or maternal toxicity in
rabbits given up to 2 mg/kg (8 times the MRHD based on BSA).
The effects of INCRELEX® on an unborn child have not been studied. Therefore, there is
insufficient medical information to determine whether there are significant risks to a fetus.
8.3 Nursing Mothers
Excretion of INCRELEX® in human milk has not been studied. Caution should be exercised
when INCRELEX® is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years of age have not been
established.
8.5 Geriatric Use
The safety and effectiveness of INCRELEX® in patients aged 65 and over has not been
established.
8.6 Renal Impairment
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
No Studies have been conducted in Primary IGFD children or adult subjects with renal
impairment [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No studies have been conducted in Primary IGFD children or adult subjects with hepatic
impairment [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
Treatment of acute overdose should be directed at reversing hypoglycemia. Oral glucose or food
should be consumed. If the overdose results in loss of consciousness, intravenous glucose or
parenteral glucagon may be required to reverse the hypoglycemic effects.
A small number of overdose cases have been reported in the post-marketing experience. In one
case of acute overdose, a 3-year old patient experienced hypoglycemia after receiving one 4 mg
dose of INCRELEX® (a 10-fold increase beyond the prescribed dose). The event resolved
following treatment with IV glucose.
Long term overdosage with INCRELEX® may result in signs and symptoms of acromegaly.
11 DESCRIPTION
INCRELEX® (mecasermin [rDNA origin] injection) contains human insulin-like growth factor-1
(rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a
single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons.
The amino acid sequence of the product is identical to that of endogenous human IGF-1. The
rhIGF-1 protein is synthesized in bacteria (E. coli) that have been modified by the addition of the
gene for human IGF-1.
INCRELEX® is a sterile, aqueous, clear and colorless solution intended for subcutaneous
injection. Each multi-dose vial of INCRELEX® contains 10 mg per mL mecasermin, 9 mg per
mL benzyl alcohol, 5.84 mg per mL sodium chloride, 2 mg per mL polysorbate 20, and 0.05M
acetate at a pH of approximately 5.4.
Reference ID: 3902304
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under
normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues,
and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor,
which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular
signaling which stimulates multiple processes resulting in statural growth. The metabolic actions
of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so
that metabolism supports growing tissues.
12.2 Pharmacodynamics
The following actions have been demonstrated for endogenous human IGF-1:
Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of
bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of
chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that
new bone is formed allowing the length of the bones to increase. This results in skeletal growth
until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are
present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an
increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with
rhIGF-1 results in whole body and organ growth.
Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates
peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory
effects on insulin secretion.
12.3 Pharmacokinetics
Absorption – The absolute bioavailability of rhIGF-1 after subcutaneous administration in
healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of
INCRELEX® given subcutaneously to subjects with primary insulin-like growth factor-1
deficiency (Primary IGFD) has not been determined.
Reference ID: 3902304
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Distribution – In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a
complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is greatly reduced in subjects with
severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to
healthy subjects. The total IGF-1 volume of distribution after subcutaneous administration in
subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) L/kg at an INCRELEX®
dose of 0.045 mg/kg, and is estimated to increase as the dose of INCRELEX® increases.
Elimination – IGF-1 is metabolized by both liver and kidney. The mean terminal t1/2 after single
subcutaneous administration of 0.12 mg/kg INCRELEX® in pediatric subjects with severe
Primary IGFD is estimated to be 5.8 hours. Clearance of INCRELEX® is inversely proportional
to IGF binding protein-3 (IGFBP-3) levels. CL/F is estimated to be 0.04 L/hr/kg at 0.5
micrograms/mL of IGFBP-3, and 0.01 L/hr/kg at 3 micrograms/mL IGFBP-3; the latter is the
median IGFBP-3 in subjects with normal IGF-1 serum levels.
Gender – In children with Primary IGFD there were no apparent differences between males and
females in the pharmacokinetics of INCRELEX®.
Race –The effect of race on pharmacokinetics of INCRELEX® has not been studied.
Summary of INCRELEX® Single-Dose Pharmacokinetic
Parameters in Children with Severe Primary IGFD
(0.12 mg/kg, SC)
Cmax
(ng/mL)
Tmax
(hr)
AUC0-8
(hr*ng/mL)
t1/2
(hr)
Vd/F
(L/kg)
CL/F
(L/hr/kg)
n
3
3
3
3
12a
12a
Mean
234
2
2932
5.8
0.257
0.0424
CV%
23
0
50
64
28
38
Cmax = maximum concentration; Tmax = time of maximum
concentration; AUC0-8 = area under the curve; t1/2 = half-life;
Vd/F = apparent volume of distribution; CL/F = apparent
systemic clearance; SC = subcutaneous injection;
CV% = coefficient of variation in %.
Male/female data combined, ages 12 to 22 years.
a Data represents 3 subjects each at doses 0.015, 0.03, 0.06, and
0.12 mg/kg SC.
PK parameters based on baseline adjusted plasma
concentrations.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Mean Total IGF-1 Concentration after a Single Subcutaneous Dose of INCRELEX® in
Children with Severe Primary IGFD (0.06 mg/kg and 0.12 mg/kg, n = 3 per group)
Renal impairment– No studies have been conducted in Primary IGFD children with renal
impairment.
Hepatic impairment– No studies have been conducted to determine the effect of hepatic
impairment on the pharmacokinetics of rhIGF-1 in Primary IGFD children with hepatic
impairment.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: INCRELEX® was tumorigenic in rats in a study using doses of 0, 0.25,
1, 4, and 10 mg/kg/day by subcutaneous injection for up to 2 years. The incidence of
adrenal medullary hyperplasia and pheochromocytoma increased in male rats given ≥1
Reference ID: 3902304
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mg/kg/day (≥ 1 times the clinical exposure with the maximum recommended human dose
[MRHD] based on AUC) and in female rats at all dose levels (≥ 30% of the clinical
exposure with the MRHD based on AUC). The incidence of keratoacanthoma in the skin
increased in male rats given 4 and 10 mg/kg/day (≥ 4 times the MRHD). The incidence of
mammary gland carcinoma in male rats increased in animals treated with 10 mg/kg/day
(7 times the MRHD based on AUC). Only doses that exceeded the maximum tolerated
dose (MTD) (based on excess mortality secondary to IGF-1 induced hypoglycemia)
caused skin and mammary tumors.
Mutagenesis: INCRELEX® was not clastogenic in the in vitro chromosome aberration
assay and the in vivo mouse micronucleus assay.
Impairment of fertility: INCRELEX® had no effects on fertility in rats using intravenous
doses 0.25, 1, and 4 mg/day (up to 4 times the clinical exposure with the MRHD based on
AUC.)
14 CLINICAL STUDIES
14.1 Effects of INCRELEX® Treatment in Children with Severe Primary Insulin-like
Growth Factor-1 Deficiency (Primary IGFD)
Five clinical studies (four open-label and one double-blind, placebo-controlled), with
subcutaneous doses of INCRELEX® generally ranging from 0.06 to 0.12 mg/kg (60 to
120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with
severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature,
slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data
from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline
characteristics for the patients evaluated in the primary and secondary efficacy analyses were
(mean, SD): chronological age (years): 6.7 3.8; height (cm): 84.8 15.3 cm; height standard
deviation score (SDS): -6.7 1.8; height velocity (cm/yr): 2.8 1.8; height velocity SDS: -3.3
1.7; IGF-1 (ng/mL): 21.6 20.6; IGF-1 SDS: -4.3 1.6; and bone age (years): 4.2 2.8. Sixty-
one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%)
had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the
Reference ID: 3902304
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subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-
pubertal at baseline.
Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 1.
Pre-treatment height velocity data were available for 58 subjects. The height velocities at a
given year of treatment were compared by paired t-tests to the pre-treatment height velocities of
the same subjects completing that treatment year.
Table 1: Annual Height Results by Number of Years Treated with INCRELEX®
Pre-Tx
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Height Velocity
(cm/yr)
N
58
58
48
38
23
21
20
16
13
Mean (SD)
2.8 (1.8) 8.0 (2.2) 5.8 (1.5) 5.5 (1.8) 4.7 (1.6) 4.7 (1.6) 4.8 (1.5) 4.6 (1.5) 4.3 (1.1)
Mean (SD) for
change from pre-
treatment
+5.2
(2.6)
+2.9
(2.4)
+2.3
(2.4)
+1.5
(2.2)
+1.5
(1.8)
+1.5
(1.7)
+1.0
(2.1)
+0.7
(2.5)
P-value for change
from pre-treatment
[1]
<0.0001 <0.0001 <0.0001 0.0045
0.0015
0.0009
0.0897
0.3059
Height Velocity SDS
N
58
58
47
37
22
19
18
15
11
Mean (SD)
-3.3 (1.7) 1.9 (3.0)
-0.2
(1.6)
-0.2
(2.0)
-0.7
(2.1)
-0.6
(2.1)
-0.4
(1.4)
-0.4
(1.9)
-0.4
(1.9)
Mean (SD) for
change from pre-
treatment
+5.2
(3.1)
+3.1
(2.3)
+2.9
(2.3)
+2.2
(2.2)
+2.5
(2.2)
+2.7
(1.7)
+2.5
(2.1)
+2.7
(2.8)
Height SDS
N
61
61
51
40
24
21
20
16
13
Mean (SD)
-6.7 (1.8)
-5.9
(1.8)
-5.6
(1.8)
-5.4
(1.8)
-5.5
(1.9)
-5.6
(1.8)
-5.4
(1.8)
-5.2
(2.0)
-5.2
(2.0)
Mean (SD) for
change from pre-
treatment
+0.8
(0.5)
+1.2
(0.8)
+1.4
(1.1)
+1.3
(1.2)
+1.4
(1.3)
+1.4
(1.2)
+1.4
(1.1)
+1.5
(1.1)
Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score
[1] P-values for comparison versus pre-treatment values are computed using paired t-
tests.
Forty-nine subjects were included in an analysis of the effects of INCRELEX® on bone age
advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean
± SD change in bone age was 5.3 ± 3.4 years.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
NDC-15054-1040-5 INCRELEX® is supplied as a 10 mg per mL sterile solution in multiple
dose glass vials (40 mg per vial).
Before Opening – Vials of INCRELEX® are stable when refrigerated [2º to 8ºC (35º to 46ºF)].
Avoid freezing the vials of INCRELEX®. Protect from direct light. Expiration dates are stated
on the labels.
After Opening – Vials of INCRELEX® are stable for 30 days after initial vial entry when stored
at 2º to 8ºC (35º to 46ºF). Avoid freezing the vials of INCRELEX®. Protect from direct light.
Vial contents should be clear without particulate matter. If the solution is cloudy or contains
particulate matter, the contents must not be injected. INCRELEX® should not be used after its
expiration date. Keep refrigerated and use within 30 days of initial vial entry. Remaining
unused material should be discarded.
17 PATIENT COUNSELING INFORMATION
Patients and/or their parents should be instructed in the proper administration of INCRELEX®.
INCRELEX® should be given shortly before or after (20 minutes on either side of) a meal or
snack. INCRELEX® should not be administered when the meal or snack is omitted. The
dose of INCRELEX® should never be increased to make up for one or more omitted doses.
INCRELEX® therapy should be initiated at a low dose and the dose should be increased only if
no hypoglycemia episodes have occurred after at least 7 days of dosing. If severe hypoglycemia
or persistent hypoglycemia occurs on treatment despite adequate food intake, INCRELEX® dose
reduction should be considered. Providers should educate patients and caregivers on how to
recognize the signs and symptoms of hypoglycemia.
Providers should educate patients and caregivers on the identification of signs and symptoms of
serious allergic reactions to INCRELEX® and the need to seek prompt medical contact should
such a reaction occur. They should be informed that if an allergic reaction occurs, INCRELEX
treatment should be discontinued.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients and/or parents should be thoroughly instructed in the importance of proper needle
disposal. A puncture-resistant container should be used for the disposal of used needles and/or
syringes (consistent with applicable state requirements). Needles and syringes must not be
reused.
Manufactured for:
Ipsen Biopharmaceuticals, Inc.
Basking Ridge, NJ 07920 USA
by:
Hospira, Incorporated
McPherson, KS 67460 USA
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
INCRELEX® (EENK-RUH-LEX)
(MECASERMIN [RDNA ORIGIN] INJECTION)
Read the Patient Information that comes with INCRELEX® before your child starts
taking INCRELEX® and each time you get a refill. There may be new information. This
leaflet does not take the place of talking with your child’s doctor about your child’s
condition or treatment.
What is INCRELEX®?
INCRELEX® is a liquid that contains man-made insulin-like growth factor-1 (IGF-1),
which is the same as the IGF-1 made by your body. INCRELEX® is used to treat
children who are very short for their age because their bodies do not make enough IGF-1.
This condition is called primary IGF-1 deficiency. IGF-1 should not be used instead of
growth hormone.
INCRELEX® has not been studied in children under 2 years of age.
Who Should Not Use INCRELEX®?
Your child should not take INCRELEX® if your child:
Has finished growing (the bone growth plates are closed)
Has cancer
Has other causes of growth failure
Is allergic to mecasermin or any of the inactive ingredients in INCRELEX®.
Check with your child’s doctor if you are not sure.
Your child should never receive INCRELEX® through a vein.
What should I tell my child’s doctor before my child starts INCRELEX®?
Tell your child’s doctor about all of your child’s health conditions, including if your
child:
Has diabetes
Reference ID: 3902304
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Has kidney problems
Has liver problems
Has a curved spine (scoliosis)
Is pregnant or breast-feeding.
Tell your child’s doctor about all the medicines your child takes, including
prescription and nonprescription medicines, vitamins, and herbal supplements.
Especially tell your child’s doctor if your child takes insulin or other anti-diabetes
medicines. A dose adjustment may be needed for these medicines.
How Should My Child Use INCRELEX®?
Use INCRELEX® exactly as prescribed for your child. Your doctor or nurse
should teach you how to inject INCRELEX®. Do not give your child
INCRELEX® unless you understand all of the instructions. See the “Instructions
for Use” at the end of this leaflet.
Inject INCRELEX® under your child’s skin shortly (20 minutes) before or after a
meal or snack. Skip your child’s dose of INCRELEX® if your child cannot eat
for any reason. Do not make up the missed dose by giving two doses the next
time.
Inject INCRELEX® just below the skin in your child’s upper arm, upper leg
(thigh), stomach area (abdomen), or buttocks. Never inject it into a vein or
muscle. Change the injection site for each injection (“rotate the injection site”).
Only use INCRELEX® that is clear and colorless. If your child’s INCRELEX® is
cloudy or slightly colored, return it for a replacement.
What are the Possible Side Effects of INCRELEX®?
INCRELEX® may cause the following side effects, which can be serious:
Low blood sugar (hypoglycemia). INCRELEX® may lower blood sugar levels like
insulin. It is important to only give your child INCRELEX® right before or right
after (20 minutes on either side of) a snack or meal to reduce the chances of low
Reference ID: 3902304
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blood sugar. Do not give your child INCRELEX® if your child is sick or cannot eat.
Signs of low blood sugar are:
o Dizziness
o Tiredness
o Restlessness
o Hunger
o Irritability
o Trouble concentrating
o Sweating
o Nausea
o Fast or irregular heartbeat
Severe hypoglycemia may cause unconsciousness, seizures, or death. If you take
INCRELEX®, you should avoid participating in high risk activities (such as driving)
within 2 to 3 hours after INCRELEX® injection, especially at the beginning of
INCRELEX® treatment.
Before beginning treatment with INCRELEX® your doctor or nurse will explain to
you how to treat hypoglycemia. You/your child should always have a source of
sugar such as orange juice, glucose gel, candy, or milk available in case symptoms
of hypoglycemia occur. For severe hypoglycemia, if your child is not responsive
and cannot drink sugar-containing fluids, you should give an injection of glucagon.
Your doctor or nurse will instruct you how to give the injection.
Glucagon raises the blood sugar when it is injected. It is important that your child
have a well-balanced diet including protein and fat such as meat and cheese in
addition to sugar-containing foods.
Enlarged tonsils. INCRELEX® may enlarge your child’s tonsils. Some signs of
enlarged tonsils include: snoring, difficulty breathing or swallowing, sleep apnea (a
condition where breathing stops briefly during sleep), or fluid in the middle-ear.
Sleep apnea can cause excessive daytime sleepiness. Call your doctor should these
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
symptoms bother your child. Your doctor should do regular exams to check your
child’s tonsils.
Increased pressure in the brain (intracranial hypertension). INCRELEX®, like
growth hormone, can sometimes cause a temporary increase in pressure within the
brain. The symptoms of intracranial hypertension can include headache and nausea
with vomiting. Tell your doctor if your child has headache with vomiting. Your
doctor can then check to see if intracranial hypertension is present. If it is present,
your doctor may decide to temporarily reduce or discontinue INCRELEX® therapy.
INCRELEX® therapy may be started again after the episode is over.
A bone problem called slipped capital femoral epiphysis. This happens when the
top of the upper leg (femur) slips apart. Get medical attention for your child right
away if your child develops a limp or has hip or knee pain.
Worsened scoliosis (caused by rapid growth). If your child has scoliosis, your child
will need to be checked often for an increase in the curve of the spine.
Allergic reactions. Your child may have a mild or serious allergic reaction with
INCRELEX®. Call your child’s doctor right away if your child gets a rash or hives.
Hives, also known as urticaria, appear as a raised, itchy skin reaction. Hives appear
pale in the middle with a red rim around it. Hives generally appear minutes to hours
after the injection and may sometimes occur at numerous places on the skin. Get
medical help immediately if your child has trouble breathing or goes into shock, with
symptoms like dizziness, pale, clammy skin and/or passing out.
INCRELEX® can cause reactions at the injection site including:
Loss of fat (lipoatrophy)
Increase of fat (lipohypertrophy)
Pain, redness, or bruising
Reference ID: 3902304
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Injection site reactions can be avoided by changing the injection site at each injection
(“injection site rotation”).
Call your child’s doctor if your child has side effects that are bothersome or that do not
go away.
These are not all the side effects of INCRELEX®. Ask your child’s doctor or pharmacist
for more information.
How Should I Store INCRELEX®?
Before Opening – Store new unopened vials of INCRELEX® in the refrigerator
(not the freezer) between 35º to 46ºF (2º to 8ºC). Do not freeze INCRELEX®.
Keep INCRELEX® out of direct heat and bright light. If a vial freezes, throw it
away.
After Opening – Once a vial of INCRELEX® is opened, you can keep it in the
refrigerator between 35º to 46ºF (2º to 8ºC) for 30 days after you start using the
vial. Do not freeze INCRELEX®. Keep INCRELEX® out of direct heat and
bright light. If a vial freezes, throw it away.
Keep INCRELEX® and all medicines out of reach of children.
General Information About INCRELEX®
Medicines are sometimes prescribed for conditions other than those described in patient
information leaflets. Do not give INCRELEX® to your child for a condition for which it
was not prescribed. Do not give INCRELEX® to a person other than your child. It may
be harmful.
This leaflet summarizes the most important information about INCRELEX®. If you
would like more information, talk to your child’s doctor. You can also ask your child’s
doctor or pharmacist for information that is written for health professionals.
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
More information is available at 1-866-837-2422.
What are the Ingredients in INCRELEX®?
Active ingredient: mecasermin
Inactive ingredients: sodium chloride, polysorbate 20, benzyl alcohol, and acetate.
Reference ID: 3902304
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For current labeling information, please visit https://www.fda.gov/drugsatfda
INSTRUCTIONS FOR USE
INCRELEX® should be administered using sterile disposable syringes and needles. The
syringes should be of small enough volume that the prescribed dose can be withdrawn
from the vial with reasonable accuracy.
Preparing the Dose:
1. Wash your hands before getting INCRELEX® ready for your child’s injection.
2. Use a new disposable needle and syringe every time you give a dose. Use syringes
and needles only once. Throw them away properly. Never share needles and
syringes.
3. Check the liquid to make sure it is clear and colorless. Do not use after the expiration
date or if it is cloudy or if you see particles.
4. If you are using a new vial, remove the protective cap. Do not remove the rubber
stopper.
5. Wipe the rubber stopper of the vial with an alcohol swab to prevent contamination of
the vial by germs that may be introduced by repeated needle insertions (see Figure 1).
Figure 1: Wipe top
with alcohol
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Before putting the needle into the vial, pull back on plunger to draw air into the
syringe equal to the INCRELEX® dose. Put the needle through the rubber top of the
vial and push the plunger to inject air into the vial (see Figure 2).
7. Leave the syringe in the vial and turn both upside down. Hold the syringe and vial
firmly (see Figure 3).
Figure 2: Inject
air into vial
Figure 3: Prepare for
extraction
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8. Make sure the tip of the needle is in the liquid (see Figure 4). Pull the plunger to
withdraw the correct dose into the syringe (see Figure 5).
9. Before you take the needle out of the vial, check the syringe for air bubbles. If
bubbles are in the syringe, hold the vial and syringe with needle straight up and tap the
side of the syringe until the bubbles float to the top. Push the bubbles out with the
plunger and draw liquid back in until you have the correct dose (see Figure 6).
10. Remove the needle from the vial. Do not let the needle touch
anything. You are now ready to inject (see figure 7).
Figure 4: Tip in
liquid
Figure 6: Remove air bubbles
and refill syringe
Figure 5: Extract
Correct Dose
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Injecting the Dose:
Inject INCRELEX® as instructed by your child’s doctor.
Do not give the INCRELEX® injection if your child is unable to eat within 20
minutes before or after the injection.
1. Decide on an injection area – upper arm, thigh, buttock, or abdomen (see below).
The injection site should be changed for each injection (“rotate the injection site”).
2. Use alcohol or soap and water to clean the skin where you are going to inject your
child. The injection site should be dry before you inject.
Figure 7: Ready
to inject
Upper arm
Thigh
Buttock
Abdomen
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Lightly pinch the skin. Stick the needle in the way your child’s doctor showed you.
Release the skin (see figure A).
4. Slowly push in the plunger of the syringe all the way, making sure you have injected
all the liquid. Pull the needle straight out and gently press on the spot where you
injected your child with gauze or a cotton ball for a few seconds. Do not rub the
area (see figure B).
5. Follow your child’s doctor’s instructions for throwing away the needle and syringe.
Do not recap the syringe. Used needle and syringe should be placed in a sharps
container (such as a red biohazard container), hard plastic container (such as a
detergent bottle), or metal container (such as an empty coffee can). Such containers
should be sealed and disposed of properly.
Figure A: Lightly pinch
the skin and inject as
instructed
Figure B: Press (don’t
rub) with gauze or
cotton
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
For additional information, call 1-866-837-2422.
Manufactured for:
Ipsen Biopharmaceuticals, Inc.
Basking Ridge, NJ 07920 USA
www.ipsenus.com
Issued: August 2005
Revised: June 2012
Reference ID: 3902304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:32.953629 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021839s017lbl.pdf', 'application_number': 21839, 'submission_type': 'SUPPL ', 'submission_number': 17} |
7,439 | This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
JEAN-MARC P GUETTIER
03/12/2015
Reference ID: 3715157
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:33.014753 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022472Orig1s005lbl.pdf', 'application_number': 22472, 'submission_type': 'SUPPL ', 'submission_number': 5} |
7,440 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AFREZZA® safely and effectively. See full prescribing information for
AFREZZA®.
AFREZZA® (insulin human) Inhalation Powder
Initial U.S. Approval: 2014
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS
WITH CHRONIC LUNG DISEASE
See full prescribing information for complete boxed warning.
• Acute bronchospasm has been observed in patients with asthma
and COPD using AFREZZA. (5.1)
• AFREZZA is contraindicated in patients with chronic lung
disease such as asthma or COPD. (4)
• Before initiating AFREZZA, perform a detailed medical history,
physical examination, and spirometry (FEV1) to identify
potential lung disease in all patients. (2.5), (5.1)
----------------------RECENT MAJOR CHANGES------------------------
• Dosage and Administration (2)
4/2015
----------------------INDICATIONS AND USAGE------------------------
• AFREZZA® is a rapid acting inhaled insulin indicated to improve
glycemic control in adult patients with diabetes mellitus. (1)
Important limitations of use:
• In patients with type 1 diabetes, must use with a long-acting insulin. (1)
• Not recommended for the treatment of diabetic ketoacidosis. (1)
• Not recommended in patients who smoke (1)
-------------------DOSAGE AND ADMINISTRATION -----------------
• Administer using a single inhalation per cartridge (2.1)
• Administer at the beginning of a meal (2.2)
• Dosing must be individualized (2.2)
• Before initiating, perform a detailed medical history, physical examination,
and spirometry (FEV1) in all patients to identify potential lung disease (2.5)
------------------DOSAGE FORMS AND STRENGTHS ---------------
AFREZZA is available as single-use cartridges of: (3)
• 4 units
• 8 units
• 12 units
------------------------ CONTRAINDICATIONS ------------------------
• During episodes of hypoglycemia (4)
• Chronic lung disease, such as asthma, or chronic obstructive pulmonary
disease (4)
• Hypersensitivity to regular human insulin or any of the AFREZZA
excipients (4 )
--------------------- WARNINGS AND PRECAUTIONS ---------------
• Acute Bronchospasm:
Acute bronchospasm has been observed in
patients with asthma and COPD. Before initiating, perform spirometry
(FEV1) in all patients. Do not use in patients with chronic lung disease
(2.5, 4, 5.1)
• Change in Insulin Regimen: Carry out under close medical supervision and
increase frequency of blood glucose monitoring. (5.2)
• Hypoglycemia: May be life-threatening. Increase frequency of glucose
monitoring with changes to: insulin dosage, co-administered glucose
lowering medications, meal pattern, physical activity; and in patients with
renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6, 7, 8.6,
8.7)
• Decline in Pulmonary Function: Assess pulmonary function (e.g.,
spirometry) before initiating, after 6 months of therapy, and annually, even
in the absence of pulmonary symptoms. (2.5, 5.4)
• Lung Cancer: AFREZZA should not be used in patients with active lung
cancer. In patients with a history of lung cancer or at risk for lung cancer,
the benefit of AFREZZA use should outweigh this potential risk. (5.5)
• Diabetic Ketoacidosis: More patients using AFREZZA experienced
diabetic ketoacidosis in clinical trials. In patients at risk for DKA, monitor
and change to alternate route of insulin delivery, if indicated. (5.6)
• Hypersensitivity Reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur with insulin products, including
AFREZZA. Discontinue AFREZZA, monitor and treat if indicated. (5.7)
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients
at risk of hypokalemia and treat if indicated. (5.8)
• Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure occurs.
(5.9)
---------------------------- ADVERSE REACTIONS ----------------------
The most common adverse reactions associated with AFREZZA (2% or
greater incidence) are hypoglycemia, cough, and throat pain or irritation (6)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
at (1-800-633-1610) or FDA at (1-800-FDA-1088) or
www.fda.gov/medwatch.
---------------------------- DRUG INTERACTIONS ----------------------
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be
needed. (7.1, 7.2, 7.3)
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.
(7.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 05/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH
CHRONIC LUNG DISEASE
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Route of Administration
2.2 Dosage Information
2.3 AFREZZA Administration for Doses Exceeding 12 units
2.4 Dosage Adjustment due to Drug Interactions
2.5 Lung Function Assessment Prior to Administration
2.6 Important Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Acute Bronchospasm in Patients with Chronic Lung Disease
5.2 Changes in Insulin Regimen
5.3 Hypoglycemia
5.4 Decline in Pulmonary Function
5.5 Lung Cancer
5.6 Diabetic Ketoacidosis
5.7 Hypersensitivity Reactions
5.8 Hypokalemia
Reference ID: 3783454
5.9 Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect
of AFREZZA
7.3 Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of AFREZZA
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
11.1 AFREZZA Cartridges
11.2 AFREZZA Inhaler
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14.3 Type 2 Diabetes
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus
14.2 Type 1 Diabetes
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FULL PRESCRIBING INFORMATION
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC
LUNG DISEASE
• Acute bronchospasm has been observed in patients with asthma and COPD
using AFREZZA. [see Warnings and Precautions (5.1)].
• AFREZZA is contraindicated in patients with chronic lung disease such as
asthma or COPD. [see Contraindications (4)].
• Before initiating AFREZZA, perform a detailed medical history, physical
examination, and spirometry (FEV1) to identify potential lung disease in all
patients [see Dosage and Administration (2.5), Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult
patients with diabetes mellitus.
Limitations of Use:
• AFREZZA is not a substitute for long-acting insulin. AFREZZA must be used in
combination with long-acting insulin in patients with type 1 diabetes mellitus.
• AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning
and Precautions (5.6)].
• The safety and efficacy of AFREZZA in patients who smoke has not been established.
The use of AFREZZA is not recommended in patients who smoke or who have recently
stopped smoking.
2 DOSAGE AND ADMINISTRATION
2.1 Route of Administration
AFREZZA should only be administered via oral inhalation using the AFREZZA Inhaler.
AFREZZA is administered using a single inhalation per cartridge.
2.2 Dosage Information
Administer AFREZZA at the beginning of the meal.
Dosage adjustment may be needed when switching from another insulin to AFREZZA [see
Warnings and Precautions (5.2)].
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Starting Mealtime Dose:
• Insulin Naïve Individuals: Start on 4 units of AFREZZA at each meal.
• Individuals Using Subcutaneous Mealtime (Prandial) Insulin: Determine the
appropriate AFREZZA dose for each meal by converting from the injected dose using
Figure 1.
• Individuals Using Subcutaneous Pre-mixed Insulin: Estimate the mealtime injected
dose by dividing half of the total daily injected pre-mixed insulin dose equally among
the three meals of the day. Convert each estimated injected mealtime dose to an
appropriate AFREZZA dose using Figure 1 Administer half of the total daily injected
pre-mixed dose as an injected basal insulin dose.
Figure 1. Mealtime AFREZZA Dose Conversion Table usage illustration
Mealtime Dose Adjustment
Adjust the dosage of AFREZZA based on the individual's metabolic needs, blood glucose
monitoring results and glycemic control goal.
Dosage adjustments may be needed with changes in physical activity, changes in meal
patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic
function or during acute illness [see Warnings and Precautions (5.3), and Use in Specific
Populations (8.6, 8.7)].
Carefully monitor blood glucose control in patients requiring high doses of AFREZZA. If, in
these patients, blood glucose control is not achieved with increased AFREZZA doses,
consider use of subcutaneous mealtime insulin.
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2.3 AFREZZA Administration for Doses Exceeding 12 units
For AFREZZA doses exceeding 12 units, inhalations from multiple cartridges are necessary.
To achieve the required total mealtime dose, patients should use a combination of 4 unit, 8
unit and 12 unit cartridges. Examples of cartridge combinations for doses of up to 24 units
are shown in Figure 1.
For doses above 24 units, combinations of different multiple
cartridges can be used.
2.4 Dosage Adjustment due to Drug Interactions
Dosage adjustment may be needed when AFREZZA is coadministered with certain drugs
[see Drug Interactions (7)].
2.5 Lung Function Assessment Prior to Administration
AFREZZA is contraindicated in patients with chronic lung disease because of the risk of
acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical
history, physical examination and spirometry (FEV1) in all patients to identify potential lung
disease [see Contraindications (4) and Warnings and Precautions (5.1)].
2.6 Important Administration Instructions
See Patient Instructions for Use for complete administration instructions with illustrations.
Keep the inhaler level with the white mouthpiece on top and purple base on the bottom after
a cartridge has been inserted into the inhaler. Loss of drug effect can occur if the inhaler is
turned upside down, held with the mouthpiece pointing down, shaken (or dropped) after the
cartridge has been inserted but before the dose has been administered. If any of the above
occur, the cartridge should be replaced before use.
3 DOSAGE FORMS AND STRENGTHS
AFREZZA (insulin human) Inhalation Powder is available as 4 unit, 8 unit and 12 unit single
use cartridges to be administered via oral inhalation with the AFREZZA Inhaler only. [see
How Supplied/Storage and Handling (16)].
4 CONTRAINDICATIONS
AFREZZA is contraindicated in patients with the following:
• During episodes of hypoglycemia
• Chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD),
because of the risk of acute bronchospasm [see Warnings and Precautions (5.1)].
• Hypersensitivity to regular human insulin or any of the AFREZZA excipients [see
Warnings and Precautions (5.7)].
5 WARNINGS AND PRECAUTIONS
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5.1 Acute Bronchospasm in Patients with Chronic Lung Disease
Because of the risk of acute bronchospasm, AFREZZA is contraindicated in patients with
chronic lung disease such as asthma or COPD [see Contraindications (4)].
Before initiating therapy with AFREZZA, evaluate all patients with a medical history,
physical examination and spirometry (FEV1) to identify potential underlying lung disease.
Acute bronchospasm has been observed following AFREZZA dosing in patients with asthma
and patients with COPD. In a study of patients with asthma, bronchoconstriction and
wheezing following AFREZZA dosing was reported in 29% (5 out of 17) and 0% (0 out of
13) of patients with and without a diagnosis of asthma, respectively. In this study, a mean
decline in FEV1 of 400 mL was observed 15 minutes after a single dose in patients with
asthma. In a study of patients with COPD (n=8), a mean decline in FEV1 of 200 mL was
observed 18 minutes after a single dose of AFREZZA. The long-term safety and efficacy of
AFREZZA in patients with chronic lung disease has not been established.
5.2 Changes in Insulin Regimen
Glucose monitoring is essential for patients receiving insulin therapy. Changes in insulin
strength, manufacturer, type, or method of administration may affect glycemic control and
predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. These
changes should be made under close medical supervision and the frequency of blood glucose
monitoring should be increased. Concomitant oral antidiabetic treatment may need to be
adjusted.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including
AFREZZA. Severe hypoglycemia can cause seizures, may be life-threatening, or cause
death. Hypoglycemia can impair concentration ability and reaction time; this may place an
individual and others at risk in situations where these abilities are important (e.g., driving or
operating other machinery).
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulation. AFREZZA has a distinct time action profile [see Clinical
Pharmacology (12)], which impacts the timing of hypoglycemia. Hypoglycemia can happen
suddenly and symptoms may differ across individuals and change over time in the same
individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients
with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain
medications [see Drug Interactions (7)], or in patients who experience recurrent
hypoglycemia. Other factors which may increase the risk of hypoglycemia include changes
in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical
activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with
renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific
Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
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Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-
monitoring of blood glucose plays an essential role in the prevention and management of
hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced
symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring
is recommended.
5.4 Decline in Pulmonary Function
AFREZZA causes a decline in lung function over time as measured by FEV1. In clinical
trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-
treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV1 decline than
comparator-treated patients. The FEV1 decline was noted within the first 3 months, and
persisted for the entire duration of therapy (up to 2 years of observation). In this population,
the annual rate of FEV1 decline did not appear to worsen with increased duration of use.
The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years
has not been established. There are insufficient data in long term studies to draw conclusions
regarding reversal of the effect on FEV1 after discontinuation of AFREZZA. The observed
changes in FEV1 were similar in patients with type 1 and type 2 diabetes.
Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy,
and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a
decline of ≥ 20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more
frequent monitoring of pulmonary function in patients with pulmonary symptoms such as
wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough.
If
symptoms persist, discontinue AFREZZA. [see Adverse Reactions (6)].
5.5 Lung Cancer
In clinical trials, two cases of lung cancer, one in controlled trials and one in uncontrolled
trials (2 cases in 2,750 patient-years of exposure), were observed in participants exposed to
AFREZZA while no cases of lung cancer were observed in comparators (0 cases in
2,169 patient-years of exposure). In both cases, a prior history of heavy tobacco use was
identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous
cell) occurred in non-smokers exposed to AFREZZA and were reported by investigators after
clinical trial completion. These data are insufficient to determine whether AFREZZA has an
effect on lung or respiratory tract tumors. In patients with active lung cancer, a prior history
of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of
AFREZZA use outweigh this potential risk.
5.6 Diabetic Ketoacidosis
In clinical trials enrolling subjects with type 1 diabetes, diabetic ketoacidosis (DKA) was
more common in subjects receiving AFREZZA (0.43%; n=13) than in subjects receiving
comparators (0.14%; n=3). In patients at risk for DKA, such as those with an acute illness or
infection, increase the frequency of glucose monitoring and consider delivery of insulin using
an alternate route of administration if indicated [see Limitations of Use (1)].
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5.7 Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including AFREZZA. If hypersensitivity reactions occur, discontinue AFREZZA,
treat per standard of care and monitor until symptoms and signs resolve [see Adverse
Reactions (6)]. AFREZZA is contraindicated in patients who have had hypersensitivity
reactions to AFREZZA or any of its excipients [see Contraindications (4)].
5.8 Hypokalemia
All insulin products, including AFREZZA, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause
respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients
at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations and patients receiving intravenously
administered insulin).
5.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma
Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)
gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients
treated with insulin, including AFREZZA, and a PPAR-gamma agonist should be observed
for signs and symptoms of heart failure. If heart failure develops, it should be managed
according to current standards of care, and discontinuation or dose reduction of the PPAR-
gamma agonist must be considered.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Acute bronchospasm in patients with chronic lung disease [see Warnings and
Precautions (5.1)]
• Hypoglycemia [see Warnings and Precautions (5.3)]
• Decline in pulmonary function [see Warnings and Precautions (5.4)]
• Lung cancer [see Warnings and Precautions (5.5)]
• Diabetic ketoacidosis [see Warnings and Precautions (5.6)]
• Hypersensitivity reactions [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying designs, the incidence of adverse
reactions reported in one clinical trial may not be easily compared to the incidence reported
in another clinical trial, and may not reflect what is observed in clinical practice.
The data described below reflect exposure of 3017 patients to AFREZZA and include
1026 patients with type 1 diabetes and 1991 patients with type 2 diabetes. The mean
exposure duration was 8.17 months for the overall population and 8.16 months and
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8.18 months for type 1 and 2 diabetes patients, respectively. In the overall population,
1874 were exposed to AFREZZA for 6 months and 724 for greater than one year. 620 and
1254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for
up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were
exposed to AFREZZA for greater than one year (median exposure = 1.8 years). AFREZZA
was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively).
The mean age of the population was 50.2 years and 20 patients were older than 75 years of
age. 50.8% of the population were men; 82.6% were White, 1.8% were Asian, and
4.9% were Black or African American. 9.7% were Hispanic. At baseline, the type 1
diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of
8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a
mean HbA1c of 8.8%. At baseline, 33.4% of the population reported peripheral neuropathy,
32.0% reported retinopathy and 19.6% had a history of cardiovascular disease.
Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use
of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse
reactions were not present at baseline, occurred more commonly on AFREZZA than on
placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.
Table 1. Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus
(excluding Hypoglycemia) Treated with AFREZZA
Placebo*
(n = 290)
AFREZZA
(n = 1991)
Non-placebo
comparators
(n=1363)
Cough
Throat pain or irritation
Headache
Diarrhea
Productive cough
Fatigue
Nausea
19.7%
3.8%
2.8%
1.4%
1.0%
0.7%
0.3%
25.6%
4.4%
3.1%
2.7%
2.2%
2.0%
2.0%
5.4%
0.9%
1.8%
2.2%
0.9%
0.6%
1.0%
*Carrier particle without insulin was used as placebo [see Description (11)].
Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use
of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These
adverse reactions were not present at baseline, occurred more commonly on AFREZZA than
on comparator, and occurred in at least 2% of patients treated with AFREZZA.
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Table 2. Common Adverse Reactions in Patients with Type 1 Diabetes Mellitus
(excluding Hypoglycemia) Treated with AFREZZA
Subcutaneous
Insulin
(n = 835)
AFREZZA
(n=1026)
Cough
Throat pain or irritation
Headache
Pulmonary function test decreased
Bronchitis
Urinary tract infection
4.9%
1.9%
2.8%
1.0%
2.0%
1.9%
29.4%
5.5%
4.7%
2.8%
2.5%
2.3%
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including AFREZZA [see Warnings and Precautions (5.3)]. The incidence of severe and
non-severe hypoglycemia of AFREZZA versus placebo in patients with type 2 diabetes is
shown in Table 3. A hypoglycemic episode was recorded if a patient reported symptoms of
hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe
hypoglycemia was defined as an event with symptoms consistent with hypoglycemia
requiring the assistance of another person and associated with either a blood glucose value
consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.
Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled
Study of Patients with Type 2 Diabetes
Placebo
(N=176)
AFREZZA
(N=177)
Severe Hypoglycemia
Non-Severe Hypoglycemia
1.7%
30%
5.1%
67%
Cough
Approximately 27% of patients treated with AFREZZA reported cough, compared to
approximately 5.2% of patients treated with comparator. In clinical trials, cough was the
most common reason for discontinuation of AFREZZA therapy (2.8% of AFREZZA-treated
patients).
Pulmonary Function Decline
In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients
treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in
forced expiratory volume in one second (FEV1) compared to patients treated with comparator
anti-diabetes treatments. The decline occurred during the first 3 months of therapy and
persisted over 2 years (Figure 2).
A decline in FEV1 of ≥ 15% occurred in 6% of
AFREZZA-treated subjects compared to 3% of comparator-treated subjects.
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Figure 2. Mean (+/-SE) Change in FEV1 (Liters) from Baseline for Type 1 and Type 2
Diabetes Patients graph
Weight Gain
Weight gain may occur with some insulin therapies, including AFREZZA. Weight gain has
been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical
trial of patients with type 2 diabetes [see Clinical Studies (14.3)], there was a mean 0.49 kg
weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss
among placebo-treated patients.
Antibody Production
Increases in anti-insulin antibody concentrations have been observed in patients treated with
AFREZZA.
Increases in anti-insulin antibodies are observed more frequently with
AFREZZA than with subcutaneously injected mealtime insulins. Presence of antibody did
not correlate with reduced efficacy, as measured by HbA1c and fasting plasma glucose, or
specific adverse reactions.
7 DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic
agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates,
fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene,
salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Dose
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adjustment and increased frequency of glucose monitoring may be required when AFREZZA
is co-administered with these drugs.
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA
The glucose lowering effect of AFREZZA may be decreased when co-administered with
atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics,
estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens
(e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g.,
albuterol, epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased
frequency of glucose monitoring may be required when AFREZZA is co-administered with
these drugs.
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
AFREZZA
The glucose lowering effect of AFREZZA may be increased or decreased when co
administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may
cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment
and increased frequency of glucose monitoring may be required when AFREZZA is co
administered with these drugs.
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine,
guanethidine, and reserpine are co-administered with AFREZZA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
AFREZZA has not been studied in pregnant women. AFREZZA should not be used during
pregnancy unless the potential benefit justifies the potential risk to the fetus.
In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major
malformations were observed at up to 100 mg/kg/day (a systemic exposure 14-21 times the
human systemic exposure, resulting from the maximum recommended daily dose of 99 mg
AFREZZA based on AUC).
In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal
effects were observed at all dose groups (at human systemic exposure following a 99 mg
AFREZZA dose, based on AUC).
In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased
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epididymis and testes weights, however, no decrease in fertility was noted, and impaired
learning were observed in pups at ≥ 30 mg/kg/day (a systemic exposure 6 times human
systemic exposure at the maximum daily AFREZZA dose of 99 mg based on AUC).
8.3 Nursing Mothers
Many drugs are excreted in human milk. A study in rats indicated that the carrier is excreted in
milk at approximately 10% of maternal exposure levels. It is therefore highly likely that the
insulin and carrier in AFREZZA is excreted in human milk. A decision should be made
whether to discontinue nursing or suspend use of the drug since AFREZZA has not been studied
in lactating women.
8.4 Pediatric Use
AFREZZA has not been studied in patients younger than 18 years of age.
8.5 Geriatric Use
In the AFREZZA clinical studies, 381 patients were 65 years of age or older, of which 20
were 75 years of age or older. No overall differences in safety or effectiveness were
observed between patients over 65 and younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age have not been
conducted.
8.6 Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of AFREZZA has not been
studied. Frequent glucose monitoring and dose adjustment may be necessary for AFREZZA
in patients with hepatic impairment [see Warnings and Precautions (5.3)].
8.7 Renal Impairment
The effect of renal impairment on the pharmacokinetics of AFREZZA has not been studied.
Some studies with human insulin have shown increased circulating levels of insulin in
patients with renal failure.
Frequent glucose monitoring and dose adjustment may be
necessary for AFREZZA in patients with renal impairment [see Warnings and Precautions
(5.3)].
10 OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and
Precautions (5.3, 5.8)].
Mild episodes of hypoglycemia can usually be treated with oral glucose. Adjustments in
drug dosage, meal patterns, or exercise, may be needed.
Severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be
treated with intramuscular / subcutaneous glucagon or concentrated intravenous glucose.
After apparent clinical recovery from hypoglycemia, continued observation and additional
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carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia
must be corrected appropriately.
11 DESCRIPTION
11.1 AFREZZA Cartridges
AFREZZA consists of single-use plastic cartridges filled with a white powder containing
insulin (human), which is administered via oral inhalation using the AFREZZA Inhaler only.
AFREZZA cartridges contain human insulin produced by recombinant DNA technology
utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human
insulin has the empirical formula C257H383N65O77S6 and a molecular weight of 5808. Human
insulin has the following primary amino acid sequence:
stru ctur
al fo rmul
a
Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and
polysorbate 80.
AFREZZA Inhalation Powder is a dry powder supplied as 4 unit, 8 unit or 12 unit cartridges.
The 4 unit cartridge contains 0.35 mg of insulin. The 8 unit cartridge contains 0.7 mg of
insulin. The 12 unit cartridge contains 1 mg of insulin.
11.2 AFREZZA Inhaler
The AFREZZA Inhaler is breath-powered by the patient. When the patient inhales through
the device, the powder is aerosolized and delivered to the lung. The amount of AFREZZA
delivered to the lung will depend on individual patient factors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal
muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in
adipocytes, inhibits proteolysis, and enhances protein synthesis.
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12.2 Pharmacodynamics
The pharmacodynamic profile for orally inhaled AFREZZA 8 units relative to
subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1
diabetes is shown in Figure 3 (A). The median time to maximum effect of AFREZZA
(measured by the peak rate of glucose infusion) was approximately 53 minutes (standard
deviation of 74 minutes) and the effect then declined to near baseline levels by about 160
minutes.
Figure 3. Baseline-Corrected Glucose Infusion Rate (A) and Baseline-Corrected Serum
Insulin Concentrations (B) after Administration of AFREZZA or
Subcutaneous Insulin Lispro in Type 1 Diabetes Patients*
8
80
graph
-30 0
30 60 90 120 150 180 210 240 270 300 330 360
graph
-30 0
30 60 90 120 150 180 210 240 270 300 330 360
7
70
6
60
5
Insulin (µU/mL)
50
40
30
GIR (mg/kg/min)
4
3
2
20
1
10
0
0
Time (minutes)
Time (minutes)
* Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable
to insulin lispro.
In a study of 32 healthy subjects, the pharmacodynamic effect of AFREZZA, measured as
area under the glucose infusion rate - time curve (AUC-GIR) from an euglycemic clamp,
increased in a less than dose-proportional manner.
This effect has been observed for
subcutaneously administered insulins, but it is unknown if the diminishing pharmacodynamic
benefit at higher dosage of AFREZZA parallels that which is seen with subcutaneously
administered insulin.
12.3 Pharmacokinetics
The insulin contained in AFREZZA is regular human insulin. Following pulmonary
absorption into systemic circulation, the metabolism and elimination are comparable to
regular human insulin.
Absorption: The pharmacokinetic profiles for orally inhaled AFREZZA 8 units relative to
subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1
diabetes are shown in Figure 3(B). The maximum serum insulin concentration was reached
by 12-15 minutes after inhalation of AFREZZA 8 units and serum insulin concentrations
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declined to baseline by approximately 180 minutes. However, the faster absorption of
insulin from Afrezza [see Figure 3(B)] did not result in a faster onset of activity compared to
insulin lispro [see Figure 3(A)].
Disposition: Systemic insulin disposition (median terminal half-life) following oral
inhalation of AFREZZA 4 and 32 units was 28-39 minutes, and 145 minutes for
subcutaneous regular human insulin 15 units.
Carrier Particles
Clinical pharmacology studies showed that carrier particles [see Description (11)] are not
metabolized and are eliminated unchanged in the urine following the lung absorption.
Following oral inhalation of AFREZZA, a mean of 39% of the inhaled dose of carrier
particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The
swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the
feces.
Drug Interaction: Bronchodilators and Inhaled Steroids
Albuterol increased the AUC insulin administered by AFREZZA by 25% in patients with
asthma. Effect of fluticasone on insulin exposures following AFREZZA administration has
not been evaluated in patients with asthma; however, no significant change in insulin
exposure was observed in a study in healthy volunteers. Frequent glucose monitoring and
dose reduction may be necessary for AFREZZA if it is co-administered with albuterol.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104 week carcinogenicity study, rats were given doses up to 46 mg/kg/day of the carrier
and up to 1.23 mg/kg/day of insulin, by nose-only inhalation. No increased incidence of
tumors was observed at systemic exposures equivalent to the insulin at a maximum daily
AFREZZA dose of 99 mg based on a comparison of relative body surface areas across
species.
In a 26 week carcinogenicity study, transgenic mice (Tg-ras-H2) given doses up to 75
mg/kg/day of carrier and up to 5 mg/kg/day of AFREZZA. No increased incidence of tumors
was observed.
AFREZZA was not genotoxic in Ames bacterial mutagenicity assay and in the chromosome
aberration assay, using human peripheral lymphocytes with or without metabolic activation.
The carrier alone was not genotoxic in the in vivo mouse micronucleus assay.
In female rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier (vehicle
without insulin) beginning 2 weeks prior to mating until gestation day 7, there were no
adverse effects on male fertility at doses up to 100 mg/kg/day (a systemic exposure 14-21
times that following the maximum daily AFREZZA dose of 99 mg based on AUC). In
female rats there was increased pre- and post-implantation loss at 100 mg/kg/day but not at
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30 mg/kg/day (14-21 times higher systemic exposure than the maximum daily AFREZZA
dose of 99 mg based on AUC).
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus
AFREZZA has been studied in adults with type 1 diabetes in combination with basal insulin.
The efficacy of AFREZZA in type 1 diabetes patients was compared to insulin aspart in
combination with basal insulin. AFREZZA has been studied in adults with type 2 diabetes in
combination with oral antidiabetic drugs. The efficacy of AFREZZA in type 2 diabetes
patients was compared to placebo inhalation.
14.2 Type 1 Diabetes
Patients with inadequately controlled type 1 diabetes participated in a 24-week, open-label,
active-controlled study to evaluate the glucose lowering effect of mealtime AFREZZA used
in combination with a basal insulin. Following a 4-week basal insulin optimization period,
344 patients were randomized to AFREZZA (n=174) or insulin aspart (n=170)administered
at each meal of the day. Mealtime insulin doses were titrated to glycemic goals for the first
12 weeks and kept stable for the last 12 weeks of the study. At Week 24, treatment with
basal insulin and mealtime AFREZZA provided a mean reduction in HbA1c that met the pre-
specified non-inferiority margin of 0.4%. AFREZZA provided less HbA1c reduction than
insulin aspart, and the difference was statistically significant. More subjects in the insulin
aspart group achieved the HbA1c target of ≤7% (Table 4).
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Table 4. Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA
plus Basal Insulin in Adults with Type 1 Diabetes
Efficacy Parameter
AFREZZA +
Basal Insulin
(N=174)
Insulin Aspart +
Basal Insulin
(N=170)
HbA1c (%)
Baseline (adjusted meana)
7.94
7.92
Change from baseline (adjusted meana,b)
-0.21
-0.40
Difference from insulin aspart (adjusted meana,b)
(95% CI)
0.19
(0.02, 0.36)
Percentage of patients achieving HbA1c ≤ 7%c
13.8
27.1
Fasting Plasma Glucose (mg/dL)
Baseline (adjusted meana)
153.9
151.6
Change from baseline (adjusted meana, b)
-25.3
10.2
Difference from insulin aspart (adjusted meana, b)
(95% CI)
-35.4
(-56.3, -14.6)
a Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent
variable and treatment, visit, region, basal insulin stratum, and treatment by visit interaction as fixed factors, and corresponding
baseline as a covariate. An autoregression (1) [AR(1)] covariance structure was used.
b Data at 24 weeks were available from 131 (75 %) and 150 (88% ) subjects randomized to the AFREZZA and insulin aspart groups,
respectively.
c The percentage was calculated based on the number of patients randomized to the trial.
14.3 Type 2 Diabetes
A total of 479 adult patients with type 2 diabetes inadequately controlled on
optimal/maximally tolerated doses of metformin only, or 2 or more oral antidiabetic (OAD)
agents participated in a 24-week, double-blind, placebo-controlled study. Following a 6
week run-in period, 353 patients were randomized to AFREZZA (n=177) or an inhaled
placebo powder without insulin (n=176). Insulin doses were titrated for the first 12 weeks
and kept stable for the last 12 weeks of the study. OADs doses were kept stable. At Week
24, treatment with AFREZZA plus OADs provided a mean reduction in HbA1c that was
statistically significantly greater compared to the HbA1c reduction observed in the placebo
group (Table 5).
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Table 5. Results at Week 24 in a Placebo-Controlled Study of AFREZZA in Adults
with Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Agents
Efficacy Parameter
AFREZZA + Oral
Anti-Diabetic
Agents
(N=177)
Placebo + Oral
Anti-Diabetic
Agents
(N=176)
HbA1c (%)
Baseline (adjusted meana)
8.25
8.27
Change from baseline (adjusted meana,b)
-0.82
-0.42
Difference from placebo (adjusted meana,b)
(95% CI)
-0.40
(-0.57, -0.23)
Percentage (%) of patients achieving HbA1C ≤7%c
32.2
15.3
Fasting Plasma Glucose (mg/dL)
Baseline (adjusted meana)
175.9
175.2
Change from baseline (adjusted meana,b)
-11.2
-3.8
Difference from placebo (adjusted meana,b)
(95% CI)
-7.4
(-18.0, 3.2)
a Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent
variable and treatment, visit, region, and treatment by visit interaction as fixed factors, and corresponding baseline as a covariate. An
autoregression (1) [AR(1)] covariance structure was used.
b Data at 24 weeks without rescue therapy were available from 139 (79%) and 129 (73%) subjects randomized to the AFREZZA and
placebo groups, respectively.
c The percentage was calculated based on the number of patients randomized to the trial.
16 HOW SUPPLIED/STORAGE AND HANDLING
AFREZZA (insulin human) Inhalation Powder is available as 4 unit, 8 unit and 12 unit
single-use cartridges. Three cartridges are contained in a single cavity of a blister strip. Each
card contains 5 blister strips separated by perforations for a total of 15 cartridges. For
convenience, the perforation allows users to remove a single strip containing 3 cartridges.
Two cards of the same cartridge strength are packaged in a foil laminate overwrap
(30 cartridges per foil package).
The cartridges are color-coded, blue for 4 units, green for 8 units and yellow for 12 units.
Each cartridge is marked with “afrezza” and “4 units”, “8 units” or “12 units”.
The AFREZZA Inhaler is individually packaged in a translucent overwrap. The inhaler is
fully assembled with a removable mouthpiece cover. The AFREZZA Inhaler can be used for
up to 15 days from the date of first use. After 15 days of use, the inhaler must be discarded
and replaced with a new inhaler.
AFREZZA is available in the following configurations:
• NDC 0024-5874-90, AFREZZA (insulin human) Inhalation Powder: 90 − 4 unit
cartridges and 2 inhalers
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• NDC 0024-5878-90, AFREZZA (insulin human) Inhalation Powder: 90 − 8 unit
cartridges and 2 inhalers
• NDC 0024-5884-63, AFREZZA (insulin human) Inhalation Powder: 90 cartridges; 60 –
4 unit cartridges and 30 − 8 unit cartridges and 2 inhalers
• NDC 0024-5882-36, AFREZZA (insulin human) Inhalation Powder: 90 cartridges; 30 –
4 unit cartridges and 60 − 8 unit cartridges and 2 inhalers
• NDC 0024-5880-18, AFREZZA (insulin human) Inhalation Powder: 180 cartridges; 90
4 unit cartridges and 90 – 8 unit cartridges and 2 inhalers
• NDC 0024-5890-90, AFREZZA (insulin human) Inhalation Powder: 90 -
12 unit and 2
Inhalers
• NDC 0024-5893-36, AFREZZA (insulin human) Inhalation Powder: 90 cartridges; 30 – 8
unit cartridges and 60 - 12 unit cartridges and 2 inhalers
• NDC 0024-5894-63, AFREZZA (insulin human) Inhalation Powder: 90 cartridges; 60 –
8 unit cartridges and 30 - 12 unit cartridges and 2 inhalers
• NDC 0024-5895-33, AFREZZA (insulin human) Inhalation Powder: 90 cartridges; 30 –
4 unit cartridges, 30 – 8 unit cartridges and 30 - 12 unit cartridges and 2 inhalers
Storage
Not in Use: Refrigerated Storage 2-8ºC (36-46ºF)
Sealed (Unopened) Foil Package
May be stored until the Expiration Date*
Sealed (Unopened) Blister Cards + Strips
May be stored for 1 month*
* If a foil package, blister card or strip is not refrigerated, the contents must be used within
10 days.
In Use: Room Temperature Storage 25ºC (77ºF), excursions permitted 15-30ºC (59-86ºF)
Sealed (Unopened) Blister Cards + Strips
Must be used within 10 days
Opened Strips
Must be used within 3 days
Do not put a blister card or strip back into the refrigerator after being stored at room
temperature
Inhaler Storage:
Store at 2-25ºC (36-77ºF); excursions permitted. Inhaler may be stored refrigerated, but
should be at room temperature before use.
Handling:
Before use, cartridges should be at room temperature for 10 minutes.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide)
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Instructions
Instruct patients to read the Medication Guide before starting AFREZZA therapy and to
reread it each time the prescription is renewed, because information may change. Instruct
patients to inform their healthcare provider or pharmacist if they develop any unusual
symptom, or if any known symptom persists or worsens.
Inform patients of the potential risks and benefits of AFREZZA and of alternative modes of
therapy. Inform patients about the importance of adherence to dietary instructions, regular
physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and
management of hypoglycemia and hyperglycemia, and assessment for diabetes
complications. Advise patients to seek medical advice promptly during periods of stress such
as fever, trauma, infection, or surgery, as medication requirements may change.
Instruct patients to use AFREZZA only with the AFREZZA inhaler.
Inform patients that the most common adverse reactions associated with the use of
AFREZZA are hypoglycemia, cough, and throat pain or irritation.
Advise women with diabetes to inform their physician if they are pregnant or are planning to
become pregnant while using AFREZZA.
Acute Bronchospasm in Patients with Chronic Lung Disease
Advise patients to inform their physicians if they have a history of lung disease, because
AFREZZA should not be used in patients with chronic lung disease (e.g., asthma, COPD, or
other chronic lung disease(s)) [see Contraindications (4) and Warnings and Precautions
(5.1)].
Advise patients that if they experience any respiratory difficulty after inhalation of
AFREZZA, they should report it to their physician immediately for assessment.
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper
inhalation technique, and management of hypoglycemia and hyperglycemia especially at
initiation of AFREZZA therapy. Instruct patients on handling of special situations such as
intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped
insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake,
and skipped meals.
Instruct patients on the management of hypoglycemia. Inform patients that their ability to
concentrate and react may be impaired as a result of hypoglycemia. Advise patients who
have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use
caution when driving or operating machinery [see Warnings and Precautions (5.3)].
Decline in Pulmonary Function and Monitoring
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Inform patients that AFREZZA can cause a decline in lung function and their lung function
will be evaluated by spirometry before initiation of AFREZZA treatment [see Warnings and
Precautions (5.4)].
Lung Cancer
Inform patients to promptly report any signs or symptoms potentially related to lung cancer
[see Warnings and Precautions (5.5)].
Diabetic Ketoacidosis
Instruct patients to carefully monitor their blood glucose during illness, infection, and other
risk situations for diabetic ketoacidosis and to contact their healthcare provider if their blood
glucose control worsens [see Warnings and Precautions (5.6)].
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions can occur with insulin therapy including
AFREZZA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings
and Precautions (5.7)].
AFREZZA is a registered trademark owned by MannKind Corporation
Patented: http://www.mannkindcorp.com/our-technology-patent-notices.htm
Manufactured by:
MannKind Corporation
Danbury, CT 06810
Distributed by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
05/2015A
Page 22 of 22
Reference ID: 3783454
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Medication Guide
AFREZZA® (uh-FREZZ-uh)
(insulin human) inhalation powder
What is the most important information I should know about AFREZZA?
AFREZZA can cause serious side effects, including:
•
Sudden lung problems (bronchospasms). Do not use AFREZZA if you have long-term
(chronic) lung problems such as asthma or chronic obstructive pulmonary disease (COPD).
Before starting AFREZZA, your healthcare provider will give you a breathing test to check how your
lungs are working.
What is AFREZZA?
•
AFREZZA is a man-made insulin that is breathed-in through your lungs (inhaled) and is used to control
high blood sugar in adults with diabetes mellitus.
•
AFREZZA is not for use in place of long-acting insulin. AFREZZA must be used with long-acting insulin
in people who have type 1 diabetes mellitus.
•
AFREZZA is not for use to treat diabetic ketoacidosis.
•
It is not known if AFREZZA is safe and effective for use in people who smoke. AFREZZA is not for use
in people who smoke or have recently stopped smoking (less than 6 months).
●
It is not known if AFREZZA is safe and effective in children under 18 years of age.
Who should not use AFREZZA?
Do not use AFREZZA if you:
•
have chronic lung problems such as asthma or COPD.
●
are allergic to regular human insulin or any of the ingredients in AFREZZA. See the end of this
Medication Guide for a complete list of ingredients in AFREZZA.
What should I tell my healthcare provider before using AFREZZA?
Before using AFREZZA, tell your healthcare provider about all your medical conditions,
including if you:
•
have lung problems such as asthma or COPD
•
have or have had lung cancer
•
are using any inhaled medications
•
smoke or have recently stopped smoking
•
have kidney or liver problems
•
are pregnant, planning to become pregnant, or are breastfeeding. AFREZZA may harm your unborn or
breastfeeding baby.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins or herbal supplements.
Before you start using AFREZZA, talk to your healthcare provider about low blood sugar and
how to manage it.
How should I use AFREZZA?
•
Read the detailed Instructions for Use that comes with your AFREZZA.
•
Take AFREZZA exactly as your healthcare provider tells you to. Your healthcare provider should tell
you how much AFREZZA to use and when to use it.
•
Know the strength of AFREZZA you use. Do not change the amount of AFREZZA you use unless your
healthcare provider tells you to.
•
Take AFREZZA at the beginning of your meal.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and
when you should check your blood sugar levels.
•
Keep AFREZZA and all medicines out of the reach of children.
Your dose of AFREZZA may need to change because of:
•
Change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in
diet, or because of other medicines you take.
What should I avoid while using AFREZZA?
While using AFREZZA do not:
•
drive or operate heavy machinery, until you know how AFREZZA affects you
•
drink alcohol or use over-the-counter medicines that contain alcohol
•
smoke
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What are the possible side effects of AFREZZA?
AFREZZA may cause serious side effects that can lead to death, including:
See “What is the most important information I should know about AFREZZA?”
•
low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
•
dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech,
shakiness, fast heartbeat, anxiety, irritability or mood change, hunger.
•
decreased lung function. Your healthcare provider should check how your lungs are working before
you start using AFREZZA, 6 months after you start using it and yearly after that.
•
lung cancer. In studies of AFREZZA in people with diabetes, lung cancer occurred in a few more
people who were taking AFREZZA than in people who were taking other diabetes medications. There
were too few cases to know if lung cancer was related to AFREZZA. If you have lung cancer, you and
your healthcare provider should decide if you should use AFREZZA.
•
diabetic ketoacidosis. Talk to your healthcare provider if you have an illness. Your AFREZZA dose or
how often you check your blood sugar may need to be changed.
•
severe allergic reaction (whole body reaction). Get medical help right away if you have any
of these signs or symptoms of a severe allergic reaction:
•
a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with AFREZZA may
cause heart failure in some people. This can happen even if you have never had heart failure or heart
problems before. If you already have heart failure it may get worse while you take TZDs with
AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with
AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure
including:
•
shortness of breath, swelling of your ankles or feet, sudden weight gain.
Treatment with TZDs and AFREZZA may need to be changed or stopped by your healthcare provider if
you have new or worse heart failure.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat,
sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of AFREZZA include:
•
low blood sugar (hypoglycemia), cough, sore throat
These are not all the possible side effects of AFREZZA. Call your doctor for medical advice about
side effects. You may report side effects to FDA at 1-800-FDA-1088 (1-800-332-1088).
General information about the safe and effective use of AFREZZA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use AFREZZA for a condition for which it was not prescribed. Do not give AFREZZA to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about AFREZZA. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for
information about AFREZZA that is written for health professionals. For more information, go to
www.AFREZZA.com or call sanofi-aventis 1-800-633-1610.
What are the ingredients in AFREZZA?
Active ingredient: human insulin
Inactive ingredients: fumaryl diketopiperazine, polysorbate 80
Manufactured By: MannKind Corporation
AFREZZA® is a registered trademark owned by MannKind Corporation
Patented: http://www.mannkindcorp.com/our-technology-patent-notices.htm
MannKind Corporation
Danbury, CT 06810
Distributed by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Reference ID: 3783454
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Instructions for Use
AFREZZA® (uh-FREZZ-uh)
(insulin human) inhalation powder
Read this Instructions for Use before you start using AFREZZA and each time you get a new
AFREZZA inhaler. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
Your healthcare provider should show you how to use your AFREZZA inhaler the right
way before you use it for the first time.
Important information about AFREZZA:
• AFREZZA comes in 3 strengths (See Figure A):
o 4 units (blue cartridge)
o 8 units (green cartridge)
o 12 units (yellow cartridge)
(Figure A) usage illustration
• If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than 1
cartridge.
• If you need to use more than 1 cartridge for your dose, throw away the used cartridge
before getting a new one. You can tell when a cartridge has been used, because the cup
has moved to the center.
• Do not try to open the AFREZZA cartridges. The AFREZZA Inhaler opens the cartridge
automatically during use.
• AFREZZA cartridges should only be used with the AFREZZA Inhaler. Do not try to
breathe in the AFREZZA insulin powder in any other way. Do not put cartridges in your
mouth and do not swallow cartridges.
• Use only 1 AFREZZA Inhaler at a time. The same inhaler should be used for the 4 unit, 8
unit or 12 unit cartridges.
• Throw away your AFREZZA Inhaler after 15 days and get a new one.
If you are having problems with your AFREZZA inhaler or if it breaks and you need a
new one, call 1-800-633-1610.
Reference ID: 3783454
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Know your AFREZZA® inhaler: usage illustration
Know your AFREZZA® cartridges: usage illustration
Reference ID: 3783454
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How to take your dose of AFREZZA:
Always be sure you have the right number of AFREZZA cartridges for your dose available before
you start. AFREZZA cartridges must only be used with the AFREZZA Inhaler.
Step 1: Select the AFREZZA cartridges for your dose usage illustration
If your prescribed AFREZZA® dose is more than 12 units you will need to use more than 1
cartridge to get your right dose.
Use the dosage chart below to determine the least number
of AFREZZA® cartridges you can use for your dose. Other
usage illustration
(Figure B) usage illustration
Select Cartridges
Important: Use the AFREZZA dose chart above (See Figure B) to help you choose the
right number of AFREZZA cartridges needed for your dose.
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Open Packages
Remove a blister card from the foil package.
Tear along perforation to remove one strip. usage illustrationusage illustration
Push Cartridges to Remove
Remove a cartridge from the strip by pressing on the clear side to
push the cartridge out. Remove the right number of cartridges for
your dose. Pushing on the cup will not damage the cartridge.
AFREZZA cartridges left over in an opened strip must be
used within 3 days. usage illustration
Before Proceeding:
Check that you have the right AFREZZA cartridge(s) for your dose.
Use only 1 inhaler for multiple cartridges. Throw away your AFREZZA inhaler after 15 days and
get a new one.
Step 2: Loading a cartridge
Hold Inhaler
Hold the inhaler level in one (1) hand with the white
mouthpiece on the top and purple base on the
bottom.
Open Inhaler
Open the inhaler by lifting the white mouthpiece to a
vertical position.
Before you put the AFREZZA cartridge in your
inhaler, make sure it has been at room
temperature for 10 minutes.
Place Cartridge
Hold the cartridge with the cup facing down.
Line up the cartridge with the opening in the inhaler.
The pointed end of the cartridge should line up with
the pointed end in the inhaler.
Place the cartridge into the inhaler. Be sure that the
cartridge lies flat in the inhaler.
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usage illustration
usage illustra
tion
Remove the Mouthpiece Cover
Important: Keep the inhaler level during and
after removal of the purple mouthpiece cover.
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Exhale
Hold the inhaler away from your mouth and
fully blow out (exhale).
Position Inhaler in Mouth
Keeping your head level, place the mouthpiece
in your mouth and tilt the inhaler down
towards your chin, as shown.
Close your lips around the mouthpiece to form
a seal.
Tilt the inhaler downward while keeping
your head level.
Inhale Deeply and Hold Breath
With your mouth closed around the
mouthpiece, inhale deeply through the
inhaler.
Hold your breath for as long as comfortable
and at the same time remove the inhaler from
your mouth. After holding your breath, exhale
and continue to breathe normally.
u
sage illustration
u
sage illustration
usage il lustration
tridge
Replace Mouthpiece Cover
Place the purple mouthpiece cover back onto
he inhaler.
Reference ID: 3783454
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usage illustration
u
s
a
g
e
i
l
lustration
Open Inhaler
Open the inhaler by lifting up the white
mouthpiece.
Remove Cartridge
Remove the cartridge from the purple base.
Throw away the Cartridge
Throw away the used cartridge in your regular
household trash.
Multiple cartridge dosing
If you need more than one (1)
AFREZZA cartridge for your dose,
See the AFREZZA dosage chart
above (Figure B).
Reference ID: 3783454
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For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store AFREZZA?
*If a foil package, blister card or strip is not refrigerated, the contents must be used within 10 days
Do not put a blister card or strip back into the refrigerator after being stored at room
temperature
Reference ID: 3783454
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Caring for your AFREZZA inhaler:
Reference ID: 3783454
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For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
age illustration
Reference ID: 3783454
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For current labeling information, please visit https://www.fda.gov/drugsatfda
This Medication Guide and Instructions for Use has been approved by the U.S.
Food and Drug Administration.
AFREZZA® is a registered trademark owned by MannKind Corporation
Patented: See http://www.mannkindcorp.com/our-technology-patent
notices.htm
Manufactured by:
MannKind Corporation
Danbury, CT 06810
Distributed by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Approved: 05/2015A
Reference ID: 3783454
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| custom-source | 2025-02-12T13:43:33.257903 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022472s006s008lbl.pdf', 'application_number': 22472, 'submission_type': 'SUPPL ', 'submission_number': 6} |
10,665 | NDA 04-782/S-115, S-130
Page 3
Premarin®
(conjugated estrogens tablets, USP)
only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the
use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose.
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke,
invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during
5 years of treatment with conjugated equine estrogens (0.625 mg) combined with
medroxyprogesterone acetate (2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY,
Clinical Studies). Other doses of conjugated estrogens and medroxyprogesterone acetate, and other
combinations of estrogens and progestins were not studied in the WHI and, in the absence of
comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or
without progestins should be prescribed at the lowest effective doses and for the shortest duration
consistent with treatment goals and risks for the individual woman.
DESCRIPTION
PREMARIN (CONJUGATED ESTROGENS TABLETS, USP) FOR ORAL ADMINISTRATION CONTAINS A
MIXTURE OF CONJUGATED EQUINE ESTROGENS OBTAINED EXCLUSIVELY FROM NATURAL SOURCES,
OCCURRING AS THE SODIUM SALTS OF WATER-SOLUBLE ESTROGEN SULFATES BLENDED TO
REPRESENT THE AVERAGE COMPOSITION OF MATERIAL DERIVED FROM PREGNANT MARES' URINE. IT
IS A MIXTURE OF SODIUM ESTRONE SULFATE AND SODIUM EQUILIN SULFATE. IT CONTAINS AS
CONCOMITANT COMPONENTS, AS SODIUM SULFATE CONJUGATES, 17α-DIHYDROEQUILIN, 17α-
ESTRADIOL, AND 17β-DIHYDROEQUILIN. TABLETS FOR ORAL ADMINISTRATION ARE AVAILABLE IN 0.3
MG, 0.45 MG, 0.625 MG, 0.9 MG, 1.25 MG, AND 2.5 MG STRENGTHS OF CONJUGATED ESTROGENS.
PREMARIN TABLETS CONTAIN THE FOLLOWING INACTIVE INGREDIENTS: CALCIUM PHOSPHATE
TRIBASIC, CALCIUM SULFATE, CARNAUBA WAX, CELLULOSE, GLYCERYL MONOOLEATE, LACTOSE,
MAGNESIUM STEARATE, METHYLCELLULOSE, PHARMACEUTICAL GLAZE, POLYETHYLENE GLYCOL,
STEARIC ACID (NOT PRESENT IN 0.45 MG TABLET), SUCROSE, AND TITANIUM DIOXIDE.
— 0.3 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C
Yellow No. 6; these tablets comply with USP Drug Release Test 1.
— 0.45 MG TABLETS ALSO CONTAIN: FD&C BLUE NO. 2; THESE TABLETS COMPLY WITH USP DRUG RELEASE
TEST 1.
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Page 4
— 0.625 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40; these
tablets comply with USP Drug Release Test 1.
— 0.9 mg tablets also contain: D&C Red No. 6, D&C Red No. 7; these tablets comply with USP
Drug Release Test 2.
— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10, FD&C Yellow No. 6; these
tablets comply with USP Drug Release Test 3.
— 2.5 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 7; these tablets comply with USP
Drug Release Test 3.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the female
reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human
estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes
70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause,
most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal
cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate,
are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
CIRCULATING ESTROGENS MODULATE THE PITUITARY SECRETION OF THE GONADOTROPINS,
LUTEINIZING HORMONE (LH) AND FOLLICLE STIMULATING HORMONE (FSH) THROUGH A NEGATIVE
FEEDBACK MECHANISM. ESTROGENS ACT TO REDUCE THE ELEVATED LEVELS OF THESE
GONADOTROPINS SEEN IN POSTMENOPAUSAL WOMEN.
PHARMACOKINETICS
ABSORPTION
CONJUGATED ESTROGENS ARE SOLUBLE IN WATER AND ARE WELL ABSORBED FROM THE
GASTROINTESTINAL TRACT AFTER RELEASE FROM THE DRUG FORMULATION. THE PREMARIN TABLET
RELEASES CONJUGATED ESTROGENS SLOWLY OVER SEVERAL HOURS. TABLE 1 SUMMARIZES THE
MEAN PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS
FOLLOWING ADMINISTRATION OF 2 X 0.3 MG, 2 X 0.45 MG, AND 2 X 0.625 MG TABLETS TO HEALTHY
POSTMENOPAUSAL WOMEN.
TABLE 1. PHARMACOKINETIC PARAMETERS FOR
PREMARIN
1.2.5.2.1.1.1.1 Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.3 mg
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Page 5
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
82 (33)
7.8 (27)
54.7 (42)
5390 (50)
Baseline-adjusted estrone
58 (42)
7.8 (27)
21.1 (45)
1467 (41)
Equilin
31 (47)
7.2 (28)
18.3 (110)
652 (68)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Estrone
2.5 (32)
6.5 (29)
25.4 (22)
61.0 (43)
Baseline-adjusted total estrone
2.4 (32)
6.5 (29)
16.2 (34)
40.8 (36)
Equilin
1.6 (40)
5.9 (27)
11.8 (21)
22.4 (42)
1.2.5.2.1.1.1.2 Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
.1.2 Estrone
2.1.3 92 (32)
2.1.4 8.7 (28)
.2.1.5 56.4 (68) 5.2.1.6 6344 (56)
.1.7 Baseline-adjusted estrone
2.1.8 65 (40)
2.1.9 8.7 (28)
2.1.10 20.3 (38)
2.1.11 1940 (40)
Equilin
35 (49)
7.6 (33)
21.9 (113)
849 (60)
1.2.5.2.1.11.1.1
1.2.5.2.1.11.1.2 Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
.1.12 Total estrone
2.8 (46)
7.1 (27)
27.6 (35)
77 (34)
.1.13 Baseline-adjusted total estrone
2.6 (46)
7.1 (27)
14.7 (42)
48 (38)
Total equilin
1.9 (53)
5.9 (32)
11.8 (32)
29 (55)
1.2.5.2.1.13.1.1 Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
.1.14 Estrone
.1.15 139 (37) 2.1.16 8.8 (20) 2.1.17 28.0 (30)
2.1.18 5016 (34)
.1.19 Baseline-adjusted estrone
.1.20 120 (41) 2.1.21 8.8 (20)
17.4 (37)
2.1.22 2956 (39)
Equilin
66 (42)
7.9 (19)
13.6 (52)
1210 (37)
1.2.5.2.1.22.1.1
1.2.5.2.1.22.1.2 Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
7.3 (41)
7.3 (24)
15.0 (25)
134 (42)
Baseline-adjusted total estrone
7.1 (41)
7.3 (24)
13.6 (23)
122 (38)
Total equilin
5.0 (42)
6.2 (26)
10.1 (26)
65 (44)
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Page 6
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex hormone
target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG)
and albumin.
Metabolism
EXOGENOUS ESTROGENS ARE METABOLIZED IN THE SAME MANNER AS ENDOGENOUS ESTROGENS.
CIRCULATING ESTROGENS EXIST IN A DYNAMIC EQUILIBRIUM OF METABOLIC INTERCONVERSIONS. THESE
TRANSFORMATIONS TAKE PLACE MAINLY IN THE LIVER. ESTRADIOL IS CONVERTED REVERSIBLY TO ESTRONE,
AND BOTH CAN BE CONVERTED TO ESTRIOL, WHICH IS THE MAJOR URINARY METABOLITE. ESTROGENS ALSO
UNDERGO ENTEROHEPATIC RECIRCULATION VIA SULFATE AND GLUCURONIDE CONJUGATION IN THE LIVER,
BILIARY SECRETION OF CONJUGATES INTO THE INTESTINE, AND HYDROLYSIS IN THE GUT FOLLOWED BY
REABSORPTION. IN POSTMENOPAUSAL WOMEN A SIGNIFICANT PROPORTION OF THE CIRCULATING ESTROGENS
EXISTS AS SULFATE CONJUGATES, ESPECIALLY ESTRONE SULFATE, WHICH SERVES AS A CIRCULATING
RESERVOIR FOR THE FORMATION OF MORE ACTIVE ESTROGENS.
Excretion
ESTRADIOL, ESTRONE, AND ESTRIOL ARE EXCRETED IN THE URINE ALONG WITH GLUCURONIDE AND
SULFATE CONJUGATES.
1.2.6 Special Populations
NO PHARMACOKINETIC STUDIES WERE CONDUCTED IN SPECIAL POPULATIONS, INCLUDING PATIENTS WITH
RENAL OR HEPATIC IMPAIRMENT.
1.2.7 Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
significantly altered. No other clinical drug-drug interaction studies have been conducted with
conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450
3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a
decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4
such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may
increase plasma concentrations of estrogens and may result in side effects.
1.2.8 Clinical Studies
Effects on Vasomotor Symptoms
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805
postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight
treatment groups, receiving either placebo or conjugated estrogens with or without
medroxyprogesterone acetate.
Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of
symptomatic women (n = 241) who had at least 7 moderate to severe hot flushes daily or at least 50
moderate to severe hot flushes during the week before randomization. Premarin (0.3 mg, 0.45 mg, and
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Page 7
0.625 mg tablets) was shown to be statistically better than placebo at weeks 4 and 12 for relief of both
the frequency and severity of moderate to severe vasomotor symptoms. Table 2 shows the adjusted
mean number of hot flushes in the Premarin 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment
groups over the initial 12-week period.
TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY–
MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS
AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE
FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF
Treatment
(No. of Patients)
------------------ No. of Hot Flushes/Day --------------------
-
TIME PERIOD
(WEEK)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change ± SD
p-Values
vs. Placebob
0.625 mg CE
(n = 27)
4
12.29 ± 3.89
1.95 ± 2.77
-10.34 ± 4.73
<0.001
12
12.29 ± 3.89
0.75 ± 1.82
-11.54 ± 4.62
<0.001
0.45 mg CE
(n = 32)
4
12.25 ± 5.04
5.04 ± 5.31
-7.21 ± 4.75
<0.001
12
12.25 ± 5.04
2.32 ± 3.32
-9.93 ± 4.64
<0.001
0.3 mg CE
(n = 30)
4
13.77 ± 4.78
4.65 ± 3.71
-9.12 ± 4.71
<0.001
12
13.77 ± 4.78
2.52 ± 3.23
-11.25 ± 4.60
<0.001
Placebo
(n = 28)
4
11.69 ± 3.87
7.89 ± 5.28
-3.80 ± 4.71
-
12
11.69 ± 3.87
5.71 ± 5.22
-5.98 ± 4.60
-
a: Standard errors based on assumption of equal variances.
b: Based on analysis of covariance with treatment as factor and baseline as covariate.
1.2.9 Effects on Vulvar and Vaginal Atrophy
Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo
were statistically significant (p<0.001) for all treatment groups (conjugated estrogens alone and
conjugated estrogens/medroxyprogesterone acetate treatment groups).
Effects on Bone Mineral Density.
IN THE 3-YEAR, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED POSTMENOPAUSAL
ESTROGEN/PROGESTIN INTERVENTIONS (PEPI) TRIAL, THE EFFECT OF PREMARIN 0.625 MG
(CONJUGATED ESTROGENS TABLETS, USP), GIVEN ALONE OR IN COMBINATION WITH
MEDROXYPROGESTERONE ACETATE (MPA), ON BONE MINERAL DENSITY (BMD) WAS EVALUATED IN
POSTMENOPAUSAL WOMEN. ONE OF THE REGIMENS EVALUATED WAS CONTINUOUS COMBINED
PREMARIN 0.625 MG/MPA 2.5 MG, A REGIMEN SIMILAR TO PREMPRO.
Intent-to-treat subjects
In the intent-to-treat subjects, BMD increased significantly (p<0.001) compared to baseline or placebo
at both the hip and the spine in women assigned to Premarin or the continuous Premarin/MPA
regimen. Spinal BMD increased 3.46% among women assigned to Premarin, increased 4.87% in
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women assigned to the Premarin/MPA regimen and decreased 1.81% in women assigned to placebo.
At the hip, women assigned to Premarin gained 1.31%, women assigned to Premarin/MPA gained
1.94%, while women assigned to placebo lost 1.62%.
Adherent subjects
IN THE ADHERENT SUBJECTS, BMD ALSO INCREASED SIGNIFICANTLY (P<0.001) COMPARED TO
BASELINE OR PLACEBO AT BOTH THE HIP AND THE SPINE IN WOMEN ASSIGNED TO PREMARIN OR
CONTINUOUS PREMARIN/MPA. SPINAL BMD INCREASED 5.16% AMONG WOMEN ASSIGNED TO
PREMARIN, INCREASED 5.49% IN WOMEN ASSIGNED TO PREMARIN/MPA AND DECREASED 2.82% IN
WOMEN ASSIGNED TO PLACEBO. AT THE HIP, WOMEN ASSIGNED TO PREMARIN GAINED 2.60%, WOMEN
ASSIGNED TO PREMARIN/MPA GAINED 2.23% WHILE WOMEN ASSIGNED TO PLACEBO LOST 2.17%.
These results are summarized in Tables 3 and 4 below.
TABLE 3. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD AT 36 MONTHS
IN INTENT-TO-TREAT SUBJECTS**
1.2.9.2 -------------Spine---------------
1.2.9.3 ------------------Hip----------------
Regimen
1.2.9.3
Mean %
Change
95% CI
n
Mean %
Change
95% CI
Premarin 0.625 mg
175
+3.46%*†
2.78, 4.14
175
+1.31%*†
0.76, 1.86
Premarin 0.625 mg/
MPA 2.5 mg
174
+4.87%*†
4.21, 5.52
174
+1.94%*†
1.50, 2.39
Placebo
174
-1.81%*
-2.51, -1.12
173
-1.62%*
-2.16, -1.08
* Denotes a statistically significant mean change from baseline at the 0.001 level.
†
Denotes mean percentage change from baseline is significantly different from placebo at the 0.001
level.
** INCLUDES ALL 523 WOMEN WHO WERE RANDOMIZED TO EITHER PREMARIN, PREMARIN/MPA OR
PLACEBO WHETHER OR NOT THEY COMPLETED THE STUDY. IF BMD WAS NOT AVAILABLE AT 36
MONTHS, THEN THE 12 MONTHS VALUE WAS CARRIED FORWARD AND ANALYZED. BASELINE
VALUES WERE CARRIED FORWARD IF 12 MONTHS AND 36 MONTHS DATA WERE UNAVAILABLE.
MOST PATIENTS WHO DISCONTINUED STUDY MEDICATION WERE FOLLOWED THROUGH MONTH 36
AND COULD HAVE BEEN OFF THERAPY FOR AN EXTENDED PERIOD PRIOR TO THEIR MONTH 36
EVALUATION.
TABLE 4. MEAN PERCENTAGE CHANGES FROM BASELINE IN BMD AT 36
MONTHS
IN ADHERENT SUBJECTS**
1.2.9.4 -------------Spine---------------
1.2.9.5 ------------------Hip----------------
Regimen
1.2.9.5
Mean %
Change
95% CI
n
Mean %
Change
95% CI
Premarin 0.625 mg
95
+5.16%*†
4.32, 6.00
95
+2.60%*†
1.97, 3.23
Premarin 0.625 mg/
MPA 2.5 mg
144
+5.49%*†
4.79, 6.18
144
+2.23%*†
1.75, 2.71
Placebo
124
-2.82%*
-3.54, -2.10
123
-2.17%*
-2.78, -1.56
* Denotes a statistically significant mean change from baseline at the 0.001 level.
†
Denotes mean percentage change from baseline is significantly different from placebo at the 0.001
level.
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Page 9
** Women who completed the study, had BMD reported at month 36, and took 80% or more of their
prescribed medication.
IN GENERAL, OLDER WOMEN (55-64 YEARS OF AGE) TAKING PLACEBO IN THE PEPI STUDY LOST BONE
AT A LOWER RATE THAN YOUNGER WOMEN (45-54 YEARS OF AGE). CONVERSELY, OLDER WOMEN
RECEIVING PREMARIN OR PREMARIN 0.625 MG/MPA 2.5 MG HAD GREATER INCREASES IN BMD THAN
YOUNGER WOMEN. TABLES 5 AND 6 PRESENT DATA FOR WOMEN 45 TO 54 YEARS OF AGE AND WOMEN
55 TO 64 YEARS OF AGE.
TABLE 5. MEAN PERCENT CHANGE FROM BASELINE IN BMD
FOR WOMEN 45 TO 54 YEARS OF AGE
1.2.9.6 Intent-To-Treat Subjects
1.2.9.7 Adherent Subjects
Regimen
1.2.9.7
Mean %
Change at
the Spine
N
Mean %
Change at
the Hip
n
Mean %
Change at
the Spine
n
Mean %
Change at
the Hip
Premarin 0.625 mg
74
+2.45%†**
74
+1.37%†**
43
+3.73%†**
43
+2.20%†**
Premarin 0.625 mg/
MPA 2.5 mg
69
+3.53%†**
69
+1.26%†**
58
+3.97%†**
58
+1.48%†**
Placebo
78
-2.82%**
78
-2.23%**
50
-4.02%**
50
-3.04%**
** Denotes a statistically significant mean change from baseline at the 0.001 level.
†
Denotes the mean percent change from baseline is significantly different from placebo at the 0.001
level.
TABLE 6. MEAN PERCENT CHANGE FROM BASELINE IN BMD
FOR WOMEN 55 TO 64 YEARS OF AGE
1.2.9.8 Intent-To-Treat Subjects
1.2.9.9 Adherent Subjects
Regimen
1.2.9.9
Mean %
Change at
the Spine
n
Mean %
Change at
the Hip
n
Mean %
Change at
the Spine
n
Mean %
Change at
the Hip
Premarin 0.625 mg
101
+4.21%†‡**
101
+1.27%†**
52
+6.34%†‡**
52
+2.93%†**
Premarin 0.625 mg/
MPA 2.5 mg
105
+5.75%†‡**
105
+2.39%†**
86
+6.51%†‡**
86
+2.73%†**
Placebo
95
-1.01%*
94
-1.14%*
73
-2.04%‡**
72
-1.60%**
* Denotes a statistically significant mean change from baseline at the 0.05 level.
** Denotes a statistically significant mean change from baseline at the 0.001 level.
†
Denotes the mean percent change from baseline is significantly different from placebo at the 0.001
level.
‡
Denotes the mean percent change from baseline in the older age group is significantly different
from the mean
percent change in the younger age group at the 0.05 level.
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg
conjugated equine estrogens per day) alone or the use of Prempro (0.625 mg conjugated equine
estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of
certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD)
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(nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse
outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer,
stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to
other cause. The study did not evaluate the effects of Premarin or Prempro on menopausal symptoms.
The Premarin-only substudy is continuing and results have not been reported. The Prempro substudy
was stopped early because, according to the predefined stopping rule, the increased risk of breast
cancer and cardiovascular events exceeded the specified benefits included in the “global index.”
Results of the Prempro substudy, which included 16,608 women (average age of 63 years, range 50 to
79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in
Table 7 below.
Table 7. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPRO
SUBSTUDY OF WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000 Person-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than the
events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosisd
2.07 (1.49-2.87)
13
26
Vertebral fracturesd
0.66 (0.44-0.98)
15
9
Other osteoporotic fracturesd
0.77 (0.69-0.86)
170
131
a:
Adapted from JAMA, 2002; 288:321-333
b:
Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c:
A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events,
invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death
due to other causes
d:
Not included in Global Index
*
Nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index,” absolute excess risks per 10,000 person-years in the
group treated with Prempro were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more
invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal
cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index”
was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause
mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the
menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy,
topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with
metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant risk of
osteoporosis and non-estrogen medications should be carefully considered.
THE MAINSTAYS FOR DECREASING THE RISK OF POSTMENOPAUSAL OSTEOPOROSIS ARE WEIGHT-
BEARING EXERCISE, ADEQUATE CALCIUM AND VITAMIN D INTAKE, AND WHEN INDICATED,
PHARMACOLOGIC THERAPY. POSTMENOPAUSAL WOMEN REQUIRE AN AVERAGE OF 1500 MG/DAY OF
ELEMENTAL CALCIUM. THEREFORE, WHEN NOT CONTRAINDICATED, CALCIUM SUPPLEMENTATION
MAY BE HELPFUL FOR WOMEN WITH SUBOPTIMAL DIETARY INTAKE. VITAMIN D SUPPLEMENTATION
OF 400-800 IU/DAY MAY ALSO BE REQUIRED TO ENSURE ADEQUATE DAILY INTAKE IN
POSTMENOPAUSAL WOMEN.
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast except in appropriately selected patients being
treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial
infarction).
6. Liver dysfunction or disease.
7. Premarin tablets should not be used in patients with known hypersensitivity to their ingredients.
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8. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There appears to
be little or no increased risk of birth defects in women who have used estrogen and progestins from
oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS.)
WARNINGS
SEE BOXED WARNINGS.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk of
endometrial cancer.
1. Cardiovascular Disorders. Estrogen and estrogen/progestin therapy have been associated with an
increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous
thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these
occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
a.
Coronary heart disease and stroke. In the Premarin substudy of the Women’s Health Initiative
study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in
women receiving Premarin compared to placebo. These observations are preliminary, and the study
is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the Prempro substudy of WHI, an increased risk of coronary heart disease (CHD) events
(defined as non-fatal myocardial infarction and CHD death) was observed in women receiving
Prempro compared to women receiving placebo (37 vs 30 per 10,000 person-years). The increase
in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving
Prempro compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase
in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with Prempro (0.625 mg conjugated
equine estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with Prempro did not reduce the
overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the Prempro-treated group than in the placebo group in year 1, but
not during the subsequent years. Two thousand three hundred and twenty one women from the
original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average
follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD
events were comparable among women in the Prempro group and the placebo group in HERS,
HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
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b. Venous thromboembolism (VTE). In the Premarin substudy of the Women's Health Initiative
(WHI), an increase in VTE has been observed in women receiving Premarin compared to placebo.
These observations are preliminary, and the study is continuing. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
In the Prempro substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis
and pulmonary embolism, was observed in women receiving Prempro compared to women
receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the Prempro group
compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was
observed during the first year and persisted.
IF FEASIBLE, ESTROGENS SHOULD BE DISCONTINUED AT LEAST 4 TO 6 WEEKS BEFORE SURGERY OF THE
TYPE ASSOCIATED WITH AN INCREASED RISK OF THROMBOEMBOLISM, OR DURING PERIODS OF PROLONGED
IMMOBILIZATION.
2. Malignant neoplasms.
a.
Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users with an intact uterus is about 2- to 12-fold greater than in
non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies
show no significant increased risk associated with the use of estrogens for less than one year.
The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold
for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years
after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule
out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal
estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a
precursor to endometrial cancer.
b. Breast cancer. Estrogen and estrogen/progestin therapy in postmenopausal women has been
associated with an increased risk of breast cancer. In the Prempro substudy of the Women's
Health Initiative study (WHI), a 26% increase of invasive breast cancer (38 vs 30 per 10,000
woman-years) after an average of 5.2 years of treatment was observed in women receiving
Prempro compared to women receiving placebo. The increased risk of breast cancer became
apparent after 4 years on Prempro. The women reporting prior postmenopausal use of estrogen
and/or estrogen with progestin had a higher relative risk for breast cancer associated with
Prempro than those who had never used these hormones. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
In the Premarin substudy of the WHI study, no increased risk of breast cancer in estrogen-treated
women compared to placebo was reported after an average of 5.2 years of therapy. These data are
preliminary and that substudy of WHI is continuing.
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Epidemiologic studies have reported an increased risk of breast cancer in association with
increasing duration of postmenopausal treatment with estrogens, with or without progestin. This
association was reanalyzed in original data from 51 studies that involved treatment with various
doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of
having breast cancer diagnosed became apparent after about 5 years of continued treatment, and
subsided after treatment had been discontinued for about 5 years. Some later studies have
suggested that treatment with estrogen and progestin increases the risk of breast cancer more than
treatment with estrogen alone.
A postmenopausal woman without a uterus who requires estrogen should receive estrogen-alone
therapy and should not be exposed unnecessarily to progestins. All postmenopausal women should
receive yearly breast exams by a healthcare provider and perform monthly breast self-
examinations. In addition, mammography examinations should be scheduled based on patient age
and risk factors.
3. Gallbladder Disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery
in postmenopausal women receiving estrogens has been reported.
4.
Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with
breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and
appropriate measures taken to reduce the serum calcium level.
5. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is sudden partial or complete loss
of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema
or retinal vascular lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or
daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a
precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens
compared to estrogen-alone regimens. These include: a possible increased risk of breast cancer,
adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of
glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals during estrogen use.
3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE
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study, the mean percent increase from baseline in serum triglycerides after one year of treatment
with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and
10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0,
and 5.5, respectively.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should
be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid hormone,
thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on
thyroid hormone replacement therapy who are also receiving estrogens may require increased
doses of their thyroid replacement therapy. These patients should have their thyroid function
monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer.
Use of estrogen-only products, in particular for ten or more years, has been associated with an
increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a
significant association. Data are insufficient to determine whether there is an increased risk with
combined estrogen/progestin therapy in postmenopausal women.
9.
EXACERBATION OF ENDOMETRIOSIS.
ENDOMETRIOSIS MAY BE EXACERBATED WITH ADMINISTRATION OF ESTROGENS.
A FEW CASES OF MALIGNANT TRANSFORMATION OF RESIDUAL ENDOMETRIAL IMPLANTS HAVE
BEEN REPORTED IN WOMEN TREATED POST-HYSTERECTOMY WITH ESTROGEN-ONLY THERAPY.
FOR PATIENTS KNOWN TO HAVE RESIDUAL ENDOMETRIOSIS POST-HYSTERECTOMY, THE ADDITION
OF PROGESTIN SHOULD BE CONSIDERED.
10. Exacerbation of other conditions.
Estrogens therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, or
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in patients with these conditions.
B. Patient Information.
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients
for whom they prescribe Premarin.
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C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose for the treatment of postmenopausal
moderate to severe vasomotor symptoms and moderate to severe symptoms of postmenopausal vulvar
and vaginal atrophy and then guided by clinical response rather than by serum hormone levels (e.g.,
estradiol, FSH). Laboratory parameters may be useful in guiding dosage for the treatment of
hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
D. Drug/Laboratory Test Interactions.
1. ACCELERATED PROTHROMBIN TIME, PARTIAL THROMBOPLASTIN TIME, AND PLATELET
AGGREGATION TIME; INCREASED PLATELET COUNT; INCREASED FACTORS II, VII ANTIGEN, VIII
ANTIGEN, VIII COAGULANT ACTIVITY, IX, X, XII, VII-X COMPLEX, II-VII-X COMPLEX, AND BETA-
THROMBOGLOBULIN; DECREASED LEVELS OF ANTI-FACTOR XA AND ANTITHROMBIN III,
DECREASED ANTITHROMBIN III ACTIVITY; INCREASED LEVELS OF FIBRINOGEN AND FIBRINOGEN
ACTIVITY; INCREASED PLASMINOGEN ANTIGEN AND ACTIVITY.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the
elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement
therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex
hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex
steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other
plasma proteins may be increased (angiotensinogen/ renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol
concentrations, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility.
Long term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See
BOXED WARNINGS, CONTRAINDICATIONS, and WARNINGS).
F. Pregnancy.
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).
G. Nursing Mothers.
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the
milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.
Caution should be exercised when Premarin is administered to a nursing woman.
H. Pediatric Use.
ESTROGEN THERAPY HAS BEEN USED FOR THE INDUCTION OF PUBERTY IN ADOLESCENTS WITH SOME
FORMS OF PUBERTAL DELAY. SAFETY AND EFFECTIVENESS IN PEDIATRIC PATIENTS HAVE NOT
OTHERWISE BEEN ESTABLISHED.
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LARGE AND REPEATED DOSES OF ESTROGEN OVER AN EXTENDED TIME PERIOD HAVE BEEN SHOWN
TO ACCELERATE EPIPHYSEAL CLOSURE, WHICH COULD RESULT IN SHORT STATURE IF TREATMENT IS
INITIATED BEFORE THE COMPLETION OF PHYSIOLOGIC PUBERTY IN NORMALLY DEVELOPING
CHILDREN. IF ESTROGEN IS ADMINISTERED TO PATIENTS WHOSE BONE GROWTH IS NOT COMPLETE,
PERIODIC MONITORING OF BONE MATURATION AND EFFECTS ON EPIPHYSEAL CENTERS IS
RECOMMENDED DURING ESTROGEN ADMINISTRATION.
ESTROGEN TREATMENT OF PREPUBERTAL GIRLS ALSO INDUCES PREMATURE BREAST DEVELOPMENT
AND VAGINAL CORNIFICATION, AND MAY INDUCE VAGINAL BLEEDING. IN BOYS, ESTROGEN
TREATMENT MAY MODIFY THE NORMAL PUBERTAL PROCESS AND INDUCE GYNECOMASTIA. SEE
INDICATIONS AND DOSAGE AND ADMINISTRATION SECTIONS.
I. Geriatric Use.
Of the total number of subjects in the Prempro substudy of the Women’s Health Initiative study, 44%
(n=7320) were 65 years and over, while 6.6% (n=1,095) were 75 and over (see CLINICAL
PHARMACOLOGY, Clinical Studies). No significant differences in safety were observed between
subjects 65 years and over compared to younger subjects. There was a higher incidence of stroke and
invasive breast cancer in women 75 and over compared to younger subjects.
WITH RESPECT TO EFFICACY IN THE APPROVED INDICATIONS, THERE HAVE NOT BEEN SUFFICIENT
NUMBERS OF GERIATRIC PATIENTS INVOLVED IN STUDIES UTILIZING PREMARIN TO DETERMINE
WHETHER THOSE OVER 65 YEARS OF AGE DIFFER FROM YOUNGER SUBJECTS IN THEIR RESPONSE TO
PREMARIN.
1.2.10 ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE
REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED
TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED
IN PRACTICE. THE ADVERSE REACTION INFORMATION FROM CLINICAL TRIALS DOES, HOWEVER,
PROVIDE A BASIS FOR IDENTIFYING THE ADVERSE EVENTS THAT APPEAR TO BE RELATED TO DRUG
USE AND FOR APPROXIMATING RATES.
During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65
years of age (88% Caucasian), 1012 women were treated with conjugated estrogens and 332 were
treated with placebo. Table 8 summarizes adverse events that occurred at a rate of ≥ 5%.
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TABLE 8. NUMBER (%) OF PATIENTS REPORTING ≥ 5%
TREATMENT EMERGENT ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Any adverse
event
93%
90%
90%
85%
Body as a Whole
Abdominal
pain
16%
15%
17%
11%
Accidental
injury
6%
12%
6%
9%
Asthenia
7%
7%
8%
5%
Back pain
14%
13%
13%
12%
Flu syndrome
11%
11%
10%
11%
Headache
26%
32%
29%
28%
Infection
18%
22%
23%
22%
Pain
17%
18%
20%
18%
Digestive System
Diarrhea
6%
7%
6%
6%
Dyspepsia
9%
9%
11%
14%
Flatulence
7%
7%
6%
3%
Nausea
9%
6%
6%
9%
Musculoskeletal System
Arthralgia
14%
12%
7%
12%
Leg cramps
5%
7%
3%
2%
Myalgia
5%
5%
9%
8%
Nervous System
Depression
7%
8%
5%
7%
Dizziness
5%
6%
4%
5%
Insomnia
6%
7%
7%
10%
Nervousness
3%
5%
2%
2%
Respiratory
System
Cough
increased
4%
7%
4%
4%
Pharyngitis
10%
10%
12%
11%
Rhinitis
6%
9%
10%
13%
Sinusitis
6%
11%
7%
7%
Upper
respiratory
infection
12%
10%
9%
11%
Skin and
Appendages
Pruritus
4%
5%
5%
2%
Urogenital
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TABLE 8. NUMBER (%) OF PATIENTS REPORTING ≥ 5%
TREATMENT EMERGENT ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
System
Breast pain
11%
12%
7%
9%
Leukorrhea
5%
7%
4%
3%
Vaginal
hemorrhage
14%
4%
2%
0
Vaginal
moniliasis
6%
5%
5%
2%
Vaginitis
7%
6%
5%
1%
THE FOLLOWING ADDITIONAL ADVERSE REACTIONS HAVE BEEN REPORTED WITH ESTROGEN AND/OR
PROGESTIN THERAPY:
1. Genitourinary system.
CHANGES IN VAGINAL BLEEDING PATTERN AND ABNORMAL WITHDRAWAL BLEEDING OR FLOW;
BREAKTHROUGH BLEEDING, SPOTTING, DYSMENORRHEA.
INCREASE IN SIZE OF UTERINE LEIOMYOMATA.
VAGINITIS, INCLUDING VAGINAL CANDIDIASIS.
CHANGE IN AMOUNT OF CERVICAL SECRETION.
CHANGE IN CERVICAL ECTROPION.
Ovarian cancer.
Endometrial hyperplasia.
Endometrial cancer.
2. Breasts.
Tenderness, enlargement, pain, discharge, galactorrhea.
Fibrocystic breast changes.
BREAST CANCER.
3. Cardiovascular
Deep and superficial venous thrombosis.
Pulmonary embolism.
Thrombophlebitis.
Myocardial infarction.
Stroke.
Increase in blood pressure.
4. Gastrointestinal.
Nausea, vomiting.
Abdominal cramps, bloating.
CHOLESTATIC JAUNDICE.
Increased incidence of gallbladder disease.
PANCREATITIS.
Enlargement of hepatic hemangiomas.
5. Skin.
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Chloasma or melasma that may persist when drug is discontinued.
Erythema multiforme.
Erythema nodosum.
Hemorrhagic eruption.
Loss of scalp hair.
Hirsutism.
Pruritus, rash.
6. Eyes.
RETINAL VASCULAR THROMBOSIS.
Steepening of corneal curvature.
Intolerance to contact lenses.
7. Central Nervous System.
Headache.
Migraine.
Dizziness
Mental depression.
Chorea.
Nervousness.
Mood disturbances.
Irritability.
Exacerbation of epilepsy.
8. Miscellaneous
Increase or decrease in weight.
Reduced carbohydrate tolerance.
Aggravation of porphyria
Edema.
Arthralgias.
Leg cramps.
Changes in libido
Urticaria, angioedema, anaphylactoid/anaphylactic reactions.
Hypocalcemia.
Exacerbation of asthma.
Increased triglycerides.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-
containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and
vomiting, and withdrawal bleeding may occur in females.
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DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin.
Use of estrogen, alone or in combination with a progestin, should be limited to the shortest duration
consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated
periodically as clinically appropriate (e.g., at 3-month to 6-month intervals) to determine if treatment is
still necessary (see BOXED WARNINGS and WARNINGS). For women with a uterus, adequate
diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out
malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of
vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the
treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products
should be considered.
PATIENTS SHOULD BE TREATED WITH THE LOWEST EFFECTIVE DOSE. GENERALLY WOMEN
SHOULD BE STARTED AT 0.3 MG PREMARIN DAILY. SUBSEQUENT DOSAGE ADJUSTMENT MAY BE
MADE BASED UPON THE INDIVIDUAL PATIENT RESPONSE. THIS DOSE SHOULD BE PERIODICALLY
REASSESSED BY THE HEALTHCARE PROVIDER.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
2.
FOR PREVENTION OF POSTMENOPAUSAL OSTEOPOROSIS:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women
at significant risk of osteoporosis and non-estrogen medications should be carefully considered. Patients should be
treated with the lowest effective dose. Generally women should be started at 0.625 mg Premarin daily. Dosage may be
adjusted depending on individual clinical and bone mineral density responses. This dose should be periodically
reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian
failure:
Female hypogonadism0.3 mg to 0.625 mg daily, administered cyclically (e.g., three weeks on
and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness
of the endometrium.
IN CLINICAL STUDIES OF DELAYED PUBERTY DUE TO FEMALE HYPOGONADISM, BREAST
DEVELOPMENT WAS INDUCED BY DOSES AS LOW AS 0.15 MG. THE DOSAGE MAY BE GRADUALLY
TITRATED UPWARD AT 6 TO 12 MONTH INTERVALS AS NEEDED TO ACHIEVE APPROPRIATE BONE
AGE ADVANCEMENT AND EVENTUAL EPIPHYSEAL CLOSURE. CLINICAL STUDIES SUGGEST THAT
DOSES OF 0.15 MG, 0.3 MG, AND 0.6 MG ARE ASSOCIATED WITH MEAN RATIOS OF BONE AGE
ADVANCEMENT TO CHRONOLOGICAL AGE PROGRESSION (∆BA/∆CA) OF 1.1, 1.5, AND 2.1,
RESPECTIVELY. (PREMARIN IN THE DOSE STRENGTH OF 0.15 MG IS NOT AVAILABLE
COMMERCIALLY). AVAILABLE DATA SUGGEST THAT CHRONIC DOSING WITH 0.625 MG IS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-115, S-130
Page 22
SUFFICIENT TO INDUCE ARTIFICIAL CYCLIC MENSES WITH SEQUENTIAL PROGESTIN TREATMENT
AND TO MAINTAIN BONE MINERAL DENSITY AFTER SKELETAL MATURITY IS ACHIEVED.
Female castration or primary ovarian failure1.25 mg daily, cyclically. Adjust dosage, upward or
downward, according to severity of symptoms and response of the patient. For maintenance, adjust
dosage to lowest level that will provide effective control.
4.
For treatment of breast cancer, for palliation only, in appropriately selected women and men
with metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2.5 mg three times daily. The effectiveness of therapy can be judged by phosphatase
determinations as well as by symptomatic improvement of the patient.
HOW SUPPLIED
Premarin (conjugated estrogens tablets, USP)
—Each oval purple tablet contains 2.5 mg, in bottles of 100 (NDC 0046-0865-81) and 1,000 (NDC
0046-0865-91).
—Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-0866-81); 1,000 (NDC
0046-0866-91); and Unit-Dose packages of 100 (NDC 0046-0866-99).
—Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-0864-81).
—Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-0867-81); 1,000
(NDC 0046-0867-91); and Unit-Dose Packages of 100 (NDC
0046-0867-99).
—EACH OVAL BLUE TABLET CONTAINS 0.45 MG, IN BOTTLES OF 100 (NDC 0046-0936-81); AND UNIT-DOSE
PACKAGES OF 100 (NDC 0046-0936-099).
—Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-0868-81) and 1,000
(NDC 0046-0868-91).
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
Store at 20-25°° (68-77°° F); excursions permitted to 15-30°° C (59-86°° F). [see
USP Controlled Room Temperature]
Dispense in a well-closed container as defined in the USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-115, S-130
Page 23
1.2.11 PATIENT INFORMATION
Premarin
(conjugated estrogens tablets, USP)
READ THIS PATIENT INFORMATION BEFORE YOU START TAKING PREMARIN AND READ WHAT YOU GET
EACH TIME YOU REFILL PREMARIN. THERE MAY BE NEW INFORMATION. THIS INFORMATION DOES NOT
TAKE THE PLACE OF TALKING TO YOUR HEALTHCARE PROVIDER ABOUT YOUR MEDICAL CONDITION
OR YOUR TREATMENT.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or
strokes.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. You and your healthcare provider should
talk regularly about whether you still need treatment with estrogens.
1.2.12 What is Premarin?
PREMARIN IS A MEDICINE THAT CONTAINS A MIXTURE OF ESTROGEN HORMONES.
Premarin is used after menopause to:
• reduce moderate to severe hot flashes. Estrogens are hormones made by a woman's ovaries. The
ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop
in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual
periods). Sometimes both ovaries are removed during an operation before natural menopause takes
place. The sudden drop in estrogen levels causes "surgical menopause."
When the estrogen levels begin dropping, some women develop very uncomfortable symptoms,
such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and
sweating ("hot flashes" or "hot flushes"). In some women the symptoms are mild, and they will not
need to take estrogens. In other women, symptoms can be more severe. You and your healthcare
provider should talk regularly about whether you still need treatment with Premarin.
• treat moderate to severe dryness, itching, and burning, in and around the vagina. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin to control these problems.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-115, S-130
Page 24
••
help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from
menopause is a thinning of the bones that makes them weaker and easier to break. If you use
Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider about
whether a different treatment or medicine without estrogens might be better for you. You and your
healthcare provider should talk regularly about whether you should continue with Premarin.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements
may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about
exercise and supplements with your healthcare provider before starting them.
Premarin is also used to:
• treat certain conditions in women before menopause if their ovaries do not make enough
estrogen naturally.
• ease symptoms of certain cancers that have spread through the body, in men and women.
1.2.13 Who should not take Premarin?
DO NOT START TAKING PREMARIN IF YOU:
•
HAVE UNUSUAL VAGINAL BLEEDING.
• currently have or have had certain cancers. Estrogens may increase the chances of getting
certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer,
talk with your healthcare provider about whether you should take Premarin.
• had a stroke or heart attack in the past year.
••
currently have or have had blood clots.
••
are allergic to Premarin tablets or any of its ingredients. See the end of this leaflet for a list of all the
ingredients in Premarin.
••
think you may be pregnant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-115, S-130
Page 25
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin can pass into your milk.
about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine,
endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels
in your blood.
••
about all the medicines you take, including prescription and nonprescription medicines, vitamins,
and herbal supplements. Some medicines may affect how Premarin works. Premarin may also
affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop taking estrogens.
HOW SHOULD I TAKE PREMARIN?
•
TAKE ONE PREMARIN TABLET AT THE SAME TIME EACH DAY.
•
IF YOU MISS A DOSE, TAKE IT AS SOON AS POSSIBLE. IF IT IS ALMOST TIME FOR YOUR NEXT DOSE,
SKIP THE MISSED DOSE AND GO BACK TO YOUR NORMAL SCHEDULE. DO NOT TAKE 2 DOSES AT
THE SAME TIME.
•
Estrogens should be used only as long as needed. You and your healthcare provider should talk
regularly (for example, every 3 to 6 months) about whether you still need treatment with Premarin.
1.2.14 What are the possible side effects of Premarin?
Less common but serious side effects include:
•
Breast cancer
•
Cancer of the uterus
•
Stroke
•
Heart attack
•
Blood clots
•
Gallbladder disease
•
Ovarian cancer
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-115, S-130
Page 26
These are some of the warning signs of serious side effects:
•
Breast lumps
•
Unusual vaginal bleeding
•
Dizziness and faintness
•
Changes in speech
•
Severe headaches
•
Chest pain
•
Shortness of breath
•
Pains in your legs
•
Changes in vision
•
Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other unusual
symptom that concerns you.
Common side effects include:
•
Headache
•
Breast pain
•
Irregular vaginal bleeding or spotting
•
Stomach/abdominal cramps, bloating
•
Nausea and vomiting
•
Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin?
•
Talk with your healthcare provider regularly about whether you should continue taking Premarin.
•
If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is
right for you.
•
See your healthcare provider right away if you get vaginal bleeding while taking Premarin.
•
Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider
tells you something else. If members of your family have had breast cancer or if you have ever had
breast lumps or an abnormal mammogram, you may need to have breast exams more often.
•
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if
you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare
provider for ways to lower your chances for getting heart disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:33.482283 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/004782s115lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 115} |
7,438 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AFREZZA® safely and effectively. See full prescribing information for
AFREZZA®.
AFREZZA® (insulin human) Inhalation Powder
Initial U.S. Approval: 2014
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS
WITH CHRONIC LUNG DISEASE
See full prescribing information for complete boxed warning.
• Acute bronchospasm has been observed in patients with asthma
and COPD using AFREZZA. (5.1)
• AFREZZA is contraindicated in patients with chronic lung
disease such as asthma or COPD. (4)
• Before initiating AFREZZA, perform a detailed medical history,
physical examination, and spirometry (FEV1) to identify
potential lung disease in all patients. (2.5), (5.1)
----------------------RECENT MAJOR CHANGES------------------------
• Dosage and Administration (2)
4/2015
----------------------INDICATIONS AND USAGE------------------------
• AFREZZA® is a rapid acting inhaled insulin indicated to improve
glycemic control in adult patients with diabetes mellitus. (1)
Important limitations of use:
• In patients with type 1 diabetes, must use with a long-acting insulin. (1)
• Not recommended for the treatment of diabetic ketoacidosis. (1)
• Not recommended in patients who smoke (1)
-------------------DOSAGE AND ADMINISTRATION -----------------
• Administer using a single inhalation per cartridge (2.1)
• Administer at the beginning of a meal (2.2)
• Dosing must be individualized (2.2)
• Before initiating, perform a detailed medical history, physical examination,
and spirometry (FEV1) in all patients to identify potential lung disease (2.5)
------------------DOSAGE FORMS AND STRENGTHS ---------------
AFREZZA is available as single-use cartridges of: (3)
• 4 units
• 8 units
• 12 units
------------------------ CONTRAINDICATIONS ------------------------
• During episodes of hypoglycemia (4)
• Chronic lung disease, such as asthma, or chronic obstructive pulmonary
disease (4)
• Hypersensitivity to regular human insulin or any of the AFREZZA
excipients (4 )
--------------------- WARNINGS AND PRECAUTIONS ---------------
• Acute Bronchospasm:
Acute bronchospasm has been observed in
patients with asthma and COPD. Before initiating, perform spirometry
(FEV1) in all patients. Do not use in patients with chronic lung disease
(2.5, 4, 5.1)
• Change in Insulin Regimen: Carry out under close medical supervision and
increase frequency of blood glucose monitoring. (5.2)
• Hypoglycemia: May be life-threatening. Increase frequency of glucose
monitoring with changes to: insulin dosage, co-administered glucose
lowering medications, meal pattern, physical activity; and in patients with
renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6, 7, 8.6,
8.7)
• Decline in Pulmonary Function: Assess pulmonary function (e.g.,
spirometry) before initiating, after 6 months of therapy, and annually, even
in the absence of pulmonary symptoms. (2.5, 5.4)
• Lung Cancer: AFREZZA should not be used in patients with active lung
cancer. In patients with a history of lung cancer or at risk for lung cancer,
the benefit of AFREZZA use should outweigh this potential risk. (5.5)
• Diabetic Ketoacidosis: More patients using AFREZZA experienced
diabetic ketoacidosis in clinical trials. In patients at risk for DKA, monitor
and change to alternate route of insulin delivery, if indicated. (5.6)
• Hypersensitivity Reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, can occur with insulin products, including
AFREZZA. Discontinue AFREZZA, monitor and treat if indicated. (5.7)
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients
at risk of hypokalemia and treat if indicated. (5.8)
• Fluid Retention and Heart Failure with Concomitant Use of
Thiazolidinediones (TZDs): Observe for signs and symptoms of heart
failure; consider dosage reduction or discontinuation if heart failure occurs.
(5.9)
---------------------------- ADVERSE REACTIONS ----------------------
The most common adverse reactions associated with AFREZZA (2% or
greater incidence) are hypoglycemia, cough, and throat pain or irritation (6)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
at (1-800-633-1610) or FDA at (1-800-FDA-1088) or
www.fda.gov/medwatch.
---------------------------- DRUG INTERACTIONS ----------------------
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be
needed. (7.1, 7.2, 7.3)
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and
reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.
(7.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 4/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH
CHRONIC LUNG DISEASE
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Route of Administration
2.2 Dosage Information
2.3 AFREZZA Administration for Doses Exceeding 12 units
2.4 Dosage Adjustment due to Drug Interactions
2.5 Lung Function Assessment Prior to Administration
2.6 Important Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Acute Bronchospasm in Patients with Chronic Lung Disease
5.2 Changes in Insulin Regimen
5.3 Hypoglycemia
5.4 Decline in Pulmonary Function
5.5 Lung Cancer
5.6 Diabetic Ketoacidosis
5.7 Hypersensitivity Reactions
5.8 Hypokalemia
Reference ID: 3734773
5.9 Fluid Retention and Heart Failure with Concomitant Use of
PPAR-gamma Agonists
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect
of AFREZZA
7.3 Drugs That May Increase or Decrease the Blood Glucose
Lowering Effect of AFREZZA
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
11.1 AFREZZA Cartridges
11.2 AFREZZA Inhaler
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.3 Type 2 Diabetes
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus
14.2 Type 1 Diabetes
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC
LUNG DISEASE
• Acute bronchospasm has been observed in patients with asthma and COPD
using AFREZZA. [see Warnings and Precautions (5.1)].
• AFREZZA is contraindicated in patients with chronic lung disease such as
asthma or COPD. [see Contraindications (4)].
• Before initiating AFREZZA, perform a detailed medical history, physical
examination, and spirometry (FEV1) to identify potential lung disease in all
patients [see Dosage and Administration (2.5), Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult
patients with diabetes mellitus.
Limitations of Use:
• AFREZZA is not a substitute for long-acting insulin. AFREZZA must be used in
combination with long-acting insulin in patients with type 1 diabetes mellitus.
• AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning
and Precautions (5.6)].
• The safety and efficacy of AFREZZA in patients who smoke has not been established.
The use of AFREZZA is not recommended in patients who smoke or who have recently
stopped smoking.
2 DOSAGE AND ADMINISTRATION
2.1 Route of Administration
AFREZZA should only be administered via oral inhalation using the AFREZZA Inhaler.
AFREZZA is administered using a single inhalation per cartridge.
2.2 Dosage Information
Administer AFREZZA at the beginning of the meal.
Dosage adjustment may be needed when switching from another insulin to AFREZZA [see
Warnings and Precautions (5.2)].
Page 3 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Starting Mealtime Dose:
• Insulin Naïve Individuals: Start on 4 units of AFREZZA at each meal.
• Individuals Using Subcutaneous Mealtime (Prandial) Insulin: Determine the
appropriate AFREZZA dose for each meal by converting from the injected dose using
Figure 1.
• Individuals Using Subcutaneous Pre-mixed Insulin: Estimate the mealtime injected
dose by dividing half of the total daily injected pre-mixed insulin dose equally among
the three meals of the day. Convert each estimated injected mealtime dose to an
appropriate AFREZZA dose using Figure 1. Administer half of the total daily
injected pre-mixed dose as an injected basal insulin dose.
Figure 1. Mealtime AFREZZA Dose Conversion Table conversion table
Mealtime Dose Adjustment
Adjust the dosage of AFREZZA based on the individual's metabolic needs, blood glucose
monitoring results and glycemic control goal.
Dosage adjustments may be needed with changes in physical activity, changes in meal
patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic
function or during acute illness [see Warnings and Precautions (5.3), and Use in Specific
Populations (8.6,8.7)].
Page 4 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carefully monitor blood glucose control in patients requiring high doses of AFREZZA. If, in
these patients, blood glucose control is not achieved with increased AFREZZA doses,
consider use of subcutaneous mealtime insulin.
2.3 AFREZZA Administration for Doses Exceeding 12 units
For AFREZZA doses exceeding 12 units, inhalations from multiple cartridges are necessary.
To achieve the required total mealtime dose, patients should use a combination of 4 unit, 8
unit and 12 unit cartridges. Examples of cartridge combinations for doses of up to 24 units
are shown in Figure 1. For doses above 24 units, combinations of different multiple
cartridges can be used.
2.4 Dosage Adjustment due to Drug Interactions
Dosage adjustment may be needed when AFREZZA is coadministered with certain drugs
[see Drug Interactions (7)].
2.5 Lung Function Assessment Prior to Administration
AFREZZA is contraindicated in patients with chronic lung disease because of the risk of
acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical
history, physical examination and spirometry (FEV1) in all patients to identify potential lung
disease [see Contraindications (4) and Warnings and Precautions (5.1)].
2.6 Important Administration Instructions
See Patient Instructions for Use for complete administration instructions with illustrations.
Keep the inhaler level with the white mouthpiece on top and purple base on the bottom after
a cartridge has been inserted into the inhaler. Loss of drug effect can occur if the inhaler is
turned upside down, held with the mouthpiece pointing down, shaken (or dropped) after the
cartridge has been inserted but before the dose has been administered. If any of the above
occur, the cartridge should be replaced before use.
3 DOSAGE FORMS AND STRENGTHS
AFREZZA (insulin human) Inhalation Powder is available as 4 unit, 8 unit and 12 unit single
use cartridges to be administered via oral inhalation with the AFREZZA Inhaler only. [see
How Supplied/Storage and Handling (16)].
4 CONTRAINDICATIONS
AFREZZA is contraindicated in patients with the following:
• During episodes of hypoglycemia
• Chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD),
because of the risk of acute bronchospasm [see Warnings and Precautions (5.1)].
• Hypersensitivity to regular human insulin or any of the AFREZZA excipients [see
Warnings and Precautions (5.7)].
Page 5 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Acute Bronchospasm in Patients with Chronic Lung Disease
Because of the risk of acute bronchospasm, AFREZZA is contraindicated in patients with
chronic lung disease such as asthma or COPD [see Contraindications (4)].
Before initiating therapy with AFREZZA, evaluate all patients with a medical history,
physical examination and spirometry (FEV1) to identify potential underlying lung disease.
Acute bronchospasm has been observed following AFREZZA dosing in patients with asthma
and patients with COPD. In a study of patients with asthma, bronchoconstriction and
wheezing following AFREZZA dosing was reported in 29% (5 out of 17) and 0% (0 out of
13) of patients with and without a diagnosis of asthma, respectively. In this study, a mean
decline in FEV1 of 400 mL was observed 15 minutes after a single dose in patients with
asthma. In a study of patients with COPD (n=8), a mean decline in FEV1 of 200 mL was
observed 18 minutes after a single dose of AFREZZA. The long-term safety and efficacy of
AFREZZA in patients with chronic lung disease has not been established.
5.2 Changes in Insulin Regimen
Glucose monitoring is essential for patients receiving insulin therapy. Changes in insulin
strength, manufacturer, type, or method of administration may affect glycemic control and
predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. These
changes should be made under close medical supervision and the frequency of blood glucose
monitoring should be increased. Concomitant oral antidiabetic treatment may need to be
adjusted.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including
AFREZZA. Severe hypoglycemia can cause seizures, may be life-threatening, or cause
death. Hypoglycemia can impair concentration ability and reaction time; this may place an
individual and others at risk in situations where these abilities are important (e.g., driving or
operating other machinery).
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulation. AFREZZA has a distinct time action profile [see Clinical
Pharmacology (12)], which impacts the timing of hypoglycemia. Hypoglycemia can happen
suddenly and symptoms may differ across individuals and change over time in the same
individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients
with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain
medications [see Drug Interactions (7)], or in patients who experience recurrent
hypoglycemia. Other factors which may increase the risk of hypoglycemia include changes
in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical
activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with
renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific
Populations ( 8.6, 8.7)].
Page 6 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-
monitoring of blood glucose plays an essential role in the prevention and management of
hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced
symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring
is recommended.
5.4 Decline in Pulmonary Function
AFREZZA causes a decline in lung function over time as measured by FEV1. In clinical
trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-
treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV1 decline than
comparator-treated patients. The FEV1 decline was noted within the first 3 months, and
persisted for the entire duration of therapy (up to 2 years of observation). In this population,
the annual rate of FEV1 decline did not appear to worsen with increased duration of use.
The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years
has not been established. There are insufficient data in long term studies to draw conclusions
regarding reversal of the effect on FEV1 after discontinuation of AFREZZA. The observed
changes in FEV1 were similar in patients with type 1 and type 2 diabetes.
Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy,
and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a
decline of ≥ 20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more
frequent monitoring of pulmonary function in patients with pulmonary symptoms such as
wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough.
If
symptoms persist, discontinue AFREZZA. [see Adverse Reactions (6)].
5.5 Lung Cancer
In clinical trials, two cases of lung cancer, one in controlled trials and one in uncontrolled
trials (2 cases in 2,750 patient-years of exposure), were observed in participants exposed to
AFREZZA while no cases of lung cancer were observed in comparators (0 cases in
2,169 patient-years of exposure). In both cases, a prior history of heavy tobacco use was
identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous
cell) occurred in non-smokers exposed to AFREZZA and were reported by investigators after
clinical trial completion. These data are insufficient to determine whether AFREZZA has an
effect on lung or respiratory tract tumors. In patients with active lung cancer, a prior history
of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of
AFREZZA use outweigh this potential risk.
5.6 Diabetic Ketoacidosis
In clinical trials enrolling subjects with type 1 diabetes, diabetic ketoacidosis (DKA) was
more common in subjects receiving AFREZZA (0.43%; n=13) than in subjects receiving
comparators (0.14%; n=3). In patients at risk for DKA, such as those with an acute illness or
infection, increase the frequency of glucose monitoring and consider delivery of insulin using
an alternate route of administration if indicated [see Limitations of Use (1)].
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5.7 Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including AFREZZA. If hypersensitivity reactions occur, discontinue AFREZZA,
treat per standard of care and monitor until symptoms and signs resolve [see Adverse
Reactions (6)]. AFREZZA is contraindicated in patients who have had hypersensitivity
reactions to AFREZZA or any of its excipients [see Contraindications (4)].
5.8 Hypokalemia
All insulin products, including AFREZZA, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause
respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients
at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking
medications sensitive to serum potassium concentrations and patients receiving intravenously
administered insulin).
5.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma
Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)
gamma agonists, can cause dose-related fluid retention, particularly when used in
combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients
treated with insulin, including AFREZZA, and a PPAR-gamma agonist should be observed
for signs and symptoms of heart failure. If heart failure develops, it should be managed
according to current standards of care, and discontinuation or dose reduction of the PPAR-
gamma agonist must be considered.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Acute bronchospasm in patients with chronic lung disease [see Warnings and
Precautions (5.1)]
• Hypoglycemia [see Warnings and Precautions (5.3)]
• Decline in pulmonary function [see Warnings and Precautions (5.4)]
• Lung cancer [see Warnings and Precautions (5.5)]
• Diabetic ketoacidosis [see Warnings and Precautions (5.6)]
• Hypersensitivity reactions [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying designs, the incidence of adverse
reactions reported in one clinical trial may not be easily compared to the incidence reported
in another clinical trial, and may not reflect what is observed in clinical practice.
The data described below reflect exposure of 3017 patients to AFREZZA and include
1026 patients with type 1 diabetes and 1991 patients with type 2 diabetes. The mean
exposure duration was 8.17 months for the overall population and 8.16 months and
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8.18 months for type 1 and 2 diabetes patients, respectively. In the overall population,
1874 were exposed to AFREZZA for 6 months and 724 for greater than one year. 620 and
1254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for
up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were
exposed to AFREZZA for greater than one year (median exposure = 1.8 years). AFREZZA
was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively).
The mean age of the population was 50.2 years and 20 patients were older than 75 years of
age. 50.8% of the population were men; 82.6% were White, 1.8% were Asian, and
4.9% were Black or African American. 9.7% were Hispanic. At baseline, the type 1
diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of
8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a
mean HbA1c of 8.8%. At baseline, 33.4% of the population reported peripheral neuropathy,
32.0% reported retinopathy and 19.6% had a history of cardiovascular disease.
Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use
of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse
reactions were not present at baseline, occurred more commonly on AFREZZA than on
placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.
Table 1. Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus
(excluding Hypoglycemia) Treated with AFREZZA
Placebo*
(n = 290)
AFREZZA
(n = 1991)
Non-placebo
comparators
(n=1363)
Cough
Throat pain or irritation
Headache
Diarrhea
Productive cough
Fatigue
Nausea
19.7%
3.8%
2.8%
1.4%
1.0%
0.7%
0.3%
25.6%
4.4%
3.1%
2.7%
2.2%
2.0%
2.0%
5.4%
0.9%
1.8%
2.2%
0.9%
0.6%
1.0%
*Carrier particle without insulin was used as placebo [see Description (11)].
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Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use
of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These
adverse reactions were not present at baseline, occurred more commonly on AFREZZA than
on comparator, and occurred in at least 2% of patients treated with AFREZZA.
Table 2. Common Adverse Reactions in Patients with Type 1 Diabetes Mellitus
(excluding Hypoglycemia) Treated with AFREZZA
Subcutaneous
Insulin
(n = 835)
AFREZZA
(n=1026)
Cough
Throat pain or irritation
Headache
Pulmonary function test decreased
Bronchitis
Urinary tract infection
4.9%
1.9%
2.8%
1.0%
2.0%
1.9%
29.4%
5.5%
4.7%
2.8%
2.5%
2.3%
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including AFREZZA [see Warnings and Precautions (5.3)]. The incidence of severe and
non-severe hypoglycemia of AFREZZA versus placebo in patients with type 2 diabetes is
shown in Table 3. A hypoglycemic episode was recorded if a patient reported symptoms of
hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe
hypoglycemia was defined as an event with symptoms consistent with hypoglycemia
requiring the assistance of another person and associated with either a blood glucose value
consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.
Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled
Study of Patients with Type 2 Diabetes
Placebo
(N=176)
AFREZZA
(N=177)
Severe Hypoglycemia
Non-Severe Hypoglycemia
1.7%
30%
5.1%
67%
Cough
Approximately 27% of patients treated with AFREZZA reported cough, compared to
approximately 5.2% of patients treated with comparator. In clinical trials, cough was the
most common reason for discontinuation of AFREZZA therapy (2.8% of AFREZZA-treated
patients).
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Pulmonary Function Decline
In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients
treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in
forced expiratory volume in one second (FEV1) compared to patients treated with comparator
anti-diabetes treatments. The decline occurred during the first 3 months of therapy and
persisted over 2 years (Figure 2).
A decline in FEV1 of ≥ 15% occurred in 6% of
AFREZZA-treated subjects compared to 3% of comparator-treated subjects.
Figure 2. Mean (+/-SE) Change in FEV1 (Liters) from Baseline for Type 1 and Type 2
Diabetes Patients graph
Weight Gain
Weight gain may occur with some insulin therapies, including AFREZZA. Weight gain has
been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical
trial of patients with type 2 diabetes [see Clinical Studies (14.3)], there was a mean 0.49 kg
weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss
among placebo-treated patients.
Antibody Production
Increases in anti-insulin antibody concentrations have been observed in patients treated with
AFREZZA.
Increases in anti-insulin antibodies are observed more frequently with
AFREZZA than with subcutaneously injected mealtime insulins. Presence of antibody did
not correlate with reduced efficacy, as measured by HbA1c and fasting plasma glucose, or
specific adverse reactions.
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7 DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic
agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates,
fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene,
salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Dose
adjustment and increased frequency of glucose monitoring may be required when AFREZZA
is co-administered with these drugs.
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA
The glucose lowering effect of AFREZZA may be decreased when co-administered with
atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics,
estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens
(e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g.,
albuterol, epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased
frequency of glucose monitoring may be required when AFREZZA is co-administered with
these drugs.
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
AFREZZA
The glucose lowering effect of AFREZZA may be increased or decreased when co
administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may
cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment
and increased frequency of glucose monitoring may be required when AFREZZA is co
administered with these drugs.
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine,
guanethidine, and reserpine are co-administered with AFREZZA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
AFREZZA has not been studied in pregnant women. AFREZZA should not be used during
pregnancy unless the potential benefit justifies the potential risk to the fetus.
In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major
malformations were observed at up to 100 mg/kg/day (a systemic exposure 14-21 times the
human systemic exposure, resulting from the maximum recommended daily dose of 99 mg
AFREZZA based on AUC).
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In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal
effects were observed at all dose groups (at human systemic exposure following a 99 mg
AFREZZA dose, based on AUC).
In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased
epididymis and testes weights, however, no decrease in fertility was noted, and impaired
learning were observed in pups at ≥ 30 mg/kg/day (a systemic exposure 6 times human
systemic exposure at the maximum daily AFREZZA dose of 99 mg based on AUC).
8.3 Nursing Mothers
Many drugs are excreted in human milk. A study in rats indicated that the carrier is excreted in
milk at approximately 10% of maternal exposure levels. It is therefore highly likely that the
insulin and carrier in AFREZZA is excreted in human milk. A decision should be made
whether to discontinue nursing or suspend use of the drug since AFREZZA has not been studied
in lactating women.
8.4 Pediatric Use
AFREZZA has not been studied in patients younger than 18 years of age.
8.5 Geriatric Use
In the AFREZZA clinical studies, 381 patients were 65 years of age or older, of which 20
were 75 years of age or older. No overall differences in safety or effectiveness were
observed between patients over 65 and younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age have not been
conducted.
8.6 Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of AFREZZA has not been
studied. Frequent glucose monitoring and dose adjustment may be necessary for AFREZZA
in patients with hepatic impairment [see Warnings and Precautions (5.3)].
8.7 Renal Impairment
The effect of renal impairment on the pharmacokinetics of AFREZZA has not been studied.
Some studies with human insulin have shown increased circulating levels of insulin in
patients with renal failure.
Frequent glucose monitoring and dose adjustment may be
necessary for AFREZZA in patients with renal impairment [see Warnings and Precautions
(5.3)].
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10 OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and
Precautions (5.3, 5.8)].
Mild episodes of hypoglycemia can usually be treated with oral glucose. Adjustments in
drug dosage, meal patterns, or exercise, may be needed.
Severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be
treated with intramuscular / subcutaneous glucagon or concentrated intravenous glucose.
After apparent clinical recovery from hypoglycemia, continued observation and additional
carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia
must be corrected appropriately.
11 DESCRIPTION
11.1 AFREZZA Cartridges
AFREZZA consists of single-use plastic cartridges filled with a white powder containing
insulin (human), which is administered via oral inhalation using the AFREZZA Inhaler only.
AFREZZA cartridges contain human insulin produced by recombinant DNA technology
utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human
insulin has the empirical formula C257H383N65O77S6 and a molecular weight of 5808. Human
insulin has the following primary amino acid sequence:
amin o ac
id se quen
ce
Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and
polysorbate 80.
AFREZZA Inhalation Powder is a dry powder supplied as 4 unit, 8 unit or 12 unit cartridges.
The 4 unit cartridge contains 0.35 mg of insulin. The 8 unit cartridge contains 0.7 mg of
insulin. The 12 unit cartridge contains 1.0 mg of insulin.
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g
r
a
ph
11.2 AFREZZA Inhaler
The AFREZZA Inhaler is breath-powered by the patient. When the patient inhales through
the device, the powder is aerosolized and delivered to the lung. The amount of AFREZZA
delivered to the lung will depend on individual patient factors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal
muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in
adipocytes, inhibits proteolysis, and enhances protein synthesis.
12.2 Pharmacodynamics
The pharmacodynamic profile for orally inhaled AFREZZA 8 units relative to
subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1
diabetes is shown in Figure 3(A). The median time to maximum effect of AFREZZA
(measured by the peak rate of glucose infusion) was approximately 53 minutes (standard
deviation of 74 minutes) and the effect then declined to near baseline levels by about 160
minutes.
Figure 3. Baseline-Corrected Glucose Infusion Rate (A) and Baseline-Corrected Serum
Insulin Concentrations (B) after Administration of AFREZZA or
Subcutaneous Insulin Lispro in Type 1 Diabetes Patients*
* Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable
to insulin lispro.
In a study of 32 healthy subjects, the pharmacodynamic effect of AFREZZA, measured as
area under the glucose infusion rate - time curve (AUC-GIR) from an euglycemic clamp,
increased in a less than dose-proportional manner.
This effect has been observed for
subcutaneously administered insulins, but it is unknown if the diminishing pharmacodynamic
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benefit at higher dosage of AFREZZA parallels that which is seen with subcutaneously
administered insulin.
12.3 Pharmacokinetics
The insulin contained in AFREZZA is regular human insulin. Following pulmonary
absorption into systemic circulation, the metabolism and elimination are comparable to
regular human insulin.
Absorption: The pharmacokinetic profiles for orally inhaled AFREZZA 8 units relative to
subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1
diabetes are shown in Figure 3(B). The maximum serum insulin concentration was reached
by 12-15 minutes after inhalation of AFREZZA 8 units and serum insulin concentrations
declined to baseline by approximately 180 minutes. However, the faster absorption of
insulin from Afrezza [see Figure 3(B)] did not result in a faster onset of activity compared to
insulin lispro [see Figure 3(A)].
Disposition: Systemic insulin disposition (median terminal half-life) following oral
inhalation of AFREZZA 4 and 32 units was 28-39 minutes, and 145 minutes for
subcutaneous regular human insulin 15 units.
Carrier Particles
Clinical pharmacology studies showed that carrier particles [see Description (11)] are not
metabolized and are eliminated unchanged in the urine following the lung absorption.
Following oral inhalation of AFREZZA, a mean of 39% of the inhaled dose of carrier
particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The
swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the
feces.
Drug Interaction: Bronchodilators and Inhaled Steroids
Albuterol increased the AUC insulin administered by AFREZZA by 25% in patients with
asthma. Effect of fluticasone on insulin exposures following AFREZZA administration has
not been evaluated in patients with asthma; however, no significant change in insulin
exposure was observed in a study in healthy volunteers. Frequent glucose monitoring and
dose reduction may be necessary for AFREZZA if it is co-administered with albuterol.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104 week carcinogenicity study, rats were given doses up to 46 mg/kg/day of the carrier
and up to 1.23 mg/kg/day of insulin, by nose-only inhalation. No increased incidence of
tumors was observed at systemic exposures equivalent to the insulin at a maximum daily
AFREZZA dose of 99 mg based on a comparison of relative body surface areas across
species.
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In a 26 week carcinogenicity study, transgenic mice (Tg-ras-H2) given doses up to 75
mg/kg/day of carrier and up to 5 mg/kg/day of AFREZZA. No increased incidence of tumors
was observed.
AFREZZA was not genotoxic in Ames bacterial mutagenicity assay and in the chromosome
aberration assay, using human peripheral lymphocytes with or without metabolic activation.
The carrier alone was not genotoxic in the in vivo mouse micronucleus assay.
In female rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier (vehicle
without insulin) beginning 2 weeks prior to mating until gestation day 7, there were no
adverse effects on male fertility at doses up to 100 mg/kg/day (a systemic exposure 14-21
times that following the maximum daily AFREZZA dose of 99 mg based on AUC). In
female rats there was increased pre- and post-implantation loss at 100 mg/kg/day but not at
30 mg/kg/day (14-21 times higher systemic exposure than the maximum daily AFREZZA
dose of 99 mg based on AUC).
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus
AFREZZA has been studied in adults with type 1 diabetes in combination with basal insulin.
The efficacy of AFREZZA in type 1 diabetes patients was compared to insulin aspart in
combination with basal insulin. AFREZZA has been studied in adults with type 2 diabetes in
combination with oral antidiabetic drugs. The efficacy of AFREZZA in type 2 diabetes
patients was compared to placebo inhalation.
14.2 Type 1 Diabetes
Patients with inadequately controlled type 1 diabetes participated in a 24-week, open-label,
active-controlled study to evaluate the glucose lowering effect of mealtime AFREZZA used
in combination with a basal insulin. Following a 4-week basal insulin optimization period,
344 patients were randomized to AFREZZA (n=174) or insulin aspart (n=170)administered
at each meal of the day. Mealtime insulin doses were titrated to glycemic goals for the first
12 weeks and kept stable for the last 12 weeks of the study. At Week 24, treatment with
basal insulin and mealtime AFREZZA provided a mean reduction in HbA1c that met the pre-
specified non-inferiority margin of 0.4%. AFREZZA provided less HbA1c reduction than
insulin aspart, and the difference was statistically significant. More subjects in the insulin
aspart group achieved the HbA1c target of ≤7% (Table 4).
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Table 4. Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA
plus Basal Insulin in Adults with Type 1 Diabetes
Efficacy Parameter
AFREZZA +
Basal Insulin
(N=174)
Insulin Aspart +
Basal Insulin
(N=170)
HbA1c (%)
Baseline (adjusted meana)
7.94
7.92
Change from baseline (adjusted meana,b)
-0.21
-0.40
Difference from insulin aspart (adjusted meana,b)
(95% CI)
0.19
(0.02, 0.36)
Percentage of patients achieving HbA1c ≤ 7%c
13.8
27.1
Fasting Plasma Glucose (mg/dL)
Baseline (adjusted meana)
153.9
151.6
Change from baseline (adjusted meana, b)
-25.3
10.2
Difference from insulin aspart (adjusted meana, b)
(95% CI)
-35.4
(-56.3, -14.6)
a Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent
variable and treatment, visit, region, basal insulin stratum, and treatment by visit interaction as fixed factors, and corresponding
baseline as a covariate. An autoregression (1) [AR(1)] covariance structure was used.
b Data at 24 weeks were available from 131 (75 %) and 150 (88% ) subjects randomized to the AFREZZA and insulin aspart groups,
respectively.
c The percentage was calculated based on the number of patients randomized to the trial.
14.3 Type 2 Diabetes
A total of 479 adult patients with type 2 diabetes inadequately controlled on
optimal/maximally tolerated doses of metformin only, or 2 or more oral antidiabetic (OAD)
agents participated in a 24-week, double-blind, placebo-controlled study. Following a 6
week run-in period, 353 patients were randomized to AFREZZA (n=177) or an inhaled
placebo powder without insulin (n=176). Insulin doses were titrated for the first 12 weeks
and kept stable for the last 12 weeks of the study. OADs doses were kept stable. At Week
24, treatment with AFREZZA plus OADs provided a mean reduction in HbA1c that was
statistically significantly greater compared to the HbA1c reduction observed in the placebo
group (Table 5).
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Table 5. Results at Week 24 in a Placebo-Controlled Study of AFREZZA in Adults
with Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Agents
Efficacy Parameter
AFREZZA + Oral
Anti-Diabetic
Agents
(N=177)
Placebo + Oral
Anti-Diabetic
Agents
(N=176)
HbA1c (%)
Baseline (adjusted meana)
8.25
8.27
Change from baseline (adjusted meana,b)
-0.82
-0.42
Difference from placebo (adjusted meana,b)
(95% CI)
-0.40
(-0.57, -0.23)
Percentage (%) of patients achieving HbA1C ≤7%c
32.2
15.3
Fasting Plasma Glucose (mg/dL)
Baseline (adjusted meana)
175.9
175.2
Change from baseline (adjusted meana,b)
-11.2
-3.8
Difference from placebo (adjusted meana,b)
(95% CI)
-7.4
(-18.0, 3.2)
a Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent
variable and treatment, visit, region, and treatment by visit interaction as fixed factors, and corresponding baseline as a covariate. An
autoregression (1) [AR(1)] covariance structure was used.
b Data at 24 weeks without rescue therapy were available from 139 (79%) and 129 (73%) subjects randomized to the AFREZZA and
placebo groups, respectively.
c The percentage was calculated based on the number of patients randomized to the trial.
16 HOW SUPPLIED/STORAGE AND HANDLING
AFREZZA (insulin human) Inhalation Powder is available as 4 unit, 8 unit and 12 unit
single-use cartridges. Three cartridges are contained in a single cavity of a blister strip. Each
card contains 5 blister strips separated by perforations for a total of 15 cartridges. For
convenience, the perforation allows users to remove a single strip containing 3 cartridges.
Two cards of the same cartridge strength are packaged in a foil laminate overwrap
(30 cartridges per foil package).
The cartridges are color-coded, blue for 4 units, green for 8 units and yellow for 12 units.
Each cartridge is marked with “afrezza” and “4 units”, “8 units” or “12 units”.
The AFREZZA Inhaler is individually packaged in a translucent overwrap. The inhaler is
fully assembled with a removable mouthpiece cover. The AFREZZA Inhaler can be used for
up to 15 days from the date of first use. After 15 days of use, the inhaler must be discarded
and replaced with a new inhaler.
AFREZZA is available in the following configurations:
• NDC 0024-5874-90, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 − 4 unit cartridges and 2 inhalers
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• NDC 0024-5878-90, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 − 8 unit cartridges and 2 inhalers
• NDC 0024-5884-63, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 cartridges; 60 – 4 unit cartridges and 30 − 8 unit cartridges and 2 inhalers
• NDC 0024-5882-36, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 cartridges; 30 – 4 unit cartridges and 60 − 8 unit cartridges and 2 inhalers
• NDC 0024-5880-18, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
180 cartridges; 90 - 4 unit cartridges and 90 – 8 unit cartridges and 2 inhalers
• NDC 0024-5890-90, AFREZZA (insulin human [rDNA origin]) Inhalation Powder: 90
12 unit and 2 Inhalers
• NDC 0024-5893-36, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 cartridges; 30 – 8 unit cartridges and 60 - 12 unit cartridges and 2 inhalers
• NDC 0024-5894-63, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 cartridges; 60 – 8 unit cartridges and 30 - 12 unit cartridges and 2 inhalers
• NDC 0024-5895-33, AFREZZA (insulin human [rDNA origin]) Inhalation Powder:
90 cartridges; 30 – 4 unit cartridges, 30 – 8 unit cartridges and 30 - 12 unit cartridges and
2 inhalers
Storage
Not in Use: Refrigerated Storage 2-8ºC (36-46ºF)
Sealed (Unopened) Foil Package
May be stored until the Expiration Date*
* If a foil package is not refrigerated, the contents must be used within 10 days.
In Use: Room Temperature Storage 25ºC (77ºF), excursions permitted 15-30ºC (59-86ºF)
Sealed (Unopened) Blister Cards + Strips
Must be used within 10 days
Opened Strips
Must be used within 3 days
Inhaler Storage:
Store at 2-25ºC (36-77ºF); excursions permitted. Inhaler may be stored refrigerated, but
should be at room temperature before use.
Handling:
Before use, cartridges should be at room temperature for 10 minutes.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide)
Instructions
Instruct patients to read the Medication Guide before starting AFREZZA therapy and to
reread it each time the prescription is renewed, because information may change. Instruct
Page 20 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients to inform their healthcare provider or pharmacist if they develop any unusual
symptom, or if any known symptom persists or worsens.
Inform patients of the potential risks and benefits of AFREZZA and of alternative modes of
therapy. Inform patients about the importance of adherence to dietary instructions, regular
physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and
management of hypoglycemia and hyperglycemia, and assessment for diabetes
complications. Advise patients to seek medical advice promptly during periods of stress such
as fever, trauma, infection, or surgery, as medication requirements may change.
Instruct patients to use AFREZZA only with the AFREZZA inhaler.
Inform patients that the most common adverse reactions associated with the use of
AFREZZA are hypoglycemia, cough, and throat pain or irritation.
Advise women with diabetes to inform their physician if they are pregnant or are planning to
become pregnant while using AFREZZA.
Acute Bronchospasm in Patients with Chronic Lung Disease
Advise patients to inform their physicians if they have a history of lung disease, because
AFREZZA should not be used in patients with chronic lung disease (e.g., asthma, COPD, or
other chronic lung disease(s)) [see Contraindications (4) and Warnings and Precautions
(5.1)].
Advise patients that if they experience any respiratory difficulty after inhalation of
AFREZZA, they should report it to their physician immediately for assessment.
Hypoglycemia
Instruct patients on self-management procedures including glucose monitoring, proper
inhalation technique, and management of hypoglycemia and hyperglycemia especially at
initiation of AFREZZA therapy. Instruct patients on handling of special situations such as
intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped
insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake,
and skipped meals.
Instruct patients on the management of hypoglycemia. Inform patients that their ability to
concentrate and react may be impaired as a result of hypoglycemia. Advise patients who
have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use
caution when driving or operating machinery [see Warnings and Precautions (5.3)].
Decline in Pulmonary Function and Monitoring
Inform patients that AFREZZA can cause a decline in lung function and their lung function
will be evaluated by spirometry before initiation of AFREZZA treatment [see Warnings and
Precautions (5.4)].
Page 21 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lung Cancer
Inform patients to promptly report any signs or symptoms potentially related to lung cancer
[see Warnings and Precautions (5.5)].
Diabetic Ketoacidosis
Instruct patients to carefully monitor their blood glucose during illness, infection, and other
risk situations for diabetic ketoacidosis and to contact their healthcare provider if their blood
glucose control worsens [see Warnings and Precautions (5.6)].
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions can occur with insulin therapy including
AFREZZA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings
and Precautions (5.7)].
AFREZZA is a registered trademark owned by MannKind Corporation
Patented: http://www.mannkindcorp.com/our-technology-patent-notices.htm
Manufactured by:
MannKind Corporation
Danbury, CT 06810
Distributed by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
4/2015
Page 22 of 22
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
AFREZZA® (uh-FREZZ-uh)
(insulin human) inhalation powder
What is the most important information I should know about AFREZZA?
AFREZZA can cause serious side effects, including:
•
Sudden lung problems (bronchospasms). Do not use AFREZZA if you have long-term
(chronic) lung problems such as asthma or chronic obstructive pulmonary disease (COPD).
Before starting AFREZZA, your healthcare provider will give you a breathing test to check how your
lungs are working.
What is AFREZZA?
•
AFREZZA is a man-made insulin that is breathed-in through your lungs (inhaled) and is used to control
high blood sugar in adults with diabetes mellitus.
•
AFREZZA is not for use in place of long-acting insulin. AFREZZA must be used with long-acting insulin
in people who have type 1 diabetes mellitus.
•
AFREZZA is not for use to treat diabetic ketoacidosis.
•
It is not known if AFREZZA is safe and effective for use in people who smoke. AFREZZA is not for use
in people who smoke or have recently stopped smoking (less than 6 months).
●
It is not known if AFREZZA is safe and effective in children under 18 years of age.
Who should not use AFREZZA?
Do not use AFREZZA if you:
•
have chronic lung problems such as asthma or COPD.
●
are allergic to regular human insulin or any of the ingredients in AFREZZA. See the end of this
Medication Guide for a complete list of ingredients in AFREZZA.
What should I tell my healthcare provider before using AFREZZA?
Before using AFREZZA, tell your healthcare provider about all your medical conditions,
including if you:
•
have lung problems such as asthma or COPD
•
have or have had lung cancer
•
are using any inhaled medications
•
smoke or have recently stopped smoking
•
have kidney or liver problems
•
are pregnant, planning to become pregnant, or are breastfeeding. AFREZZA may harm your unborn or
breastfeeding baby.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins or herbal supplements.
Before you start using AFREZZA, talk to your healthcare provider about low blood sugar and
how to manage it.
How should I use AFREZZA?
•
Read the detailed Instructions for Use that comes with your AFREZZA.
•
Take AFREZZA exactly as your healthcare provider tells you to. Your healthcare provider should tell
you how much AFREZZA to use and when to use it.
•
Know the strength of AFREZZA you use. Do not change the amount of AFREZZA you use unless your
healthcare provider tells you to.
•
Take AFREZZA at the beginning of your meal.
•
Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and
when you should check your blood sugar levels.
•
Keep AFREZZA and all medicines out of the reach of children.
Your dose of AFREZZA may need to change because of:
•
Change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in
diet, or because of other medicines you take.
What should I avoid while using AFREZZA?
While using AFREZZA do not:
•
drive or operate heavy machinery, until you know how AFREZZA affects you
•
drink alcohol or use over-the-counter medicines that contain alcohol
•
smoke
Reference ID: 3734773
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What are the possible side effects of AFREZZA?
AFREZZA may cause serious side effects that can lead to death, including:
See “What is the most important information I should know about AFREZZA?”
•
low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
•
dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech,
shakiness, fast heartbeat, anxiety, irritability or mood change, hunger.
•
decreased lung function. Your healthcare provider should check how your lungs are working before
you start using AFREZZA, 6 months after you start using it and yearly after that.
•
lung cancer. In studies of AFREZZA in people with diabetes, lung cancer occurred in a few more
people who were taking AFREZZA than in people who were taking other diabetes medications. There
were too few cases to know if lung cancer was related to AFREZZA. If you have lung cancer, you and
your healthcare provider should decide if you should use AFREZZA.
•
diabetic ketoacidosis. Talk to your healthcare provider if you have an illness. Your AFREZZA dose or
how often you check your blood sugar may need to be changed.
•
severe allergic reaction (whole body reaction). Get medical help right away if you have any
of these signs or symptoms of a severe allergic reaction:
•
a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.
•
low potassium in your blood (hypokalemia).
•
heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with AFREZZA may
cause heart failure in some people. This can happen even if you have never had heart failure or heart
problems before. If you already have heart failure it may get worse while you take TZDs with
AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with
AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure
including:
•
shortness of breath, swelling of your ankles or feet, sudden weight gain.
Treatment with TZDs and AFREZZA may need to be changed or stopped by your healthcare provider if
you have new or worse heart failure.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat,
sweating, extreme drowsiness, dizziness, confusion.
The most common side effects of AFREZZA include:
•
low blood sugar (hypoglycemia), cough, sore throat
These are not all the possible side effects of AFREZZA. Call your doctor for medical advice about
side effects. You may report side effects to FDA at 1-800-FDA-1088 (1-800-332-1088).
General information about the safe and effective use of AFREZZA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use AFREZZA for a condition for which it was not prescribed. Do not give AFREZZA to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about AFREZZA. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for
information about AFREZZA that is written for health professionals. For more information, go to
www.AFREZZA.com or call sanofi-aventis 1-800-633-1610.
What are the ingredients in AFREZZA?
Active ingredient: human insulin
Inactive ingredients: fumaryl diketopiperazine, polysorbate 80
Manufactured By: MannKind Corporation
AFREZZA® is a registered trademark owned by MannKind Corporation
Patented: http://www.mannkindcorp.com/our-technology-patent-notices.htm
MannKind Corporation
Danbury, CT 06810
Distributed by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for Use
AFREZZA® (uh-FREZZ-uh)
(insulin human) inhalation powder
Read this Instructions for Use before you start using AFREZZA and each time you get a new
AFREZZA inhaler. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
Your healthcare provider should show you how to use your AFREZZA inhaler the right
way before you use it for the first time.
Important information about AFREZZA:
• AFREZZA comes in 3 strengths (See Figure A):
o 4 units (blue cartridge)
o 8 units (green cartridge)
o 12 units (yellow cartridge)
(Figure A) usage illustration
• If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than 1
cartridge.
• If you need to use more than 1 cartridge for your dose, throw away the used cartridge
before getting a new one. You can tell when a cartridge has been used, because the cup
has moved to the center.
• Do not try to open the AFREZZA cartridges. The AFREZZA Inhaler opens the cartridge
automatically during use.
• AFREZZA cartridges should only be used with the AFREZZA Inhaler. Do not try to
breathe in the AFREZZA insulin powder in any other way. Do not put cartridges in your
mouth and do not swallow cartridges.
• Use only 1 AFREZZA Inhaler at a time. The same inhaler should be used for the 4 unit, 8
unit or 12 unit cartridges.
• Throw away your AFREZZA Inhaler after 15 days and get a new one.
If you are having problems with your AFREZZA inhaler or if it breaks and you need a
new one, call 1-800-633-1610.
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know your AFREZZA® inhaler: usage illustration
Know your AFREZZA® cartridges: usage illustration
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How to take your dose of AFREZZA:
Always be sure you have the right number of AFREZZA cartridges for your dose available before
you start. AFREZZA cartridges must only be used with the AFREZZA Inhaler.
Step 1: Select the AFREZZA cartridges for your dose usage illustration
If your prescribed AFREZZA® dose is more than 12 units you will need to use more than 1
cartridge to get your right dose. usage illustration
(Figure B) usage illustration
Select Cartridges
Important: Use the AFREZZA dose chart above (See Figure B) to help you choose the
right number of AFREZZA cartridges needed for your dose. usage illustration
Open Packages
Remove a blister card from the foil package.
Tear along perforation to remove one strip.
Reference ID: 3734773
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Push Cartridges to Remove
Remove a cartridge from the strip by pressing on the clear side to
push the cartridge out. Remove the right number of cartridges for
your dose. Pushing on the cup will not damage the cartridge.
AFREZZA cartridges left over in an opened strip must be
used within 3 days. usage illustrationusage illustration
Before Proceeding:
Check that you have the right AFREZZA cartridge(s) for your dose.
Use only 1 inhaler for multiple cartridges. Throw away your AFREZZA inhaler after 15 days and
get a new one.
Step 2: Loading a cartridge
Hold Inhaler
Hold the inhaler level in one (1) hand with the white
mouthpiece on the top and purple base on the
bottom.
Open Inhaler
Open the inhaler by lifting the white mouthpiece to a
vertical position.
Before you put the AFREZZA cartridge in your
inhaler, make sure it has been at room
temperature for 10 minutes.
Place Cartridge
Hold the cartridge with the cup facing down.
Line up the cartridge with the opening in the inhaler.
The pointed end of the cartridge should line up with
the pointed end in the inhaler.
Place the cartridge into the inhaler. Be sure that the
cartridge lies flat in the inhaler.
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
sa
g
e illustration
usage illustra
tion
Remove the Mouthpiece Cover
Important: Keep the inhaler level during and
after removal of the purple mouthpiece cover.
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exhale
Hold the inhaler away from your mouth and
fully blow out (exhale).
Position Inhaler in Mouth
Keeping your head level, place the mouthpiece
in your mouth and tilt the inhaler down
towards your chin, as shown.
Close your lips around the mouthpiece to form
a seal.
Tilt the inhaler downward while keeping
your head level.
Inhale Deeply and Hold Breath
With your mouth closed around the
mouthpiece, inhale deeply through the
inhaler.
Hold your breath for as long as comfortable
and at the same time remove the inhaler from
your mouth. After holding your breath, exhale
and continue to breathe normally.
us
age illu stration
usage illustration
tridge
Replace Mouthpiece Cover
Place the purple mouthpiece cover back onto
the inhaler.
Reference ID: 3734773
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For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
usage illustration
u
sage illustration
Open Inhaler
Open the inhaler by lifting up the white
mouthpiece.
Remove Cartridge
Remove the cartridge from the purple base.
Throw away the Cartridge
Throw away the used cartridge in your regular
household trash.
Multiple cartridge dosing
If you need more than one (1)
AFREZZA cartridge for your dose,
See the AFREZZA dosage chart
above (Figure B).
Repeat steps 2 through 4 for each AFREZZA cartridge you need for your
prescribed AFREZZA dose.
Reference ID: 3734773
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For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
g
e
i
llustration
Reference ID: 3734773
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Caring for your
AFREZZA inhaler:
Reference ID: 3734773
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For current labeling information, please visit https://www.fda.gov/drugsatfda
u
sage illustration
Switching between AFREZZA and injected insulin:
Contact your healthcare provider before switching insulins.
AFREZZA® is a mealtime insulin.
Do not switch from AFREZZA to a long acting insulin.
Do not switch from a long acting insulin to AFREZZA® .
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Medication Guide and Instructions for Use has been approved by the U.S.
Food and Drug Administration.
AFREZZA® is a registered trademark owned by MannKind Corporation
Patented: See http://www.mannkindcorp.com/our-technology-patent
notices.htm
Manufactured by:
MannKind Corporation
Danbury, CT 06810
Distributed by:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Approved: 4/2015
Reference ID: 3734773
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:33.588795 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022472s002lbl.pdf', 'application_number': 22472, 'submission_type': 'SUPPL ', 'submission_number': 2} |
7,497 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PANCREAZE® safely and effectively. See full prescribing information for
PANCREAZE® .
PANCREAZE® (pancrelipase) delayed-release capsules
Initial U.S. Approval – 2010
----------------------------INDICATIONS AND USAGE--------------------------
PANCREAZE® is a combination of porcine-derived lipases, proteases, and
amylases indicated for the treatment of exocrine pancreatic insufficiency due
to cystic fibrosis or other conditions (1)
-----------------------DOSAGE AND ADMINISTRATION----------------------
Dosage
PANCREAZE® is not interchangeable with any other pancrelipase product.
Infants (up to 12 months)
• Infants may be given 2,600 lipase units per 120 mL of formula or per
breast-feeding. (2.1)
• Do not mix PANCREAZE capsule contents directly into formula or breast
milk prior to administration. (2.2)
Children Older than 12 Months and Younger than 4 Years
• Enzyme dosing should begin with 1,000 lipase units/kg of body weight per
meal to a maximum of 2,500 lipase units/kg of body weight per meal (or
less than or equal to 10,000 lipase units/kg of body weight per day), or less
than 4,000 lipase units/g fat ingested per day. (2.1)
Children 4 Years and Older and Adults
• Enzyme dosing should begin with 500 lipase units/kg of body weight per
meal to a maximum of 2,500 lipase units/kg of body weight per meal (or
less than or equal to 10,000 lipase units/kg of body weight per day), or less
than 4,000 lipase units/g fat ingested per day. (2.1)
Limitations on Dosing
• Dosing should not exceed the recommended maximum dosage set forth by
the Cystic Fibrosis Foundation Consensus Conferences Guidelines. (2.1)
Administration
• PANCREAZE should be swallowed whole. For infants or patients unable
to swallow intact capsules, the contents may be sprinkled on soft acidic
food with a pH of 4.5 or less, e.g., applesauce. (2.2)
--------------------DOSAGE FORMS AND STRENGTHS---------------------
• Capsules: 2,600 USP units of lipase; 6,200 USP units of protease;
10,850 USP units of amylase. Capsules have a light orange opaque body
and clear cap, printed with “McNEIL” and “MT 2” (3)
• Capsules: 4,200 USP units of lipase; 10,000 USP units of protease;
17,500 USP units of amylase. Capsules have a yellow opaque body and
clear cap, printed with “McNEIL” and “MT 4” (3)
• Capsules: 10,500 USP units of lipase; 25,000 USP units of protease;
43,750 USP units of amylase. Capsules have a pink opaque body and clear
cap, printed with “McNEIL” and “MT 10” (3)
• Capsules: 16,800 USP units of lipase; 40,000 USP units of protease;
70,000 USP units of amylase. Capsules have a salmon opaque body and
clear cap, printed with “McNEIL” and “MT 16” (3)
• Capsules: 21,000 USP units of lipase; 37,000 USP units of protease;
61,000 USP units of amylase. Capsules have a white opaque body and cap,
printed with “McNEIL” and “MT 20” (3)
-------------------------------CONTRAINDICATIONS-----------------------------
None. (4)
---------------------------WARNINGS AND PRECAUTIONS-------------------
• Fibrosing colonopathy is associated with high-dose use of pancreatic
enzyme replacement. Exercise caution when doses of PANCREAZE
exceed 2,500 lipase units/kg of body weight per meal (or greater than
10,000 lipase units/kg of body weight per day). (5.1)
• To avoid irritation of oral mucosa, do not chew PANCREAZE or retain in
the mouth. (5.2)
• Exercise caution when prescribing PANCREAZE to patients with gout,
renal impairment, or hyperuricemia. (5.3)
• There is theoretical risk of viral transmission with all pancreatic enzyme
products including PANCREAZE. (5.4)
• Exercise caution when administering pancrelipase to a patient with a
known allergy to proteins of porcine origin. (5.5)
------------------------------ADVERSE REACTIONS---------------------------
• Treatment-emergent adverse events occurring in at least 2 patients (greater
than or equal to 10%) receiving PANCREAZE or placebo are abdominal
pain, abdominal pain upper, flatulence, diarrhea, abnormal feces, and
fatigue. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen
Pharmaceuticals Inc., at 1-800-526-7736 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
-----------------------USE IN SPECIFIC POPULATIONS----------------------
Pediatric Patients
• The safety and effectiveness of PANCREAZE were assessed in pediatric
patients, aged 6 to 30 months old and aged 8 to 17 years old. (8.4)
• The safety and efficacy of pancreatic enzyme products with different
formulations of pancrelipase in pediatric patients have been described in
the medical literature and through clinical experience. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 03 2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dosage
2.2
Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Fibrosing Colonopathy
5.2
Potential for Irritation to Oral Mucosa
5.3
Potential for Risk of Hyperuricemia
5.4
Potential Viral Exposure from the Product Source
5.5
Allergic Reactions
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Dosing and Administration
17.2 Fibrosing Colonopathy
17.3 Allergic Reactions
[*Sections or subsections omitted from the full prescribing information
are not listed]
Reference ID: 3467367
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
PANCREAZE (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency
due to cystic fibrosis or other conditions.
2
DOSAGE AND ADMINISTRATION
2.1 Dosage
PANCREAZE is not interchangeable with other pancrelipase products.
PANCREAZE is orally administered. Therapy should be initiated at the lowest recommended
dose and gradually increased. The dosage of PANCREAZE should be individualized based on
clinical symptoms, the degree of steatorrhea present, and the fat content of the diet (see
Limitations on Dosing below).
Dosage recommendations for pancreatic enzyme replacement therapy were published following
the Cystic Fibrosis Foundation Consensus Conferences.1,2,3 PANCREAZE should be
administered in a manner consistent with the recommendations of the Conferences provided in
the following paragraphs with one exception. The Conferences recommend doses of 2,000 to
4,000 lipase units in infants up to 12 months. PANCREAZE is available in a 2,600 lipase unit
capsule. The recommended dose of PANCREAZE in infants up to 12 months is 2,600 lipase
units per 120 mL of formula or per breast-feeding. Patients may be dosed on a fat
ingestion-based or actual body weight-based dosing scheme.
Infants (up to 12 months)
Infants may be given 2,600 lipase units per 120 mL of formula or per breast-feeding. Do not mix
PANCREAZE capsule contents directly into formula or breast milk prior to administration [see
Dosage and Administration (2.2)].
Children Older than 12 Months and Younger than 4 Years
Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less
than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or
equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat
ingested per day.
Children 4 Years and Older and Adults
Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older
than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or
equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat
ingested per day.
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Usually, half of the prescribed PANCREAZE dose for an individualized full meal should be
given with each snack. The total daily dose should reflect approximately three meals plus two or
three snacks per day.
Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older
patients because they weigh more but tend to ingest less fat per kilogram of body weight.
Limitations on Dosing
Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis
Foundation Consensus Conferences Guidelines.1,2,3
If symptoms and signs of steatorrhea persist, the dosage may be increased by a healthcare
professional. Patients should be instructed not to increase the dosage on their own. There is great
inter-individual variation in response to enzymes; thus, a range of doses is recommended.
Changes in dosage may require an adjustment period of several days. If doses are to exceed
2,500 lipase units/kg of body weight per meal, further investigation is warranted.
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase
units/kg of body weight per day) should be used with caution and only if they are documented to
be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat
absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been
associated with colonic strictures, indicative of fibrosing colonopathy, in children with cystic
fibrosis less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently
receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined
and the dosage either immediately decreased or titrated downward to a lower range.
2.2 Administration
PANCREAZE should always be taken as prescribed by a healthcare professional.
Infants (up to 12 months)
PANCREAZE should be administered to infants immediately prior to each feeding, using a
dosage of 2,600 lipase units per 120 mL of formula or per breast-feeding (i.e., one capsule with
2,600 USP units of lipase). Contents of the capsule may be sprinkled on small amounts of acidic
soft food with a pH of 4.5 or less (e.g., applesauce) and given to the infant within 15 minutes.
Contents of the capsule may also be administered directly to the mouth. Administration should
be followed by breast milk or formula. Contents of the capsule should not be mixed directly into
formula or breast milk as this may diminish efficacy. Care should be taken to ensure that
PANCREAZE is not crushed or chewed or retained in the mouth, to avoid irritation of the oral
mucosa.
Children and Adults
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PANCREAZE should be taken during meals or snacks, with sufficient fluid. PANCREAZE
capsules and capsule contents should not be crushed or chewed. Capsules should be
swallowed whole.
For patients who are unable to swallow intact capsules, the capsules may be carefully opened and
the contents sprinkled on small amounts of acidic soft food with a pH of 4.5 or less (e.g.,
applesauce). The PANCREAZE-soft food mixture should be swallowed immediately without
crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should
be taken to ensure that no drug is retained in the mouth.
3
DOSAGE FORMS AND STRENGTHS
The active ingredient in PANCREAZE evaluated in clinical trials is lipase. PANCREAZE is
dosed by lipase units.
PANCREAZE is available in 5 color coded capsule strengths.
Other active ingredients include protease and amylase. Each PANCREAZE capsule strength
contains the specified amounts of lipase, protease, and amylase as follows:
• 2,600 USP units of lipase; 6,200 USP units of protease; 10,850 USP units of amylase
capsules have a light orange opaque body and clear cap, printed with “McNEIL” and “MT
2”
• 4,200 USP units of lipase; 10,000 USP units of protease; 17,500 USP units of amylase
capsules have a yellow opaque body and clear cap, printed with “McNEIL” and “MT 4”
• 10,500 USP units of lipase; 25,000 USP units of protease; 43,750 USP units of amylase
capsules have a pink opaque body and clear cap, printed with “McNEIL” and “MT 10”
• 16,800 USP units of lipase; 40,000 USP units of protease; 70,000 USP units of amylase
capsules have a salmon opaque body and clear cap, printed with “McNEIL” and “MT 16”
• 21,000 USP units of lipase; 37,000 USP units of protease; 61,000 USP units of amylase
capsules have a white opaque body and cap, printed with “McNEIL” and “MT 20”
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1 Fibrosing Colonopathy
Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme
products.4,5 Fibrosing colonopathy is a rare serious adverse reaction initially described in
association with high-dose pancreatic enzyme use, usually with use over a prolonged period of
time and most commonly reported in pediatric patients with cystic fibrosis. The underlying
mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products
exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic
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strictures in children less than 12 years of age.1 Patients with fibrosing colonopathy should be
closely monitored because some patients may be at risk of progressing to stricture formation. It is
uncertain whether regression of fibrosing colonopathy occurs.1 It is generally recommended,
unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body
weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than
4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.1)].
Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase
units/kg of body weight per day) should be used with caution and only if they are documented to
be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat
absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal
should be examined and the dosage either immediately decreased or titrated downward to a
lower range.
5.2 Potential for Irritation to Oral Mucosa
Care should be taken to ensure that no drug is retained in the mouth. PANCREAZE should not
be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt
the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa,
and/or loss of enzyme activity [see Dosage and Administration (2.2) and Patient Counseling
Information (17)]. For patients who are unable to swallow intact capsules, the capsules may be
carefully opened and the contents sprinkled to a small amount of acidic soft food with a pH of
4.5 or less, such as applesauce. The PANCREAZE-soft food mixture should be swallowed
immediately and followed with water or juice to ensure complete ingestion.
5.3 Potential for Risk of Hyperuricemia
Caution should be exercised when prescribing PANCREAZE to patients with gout, renal
impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that
may increase blood uric acid levels.
5.4 Potential Viral Exposure from the Product Source
PANCREAZE is sourced from pancreatic tissue from swine used for food consumption.
Although the risk that PANCREAZE will transmit an infectious agent to humans has been
reduced by testing for certain viruses during manufacturing and by inactivating certain viruses
during manufacturing, there is a theoretical risk for transmission of viral disease, including
diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might
infect humans cannot be definitely excluded. However, no cases of transmission of an infectious
illness associated with the use of porcine pancreatic extracts have been reported.
5.5 Allergic Reactions
Caution should be exercised when administering pancrelipase to a patient with a known allergy
to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma,
hives, and pruritus have been reported with other pancreatic enzyme products with different
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formulations of the same active ingredient (pancrelipase). The risks and benefits of continued
PANCREAZE treatment in patients with severe allergy should be taken into consideration with
the overall clinical needs of the patient.
6
ADVERSE REACTIONS
The most serious adverse reactions reported with different pancreatic enzyme products of the
same active ingredient (pancrelipase) include fibrosing colonopathy, hyperuricemia and allergic
reactions [see Warnings and Precautions (5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical
trials of another drug and may not reflect the rates observed in clinical practice.
The short-term safety of PANCREAZE was assessed in two clinical trials conducted in
57 patients with exocrine pancreatic insufficiency (EPI) due to CF. Study 1 was conducted in
40 patients, ages 8 years to 57 years; Study 2 was conducted in 17 patients, ages 6 months to
30 months. In Study 1, PANCREAZE was administered in a dose of approximately 6,300 lipase
units per kilogram per day for lengths of treatment ranging from 8 to 26 days; in Study 2,
PANCREAZE was administered in four treatment arms (doses of 1,375, 2,875, 4,735, and
5,938 lipase units per kilogram per day) for lengths of treatment ranging from 6 to 11 days. The
population was nearly evenly distributed in gender, and approximately 96% of patients were
Caucasian.
Study 1 was a randomized, double-blind, placebo-controlled study of 40 patients, ages 8 to
57 years, with EPI due to CF. In this study, patients received PANCREAZE at individually
titrated doses (not to exceed 2,500 lipase units per kilogram per meal) for 14 days, followed by
randomization to PANCREAZE or matching placebo for 7 days of treatment. The mean
exposure to PANCREAZE during this study, including titration period and randomized
withdrawal period, was 18 days.
The incidence of adverse events (regardless of causality) was higher during placebo treatment
(60%) than during PANCREAZE treatment (40%). The most common adverse events reported
during the study were gastrointestinal complaints, which were reported more commonly during
placebo treatment (55%) than during PANCREAZE treatment (30%). The type and incidence of
adverse events were similar in children (8 to 11 years), adolescents (12 to 17 years), and adults
(greater than 18 years).
Table 1 enumerates treatment-emergent adverse events that occurred in at least 2 patients
(greater than or equal to 10%) treated with either PANCREAZE or placebo in Study 1. Adverse
events were classified by Medical Dictionary for Regulatory Activities (MedDRA) terminology.
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Table 1:
Treatment-Emergent Adverse Events Occurring in at Least 2 Patients (Greater Than or
Equal to 10%) in Either Treatment Group of the Placebo-Controlled, Clinical Study of
PANCREAZE
MedDRA Primary System Organ Class
Preferred Term
PANCREAZE
(N=20)
n (%)
Placebo
(N=20)
n (%)
Gastrointestinal Disorders
Abdominal pain
2 (10%)
3 (15%)
Abdominal pain upper
1 (5%)
3 (15%)
Flatulence
1 (5%)
3 (15%)
Diarrhea
0 (0%)
4 (20%)
Abnormal feces
0 (0%)
3 (15%)
General Disorders and Administration Site Conditions
Fatigue
0 (0%)
2 (10%)
Study 2 was a randomized, investigator-blinded, dose-ranging study of 17 patients, ages
6 months to 30 months, with EPI due to CF. All patients were transitioned from their usual PEP
treatment to PANCREAZE at 375 lipase units per kilogram body weight per meal for a 6 day
run-in period. Patients were then randomized to receive PANCREAZE at one of four doses (375,
750, 1,125, and 1,500 lipase units per kilogram body weight per meal) for 5 days. Adverse
events were collected on patient diary entries and at each study visit.
The most commonly reported adverse events were gastrointestinal, including diarrhea and
vomiting, and were similar in type and frequency across treatment arms and to those reported in
the double-blind, placebo-controlled trial (Study 1).
6.2 Postmarketing Experience
Postmarketing data for PANCREAZE have been available since 1988. The safety data are
similar to those described below.
Delayed- and immediate-release pancreatic enzyme products with different formulations of the
same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine
pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis.
The long-term safety profile of these products has been described in the medical literature. The
most serious adverse events included fibrosing colonopathy, distal intestinal obstruction
syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including
anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were
gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and
nausea, and skin disorders including pruritus, urticaria and rash. In general, these products have a
well-defined and favorable risk-benefit profile in exocrine pancreatic insufficiency.
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Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
7
DRUG INTERACTIONS
No drug interactions have been identified. No formal interaction studies have been conducted.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic effects
Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase.
It is not known whether pancrelipase can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. PANCREAZE should be given to a pregnant woman
only if clearly needed. The risk and benefit of pancrelipase should be considered in the context
of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic
insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight
gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with
adverse pregnancy outcomes.
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PANCREAZE is administered to a nursing
woman. The risk and benefit of pancrelipase should be considered in the context of the need to
provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.
8.4 Pediatric Use
The short-term safety and effectiveness of PANCREAZE were assessed in two clinical studies in
pediatric patients with EPI due to CF; one study included patients ages 6 to 30 months, and the
other included patients ages 8 years to 17 years.
Study 1 was a randomized, double-blind, placebo-controlled study in 40 patients, 14 of whom
were pediatric patients, including 7 children aged 8 to 11 years, and 7 adolescents aged 12 to
17 years. The safety and efficacy in pediatric patients in this study were similar to adult patients
[see Adverse Reactions (6.1) and Clinical Studies (14)].
Study 2 was a randomized, investigator-blinded, dose-ranging study in 17 pediatric patients aged
6 to 30 months. When patient regimen was switched from their usual PEP regimen to
PANCREAZE, patients showed similar control of their fat malabsorption [see Adverse Reactions
(6.1) and Clinical Studies (14)].
The safety and efficacy of pancreatic enzyme products with different formulations of
pancrelipase consisting of the same active ingredients (lipases, proteases, and amylases) for
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treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis has been
described in the medical literature and through clinical experience.
Dosing of pediatric patients should be in accordance with recommended guidance from the
Cystic Fibrosis Foundation Consensus Conferences [see Dosage and Administration (2.1)].
Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per
meal have been associated with fibrosing colonopathy and colonic strictures in children less than
12 years of age [see Warnings and Precautions (5.1)].
10 OVERDOSAGE
In Study 1, a 10 year-old patient was administered a PANCREAZE dose of 12,399 lipase units
per kilogram per day for the duration of the open-label and randomized withdrawal periods. The
patient experienced mild abdominal pain throughout both study periods. Abnormal chemistry
data at the end of the study included mild elevations of aspartate aminotransferase (AST),
alanine aminotransferase (ALT), and serum phosphate. Abnormal hematology data at the end of
the study included mild elevations of hematocrit. No abnormalities from analyses of urinalysis or
uric acid were noted.
Chronic high doses of pancreatic enzyme products have been associated with fibrosing
colonopathy and colonic strictures [see Dosage and Administration (2.1) and Warnings and
Precautions (5.1)]. High doses of pancreatic enzyme products have been associated with
hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of
hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].
11 DESCRIPTION
PANCREAZE is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived
from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including
porcine-derived lipases, proteases, and amylases.
Each capsule for oral administration contains enteric-coated microtablets that are each
approximately 2 mm in diameter.
The active ingredient evaluated in clinical trials is lipase. PANCREAZE is dosed by lipase units.
Other active ingredients include protease and amylase.
Inactive ingredients in PANCREAZE 2,600 USP units of lipase include microcrystalline
cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, methacrylic acid ethyl
acrylate copolymer, montan glycol wax, simethicone emulsion, talc and triethyl citrate.
Inactive ingredients in other strengths of PANCREAZE include cellulose, colloidal anhydrous
silica, crospovidone, magnesium stearate, methacrylic acid ethyl acrylate copolymer, montan
glycol wax, simethicone emulsion, talc and triethyl citrate.
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PANCREAZE is available in five color coded strengths. Each PANCREAZE capsule strength
contains the specified amounts of lipase, protease, and amylase as follows:
2,600 USP units of lipase; 6,200 USP units of protease; 10,850 USP units of amylase. The
hypromellose capsules have a light orange opaque body and clear cap imprinted with “McNEIL”
and “MT 2”. The capsule shell contains hypromellose, titanium dioxide, iron oxide, and imprint
ink contains iron oxide, shellac, ammonium hydroxide, propylene glycol, potassium hydroxide.
4,200 USP units of lipase; 10,000 USP units of protease; 17,500 USP units of amylase. The hard
gelatin capsules have a yellow opaque body and clear cap imprinted with “McNEIL” and “MT
4”. The capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate, sorbitan
monolaurate, iron oxide, and gelatin capsule imprint ink.
10,500 USP units of lipase; 25,000 USP units of protease; 43,750 USP units of amylase. The
hard gelatin capsules have a pink opaque body and clear cap imprinted with “McNEIL” and “MT
10”. The capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate, sorbitan
monolaurate, iron oxide, and gelatin capsule imprint ink.
16,800 USP units of lipase; 40,000 USP units of protease; 70,000 USP units of amylase. The
hard gelatin capsules have a salmon opaque body and clear cap imprinted with “McNEIL” and
“MT 16”. The capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate, sorbitan
monolaurate, iron oxide, and gelatin capsule imprint ink.
21,000 USP units of lipase; 37,000 USP units of protease; 61,000 USP units of amylase. The
hard gelatin capsules have a white opaque body and cap imprinted with “McNEIL” and “MT
20”. The capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate, sorbitan
monolaurate, and gelatin capsule imprint ink.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The pancreatic enzymes in PANCREAZE catalyze the hydrolysis of fats to monoglyceride,
glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins
and short chain sugars such as maltose and maltriose in the duodenum and proximal small
intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.
12.3 Pharmacokinetics
The pancreatic enzymes in PANCREAZE are enteric-coated to minimize destruction or
inactivation in gastric acid. PANCREAZE is expected to release most of the enzymes in vivo at
pH greater than 5.5. Pancreatic enzymes are not absorbed from the gastrointestinal tract in
appreciable amounts.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with
pancrelipase.
14 CLINICAL STUDIES
The short-term safety and efficacy of PANCREAZE were evaluated in two studies conducted in
57 patients with exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF).
Study 1 was a randomized, double-blind, placebo-controlled study of 40 patients, ages 8 to
57 years, with EPI due to CF. In this study, patients received PANCREAZE at individually
titrated doses (not to exceed 2,500 lipase units per kilogram per meal) for 14 days (open-label
period) followed by randomization to PANCREAZE or matching placebo for 7 days of treatment
(double-blind withdrawal period). Only patients with coefficient of fat absorption (CFA) ≥80%
in the open-label period were randomized to the double-blind withdrawal period. The mean dose
during the controlled treatment period was 6,400 lipase units per kilogram per day. All patients
consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment
period.
The primary efficacy endpoint was the change in CFA from the open label period to the end of
the double-blind withdrawal period. The CFA was determined by a 72-hour stool collection
period during both treatment periods, when both fat excretion and fat ingestion were measured
(Table 2).
Table 2.
Change in CFA in Study 1 (Open-Label Period to End of Double-Blind Withdrawal Period)
PANCREAZE
n=20
Placebo
n=20
CFA [%]
Open-Label Period* (Mean, SD)
88 (5)
91 (5)
End of Double-Blind Withdrawal Period# (Mean, SD)
87 (8)
56 (25)
Change in CFA† [%]
Open-Label Period to End of Double-Blind Withdrawal Period (Mean, SD)
-2 (6)
-34 (23)
Treatment Difference Point Estimate (95% CI)
33 (25, 40)
*Minimum of 72 hours from start of open label period.
#Double-blind withdrawal period ranged from 4 to 7 days.
†p<0.001
At the end of the double-blind withdrawal period, the mean change in CFA from the open-label
period to the end of the double-blind withdrawal period was -2% with PANCREAZE treatment
compared to -34% with placebo treatment. There were similar responses to PANCREAZE by
age and gender.
Study 2 was a randomized, investigator-blinded, dose-ranging study of 17 patients, ages
6 months to 30 months (mean 18 months) with EPI due to CF. The final analysis population was
limited to 16 patients; 1 patient was excluded due to withdrawal of consent. All patients were
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transitioned from their usual PEP treatment to PANCREAZE at 375 lipase units per kilogram
body weight per meal for a 6-day run-in period. Patients were then randomized to receive
PANCREAZE at one of four doses (375, 750, 1,125, and 1,500 lipase units per kilogram body
weight per meal) for 5 days. The CFA was measured at the end of the run-in period and at the
end of the randomized period (Table 3).
Table 3.
Change in CFA in Study 2 (End of Run-in Period to End of Study)
375 units
lipase/kg/meal
n=4
750 units
lipase/kg/meal
n=4
1,125 units
lipase/kg/meal
n=4
1,500 units
lipase/kg/meal
n=4
CFA (%)
Day 6* (Mean, SD)
93 (2)
90 (5)
81 (11)
93 (3)
Day 11# (Mean, SD)
92 (3)
91 (4)
80 (13)
91 (2)
Change in CFA (%)
Day 6 to Day 11 (Mean, SD)
-2 (3)
1 (3)
-1 (3)
-2 (3)
*End of Run-in Period; #End of Study
Overall, patients showed similar CFA at the end of the run-in period (mean PANCREAZE dose
of 1,600 lipase units per kilogram body weight per day) as at the end of the study across the four
treatment arms.
15 REFERENCES
1.
Borowitz DS, Grand RJ, Durie PR, et al. Use of pancreatic enzyme supplements for
patients with cystic fibrosis in the context of fibrosing colonopathy. Journal of
Pediatrics. 1995; 127: 681-684.
2.
Borowitz DS, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients
with cystic fibrosis. Journal of Pediatric Gastroenterology Nutrition. 2002 Sep; 35: 246
259.
3.
Stallings VA, Start LJ, Robinson KA, et al. Evidence-based practice recommendations
for nutrition-related management of children and adults with cystic fibrosis and
pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic
Association. 2008; 108: 832-839.
4.
Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a
case-control study. Lancet. 1995; 346: 1247-1251.
5.
FitzSimmons SC, Burkhart GA, Borowitz DS, et al. High-dose pancreatic-enzyme
supplements and fibrosing colonopathy in children with cystic fibrosis. New England
Journal of Medicine. 1997; 336: 1283-1289.
16 HOW SUPPLIED/STORAGE AND HANDLING
PANCREAZE (pancrelipase) Delayed-Release Capsules
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2,600 USP units of lipase; 6,200 USP units of protease; 10,850 USP units of amylase.
PANCREAZE (pancrelipase) is supplied as hypromellose capsules with a light orange opaque
body and clear cap imprinted with “McNEIL” and “MT 2” and packaged in bottles of 100-(NDC
50458-347-60).
PANCREAZE (pancrelipase) Delayed-Release Capsules
4,200 USP units of lipase; 10,000 USP units of protease; 17,500 USP units of amylase.
PANCREAZE (pancrelipase) is supplied as hard gelatin capsules with a yellow opaque body and
clear cap imprinted with “McNEIL” and “MT 4” and packaged in bottles of 100–(NDC 50458
341-60).
PANCREAZE (pancrelipase) Delayed-Release Capsules
10,500 USP units of lipase; 25,000 USP units of protease; 43,750 USP units of amylase.
PANCREAZE (pancrelipase) is supplied as hard gelatin capsules with a pink opaque body and
clear cap imprinted with “McNEIL” and “MT 10” and packaged in bottles of 100–(NDC 50458
342-60).
PANCREAZE (pancrelipase) Delayed-Release Capsules
16,800 USP units of lipase; 40,000 USP units of protease; 70,000 USP units of amylase.
PANCREAZE (pancrelipase) is supplied as hard gelatin capsules with a salmon opaque body
and clear cap imprinted with “McNEIL” and “MT 16” and packaged in bottles of 100–(NDC
50458-343-60).
PANCREAZE (pancrelipase) Delayed-Release Capsules
21,000 USP units of lipase; 37,000 USP units of protease; 61,000 USP units of amylase.
PANCREAZE (pancrelipase) is supplied as hard gelatin capsules with a white opaque body and
cap imprinted with “McNEIL” and “MT 20” and packaged in bottles of 100–(NDC 50458-346
60).
Storage and Handling
Avoid heat. PANCREAZE capsules should be stored in a dry place in the original container.
After opening, KEEP THE CONTAINER TIGHTLY CLOSED between uses to PROTECT
FROM MOISTURE. Do not store above 25°C (77°F).
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The PANCREAZE 2,600 USP units of lipase, the PANCREAZE 4,200 USP units of lipase and
the PANCREAZE 21,000 USP units of lipase bottles contain a desiccant canister. Do not eat or
throw away the desiccant canister in your medicine bottle. This canister will protect your
medicine from moisture.
Keep out of reach of children.
DO NOT CRUSH PANCREAZE delayed-release capsules or the capsule contents.
17 PATIENT COUNSELING INFORMATION
See Medication Guide
17.1 Dosing and Administration
• Instruct patients and caregivers that PANCREAZE should only be taken as directed by their
healthcare professional. Patients should be advised that the total daily dose should not exceed
10,000 lipase units/kg body weight/day unless clinically indicated. This needs to be
especially emphasized for patients eating multiple snacks and meals per day. Patients should
be informed that if a dose is missed, the next dose should be taken with the next meal or
snack as directed. Doses should not be doubled [see Dosage and Administration (2)].
• Instruct patients and caregivers that PANCREAZE should always be taken with food.
Patients should be advised that PANCREAZE delayed-release capsules and the capsule
contents must not be crushed or chewed as doing so could cause early release of enzymes
and/or loss of enzymatic activity. Patients should swallow the intact capsules with adequate
amounts of liquid at mealtimes. If necessary, the capsule contents can also be sprinkled on
soft acidic foods. [see Dosage and Administration (2)].
• Instruct patients to notify their healthcare professional if they are pregnant or are thinking of
becoming pregnant during treatment with PANCREAZE [see Use in Specific Populations
(8.1)].
• Instruct patients to notify their healthcare professional if they are breastfeeding or are
thinking of breastfeeding during treatment with PANCREAZE [see Use in Specific
Populations (8.3)].
17.2 Fibrosing Colonopathy
Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic
enzyme products exceeding 6,000 lipase units/kg of body weight per meal (10,000 lipase
units/kg of body weight/day) have been associated with colonic strictures in children below the
age of 12 years [see Dosage and Administration (2)].
17.3 Allergic Reactions
Advise patients and caregivers to contact their healthcare professional immediately if allergic
reactions to PANCREAZE develop [see Warnings and Precautions (5.5)].
Reference ID: 3467367
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Product of Germany
Finished Product Manufactured by:
Nordmark Arzneimittel GmbH & Co. KG
25436 Uetersen, Germany.
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560.
Revised: MMM YYYY
Janssen Pharmaceuticals, Inc. 2010
Reference ID: 3467367
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
PANCREAZE (pan-kre-aze)
(pancrelipase)
delayed-release capsules
Read this Medication Guide before you start taking PANCREAZE and each
time you get a refill. There may be new information. This information does
not take the place of talking to your doctor about your medical condition or
treatment.
What is the most important information I should know about
PANCREAZE?
PANCREAZE may increase your chance of having a rare bowel disorder called
fibrosing colonopathy. This condition is serious and may require surgery. The
risk of having this condition may be reduced by following the dosing
instructions that your doctor gave you.
•
Call your doctor right away if you have any unusual or severe:
• stomach area (abdominal) pain
• bloating
• trouble passing stool (having bowel movements)
• nausea, vomiting, or diarrhea
Take PANCREAZE exactly as prescribed by your doctor. Do not take more or
less PANCREAZE than directed by your doctor.
What is PANCREAZE?
PANCREAZE is a prescription medicine used to treat people who cannot
digest food normally because their pancreas does not make enough enzymes
due to cystic fibrosis or other conditions. PANCREAZE may help your body
use fats, proteins, and sugars from food.
PANCREAZE contains a mixture of digestive enzymes including lipases,
proteases, and amylases from pig pancreas.
PANCREAZE is safe and effective in children when taken as prescribed by
your doctor.
Reference ID: 3467367
16
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I tell my doctor before taking PANCREAZE?
Before taking PANCREAZE, tell your doctor about all your medical
conditions, including if you:
• are allergic to pork (pig) products.
• have a history of blockage of your intestines, or scarring or thickening
of your bowel wall (fibrosing colonopathy)
• have gout, kidney disease, or high blood uric acid (hyperuricemia)
• have trouble swallowing capsules
• have any other medical condition
• are pregnant or plan to become pregnant. It is not known if
PANCREAZE will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if PANCREAZE
passes into your breast milk. You and your doctor should decide if you
will take PANCREAZE or breastfeed.
Tell your doctor about all the medicines you take, including prescription
and over-the-counter medicines, vitamins, or herbal supplements.
Know the medicines you take. Keep a list of them and show it to your doctor
and pharmacist when you get a new medicine.
How should I take PANCREAZE?
Take PANCREAZE exactly as your doctor tells you.
• Do not take more capsules in a day than the number your doctor tells you
to take (total daily dose).
• Always take PANCREAZE with a meal or snack and plenty of fluid. If you
eat a lot of meals or snacks in a day, be careful not to go over your total
daily dose.
• Your doctor may change your dose based on the amount of fatty foods you
eat or based on your weight.
• Do not crush or chew the PANCREAZE capsules or their contents,
and do not hold the capsule or contents in your mouth. Crushing,
chewing or holding the PANCREAZE capsules in your mouth may cause
irritation in your mouth or change the way PANCREAZE works in your
body.
Reference ID: 3467367
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Giving PANCREAZE to infants (children up to 12 months):
1. Give PANCREAZE right before each feeding of formula or breast milk.
2. Do not mix PANCREAZE capsule contents directly into formula or
breast milk.
3. Open the capsules and sprinkle the contents directly into your infant’s
mouth or mix the contents in a small amount of soft food such as
applesauce. These foods should be the kind found in baby food jars
that you buy at the store, or other food recommended by your doctor.
4. If you sprinkle the PANCREAZE on food, give the PANCREAZE and food
mixture to your child right away. Do not store PANCREAZE that is
mixed with food.
5. Give your child enough liquid to completely swallow the PANCREAZE
contents or the PANCREAZE and food mixture.
6. Look into your child’s mouth to make sure that all of the medicine has
been swallowed.
Giving PANCREAZE to children and adults:
1. Swallow PANCREAZE capsules whole and take them with enough liquid
to swallow them right away.
2. If you have trouble swallowing capsules, open the capsules and
sprinkle the contents on a small amount of acidic food such as
applesauce. Ask your doctor about other foods you can mix with
PANCREAZE.
3. If you sprinkle PANCREAZE on food, swallow it right after you mix it
and drink plenty of water or juice to make sure the medicine is
swallowed completely. Do not store PANCREAZE that is mixed with
food.
4. If you forget to take PANCREAZE, call your doctor or wait until your
next meal and take your usual number of capsules. Take your next
dose at your usual time. Do not make up for missed doses.
What are the possible side effects of PANCREAZE?
PANCREAZE may cause serious side effects, including:
Reference ID: 3467367
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• See “What is the most important information I should know about
PANCREAZE?”
• Irritation of the inside of your mouth. This can happen if PANCREAZE
is not swallowed completely.
• Increase in blood uric acid levels. This may cause worsening of
swollen, painful joints (gout) caused by an increase in your blood uric acid
levels.
• Allergic reactions including trouble with breathing, skin rashes, or
swollen lips.
• Call your doctor right away if you have any of these symptoms.
The most common side effects of PANCREAZE include:
• Pain in your stomach (abdominal area)
• Gas
Other possible side effects of PANCREAZE:
PANCREAZE and other pancreatic enzyme products are made from the
pancreas of pigs, the same pigs people eat as pork. These pigs may carry
viruses. Although it has never been reported, it may be possible for a person
to get a viral infection from taking pancreatic enzyme products that come
from pigs.
Tell your doctor if you have any side effect that bothers you or does not go
away.
These are not all the possible side effects of PANCREAZE. For more
information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
You may also report side effects to Janssen Pharmaceuticals, Inc. at
1-800-526-7736.
How should I store PANCREAZE?
• Store PANCREAZE at room temperature below 77°F (25°C). Avoid heat.
• Keep PANCREAZE in a dry place and in the original container.
Reference ID: 3467367
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• After opening the bottle, keep it closed tightly between uses.
• The PANCREAZE 2,600 USP units of lipase, PANCREAZE 4,200 USP
units of lipase and PANCREAZE 21,000 USP units of lipase bottles
contain a desiccant canister. Do Not eat or throw away the desiccant
canister
in your medicine bottle. This canister will protect your
medicine from moisture.
Keep PANCREAZE and all medicines out of the reach of children.
General information about PANCREAZE
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use PANCREAZE for a condition for which it was not
prescribed. Do not give PANCREAZE to other people to take, even if they
have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about
PANCREAZE. If you would like more information, talk to your doctor. You can
ask your pharmacist or doctor for information about PANCREAZE that is
written for healthcare professionals.
For more information go to www.RXFORSAFETY.com or call 1-800-526-7736.
What are the ingredients in PANCREAZE?
Active Ingredient: lipase, protease, amylase
Inactive ingredients in PANCREAZE 2,600 USP units of lipase:
microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium
stearate, methacrylic acid ethyl acrylate copolymer, montan glycol wax,
simethicone emulsion, talc and triethyl citrate.
The capsule shell contains hypromellose, titanium dioxide, iron oxide, and
imprint ink contains iron oxide, shellac, ammonium hydroxide, propylene
glycol, potassium hydroxide.
Inactive Ingredients in other strengths: cellulose, colloidal anhydrous
silica, crospovidone, magnesium stearate, methacrylic acid ethyl acrylate
copolymer, montan glycol wax, simethicone emulsion, talc and triethyl
citrate.
Reference ID: 3467367
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate,
sorbitan monolaurate, and gelatin capsule imprint ink. PANCREAZE 4,200,
10,500, and 16,800 USP units of lipase also contain iron oxide.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Product of Germany
Finished Product Manufactured by:
Nordmark Arzneimittel GmbH & Co. KG
25436 Uetersen, Germany.
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560.
Revised: 03 2014
Janssen Pharmaceuticals, Inc. 2010
Reference ID: 3467367
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:33.642436 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022523s004lbl.pdf', 'application_number': 22523, 'submission_type': 'SUPPL ', 'submission_number': 4} |
10,666 | NDA 04-782/S-128
Page 3
Premarin®
(conjugated estrogens tablets, USP)
only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the
use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose.
DESCRIPTION
Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated
equine estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-
soluble estrogen sulfates blended to represent the average composition of material derived from
pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains
as concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17
β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg,
and 2.5 mg strengths of conjugated estrogens.
Premarin Tablets contain the following inactive ingredients: calcium phosphate tribasic, calcium
sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose,
pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, titanium dioxide.
—0.3 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C
Yellow No. 6; these tablets comply with USP Drug Release Test 1.
—0.625 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40; these
tablets comply with USP Drug Release Test 1.
—0.9 mg tablets also contain: D&C Red No. 6, D&C Red No. 7; these tablets comply with USP Drug
Release Test 2.
—1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10, FD&C Yellow No. 6; these
tablets comply with USP Drug Release Test 3.
—2.5 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 7; these tablets comply with USP
Drug Release Test 3.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the female
reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human
estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes
70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
Page 4
adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone
sulfate, are the most abundant circulating estrogen in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH)
and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogen replacement
therapy acts to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after
release from the drug formulation. The Premarin tablet releases conjugated estrogens slowly over
several hours. The pharmacokinetic profile of unconjugated and conjugated estrogens following a dose
of 2 x 0.625 mg is provided in Table 1.
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex hormone
target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG)
and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take
place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to
estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via
sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and
hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the
circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a
circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
Page 5
Table 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg*
Drug
Cmax
tmax
t1/2**
AUC
(pg/mL)
(h)
(h)
(pg•h/mL)
estrone
139 (37)
8.8 (20)
28.0 (13)
5016 (34)
baseline-adjusted estrone
120 (42)
8.8 (20)
17.4 (37)
2956 (39)
equilin
66 (42)
7.9 (19)
13.6 (52)
1210 (37)
*Mean (Coefficient of Variation, %)
** t1/2 = terminal-phase disposition half-life (0.693/γ2)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.625 mg*
Drug
Cmax
tmax
t1/2**
AUC
(ng/mL)
(h)
(h)
(ng•h/mL)
total estrone
7.3 (41)
7.3 (51)
15.0 (25)
134 (42)
baseline-adjusted total estrone
7.1 (41)
7.3 (25)
13.6 (27)
122 (39)
total equilin
5.0 (42)
6.2 (26)
10.1 (27)
65 (45)
*Mean (Coefficient of Variation, %)
** t1/2 = terminal-phase disposition half-life (0.693/γ2)
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or
hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
significantly altered. No other clinical drug-drug interaction studies have been conducted with
conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450
3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a
decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4
such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may
increase plasma concentrations of estrogens and may result in side effects.
Clinical Studies
Effects on bone mineral density.
In the 3-year, randomized, double-blind, placebo-controlled Postmenopausal Estrogen/Progestin
Interventions (PEPI) trial, the effect of Premarin 0.625 mg (conjugated estrogens tablets, USP), given
alone or in combination with medroxyprogesterone acetate (MPA), on bone mineral density (BMD)
was evaluated in postmenopausal women. One of the regimens evaluated was continuous combined
Premarin 0.625 mg/MPA 2.5 mg, a regimen similar to Prempro™.
Intent-to-treat subjects
In the intent-to-treat subjects, BMD increased significantly (p<0.001) compared to baseline or placebo
at both the hip and the spine in women assigned to Premarin or the continuous Premarin/MPA
regimen. Spinal BMD increased 3.46% among women assigned to Premarin, increased 4.87% in
women assigned to the Premarin/MPA regimen and decreased 1.81% in women assigned to placebo.
At the hip, women assigned to Premarin gained 1.31%, women assigned to Premarin/MPA gained
1.94%, while women assigned to placebo lost 1.62%.
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NDA 04-782/S-128
Page 6
Adherent subjects
In the adherent subjects, BMD also increased significantly (p<0.001) compared to baseline or placebo
at both the hip and the spine in women assigned to Premarin or continuous Premarin/MPA. Spinal
BMD increased 5.16% among women assigned to Premarin, increased 5.49% in women assigned to
Premarin/MPA and decreased 2.82% in women assigned to placebo. At the hip, women assigned to
Premarin gained 2.60%, women assigned to Premarin/MPA gained 2.23%, while women assigned to
placebo lost 2.17%.
These results are summarized in Tables 2 and 3 below.
Table 2. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD AT 36 MONTHS
IN INTENT-TO-TREAT SUBJECTS**
Spine
Hip
Regimen
n
Mean % Change
95% CI
n
Mean % Change
95% CI
Premarin 0.625 mg
175
+3.46%*†
2.78, 4.14
175
+1.31%*†
0.76, 1.86
Premarin 0.625 mg/
MPA 2.5 mg
174
+4.87%*†
4.21, 5.52
174
+1.94%*†
1.50, 2.39
Placebo
174
-1.81%*
-2.51, -1.12
173
-1.62%*
-2.16, -1.08
*
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
** includes all 523 women who were randomized to either Premarin, Premarin/MPA or placebo whether or not they
completed the study. If BMD was not available at 36 months, then the 12 months value was carried forward and
analyzed. Baseline values were carried forward if 12 months and 36 months data were unavailable. Most patients who
discontinued study medication were followed through month 36 and could have been off therapy for an extended
period prior to their month 36 evaluation.
Table 3. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD AT 36 MONTHS
IN ADHERENT SUBJECTS**
Spine
Hip
Regimen
n
Mean % Change
95% CI
n
Mean % Change
95% CI
Premarin 0.625 mg
95
+5.16%*†
4.32, 6.00
95
+2.60%*†
1.97, 3.23
Premarin 0.625 mg/
MPA 2.5 mg
144
+5.49%*†
4.79, 6.18
144
+2.23%*†
1.75, 2.71
Placebo
124
-2.82%*
-3.54, -2.10
123
-2.17%*
-2.78, -1.56
*
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
** women who completed the study, had BMD reported at month 36, and took 80% or more of their prescribed
medication.
In general, older women (55-64 years of age) taking placebo in the PEPI study lost bone at a lower rate
than younger women (45-54 years of age). Conversely, older women receiving Premarin or Premarin
0.625 mg/MPA 2.5 mg had greater increases in BMD than younger women. Tables 4 and 5 present
data for women 45 to 54 years of age and women 55 to 64 years of age.
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NDA 04-782/S-128
Page 7
Table 4. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD FOR WOMEN
45 TO 54 YEARS OF AGE
Intent-To-Treat Subjects
Adherent Subjects
Regimen
n
Mean %
Change at the
Spine
n
Mean %
Change at the
Hip
n
Mean %
Change at the
Spine
n
Mean %
Change at the
Hip
Premarin 0.625 mg
74
+2.45%†**
74
+1.37%†**
43
+3.73%†**
43
+2.20%†**
Premarin 0.625 mg/
MPA 2.5 mg
69
+3.53%†**
69
+1.26%†**
58
+3.97%†**
58
+1.48%†**
Placebo
78
-2.82%**
78
-2.23%**
50
-4.02%**
50
-3.04%**
**
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
Table 5. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD FOR WOMEN
55 TO 64 YEARS OF AGE
Intent-To-Treat Subjects
Adherent Subjects
Regimen
n
Mean %
Change at the
Spine
n
Mean %
Change at
the Hip
n
Mean %
Change at
the Spine
n
Mean %
Change at the
Hip
Premarin 0.625 mg 101
+4.21%†‡**
101
+1.27%†**
52
+6.34%†‡**
52
+2.93%†**
Premarin 0.625 mg/
MPA 2.5 mg
105
+5.75%†‡**
105
+2.39%†**
86
+6.51%†‡**
86
+2.73%†**
Placebo
95
-1.01%*
94
-1.14%*
73
-2.04%‡**
72
-1.60%**
*
denotes a statistically significant mean change from baseline at the 0.05 level.
**
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
‡
denotes mean percentage change from baseline in the older age group is significantly different from the mean
percentage change in the younger age group at the 0.05 level.
Women’s Health Initiative Studies.
Two subsets of the Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either long-term use of Premarin (0.625 mg
conjugated equine estrogens per day) alone or long-term use of Prempro (0.625 mg conjugated equine
estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of
certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD)
(nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse
outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer,
stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to
other cause. The study did not evaluate the effects of Premarin or Prempro on menopausal symptoms.
The Premarin-only subset is continuing and results have not been reported. The Prempro subset of the
study was stopped early because, according to the predefined stopping rule, the increased risk of breast
cancer and cardiovascular events exceeded the specified long-term benefits included in the “global
index”. Results of the Prempro subset, which included 16,608 women (average age of 63 years, range
50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are
presented in Table 6 below:
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NDA 04-782/S-128
Page 8
Table 6. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPRO SUBSET OF
WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000 Person-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than the
events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosis d
2.07 (1.49-2.87)
13
26
Vertebral fractures d
0.66 (0.44-0.98)
15
9
Other osteoporotic fractures d
0.77 (0.69-0.86)
170
131
a
adapted from JAMA, 2002; 288:321-333
b
includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c
a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive
breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other
causes
d
not included in Global Index
*
nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index”, absolute excess risks per 10,000 person-years in the
group treated with Prempro were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more
invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal
cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index”
was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause
mortality. (See WARNINGS and PRECAUTIONS.)
INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of vulvar and vaginal atrophy.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with
metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
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6. Prevention of postmenopausal osteoporosis.
Premarin alone or in combination with a progestin is not indicated and should not be used to
prevent coronary heart disease (see WARNINGS).
Because of the potential increased risks of cardiovascular events, breast cancer and venous
thromboembolic events, use of Premarin alone or in combination with a progestin should be
limited to the shortest duration consistent with treatment goals and risks for the individual
woman, and should be periodically reevaluated. When used solely for the prevention of
postmenopausal osteoporosis, alternative treatments should be carefully considered. (See
WARNINGS and CLINICAL PHARMACOLOGY, Clinical Studies.)
Postmenopausal estrogen therapy reduces bone resorption and retards postmenopausal bone loss. Case-
control studies have shown an approximately 60% reduction in hip and wrist fractures in women
whose estrogen therapy was begun within a few years of menopause. Studies also suggest that estrogen
reduces the rate of vertebral fractures. Even when started as late as 6 years after menopause, estrogen
may prevent further loss of bone mass for as long as the treatment is continued. When estrogen therapy
is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal
period.
The mainstays of prevention of postmenopausal osteoporosis are weight-bearing exercise, adequate
calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women
absorb dietary calcium less efficiently than premenopausal women and require an average of
1500 mg/day of elemental calcium to remain in neutral calcium balance. The average calcium intake in
the USA is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be
helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may
also be required to ensure adequate daily intake in postmenopausal women.
Early menopause is one of the strongest predictors for the development of osteoporosis. In addition,
other factors affecting the skeleton that are associated with osteoporosis include genetic factors (small
build, family history), endocrine factors (nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing’s
syndrome, hyperprolactinemia, Type I diabetes), lifestyle (cigarette smoking, alcohol abuse, sedentary
exercise habits), and nutrition (below average body weight, dietary calcium intake).
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Known or suspected pregnancy. Estrogens may cause fetal harm when administered to a pregnant
woman. (See PRECAUTIONS.)
2. Undiagnosed abnormal genital bleeding.
3. Known or suspected cancer of the breast except in appropriately selected patients being treated for
metastatic disease.
4. Known or suspected estrogen-dependent neoplasia.
5. Active deep vein thrombosis/pulmonary embolism or a history of these conditions.
6. Active or recent arterial thromboembolic disease (eg, stroke, myocardial infarction).
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7. Premarin Tablets should not be used in patients with known hypersensitivity to their ingredients.
WARNINGS
Because of the potential increased risks of cardiovascular events, breast cancer and venous
thromboembolic events, use of Premarin alone or in combination with a progestin should be
limited to the shortest duration consistent with treatment goals and risks for the individual
woman, and should be periodically reevaluated. When used solely for the prevention of
postmenopausal osteoporosis, alternative treatments should be carefully considered. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
The use of unopposed estrogens in women with an intact uterus is associated with an increased risk of
endometrial cancer.
1.
Cardiovascular disorders.
Postmenopausal estrogen and estrogen/progestin therapy have been associated with an increased risk
of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and
pulmonary embolism (venous thromboembolism or VTE).
Should any of these occur or be suspected, estrogen therapy should be discontinued immediately.
Patients who have risk factors for thrombotic disorders should be kept under careful observation.
a. Coronary heart disease and stroke. In the Premarin subset of the Women’s Health Initiative study
(WHI), an increase in the number of myocardial infarctions and stroke has been observed in women
receiving estrogen compared to placebo. These observations are preliminary, and the study is
continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the Prempro subset of WHI an increased risk of coronary heart disease (CHD) events (defined as
non-fatal myocardial infarction and CHD death) was observed in women receiving Prempro compared
to women receiving placebo (37 vs 30 per 10,000 person-years). The increase in risk was observed in
year one and persisted.
In the same subset of WHI, an increased risk of stroke was observed in women receiving Prempro
compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was
observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with Prempro (0.625 mg conjugated equine
estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular benefit.
During an average follow-up of 4.1 years, treatment with Prempro did not reduce the overall rate of
CHD events in postmenopausal women with established coronary heart disease. There were more
CHD events in the Prempro-treated group than in the placebo group in year 1, but not during the
subsequent years. Two thousand three hundred and twenty one women from the original HERS trial
agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was
an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among
women in the Prempro group and the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer
of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the
risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
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b. Venous thromboembolism (VTE). In the Premarin subset of the Women’s Health Initiative study
(WHI), an increase in VTE has been observed in women receiving estrogen compared to placebo.
These observations are preliminary, and the study is continuing. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
In the Prempro subset of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and
pulmonary embolism, was observed in women receiving Prempro compared to women receiving
placebo. The rate of VTE was 34 per 10,000 woman-years in the Prempro group compared to 16 per
10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year
and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated
with an increased risk of thromboembolism, or during periods of prolonged immobilization.
2.
Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with an intact uterus has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among
unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on
duration of treatment and on estrogen dose. Most studies show no significant increased risk associated
with use of estrogens for less than one year. The greatest risk appears associated with prolonged use,
with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to
persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no
evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic
estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has
been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial
cancer.
b. Breast cancer. Long-term postmenopausal estrogen and estrogen/progestin therapy has been
associated with an increased risk of breast cancer.
In the Prempro subset of the Women’s Health Initiative study (WHI), a 26% increase of invasive
breast cancer (38 vs 30 per 10,000 woman-years) after an average of 5.2 years of treatment was
observed in women receiving Prempro compared to women receiving placebo. The increased risk of
breast cancer became apparent after 4 years on Prempro. The women reporting prior postmenopausal
hormone use had a higher relative risk for breast cancer associated with Prempro than those who had
never used postmenopausal hormones. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the Premarin subset of WHI, no increased risk of breast cancer in estrogen-treated women compared
to placebo was reported after an average of 5.2 years of therapy. These data are preliminary and that
subset of WHI is continuing.
A reanalysis of original data from 51 epidemiological studies (including Premarin and other
postmenopausal hormone therapies) reported an increase in the probability of having breast cancer
diagnosed in women currently or recently using postmenopausal hormone (estrogen and/or
This label may not be the latest approved by FDA.
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NDA 04-782/S-128
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estrogen/progestin) therapy. The authors estimate that among 1,000 women who begin hormone
therapy at age 50 and continue for 5 years, 10 years or 15 years, the additional number of cases of
breast cancer that would occur by age 70 would be 2 cases, 6 cases and 12 cases, respectively. The
probability of a diagnosis of breast cancer approached normal by five years after stopping
postmenopausal hormone therapy. Additional epidemiological studies suggest that the addition of
progestins increases the risk of breast cancer compared to the use of estrogens alone.
Women without a uterus who require postmenopausal hormone therapy should receive estrogen-alone
therapy, and should not be exposed unnecessarily to progestins. Women with a uterus who are
candidates for use of postmenopausal estrogen/progestin therapy should be advised of potential
benefits and risks (including the potential for an increased risk of breast cancer). All women should
receive yearly breast exams by a healthcare provider and perform monthly breast self-examinations. In
addition, mammography examinations should be scheduled as suggested by providers based on patient
age and risk factors.
c. Ovarian cancer. The association between postmenopausal estrogen therapy and ovarian cancer was
evaluated in several case-control and cohort studies. Two large cohort studies suggested an increased
risk of ovarian cancer associated with long-term postmenopausal estrogen-only therapy, particularly
for 10 or more years of use. In one of these studies, the baseline incidence among untreated
postmenopausal women was reported to be 4.4 cases per 10,000 woman-years, compared to 6.5 cases
per 10,000 woman-years among women using postmenopausal estrogen therapy. Other epidemiologic
studies of postmenopausal estrogen therapy and ovarian cancer did not show a significant association.
Data are insufficient to determine whether there is an increased risk with postmenopausal
estrogen/progestin therapy.
3. Gallbladder disease.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women
receiving postmenopausal estrogens has been reported.
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4. Hypercalcemia.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone
metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken
to reduce the serum calcium level.
5.
Visual abnormalities.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication
pending examination if there is sudden partial or complete loss of vision, or a sudden onset of
proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions,
Premarin should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily
with estrogen in a continuous regimen have reported a lowered incidence of endometrial hyperplasia
than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to
endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins in postmenopausal
hormone therapy regimens compared to estrogen-alone regimens. These include: an increased risk of
breast cancer (see WARNINGS, Malignant neoplasms), adverse effects on lipoprotein metabolism
(eg, lowering HDL, raising LDL) and impairment of glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure during postmenopausal
estrogen therapy have been attributed to idiosyncratic reactions to estrogens. In a large, randomized,
placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not
seen. Blood pressure should be monitored at regular intervals with estrogen use.
3. Familial hyperlipoproteinemia.
In patients with familial defects of lipoprotein metabolism, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be
exercised and in the case of recurrence, medication should be discontinued.
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5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal
thyroid function can compensate for the increased TBG by making more thyroid hormone, thus
maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid
hormone replacement therapy who are also receiving estrogens may require increased doses of their
thyroid replacement therapy. These patients should have their thyroid function monitored in order to
maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might be
influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when
estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
9. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or
porphyria and should be used with caution in patients with these conditions.
B.
Patient Information
See text of Patient Information insert after the HOW SUPPLIED section.
C.
Laboratory Tests
Estrogen administration should be guided by clinical response at the lowest dose for the treatment of
vasomotor symptoms and vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding
dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian
failure.
D.
Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII,
VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa
and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone,
as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3
levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and
free T3 concentrations are unaltered.
3. Other binding proteins may be elevated in serum, ie, corticosteroid binding globulin (CBG), sex
hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex
steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other
plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
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Page 15
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol
concentration, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.
E.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See
CONTRAINDICATIONS and WARNINGS.)
F.
Pregnancy Category X
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS.)
G.
Nursing Mothers
The administration of any drug to nursing mothers should be done only when clearly necessary since
many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has
been shown to decrease the quantity and quality of the milk. Estrogens are not indicated for the
prevention of postpartum breast engorgement.
H.
Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal
delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to accelerate
epiphyseal closure, which could result in short adult stature if treatment is initiated before the
completion of physiologic puberty in normally developing children. If estrogen is administered to
patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on
epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal
pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I.
Geriatric Use
There have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin to
determine whether those over 65 years of age differ from younger subjects in their response to
Premarin.
ADVERSE REACTIONS
See WARNINGS regarding cardiovascular disorders (including myocardial infarction, stroke and
venous thromboembolism), malignant neoplasms (including endometrial cancer, breast cancer and
ovarian cancer), gallbladder disease, hypercalcemia and visual abnormalities. See PRECAUTIONS
regarding elevated blood pressure, familial hyperlipoproteinemia, impaired liver function and past
history of cholestatic jaundice, hypothyroidism, fluid retention, hypocalcemia, and exacerbation of
endometriosis and other conditions.
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The following additional adverse reactions have been reported with estrogen therapy and/or progestin
therapy:
1. Genitourinary system
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough
bleeding, spotting.
Increase in size of uterine leiomyomata.
Vaginitis, including vaginal candidiasis.
Change in amount of cervical secretion.
Change in cervical ectropion.
Ovarian cancer.
2. Breasts
Tenderness, enlargement, pain, discharge, galactorrhea.
Fibrocystic breast changes.
3. Gastrointestinal
Nausea, vomiting.
Abdominal cramps, bloating.
Cholestatic jaundice.
Increased incidence of gallbladder disease.
Pancreatitis.
4. Skin
Chloasma or melasma that may persist when drug is discontinued.
Erythema multiforme.
Erythema nodosum.
Hemorrhagic eruption.
Loss of scalp hair.
Hirsutism.
Pruritus, rash.
5. Cardiovascular
Venous thromboembolism.
Pulmonary embolism.
Superficial thrombophlebitis.
Myocardial infarction.
Stroke.
6. Eyes
Steepening of corneal curvature.
Intolerance to contact lenses.
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7. Central Nervous System
Headache.
Migraine.
Dizziness.
Mental depression.
Chorea.
Nervousness.
Mood disturbances.
Irritability.
8. Miscellaneous
Increase or decrease in weight.
Reduced carbohydrate tolerance.
Aggravation of porphyria.
Edema.
Arthralgias.
Leg cramps.
Changes in libido.
Anaphylactoid/anaphylactic reactions including urticaria and angioedema.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-
containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and
vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
Use of postmenopausal estrogen therapy, alone or in combination with a progestin, should be limited
to the shortest duration consistent with treatment goals and risks for the individual woman, and should
be periodically reevaluated. (See WARNINGS.)
1. For treatment of moderate-to-severe vasomotor symptoms, and/or vulvar and vaginal atrophy
associated with the menopause, the lowest dose and regimen that will control symptoms should be
chosen.
Vasomotor symptoms—0.625 mg daily.
Vulvar and vaginal atrophy—0.3 mg to 1.25 mg or more daily, depending upon the tissue response
of the individual patient.
Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian
failure:
Female hypogonadism—0.3 mg to 0.625 mg daily, administered cyclically (eg, three weeks on and
one week off). Doses are adjusted depending on the severity of symptoms and responsiveness of
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Page 18
the endometrium.
In clinical studies of delayed puberty due to female hypogonadism, breast development was
induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12 month
intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure.
Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios
of bone age advancement to chronological age progression (∆BA/∆CA) of 1.1, 1.5, and 2.1,
respectively. (Premarin in the dose strength of 0.15 mg is not available commercially). Available
data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with
sequential progestin treatment and to maintain bone mineral density after skeletal maturity is
achieved.
Female castration or primary ovarian failure—1.25 mg daily, cyclically. Adjust dosage, upward or
downward, according to severity of symptoms and response of the patient. For maintenance, adjust
dosage to lowest level that will provide effective control.
3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with
metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2.5 mg three times daily. The effectiveness of therapy can be judged by phosphatase
determinations as well as by symptomatic improvement of the patient.
5. For prevention of osteoporosis:
0.625 mg daily. Premarin therapy may be given continuously with no interruption in therapy, or in
cyclical regimens (regimens such as 25 days on drug followed by five days off drug) as is
medically appropriate on an individualized basis. When using Premarin solely for the prevention of
postmenopausal osteoporosis, alternative treatments should be carefully considered.
HOW SUPPLIED
Premarin® (conjugated estrogens tablets, USP)
—Each oval purple tablet contains 2.5 mg, in bottles of 100 (NDC 0046-0865-81) and
1,000 (NDC 0046-0865-91).
—Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-0866-81);
1,000 (NDC 0046-0866-91); 5,000 (NDC 0046-0866-95); and Unit-Dose Packages of
100 (NDC 0046-0866-99).
—Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-0864-81).
—Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-0867-81);
1,000 (NDC 0046-0867-91); 5,000 (NDC 0046-0867-95); and Unit-Dose Packages of
100 (NDC 0046-0867-99).
—Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-0868-81) and
1,000 (NDC 0046-0868-91).
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The appearance of these tablets is a trademark of Wyeth-Ayerst Laboratories.
Store at room temperature (approximately 25°C).
Dispense in a well-closed container as defined in the USP.
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PATIENT INFORMATION
This leaflet summarizes the major risks and benefits of treatment with Premarin. Read this PATIENT
INFORMATION before using the product and each time you get medicine because there may be new
information. Talk with your healthcare provider if you have any questions about this medicine.
What is the most important information I should know about Premarin?
ESTROGENS INCREASE THE RISK OF CANCER OF THE UTERUS.
If you take any estrogen-containing medicine, it is important to visit your doctor regularly and report
any unusual vaginal bleeding right away. Vaginal bleeding after menopause may be a warning sign of
uterine cancer. Your healthcare provider should check any unusual vaginal bleeding to find out the
cause. Women who do not have a uterus have almost no risk of endometrial cancer.
What is Premarin?
Premarin is a mixture of estrogens obtained from natural sources.
What is Premarin used for?
The use of Premarin, alone or in combination with a progestin, may increase your risk of getting
breast cancer, blood clots, heart attacks, and strokes. Premarin should be used only as long as
needed. Periodically, you and your healthcare provider should discuss whether you still need
treatment.
Premarin should not be used to prevent heart disease.
Premarin is used:
••••
To reduce moderate to severe menopausal symptoms.
Estrogens are hormones produced by a woman’s ovaries. Between ages 45 and 55, the ovaries
normally stop making estrogens. This drop in body estrogen levels causes the “change of life” or
menopause (the end of monthly menstrual periods). Sometimes both ovaries are removed during an
operation before natural menopause takes place. The sudden drop in estrogen levels causes
“surgical menopause.”
When the estrogen levels begin dropping, some women develop very uncomfortable symptoms,
such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and
sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild and in others
they can be severe. Taking Premarin can help reduce these symptoms.
Every 3 to 6 months you and your healthcare provider should discuss whether you still need
Premarin to control your hot flushes.
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To treat itching, burning, dryness in or around the vagina due to menopause.
Every 3 to 6 months you and your healthcare provider should discuss whether you still need
Premarin to control your vaginal symptoms.
To treat certain conditions in which a young woman’s ovaries do not produce enough
estrogen naturally.
To treat certain cancers in special situations, in men and women.
To help reduce your chance of getting osteoporosis (thin weak bones).
Osteoporosis is a thinning of the bones that makes them weaker and allows them to break more
easily.
If you use Premarin, alone or in combination with a progestin, only to prevent osteoporosis,
discuss with your healthcare provider whether a different treatment might be more
appropriate for you.
Women who have menopause at an early age, are thin, smoke and/or have a family history of
osteoporosis are more likely to develop osteoporosis.
Premarin may be used as part of a program which includes weight-bearing exercise, like walking or
running, and taking calcium and vitamin D supplements to reduce your chances of getting
osteoporosis. Before you change your exercise habits or calcium or vitamin D intake, it is
important to discuss these lifestyle changes with your healthcare provider to find out if they are
safe for you. Before you make any change in your use of Premarin, talk with your healthcare
provider.
During menopause, some women develop nervous symptoms or depression. Estrogens do not relieve
these symptoms. You may have heard that taking estrogens for years after menopause will keep your
skin soft and supple and keep you feeling young. There is no evidence for this.
Who should not take Premarin?
Do not take Premarin
••••
If you think you may be pregnant.
Taking Premarin while you are pregnant may harm your unborn child. Do not take Premarin to
prevent miscarriage.
•••• If you have unusual vaginal bleeding.
Unusual vaginal bleeding can be a warning sign of a serious condition including cancer of the
uterus, especially if it happens after menopause. If you develop vaginal bleeding while taking
Premarin, you may need further evaluation. Your healthcare provider needs to find out the cause of
the bleeding so that you can receive proper treatment. If you develop vaginal bleeding while taking
Premarin, talk with your healthcare provider about proper treatment.
••••
If you have or had certain cancers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
Page 22
Estrogens may increase the risks of certain types of cancers, including cancer of the breast or
uterus. If you have or have had cancer, talk with your healthcare provider about whether you
should take Premarin.
••••
If you have or had blood clots, a heart attack, or a stroke.
Talk with your healthcare provider if you have or had these conditions, or if you have abnormal
blood-clotting conditions.
••••
If you have recently had a baby.
Premarin can be passed to the nursing baby in the breastmilk. The effect of this on the baby is not
known. Do not take Premarin to stop your breast from filling with milk after a baby is born.
••••
If you are allergic to Premarin tablets or any of their ingredients.
How should I take Premarin?
•
Take one Premarin tablet each day at about the same time.
• If you miss a dose, take it as soon as you remember. However, if it is almost time for your next
dose, skip the missed dose and take only your next regularly scheduled dose. Do not take two doses
at the same time.
Premarin comes in several strengths. Check with your healthcare provider periodically to make sure
you are using the appropriate dose.
Premarin use may increase your risk of getting breast cancer, blood clots, heart attacks, and strokes.
Premarin should be used only as long as needed. Periodically, you and your healthcare provider should
discuss whether you still need treatment.
What are the possible risks and side effects of Premarin?
1. Heart disease, stroke and blood clots
The use of Premarin, alone or in combination with progestins, may increase your chance of having
a heart attack, a stroke, blood clots, a pulmonary embolus (a blood clot formed in the legs or pelvis
that breaks off and travels to the lungs), retinal thrombosis (a clot in a blood vessel of the eye), or
other blood clotting problems. Any of these conditions may cause death or serious long-term
disability. These conditions have been seen in healthy, postmenopausal women, as well as in
women with a history of heart disease.
2. Cancer of the uterus
The risk of cancer of the uterus increases when Premarin is used alone, the longer it is used, and
when larger doses are taken. Also, Premarin increases the risk of getting a condition (endometrial
hyperplasia) that may lead to cancer of the lining of the uterus. Taking progestins, another
hormonal drug, with Premarin lowers the risk of getting this condition. Therefore, if your uterus
has not been removed, your healthcare provider may prescribe a progestin for you to take together
with Premarin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
Page 23
3. Cancer of the breast
Long-term use of Premarin, alone or in combination with progestins, may increase your chance of
having breast cancer. Regular breast exams by a healthcare professional and monthly self-exams
are recommended for all women. Mammography should be scheduled depending on your age and
risk factors.
4. Ovarian cancer
Some studies suggest that there is a greater risk of ovarian cancer in women who have used
estrogen (such as Premarin) alone for a long period of time, especially 10 years or more. Other
studies have not shown this risk. The risk with combined estrogen/progestin treatment is unclear.
5. Vaginal bleeding
If you develop vaginal bleeding while taking Premarin and progestins, discuss your bleeding
pattern with your healthcare provider. This is because vaginal bleeding after menopause may be a
warning sign of a serious condition, including cancer of the uterus.
6. Gallbladder disease
Women who use Premarin after menopause are more likely to develop gallbladder disease needing
surgery than women who do not use estrogens.
7. Blood pressure
Some women who are taking Premarin may have increases in blood pressure.
8. Liver problems
If you had yellowing of your skin or eyes associated with pregnancy, or with taking estrogens (eg,
oral contraceptives), this condition may occur again with Premarin treatment.
9. Hypothyroidism
Women who are taking Premarin, and who use thyroid replacement therapy may require increased
doses of their thyroid medication.
10. Endometriosis
Taking Premarin may worsen endometriosis. Talk with your healthcare provider if you have had
endometriosis.
11. Effects on blood sugar
Taking Premarin may affect blood sugar levels, which might make a diabetic condition worse.
12. Other conditions
Fluid retention due to Premarin treatment may make some conditions worse, such as heart disease
or kidney disease. Premarin treatment may also worsen asthma, epilepsy, migraine, porphyria and
endometriosis.
In addition to the risks listed above, the following side effects have been reported with estrogen
use:
•
Nausea and vomiting, cramps, or bloating in the abdomen.
•
Hair loss or abnormal hairiness.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
Page 24
•
Breast tenderness or enlargement, pain and discharge.
•
Enlargement of benign tumors (“fibroids”) of the uterus.
•
Change in amount of cervical secretion.
•
Vaginal yeast infections.
• Retention of fluid (edema).
•
A spotty darkening of the skin, particularly on the face, reddening of the skin, skin rashes.
• Headache, migraines, dizziness, or changes in vision (including intolerance to contact lenses).
•
Involuntary muscle spasms.
•
Increase or decrease in weight.
•
Changes in sex drive.
What can I do to lower my chances of getting a serious side effect with Premarin?
If you take Premarin, you can reduce your risks by doing these things:
• See your healthcare provider regularly.
Check with your healthcare provider to make sure you do not stay on treatment longer than needed.
While you are taking Premarin, it is important to visit your healthcare provider at least once a year for
a check-up. If you develop vaginal bleeding while taking Premarin, you may need further evaluation.
Every 3 to 6 months you and your healthcare provider should discuss whether or not you still need
Premarin to control your hot flushes and vaginal symptoms.
You should talk with your healthcare provider about stopping Premarin 4 to 6 weeks before surgery or
during prolonged bedrest.
If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal
mammogram (breast X-ray), you may need to have more frequent breast examinations. Examine your
breasts for changes every month.
• Be alert to signs of trouble.
If any of the following warning signals (or any other unusual symptoms) happen while you are using
Premarin, call your healthcare provider immediately:
• Abnormal bleeding from the vagina (possible uterine cancer).
• Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible
clots in the legs, heart, or lungs).
• Severe headache or vomiting, dizziness, faintness, or changes in vision or speech,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-128
Page 25
weakness or numbness of an arm or leg (possible clot in the brain or eye).
• Breast lumps (possible breast cancer). Check your breasts every month. Ask your
healthcare provider to show you how to examine your breasts.
• Yellowing of the skin or whites of the eyes (possible liver problem).
• Pain, swelling, or tenderness in the abdomen (stomach area, possible gallbladder
problem).
Other information
1. Your healthcare provider prescribed this drug for you and you alone. Do not give this drug to
anyone else.
2. Keep this and all drugs out of reach of children. In case of overdose, call your doctor, or healthcare
provider, hospital or poison control center right away.
HOW SUPPLIED
Premarin® (conjugated estrogens tablets, USP) - tablets for oral administration.
Each oval purple tablet contains 2.5 mg.
Each oval yellow tablet contains 1.25 mg.
Each oval white tablet contains 0.9 mg.
Each oval maroon tablet contains 0.625 mg.
Each oval green tablet contains 0.3 mg.
The appearance of these tablets is a trademark of Wyeth-Ayerst Laboratories.
Ayerst Laboratories
A Wyeth-Ayerst Company
Philadelphia, PA 19101
CI 7755-1
Revised August 20, 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:33.750476 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/04782slr128_Premarin_lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 128} |
10,667 | 1
Premarin®
(conjugated estrogens tablets, USP)
only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic
measures, including endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There
is no evidence that the use of “natural” estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose.
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular
disease.
The Women’s Health Initiative (WHI) reported increased risks of myocardial infarction, stroke,
invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women
during 5 years of treatment with conjugated equine estrogens (0.625 mg) combined with
medroxyprogesterone acetate (2.5 mg) relative to placebo (see CLINICAL
PHARMACOLOGY, Clinical Studies). Other doses of conjugated estrogens and
medroxyprogesterone acetate, and other combinations of estrogens and progestins were not
studied in the WHI and, in the absence of comparable data, these risks should be assumed to be
similar. Because of these risks, estrogens with or without progestins should be prescribed at the
lowest effective doses and for the shortest duration consistent with treatment goals and risks for
the individual woman.
DESCRIPTION
Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture of
conjugated equine estrogens obtained exclusively from natural sources, occurring as the sodium
salts of water-soluble estrogen sulfates blended to represent the average composition of material
derived from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin
sulfate. It contains as concomitant components, as sodium sulfate conjugates,
17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Tablets for oral administration are
available in 0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg, and 2.5 mg strengths of conjugated estrogens.
Premarin Tablets contain the following inactive ingredients: calcium phosphate tribasic, calcium
sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate,
methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, titanium
dioxide.
—0.3 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2,
FD&C Yellow No. 6; these tablets comply with USP Drug Release Test 1.
This label may not be the latest approved by FDA.
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2
—0.625 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40; these
tablets comply with USP Drug Release Test 1.
—0.9 mg tablets also contain: D&C Red No. 6, D&C Red No. 7; these tablets comply with USP
Drug Release Test 2.
—1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10, FD&C Yellow No. 6;
these tablets comply with USP Drug Release Test 3.
—2.5 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 7; these tablets comply with
USP Drug Release Test 3.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle.
After menopause, most endogenous estrogen is produced by conversion of androstenedione,
secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the
sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogen in
postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens
act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract
after release from the drug formulation. The Premarin tablet releases conjugated estrogens
slowly over several hours. The pharmacokinetic profile of unconjugated and conjugated
estrogens following a dose of 2 x 0.625 mg is provided in Table 1.
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding
globulin (SHBG) and albumin.
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3
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women
a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone
sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Table 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg*
Drug
Cmax
tmax
t1/2**
AUC
(pg/mL)
(h)
(h)
(pg•h/mL)
estrone
139 (37)
8.8 (20)
28.0 (13)
5016 (34)
baseline-adjusted estrone
120 (42)
8.8 (20)
17.4 (37)
2956 (39)
equilin
66 (42)
7.9 (19)
13.6 (52)
1210 (37)
*Mean (Coefficient of Variation, %)
** t1/2 = terminal-phase disposition half-life (0.693/γ2)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.625 mg*
Drug
Cmax
tmax
t1/2**
AUC
(ng/mL)
(h)
(h)
(ng•h/mL)
total estrone
7.3 (41)
7.3 (51)
15.0 (25)
134 (42)
baseline-adjusted total estrone
7.1 (41)
7.3 (25)
13.6 (27)
122 (39)
total equilin
5.0 (42)
6.2 (26)
10.1 (27)
65 (45)
*Mean (Coefficient of Variation, %)
** t1/2 = terminal-phase disposition half-life (0.693/γ2)
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal
or hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
significantly altered. No other clinical drug-drug interaction studies have been conducted with
conjugated estrogens.
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4
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum),
phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in
side effects.
Clinical Studies
Effects on bone mineral density.
In the 3-year, randomized, double-blind, placebo-controlled Postmenopausal Estrogen/Progestin
Interventions (PEPI) trial, the effect of Premarin 0.625 mg (conjugated estrogens tablets, USP),
given alone or in combination with medroxyprogesterone acetate (MPA), on bone mineral
density (BMD) was evaluated in postmenopausal women. One of the regimens evaluated was
continuous combined Premarin 0.625 mg/MPA 2.5 mg, a regimen similar to Prempro™.
Intent-to-treat subjects
In the intent-to-treat subjects, BMD increased significantly (p<0.001) compared to baseline or
placebo at both the hip and the spine in women assigned to Premarin or the continuous
Premarin/MPA regimen. Spinal BMD increased 3.46% among women assigned to Premarin,
increased 4.87% in women assigned to the Premarin/MPA regimen and decreased 1.81% in
women assigned to placebo. At the hip, women assigned to Premarin gained 1.31%, women
assigned to Premarin/MPA gained 1.94%, while women assigned to placebo lost 1.62%.
Adherent subjects
In the adherent subjects, BMD also increased significantly (p<0.001) compared to baseline or
placebo at both the hip and the spine in women assigned to Premarin or continuous
Premarin/MPA. Spinal BMD increased 5.16% among women assigned to Premarin, increased
5.49% in women assigned to Premarin/MPA and decreased 2.82% in women assigned to
placebo. At the hip, women assigned to Premarin gained 2.60%, women assigned to
Premarin/MPA gained 2.23%, while women assigned to placebo lost 2.17%.
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5
These results are summarized in Tables 2 and 3 below.
Table 2. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD AT 36 MONTHS
IN INTENT-TO-TREAT SUBJECTS**
Spine
Hip
Regimen
n
Mean % Change
95% CI
n
Mean % Change
95% CI
Premarin 0.625 mg
175
+3.46%*†
2.78, 4.14
175
+1.31%*†
0.76, 1.86
Premarin 0.625 mg/
MPA 2.5 mg
174
+4.87%*†
4.21, 5.52
174
+1.94%*†
1.50, 2.39
Placebo
174
-1.81%*
-2.51, -1.12
173
-1.62%*
-2.16, -1.08
*
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
**
includes all 523 women who were randomized to either Premarin, Premarin/MPA or placebo whether or not
they completed the study. If BMD was not available at 36 months, then the 12 months value was carried
forward and analyzed. Baseline values were carried forward if 12 months and 36 months data were unavailable.
Most patients who discontinued study medication were followed through month 36 and could have been off
therapy for an extended period prior to their month 36 evaluation.
Table 3. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD AT 36 MONTHS
IN ADHERENT SUBJECTS**
Spine
Hip
Regimen
n
Mean % Change
95% CI
n
Mean % Change
95% CI
Premarin 0.625 mg
95
+5.16%*†
4.32, 6.00
95
+2.60%*†
1.97, 3.23
Premarin 0.625 mg/
MPA 2.5 mg
144
+5.49%*†
4.79, 6.18
144
+2.23%*†
1.75, 2.71
Placebo
124
-2.82%*
-3.54, -2.10
123
-2.17%*
-2.78, -1.56
*
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
**
women who completed the study had BMD reported at month 36, and took 80% or more of their prescribed
medication.
In general, older women (55-64 years of age) taking placebo in the PEPI study lost bone at a
lower rate than younger women (45-54 years of age). Conversely, older women receiving
Premarin or Premarin 0.625 mg/MPA 2.5 mg had greater increases in BMD than younger
women. Tables 4 and 5 present data for women 45 to 54 years of age and women 55 to 64 years
of age.
Table 4. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD FOR WOMEN
45 TO 54 YEARS OF AGE
Intent-To-Treat Subjects
Adherent Subjects
Regimen
n
Mean %
Change at the
Spine
n
Mean %
Change at the
Hip
n
Mean %
Change at the
Spine
n
Mean %
Change at the
Hip
Premarin 0.625 mg
74
+2.45%†**
74
+1.37%†**
43
+3.73%†**
43
+2.20%†**
Premarin 0.625 mg/
MPA 2.5 mg
69
+3.53%†**
69
+1.26%†**
58
+3.97%†**
58
+1.48%†**
Placebo
78
-2.82%**
78
-2.23%**
50
-4.02%**
50
-3.04%**
**
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Table 5. MEAN PERCENTAGE CHANGE FROM BASELINE IN BMD FOR WOMEN
55 TO 64 YEARS OF AGE
Intent-To-Treat Subjects
Adherent Subjects
Regimen
n
Mean %
Change at the
Spine
n
Mean %
Change at
the Hip
n
Mean %
Change at
the Spine
n
Mean %
Change at the
Hip
Premarin 0.625 mg
101
+4.21%†‡**
101
+1.27%†**
52
+6.34%†‡**
52
+2.93%†**
Premarin 0.625 mg/
MPA 2.5 mg
105
+5.75%†‡**
105
+2.39%†**
86
+6.51%†‡**
86
+2.73%†**
Placebo
95
-1.01%*
94
-1.14%*
73
-2.04%‡**
72
-1.60%**
*
denotes a statistically significant mean change from baseline at the 0.05 level.
**
denotes a statistically significant mean change from baseline at the 0.001 level.
†
denotes mean percentage change from baseline is significantly different from placebo at the 0.001 level.
‡
denotes mean percentage change from baseline in the older age group is significantly different from the mean
percentage change in the younger age group at the 0.05 level.
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg
conjugated equine estrogens per day) alone or the use of Prempro (0.625 mg conjugated equine
estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the
prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart
disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as
the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD,
invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer,
hip fracture, or death due to other cause. The study did not evaluate the effects of Premarin or
Prempro on menopausal symptoms.
The Premarin-only substudy is continuing and results have not been reported. The Prempro
substudy was stopped early because, according to the predefined stopping rule, the increased risk
of breast cancer and cardiovascular events exceeded the specified benefits included in the
“global index.” Results of the Prempro substudy, which included 16,608 women (average age of
63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up
of 5.2 years are presented in Table 6 below:
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7
Table 6. RELATIVE AND ABSOLUTE RISK SEEN IN THE PREMPRO
SUBSTUDY OF WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000 Person-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than the
events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosis d
2.07 (1.49-2.87)
13
26
Vertebral fractures d
0.66 (0.44-0.98)
15
9
Other osteoporotic fractures d
0.77 (0.69-0.86)
170
131
a
adapted from JAMA, 2002; 288:321-333
b
includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c
a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events,
invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or
death due to other causes
d
not included in Global Index
*
nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index”, absolute excess risks per 10,000 person-years
in the group treated with Prempro were 7 more CHD events, 8 more strokes, 8 more PEs, and 8
more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6
fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in
the “global index” was 19 per 10,000 person-years. There was no difference between the groups
in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and
PRECAUTIONS.)
INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the
menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal
atrophy, topical vaginal products should be considered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men
with metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant
risk of osteoporosis and non-estrogen medications should be carefully considered.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing
exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic
therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium.
Therefore, when not contraindicated, calcium supplementation may be helpful for women
with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be
required to ensure adequate daily intake in postmenopausal women.
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast except in appropriately selected patients
being treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke,
myocardial infarction).
6. Premarin Tablets should not be used in patients with known hypersensitivity to their
ingredients.
7. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There
appears to be little or no increased risk of birth defects in women who have used estrogen
and progestins from oral contraceptives inadvertently during pregnancy. (See
PRECAUTIONS.)
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9
WARNINGS
See BOXED WARNINGS.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk
of endometrial cancer.
1. Cardiovascular disorders.
Estrogen and estrogen/progestin therapy have been associated with an increased risk of
cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and
pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be
suspected, estrogens should be discontinued immediately.
Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) should be managed appropriately.
a. Coronary heart disease and stroke. In the Premarin substudy of the Women’s Health
Initiative (WHI), an increase in the number of myocardial infarctions and strokes has been
observed in women receiving Premarin compared to placebo. These observations are
preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
In the Prempro substudy of WHI, an increased risk of coronary heart disease (CHD) events
(defined as non-fatal myocardial infarction and CHD death) was observed in women receiving
Prempro compared to women receiving placebo (37 vs 30 per 10,000 person-years). The increase
in risk was observed in year one and persisted.
In the same substudy of the WHI, an increased risk of stroke was observed in women receiving
Prempro compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase
in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with Prempro (0.625 mg conjugated
equine estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no
cardiovascular benefit. During an average follow-up of 4.1 years, treatment with Prempro did not
reduce the overall rate of CHD events in postmenopausal women with established coronary heart
disease. There were more CHD events in the Prempro-treated group than in the placebo group in
year 1, but not during the subsequent years. Two thousand three hundred and twenty one women
from the original HERS trial agreed to participate in an open label extension of HERS, HERS II.
Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates
of CHD events were comparable among women in the Prempro group and the placebo group in
HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
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10
b. Venous thromboembolism (VTE). In the Premarin substudy of the Women’s Health Initiative
(WHI), an increase in VTE has been observed in women receiving Premarin compared to
placebo. These observations are preliminary, and the study is continuing. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
In the Prempro substudy of WHI, a 2-fold greater rate of VTE, including deep venous
thrombosis and pulmonary embolism, was observed in women receiving Prempro compared to
women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the Prempro
group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk
was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears
dependent on duration of treatment and on estrogen dose. Most studies show no significant
increased risk associated with use of estrogens for less than one year. The greatest risk appears
associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more
and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is
discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important.
Adequate diagnostic measures, including endometrial sampling when indicated, should be
undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal
vaginal bleeding. There is no evidence that the use of natural estrogens results in a different
endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin
to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.
b. Breast cancer. Estrogen and estrogen/progestin therapy in postmenopausal women have been
associated with an increased risk of breast cancer. In the Prempro substudy of the Women’s
Health Initiative study (WHI), a 26% increase of invasive breast cancer (38 vs 30 per 10,000
woman-years) after an average of 5.2 years of treatment was observed in women receiving
Prempro compared to women receiving placebo. The increased risk of breast cancer became
apparent after 4 years on Prempro. The women reporting prior postmenopausal use of estrogen
and/or estrogen with progestin had a higher relative risk for breast cancer associated with
Prempro than those who had never used these hormones. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
In the Premarin substudy of WHI, no increased risk of breast cancer in estrogen-treated women
compared to placebo was reported after an average of 5.2 years of therapy. These data are
preliminary and that substudy of WHI is continuing.
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Epidemiologic studies have reported an increased risk of breast cancer in association with
increasing duration of postmenopausal treatment with estrogens, with or without progestin. This
association was reanalyzed in original data from 51 studies that involved treatment with various
doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of
having breast cancer diagnosed became apparent after about 5 years of continued treatment, and
subsided after treatment had been discontinued for about 5 years. Some later studies have
suggested that treatment with estrogen and progestin increases the risk of breast cancer more
than treatment with estrogen alone.
A postmenopausal woman without a uterus who requires estrogen should receive estrogen-alone
therapy, and should not be exposed unnecessarily to progestins. All postmenopausal women
should receive yearly breast exams by a healthcare provider and perform monthly breast self-
examinations. In addition, mammography examinations should be scheduled based on patient
age and risk factors.
3. Gallbladder disease.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving postmenopausal estrogens has been reported.
4. Hypercalcemia.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
5. Visual abnormalities.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or
daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be
a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast
cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and
impairment of glucose tolerance.
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2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals with estrogen use.
3. Familial hyperlipoproteinemia.
In patients with familial defects of lipoprotein metabolism, estrogen therapy may be associated
with elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution
should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These patients should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might
be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation
when estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer
Use of estrogen-only products, in particular for ten or more years, has been associated with an
increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a
significant association. Data are insufficient to determine whether there is an increased risk with
combined estrogen/progestin therapy in postmenopausal women.
9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or
porphyria and should be used with caution in patients with these conditions.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with
patients for whom they prescribe Premarin.
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13
C. Laboratory Tests
Estrogen administration should be guided by clinical response at the lowest dose for the
treatment of postmenopausal moderate to severe vasomotor symptoms and moderate to severe
symptoms of postmenopausal vulvar and vaginal atrophy. Laboratory parameters may be useful
in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and
primary ovarian failure.
D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant
activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased
levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased
levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on
thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG),
sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and
sex steroids, respectively. Free or biologically active hormone concentrations are unchanged.
Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-
antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL
cholesterol concentration, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See
BOXED WARNINGS, CONTRAINDICATIONS, and WARNINGS.)
F. Pregnancy
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS.)
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality
of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers
receiving the drug. Caution should be exercised when Premarin is administered to a nursing
woman.
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14
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of
pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to
accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated
before the completion of physiologic puberty in normally developing children. If estrogen is
administered to patients whose bone growth is not complete, periodic monitoring of bone
maturation and effects on epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the
normal pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I.
Geriatric Use
Of the total number of subjects in the Prempro substudy of the Women’s Health Initiative study,
44% (n=7320) were 65 years and over, while 6.6% (n=1,095) were 75 and over (see CLINICAL
PHARMACOLOGY, Clinical Studies). No significant differences in safety were observed
between subjects 65 years and over compared to younger subjects. There was a higher incidence
of stroke and invasive breast cancer in women 75 and over compared to younger subjects.
With respect to efficacy in the approved indications, there have not been sufficient numbers of
geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years
of age differ from younger subjects in their response to Premarin.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
The following additional adverse reactions have been reported with estrogen therapy and/or
progestin therapy:
1. Genitourinary system
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough
bleeding, spotting.
Increase in size of uterine leiomyomata.
Vaginitis, including vaginal candidiasis.
Change in amount of cervical secretion.
Change in cervical ectropion.
Ovarian cancer.
Endometrial hyperplasia.
Endometrial cancer.
2. Breasts
Tenderness, enlargement, pain, discharge, galactorrhea.
Fibrocystic breast changes.
Breast cancer.
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15
3. Cardiovascular
Deep and superficial venous thrombosis.
Pulmonary embolism.
Thrombophlebitis.
Myocardial infarction.
Stroke.
Increase in blood pressure.
4. Gastrointestinal
Nausea, vomiting.
Abdominal cramps, bloating.
Cholestatic jaundice.
Increased incidence of gallbladder disease.
Pancreatitis.
5. Skin
Chloasma or melasma that may persist when drug is discontinued.
Erythema multiforme.
Erythema nodosum.
Hemorrhagic eruption.
Loss of scalp hair.
Hirsutism.
Pruritus, rash.
6. Eyes
Retinal vascular thrombosis.
Steepening of corneal curvature.
Intolerance to contact lenses.
7. Central Nervous System
Headache.
Migraine.
Dizziness.
Mental depression.
Chorea.
Nervousness.
Mood disturbances.
Irritability.
Exacerbation of epilepsy.
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16
8. Miscellaneous
Increase or decrease in weight.
Reduced carbohydrate tolerance.
Aggravation of porphyria.
Edema.
Arthralgias.
Leg cramps.
Changes in libido.
Anaphylactoid/anaphylactic reactions including urticaria and angioedema.
Hypocalcemia.
Exacerbation of asthma.
Increased triglycerides.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-
containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and
vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need
progestin. Use of estrogen, alone or in combination with a progestin, should be limited to the
shortest duration consistent with treatment goals and risks for the individual woman. Patients
should be re-evaluated periodically as clinically appropriate (e.g., at 3-month to 6-month
intervals) to determine if treatment is still necessary (see BOXED WARNINGS and
WARNINGS). For women who have a uterus, adequate diagnostic measures, such as
endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of
undiagnosed persistent or recurring abnormal vaginal bleeding.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe
symptoms of vulvar and vaginal atrophy associated with the menopause:
Patients should be started at the lowest dose.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
2. For prevention of postmenopausal osteoporosis.
0.625 mg daily.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis. When using Premarin solely for the prevention of
postmenopausal osteoporosis, alternative non-estrogen treatments should be carefully
considered.
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17
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary
ovarian failure:
Female hypogonadism—0.3 mg to 0.625 mg daily, administered cyclically (e.g., three weeks
on and one week off). Doses are adjusted depending on the severity of symptoms and
responsiveness of the endometrium.
In clinical studies of delayed puberty due to female hypogonadism, breast development was
induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12
month intervals as needed to achieve appropriate bone age advancement and eventual
epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are
associated with mean ratios of bone age advancement to chronological age progression
(∆BA/∆CA) of 1.1, 1.5, and 2.1, respectively. (Premarin in the dose strength of 0.15 mg is
not available commercially). Available data suggest that chronic dosing with 0.625 mg is
sufficient to induce artificial cyclic menses with sequential progestin treatment and to
maintain bone mineral density after skeletal maturity is achieved.
Female castration or primary ovarian failure—1.25 mg daily, cyclically. Adjust dosage,
upward or downward, according to severity of symptoms and response of the patient. For
maintenance, adjust dosage to lowest level that will provide effective control.
4. For treatment of breast cancer, for palliation only, in appropriately selected women and men
with metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2.5 mg three times daily. The effectiveness of therapy can be judged by
phosphatase determinations as well as by symptomatic improvement of the patient.
HOW SUPPLIED
Premarin® (conjugated estrogens tablets, USP)
—Each oval purple tablet contains 2.5 mg, in bottles of 100 (NDC 0046-0865-81) and
1,000 (NDC 0046-0865-91).
—Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-0866-81);
1,000 (NDC 0046-0866-91); 5,000 (NDC 0046-0866-95); and Unit-Dose Packages of
100 (NDC 0046-0866-99).
—Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-0864-81).
—Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-0867-81);
1,000 (NDC 0046-0867-91); 5,000 (NDC 0046-0867-95); and Unit-Dose Packages of
100 (NDC 0046-0867-99).
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18
—Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-0868-81) and
1,000 (NDC 0046-0868-91).
The appearance of these tablets is a trademark of Wyeth-Ayerst Laboratories.
Store at room temperature (approximately 25°C).
Dispense in a well-closed container as defined in the USP.
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PATIENT INFORMATION
(Updated January 3, 2003)
Premarin
(conjugated estrogens, USP)
Read this PATIENT INFORMATION before you start taking Premarin and read what you get
each time you refill Premarin. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
•
Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
•
Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or
strokes.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. You and your healthcare provider should talk
regularly about whether you still need treatment with estrogens.
What is Premarin?
Premarin is a medicine that contains a mixture of estrogen hormones.
Premarin is used after menopause to:
••••
reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s
ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55
years old. This drop in body estrogen levels causes the “change of life” or menopause (the
end of monthly menstrual periods). Sometimes both ovaries are removed during an operation
before natural menopause takes place. The sudden drop in estrogen levels causes “surgical
menopause.”
When the estrogen levels begin dropping, some women develop very uncomfortable
symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings
of heat and sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild,
and they will not need to take estrogens. In other women, symptoms can be more severe. You
and your healthcare provider should talk regularly about whether you still need treatment
with Premarin.
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20
••••
treat moderate to severe dryness, itching, and burning, in or around the vagina. You
and your healthcare provider should talk regularly about whether you still need treatment
with Premarin to control these problems.
••••
help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from
menopause is a thinning of the bones that makes them weaker and easier to break. If you use
Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider
about whether a different treatment or medicine without estrogens might be better for you.
You and your healthcare provider should talk regularly about whether you should continue
with Premarin.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D
supplements may also lower your chances for getting postmenopausal osteoporosis. It is
important to talk about exercise and supplements with your healthcare provider before
starting them.
Premarin is also used to:
••••
treat certain conditions in women before menopause if their ovaries do not make
enough estrogen.
••••
ease symptoms of certain cancers that have spread through the body, in men and
women.
Who should not take Premarin?
Do not start taking Premarin if you:
••••
have unusual vaginal bleeding.
••••
currently have or have had certain cancers.
Estrogens may increase the chances of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider about
whether you should take Premarin.
•
had a stroke or heart attack in the past year.
••••
currently have or have had blood clots.
••••
are allergic to Premarin tablets or any of its ingredients.
See the end of this leaflet for a list of all the ingredients in Premarin.
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21
••••
think you may be pregnant.
Tell your healthcare provider:
••••
if you are breast feeding. The hormones in Premarin can pass into your milk.
••••
about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures),
migraine, endometriosis, or problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
••••
about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Some medicines may affect how Premarin works.
Premarin may also affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop taking
estrogens.
How should I take Premarin?
•
Take one Premarin tablet at the same time each day.
•
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose,
skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same
time.
•
Estrogens should be used only as long as needed. You and your healthcare provider should
talk regularly (for example, every 3 to 6 months) about whether you still need treatment with
Premarin.
What are the possible side effects of Premarin?
Less common but serious side effects include:
•
Breast cancer
•
Cancer of the uterus
•
Stroke
•
Heart attack
•
Blood clots
•
Gallbladder disease
•
Ovarian cancer
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22
These are some of the warning signs of serious side effects:
•
Breast lumps
•
Unusual vaginal bleeding
•
Dizziness and faintness
•
Changes in speech
•
Severe headaches
•
Chest pain
•
Shortness of breath
•
Pains in your legs
•
Changes in vision
•
Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other
unusual symptom that concerns you.
Common side effects include:
•
Headache
•
Breast pain
•
Irregular vaginal bleeding or spotting
•
Stomach/abdominal cramps, bloating
•
Nausea and vomiting
•
Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin?
•
Talk with your healthcare provider about whether you should continue taking Premarin.
•
See your healthcare provider right away if you get vaginal bleeding while taking Premarin.
•
Have a breast exam and mammogram (breast X-ray) every year unless your healthcare
provider tells you something else. If members of your family have had breast cancer or if you
have ever had breast lumps or an abnormal mammogram, you may need to have breast exams
more often.
•
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight,
or if you use tobacco, you may have higher chances for getting heart disease. Ask your
healthcare provider for ways to lower your chances for getting heart disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
General information about the safe and effective use of Premarin
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take Premarin for conditions for which it was not prescribed. Do not give
Premarin to other people, even if they have the same symptoms you have. It may harm them.
Keep Premarin out of the reach of children.
This leaflet provides a summary of the most important information about Premarin. If you would
like more information, talk with your healthcare provider or pharmacist. You can ask for
information about Premarin that is written for health professionals. You can get more
information by calling the toll free number 800-934-5556.
What are the ingredients in Premarin?
Premarin contains a mixture of conjugated equine estrogens, which are a mixture of sodium
estrone sulfate and sodium equilin sulfate and other components including sodium sulfate
conjugates, 17 "-dihydroequilin, 17 "-estradiol, and 17 $-dihydroequilin. Premarin also contains
calcium phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate,
lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic
acid, sucrose, and titanium dioxide. The tablets come in different strengths and each strength
tablet is a different color. The color ingredients are:
0.3 mg tablet (green color): D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2,
and FD&C Yellow No. 6.
0.625 mg tablet (maroon color): FD&C Blue No. 2, D&C Red No. 27, and FD&C Red
No. 40.
0.9 mg tablet (white color): D&C Red No. 6 and D&C Red No. 7.
1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow
No. 6.
2.5 mg tablet (purple color): FD&C Blue No. 2 and D&C Red No. 7.
Ayerst Laboratories
A Wyeth-Ayerst Company
Philadelphia, PA 19101
W10405C003
ET01
Revised January 3, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:33.919719 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/04782s129lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 129} |
10,670 |
Premarin
(conjugated estrogens tablets, USP)
Rx only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic
measures, including endometrial sampling when indicated, should be undertaken to rule out
malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There
is no evidence that the use of “natural” estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose.
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular
disease.
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction,
stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal
women (50 to 79 years of age) during 5 years of treatment with conjugated estrogens (0.625 mg)
combined with medroxyprogesterone acetate (2.5 mg) relative to placebo. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported
increased risk of developing probable dementia in postmenopausal women 65 years of age or
older during 4 years of treatment with conjugated estrogens plus medroxyprogesterone acetate
relative to placebo. It is unknown whether this finding applies to younger postmenopausal
women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY,
Clinical Studies.)
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations
and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in
the absence of comparable data, these risks should be assumed to be similar. Because of these
risks, estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture of
conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of
water-soluble estrogen sulfates blended to represent the average composition of material derived
from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate.
It contains as concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin,
17α-estradiol, and 17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg,
0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Premarin 0.3 mg, 0.45 mg, 0.625 mg, and 0.9 mg tablets contain the following inactive
ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax, microcrystalline
cellulose, powdered cellulose, glyceryl monooleate, lactose monohydrate, magnesium stearate,
methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid (not present in 0.45 mg
tablet), sucrose, and titanium dioxide.
Premarin 1.25 mg tablets contain the following inactive ingredients: calcium phosphate tribasic,
hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose
monohydrate, magnesium stearate, polyethylene glycol, sucrose, and titanium dioxide.
— 0.3 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1,
FD&C Blue No. 2, FD&C Yellow No. 6.
— 0.45 mg tablets also contain: FD&C Blue No. 2.
— 0.625 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40.
— 0.9 mg tablets also contain: D&C Red No. 6, D&C Red No. 7.
— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10, FD&C Yellow No. 6.
Premarin tablets comply with USP Drug Release Test criteria as outlined below:
Premarin 0.3 mg, 0.45 mg,
and 0.625 mg tablets
Test 1
Premarin 0.9 mg tablets
Test 2
Premarin 1.25 mg tablets
USP Drug Release Test Pending
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted
by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated
form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
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Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens
act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract
after release from the drug formulation. The Premarin tablet releases conjugated estrogens
slowly over several hours. Table 1 summarizes the mean pharmacokinetic parameters for
unconjugated and conjugated estrogens following administration of 2 x 0.3 mg, 2 x 0.45 mg, and
2 x 0.625 mg tablets to healthy postmenopausal women.
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
82 (33)
7.8 (27)
54.7 (42)
5390 (50)
Baseline-adjusted estrone
58 (42)
7.8 (27)
21.1 (45)
1467 (41)
Equilin
31 (47)
7.2 (28)
18.3 (110)
652 (68)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Estrone
2.5 (32)
6.5 (29)
25.4 (22)
61.0 (43)
Baseline-adjusted total estrone
2.4 (32)
6.5 (29)
16.2 (34)
40.8 (36)
Equilin
1.6 (40)
5.9 (27)
11.8 (21)
22.4 (42)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
92 (32)
8.7 (28)
56.4 (68)
6344 (56)
Baseline-adjusted estrone
65 (40)
8.7 (28)
20.3 (38)
1940 (40)
Equilin
35 (49)
7.6 (33)
21.9 (113)
849 (60)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
2.8 (46)
7.1 (27)
27.6 (35)
77 (34)
Baseline-adjusted total estrone
2.6 (46)
7.1 (27)
14.7 (42)
48 (38)
Total equilin
1.9 (53)
5.9 (32)
11.8 (32)
29 (55)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
139 (37)
8.8 (20)
28.0 (30)
5016 (34)
Baseline-adjusted estrone
120 (41)
8.8 (20)
17.4 (37)
2956 (39)
Equilin
66 (42)
7.9 (19)
13.6 (52)
1210 (37)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
7.3 (41)
7.3 (24)
15.0 (25)
134 (42)
Baseline-adjusted total estrone
7.1 (41)
7.3 (24)
13.6 (23)
122 (38)
Total equilin
5.0 (42)
6.2 (26)
10.1 (26)
65 (44)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
124 (30)
10.0 (32)
38.1 (37)
6332 (44)
Baseline-adjusted estrone
102 (35)
10.0 (32)
19.7 (48)
3159 (53)
Equilin
59 (43)
8.8 (36)
10.9 (47)
1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total Estrone
4.5 (39)
8.2 (58)
26.5 (40)
109 (46)
Baseline-adjusted total estrone
4.3 (41)
8.2 (58)
17.5 (41)
87 (44)
Total equilin
2.9 (42)
6.8 (49)
12.5 (34)
48 (51)
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding
globulin (SHBG) and albumin.
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Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women
a significant proportion of the circulating estrogens exists as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal
or hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have
been conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum),
phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in
side effects.
Clinical Studies
Effects on vasomotor symptoms.
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of
2805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of
eight treatment groups, receiving either placebo or conjugated estrogens with or without
medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first
12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least 7 moderate
to severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before
randomization. Premarin (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically
better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to
severe vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the
Premarin 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week
period.
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TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER
DAY– MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE
TREATMENT GROUPS AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST
7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT
BASELINE, LOCF
Treatment
(No. of Patients)
--------------- No. of Hot Flushes/Day ------------------
Time Period
(week)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change ± SD
p-Values
vs. Placeboa
0.625 mg CE
(n = 27)
4
12.29 ± 3.89
1.95 ± 2.77
-10.34 ± 4.73
<0.001
12
12.29 ± 3.89
0.75 ± 1.82
-11.54 ± 4.62
<0.001
0.45 mg CE
(n = 32)
4
12.25 ± 5.04
5.04 ± 5.31
-7.21 ± 4.75
<0.001
12
12.25 ± 5.04
2.32 ± 3.32
-9.93 ± 4.64
<0.001
0.3 mg CE
(n = 30)
4
13.77 ± 4.78
4.65 ± 3.71
-9.12 ± 4.71
<0.001
12
13.77 ± 4.78
2.52 ± 3.23
-11.25 ± 4.60
<0.001
Placebo
(n = 28)
4
11.69 ± 3.87
7.89 ± 5.28
-3.80 ± 4.71
-
12
11.69 ± 3.87
5.71 ± 5.22
-5.98 ± 4.60
-
a: Based on analysis of covariance with treatment as factor and baseline as covariate.
Effects on vulvar and vaginal atrophy.
Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from
placebo were statistically significant (p<0.001) for all treatment groups (conjugated estrogens
alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).
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Effects on bone mineral density.
Health and Osteoporosis, Progestin and Estrogen (HOPE) Study
The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter
study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9
years) were 2.3 ± 0.9 years, on average, since menopause, and took one 600-mg tablet of
elemental calcium (Caltrate) daily. Subjects were not given vitamin D supplements. They were
treated with Premarin 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was
assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior
lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and
trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used
as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.
Intent-to-treat subjects
All active treatment groups showed significant differences from placebo in each of the 4 BMD
endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy
measure (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed
and the last available evaluation for those who discontinued early) were 2.46% with 0.625 mg,
2.26% with 0.45 mg, and 1.13% with 0.3 mg. The placebo group showed a mean percent
decrease from baseline at the final evaluation of 2.45%. These results show that the lower
dosages of Premarin were effective in increasing L2 to L4 BMD compared with placebo and,
therefore, support the efficacy of the lower doses.
The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in
femoral trochanter that were generally larger than those seen for L2 to L4 and changes in femoral
neck and total body that were generally smaller than those seen for L2 to L4. Significant
differences between groups indicated that each of the Premarin treatments was more effective
than placebo for all 3 of these additional BMD endpoints. With regard to femoral neck and total
body, the active treatment groups all showed mean percent increases in BMD while placebo
treatment was accompanied by mean percent decreases. For femoral trochanter, each of the
Premarin dose groups showed a mean percent increase that was significantly greater than the
small increase seen in the placebo group. The percent changes from baseline to final evaluation
are shown in Table 3.
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TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON
BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT
POPULATION,
LAST OBSERVATION CARRIED FORWARD
Region Evaluated
Treatment Groupa
No. of
Subjects
Baseline (g/cm2)
Mean ± SD
Change from Baseline (%)
Adjusted Mean ± SE
p-Value vs
Placebo
L2 to L4 BMD
0.625
83
1.17 ± 0.15
2.46 ± 0.37
<0.001
0.45
91
1.13 ± 0.15
2.26 ± 0.35
<0.001
0.3
87
1.14 ± 0.15
1.13 ± 0.36
<0.001
Placebo
85
1.14 ± 0.14
-2.45 ± 0.36
Total Body BMD
0.625
84
1.15 ± 0.08
0.68 ± 0.17
<0.001
0.45
91
1.14 ± 0.08
0.74 ± 0.16
<0.001
0.3
87
1.14 ± 0.07
0.40 ± 0.17
<0.001
Placebo
85
1.13 ± 0.08
-1.50 ± 0.17
Femoral Neck BMD
0.625
84
0.91 ± 0.14
1.82 ± 0.45
<0.001
0.45
91
0.89 ± 0.13
1.84 ± 0.44
<0.001
0.3
87
0.86 ± 0.11
0.62 ± 0.45
<0.001
Placebo
85
0.88 ± 0.14
-1.72 ± 0.45
Femoral Trochanter BMD
0.625
84
0.78 ± 0.13
3.82 ± 0.58
<0.001
0.45
91
0.76 ± 0.12
3.16 ± 0.56
0.003
0.3
87
0.75 ± 0.10
3.05 ± 0.57
0.005
Placebo
85
0.75 ± 0.12
0.81 ± 0.58
a: Identified by dosage (mg) of Premarin or placebo.
Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or
greater than the value shown on the x-axis.
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Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE
IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND
PLACEBO GROUPS
The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone
density study are shown with standard error bars by treatment group in Figure 2. Significant
differences between each of the Premarin dosage groups and placebo were found at cycles 6,
13, 19, and 26.
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Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH
CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS
AND PLACEBO
The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased
(p<0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo
group. Larger mean decreases from baseline were seen with the active groups than with the
placebo group. Significant differences from placebo were seen less frequently in urine calcium.
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg
conjugated estrogens per day) alone or the use of PREMPRO (0.625 mg conjugated estrogens
plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of
certain chronic diseases. The primary endpoint was the incidence of coronary heart disease
(CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the
primary adverse outcome studied. A “global index” included the earliest occurrence of CHD,
invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer,
hip fracture, or death due to other cause. The study did not evaluate the effects of Premarin or
PREMPRO on menopausal symptoms.
The Premarin-only substudy results have not been reported. The estrogen plus progestin
substudy was stopped early because, according to the predefined stopping rule, the increased risk
of breast cancer and cardiovascular events exceeded the specified benefits included in the
“global index.” Results of the estrogen plus progestin substudy, which included 16,608 women
(average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an
average follow-up of 5.2 years are presented in Table 4 below.
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TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000
Women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than
the events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosisd
2.07 (1.49-2.87)
13
26
Vertebral fracturesd
0.66 (0.44-0.98)
15
9
Other osteoporotic fracturesd
0.77 (0.69-0.86)
170
131
a: adapted from JAMA, 2002; 288:321-333
b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
d: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the “global index,” the absolute excess risks per
10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more
strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per
10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute
excess risk of events included in the “global index” was 19 per 10,000 women-years. There was
no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS,
WARNINGS, and PRECAUTIONS.)
Women’s Health Initiative Memory Study.
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled
4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age
65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate
the effects of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone
acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the hormone therapy group
was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became
apparent in the first year of treatment. It is unknown whether these findings apply to younger
postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)
INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the
menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal
atrophy, topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men
with metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant
risk of osteoporosis and for whom non-estrogen medications are not considered to be
appropriate. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing
exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic
therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium.
Therefore, when not contraindicated, calcium supplementation may be helpful for women
with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be
required to ensure adequate daily intake in postmenopausal women.
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast except in appropriately selected patients
being treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke,
myocardial infarction).
6. Liver dysfunction or disease.
7. Premarin tablets should not be used in patients with known hypersensitivity to their
ingredients.
8. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There
appears to be little or no increased risk of birth defects in children born to women who have
used estrogen and progestins from oral contraceptives inadvertently during pregnancy. (See
PRECAUTIONS.)
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated
with an increased risk of cardiovascular events such as myocardial infarction and stroke, as
well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE).
Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history
or family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
a. Coronary heart disease and stroke. In the Premarin progestin substudy of the Women’s
Health Initiative (WHI) study, an increase in the number of myocardial infarctions and
strokes has been observed in women receiving Premarin compared to placebo. These
observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease
(CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in
women receiving PREMPRO compared to women receiving placebo (37 vs 30 per
10,000 women-years). The increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving
PREMPRO compared to women receiving placebo (29 vs 21 per 10,000 women-years). The
increase in risk was observed after the first year and persisted.
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In postmenopausal women with documented heart disease (n = 2,763, average age
66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease
(Heart and Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO
(0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate per day)
demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment
with PREMPRO did not reduce the overall rate of CHD events in postmenopausal women
with established coronary heart disease. There were more CHD events in the
PREMPRO-treated group than in the placebo group in year 1, but not during the subsequent
years. Two thousand three hundred and twenty one women from the original HERS trial
agreed to participate in an open label extension of HERS, HERS II. Average follow-up in
HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events
were comparable among women in the PREMPRO group and the placebo group in HERS,
HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to
treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in
men to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and
thrombophlebitis.
b. Venous thromboembolism (VTE). In the Premarin progestin substudy of the Women’s
Health Initiative (WHI), an increase in VTE has been observed in women receiving Premarin
compared to placebo. These observations are preliminary. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO
compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in
the PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The
increase in VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users with an intact uterus is about 2- to 12-fold greater than in
non-users, and appears dependent on duration of treatment and on estrogen dose. Most
studies show no significant increased risk associated with the use of estrogens for less than
one year. The greatest risk appears associated with prolonged use, with increased risks of
15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least
8 to 15 years after estrogen therapy is discontinued.
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Clinical surveillance of all women taking estrogen/progestin combinations is important.
Adequate diagnostic measures, including endometrial sampling when indicated, should be
undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring
abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a
different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.
Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer.
b. Breast cancer. The use of estrogens and progestins by postmenopausal women has been
reported to increase the risk of breast cancer. The most important randomized clinical trial
providing information about this issue is the Women’s Health Initiative (WHI) trial of
estrogen plus progestin (see CLINICAL PHARMACOLOGY, Clinical Studies). The
results from observational studies are generally consistent with those of the WHI clinical
trial.
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer
in women who took estrogen plus progestin. Observational studies have also reported an
increased risk for estrogen/progestin combination therapy, and a smaller increased risk for
estrogen alone therapy, after several years of use. For both findings, the excess risk increased
with duration of use, and appeared to return to baseline over about five years after stopping
treatment (only the observational studies have substantial data on risk after stopping). In
these studies, the risk of breast cancer was greater, and became apparent earlier, with
estrogen/progestin combination therapy as compared to estrogen alone therapy. However,
these studies have not found significant variation in the risk of breast cancer among different
estrogens or among different estrogen/progestin combinations, doses, or routes of
administration.
In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen
alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6
years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24
(95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per
10,000 women-years, for estrogen plus progestin compared with placebo. Among women
who reported prior use of hormone therapy, the relative risk of invasive breast cancer was
1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus
progestin compared with placebo. Among women who reported no prior use of hormone
therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was
40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo.
In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage
in the estrogen plus progestin group compared with the placebo group. Metastatic disease
was rare with no apparent difference between the two groups. Other prognostic factors such
as histologic subtype, grade and hormone receptor status did not differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality
due to breast cancer among current users of estrogens alone or estrogens plus progestins
compared to never users, while the estrogen plus progestin sub-study of WHI showed no
effect on breast cancer mortality with a mean follow-up of 5.6 years.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast
examinations by a healthcare provider and perform monthly breast self-examinations. In
addition, mammography examinations should be scheduled based on patient age, risk factors,
and prior mammogram results.
3. Dementia. In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally
healthy postmenopausal women 65 years of age and older were studied, of whom 35% were
70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years,
40 women being treated with PREMPRO (1.8%, n = 2,229) and 21 women in the placebo
group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for
PREMPRO versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar
for women with and without histories of menopausal hormone use before WHIMS. The
absolute risk of probable dementia for PREMPRO versus placebo was 45 versus 22 cases per
10,000 women-years, and the absolute excess risk for PREMPRO was 23 cases per
10,000 women-years. It is unknown whether these findings apply to younger postmenopausal
women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS,
Geriatric Use.)
The results of the estrogen alone sub-study of the Women’s Health Initiative Memory Study
have not been reported. It is unknown whether these findings apply to estrogen alone therapy.
4. Gallbladder Disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring
surgery in postmenopausal women receiving estrogens has been reported.
5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with
breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be
stopped and appropriate measures taken to reduce the serum calcium level.
6. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is sudden partial or complete
loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals
papilledema or retinal vascular lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen
administration, or daily with estrogen in a continuous regimen, have reported a lowered
incidence of endometrial hyperplasia than would be induced by estrogen treatment alone.
Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include: a possible increased risk of
breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL)
and impairment of glucose tolerance.
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2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been
attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled
clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood
pressure should be monitored at regular intervals during estrogen use.
3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications. In the
HOPE study, the mean percent increase from baseline in serum triglycerides after one year of
treatment with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were
34.3, 30.2, 25.1, and 10.7, respectively. After two years of treatment, the mean percent
changes were 47.6, 32.5, 19.0, and 5.5, respectively.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients
with a history of cholestatic jaundice associated with past estrogen use or with pregnancy,
caution should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients
with normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These patients should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that
might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful
observation when estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer.
The estrogen plus progestin substudy of WHI reported that after an average follow-up of
5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was
1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute
risk of estrogen plus progestin versus placebo was 4.2 versus 2.7 cases per
10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in
particular for ten or more years, has been associated with an increased risk of ovarian cancer.
Other epidemiologic studies have not found these associations.
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9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported
in women treated post-hysterectomy with estrogen alone therapy. For patients known to have
residual endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in patients with these conditions.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with
patients for whom they prescribe Premarin.
C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose for the treatment of
postmenopausal moderate to severe vasomotor symptoms and moderate to severe symptoms of
postmenopausal vulvar and vaginal atrophy and then guided by clinical response rather than by
serum hormone levels (e.g., estradiol, FSH). Laboratory parameters may be useful in guiding
dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary
ovarian failure.
D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant
activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased
levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased
levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on
thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG),
sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids
and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma
proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL
cholesterol concentrations, increased triglyceride levels.
5. Impaired glucose tolerance.
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6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality
of the milk. Detectable amounts of estrogens have been identified in the milk of mothers
receiving this drug. Caution should be exercised when Premarin is administered to a nursing
woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of
pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to
accelerate epiphyseal closure, which could result in short stature if treatment is initiated before
the completion of physiologic puberty in normally developing children. If estrogen is
administered to patients whose bone growth is not complete, periodic monitoring of bone
maturation and effects on epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the
normal pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I. Geriatric Use
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health
Initiative study, 44% (n=7,320) were 65 years and over, while 6.6% (n=1,095) were 75 years and
over (see CLINICAL PHARMACOLOGY, Clinical Studies). There was a higher relative risk
(PREMPRO vs placebo) of stroke and invasive breast cancer in women 75 and over compared to
women less than 75 years of age.
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and
older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803)
were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with
conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold
increase in the risk of developing probable dementia. Alzheimer’s disease was the most common
classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone
acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred
in the 54% of women that were older than 70. (See WARNINGS, Dementia.)
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The estrogen alone substudy of the Women’s Health Initiative Memory Study is currently
ongoing. No data are available. It is unknown whether these findings apply to estrogen alone
therapy.
With respect to efficacy in the approved indications, there have not been sufficient numbers of
geriatric patients involved in studies utilizing Premarin to determine whether those over 65 years
of age differ from younger subjects in their response to Premarin.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice. The adverse reaction
information from clinical trials does, however, provide a basis for identifying the adverse events
that appear to be related to drug use and for approximating rates.
During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and
65 years of age (88% Caucasian), 1012 women were treated with conjugated estrogens and
332 were treated with placebo. Table 5 summarizes adverse events that occurred at a rate of
≥ 5%.
TABLE 5. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Any adverse event
323 (93%)
305 (90%)
292 (90%)
281 (85%)
Body as a Whole
Abdominal pain
56 (16%)
50 (15%)
54 (17%)
37 (11%)
Accidental injury
21 (6%)
41 (12%)
20 (6%)
29 (9%)
Asthenia
25 (7%)
23 (7%)
25 (8%)
16 (5%)
Back pain
49 (14%)
43 (13%)
43 (13%)
39 (12%)
Flu syndrome
37 (11%)
38 (11%)
33 (10%)
35 (11%)
Headache
90 (26%)
109 (32%)
96 (29%)
93 (28%)
Infection
61 (18%)
75 (22%)
74 (23%)
74 (22%)
Pain
58 (17%)
61 (18%)
66 (20%)
61 (18%)
Digestive System
Diarrhea
21 (6%)
25 (7%)
19 (6%)
21 (6%)
Dyspepsia
33 (9%)
32 (9%)
36 (11%)
46 (14%)
Flatulence
24 (7%)
23 (7%)
18 (6%)
9 (3%)
Nausea
32 (9%)
21 (6%)
21 (6%)
30 (9%)
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TABLE 5. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Musculoskeletal System
Arthralgia
47 (14%)
42 (12%)
22 (7%)
39 (12%)
Leg cramps
19 (5%)
23 (7%)
11 (3%)
7 (2%)
Myalgia
18 (5%)
18 (5%)
29 (9%)
25 (8%)
Nervous System
Depression
25 (7%)
27 (8%)
17 (5%)
22 (7%)
Dizziness
19 (5%)
20 (6%)
12 (4%)
17 (5%)
Insomnia
21 (6%)
25 (7%)
24 (7%)
33 (10%)
Nervousness
12 (3%)
17 (5%)
6 (2%)
7 (2%)
Respiratory System
Cough increased
13 (4%)
22 (7%)
14 (4%)
14 (4%)
Pharyngitis
35 (10%)
35 (10%)
40 (12%)
38 (11%)
Rhinitis
21 (6%)
30 (9%)
31 (10%)
42 (13%)
Sinusitis
22 (6%)
36 (11%)
24 (7%)
24 (7%)
Upper respiratory infection
42 (12%)
34 (10%)
28 (9%)
35 (11%)
Skin and Appendages
Pruritus
14 (4%)
17 (5%)
16 (5%)
7 (2%)
Urogenital System
Breast pain
38 (11%)
41 (12%)
24 (7%)
29 (9%)
Leukorrhea
18 (5%)
22 (7%)
13 (4%)
9 (3%)
Vaginal hemorrhage
47 (14%)
14 (4%)
7 (2%)
0
Vaginal moniliasis
20 (6%)
18 (5%)
17 (5%)
6 (2%)
Vaginitis
24 (7%)
20 (6%)
16 (5%)
4 (1%)
The following additional adverse reactions have been reported with estrogen and/or progestin
therapy:
1. Genitourinary system
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough
bleeding, spotting, dysmenorrhea
Increase in size of uterine leiomyomata
Vaginitis, including vaginal candidiasis
Change in amount of cervical secretion
Change in cervical ectropion
Ovarian cancer
Endometrial hyperplasia
Endometrial cancer
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2. Breasts
Tenderness, enlargement, pain, discharge, galactorrhea
Fibrocystic breast changes
Breast cancer
3. Cardiovascular
Deep and superficial venous thrombosis
Pulmonary embolism
Thrombophlebitis
Myocardial infarction
Stroke
Increase in blood pressure
4. Gastrointestinal
Nausea, vomiting
Abdominal cramps, bloating
Cholestatic jaundice
Increased incidence of gallbladder disease
Pancreatitis
Enlargement of hepatic hemangiomas
5. Skin
Chloasma or melasma that may persist when drug is discontinued
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Loss of scalp hair
Hirsutism
Pruritus, rash
6. Eyes
Retinal vascular thrombosis
Intolerance to contact lenses
7. Central Nervous System
Headache
Migraine
Dizziness
Mental depression
Chorea
Nervousness
Mood disturbances
Irritability
Exacerbation of epilepsy
Dementia
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8. Miscellaneous
Increase or decrease in weight
Reduced carbohydrate tolerance
Aggravation of porphyria
Edema
Arthralgias
Leg cramps
Changes in libido
Urticaria, angioedema, anaphylactoid/anaphylactic reactions
Hypocalcemia
Exacerbation of asthma
Increased triglycerides
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea
and vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need
progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest
effective dose and for the shortest duration consistent with treatment goals and risks for the
individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., at
3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED
WARNINGS and WARNINGS). For women with a uterus, adequate diagnostic measures, such
as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases
of undiagnosed persistent or recurring abnormal vaginal bleeding.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe
symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing
solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy,
topical vaginal products should be considered.
Patients should be treated with the lowest effective dose. Generally women should be started
at 0.3 mg Premarin daily. Subsequent dosage adjustment may be made based upon the
individual patient response. This dose should be periodically reassessed by the healthcare
provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. For prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should
be considered only for women at significant risk of osteoporosis and for whom non-estrogen
medications are not considered to be appropriate. Patients should be treated with the lowest
effective dose. Generally women should be started at 0.3 mg Premarin daily. Subsequent
dosage adjustment may be made based upon the individual clinical and bone mineral density
responses. This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary
ovarian failure:
Female hypogonadism0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks
on and one week off). Doses are adjusted depending on the severity of symptoms and
responsiveness of the endometrium.
In clinical studies of delayed puberty due to female hypogonadism, breast development was
induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward
at 6 to 12 month intervals as needed to achieve appropriate bone age advancement and
eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and
0.6 mg are associated with mean ratios of bone age advancement to chronological age
progression (∆BA/∆CA) of 1.1, 1.5, and 2.1, respectively. (Premarin in the dose strength of
0.15 mg is not available commercially). Available data suggest that chronic dosing with
0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment
and to maintain bone mineral density after skeletal maturity is achieved.
Female castration or primary ovarian failure1.25 mg daily, cyclically. Adjust dosage,
upward or downward, according to severity of symptoms and response of the patient. For
maintenance, adjust dosage to lowest level that will provide effective control.
4. For treatment of breast cancer, for palliation only, in appropriately selected women and men
with metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by
phosphatase determinations as well as by symptomatic improvement of the patient.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Premarin (conjugated estrogens tablets, USP)
— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81); and
1,000 (NDC 0046-1104-91).
— Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-0864-81).
— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-0867-81);
1,000 (NDC 0046-0867-91); and Unit-Dose Packages of 100 (NDC 0046-0867-99).
— Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-0936-81).
— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-0868-81) and
1,000 (NDC 0046-0868-91).
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
Store at 20-25° C (68-77° F); excursions permitted to 15-30° C (59-86° F) [see
USP Controlled Room Temperature].
Dispense in a well-closed container as defined in the USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
(Updated August 15, 2004)
Premarin
(conjugated estrogens tablets, USP)
Read this PATIENT INFORMATION before you start taking Premarin and read what you get
each time you refill Premarin. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or
strokes.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may
increase your risk of dementia, based on a study of women age 65 years or older. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin.
What is Premarin?
Premarin is a medicine that contains a mixture of estrogen hormones.
Premarin is used after menopause to:
• reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s
ovaries. The ovaries normally stop making estrogens when a woman is between 45 and
55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the
end of monthly menstrual periods). Sometimes both ovaries are removed during an operation
before natural menopause takes place. The sudden drop in estrogen levels causes “surgical
menopause.”
When the estrogen levels begin dropping, some women get very uncomfortable symptoms,
such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and
sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they
will not need to take estrogens. In other women, symptoms can be more severe. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• treat moderate to severe dryness, itching, and burning, in and around the vagina. You
and your healthcare provider should talk regularly about whether you still need treatment
with Premarin to control these problems. If you use Premarin only to treat your dryness,
itching, and burning in and around your vagina, talk with your healthcare provider about
whether a topical vaginal product would be better for you.
• help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from
menopause is a thinning of the bones that makes them weaker and easier to break. If you use
Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider
about whether a different treatment or medicine without estrogens might be better for you.
You and your healthcare provider should talk regularly about whether you should continue
with Premarin.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D
supplements may also lower your chances for getting postmenopausal osteoporosis. It is
important to talk about exercise and supplements with your healthcare provider before
starting them.
Premarin is also used to:
• treat certain conditions in women before menopause if their ovaries do not make
enough estrogen naturally.
• ease symptoms of certain cancers that have spread through the body, in men and
women.
Who should not take Premarin?
Do not start taking Premarin if you:
• have unusual vaginal bleeding.
• currently have or have had certain cancers. Estrogens may increase the chances of getting
certain types of cancers, including cancer of the breast or uterus. If you have or have had
cancer, talk with your healthcare provider about whether you should take Premarin.
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have liver problems.
• are allergic to Premarin tablets or any of its ingredients. See the end of this leaflet for a
list of all the ingredients in Premarin.
• think you may be pregnant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin can pass into your milk.
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures),
migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have
high calcium levels in your blood.
• about all the medicines you take, including prescription and nonprescription medicines,
vitamins, and herbal supplements. Some medicines may affect how Premarin works.
Premarin may also affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop taking
estrogens.
How should I take Premarin?
• Take one Premarin tablet at the same time each day.
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the
missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• Estrogens should be used at the lowest dose possible for your treatment only as long as
needed. You and your healthcare provider should talk regularly (for example, every
3 to 6 months) about the dose you are taking and whether you still need treatment with
Premarin.
What are the possible side effects of Premarin?
Less common but serious side effects include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other
unusual symptom that concerns you.
Common side effects include:
• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What can I do to lower my chances of getting a serious side effect with Premarin?
• Talk with your healthcare provider regularly about whether you should continue taking
Premarin.
• If you have a uterus, talk to your healthcare provider about whether the addition of a
progestin is right for you.
• See your healthcare provider right away if you get vaginal bleeding while taking Premarin.
• Have a breast exam and mammogram (breast X-ray) every year unless your healthcare
provider tells you something else. If members of your family have had breast cancer or if you
have ever had breast lumps or an abnormal mammogram, you may need to have breast exams
more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight,
or if you use tobacco, you may have higher chances for getting heart disease. Ask your
healthcare provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take Premarin for conditions for which it was not prescribed. Do not give
Premarin to other people, even if they have the same symptoms you have. It may harm them.
Keep Premarin out of the reach of children.
This leaflet provides a summary of the most important information about Premarin. If you would
like more information, talk with your healthcare provider or pharmacist. You can ask for
information about Premarin that is written for health professionals. You can get more
information by calling the toll free number 800-934-5556.
What are the ingredients in Premarin?
Premarin contains a mixture of conjugated estrogens, which are a mixture of sodium estrone
sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates,
17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin 0.3 mg, 0.45 mg,
0.625 mg, and 0.9 mg tablets also contains the following inactive ingredients: calcium phosphate
tribasic, calcium sulfate, carnauba wax, microcrystalline cellulose, powdered cellulose, glyceryl
monooleate, lactose monohydrate, magnesium stearate, methylcellulose, pharmaceutical glaze,
polyethylene glycol, stearic acid (not present in 0.45 mg tablet), sucrose, and titanium dioxide.
Premarin 1.25 mg tablets contain the following inactive ingredients: calcium phosphate tribasic,
hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose
monohydrate, magnesium stearate, polyethylene glycol, sucrose and titanium dioxide.
The tablets come in different strengths and each strength tablet is a different color. The color
ingredients are:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
0.3 mg tablet (green color): D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2,
and FD&C Yellow No. 6.
0.45 mg tablet (blue color): FD&C Blue No. 2.
0.625 mg tablet (maroon color): FD&C Blue No. 2, D&C Red No. 27, and FD&C
Red No. 40.
0.9 mg tablet (white color): D&C Red No. 6 and D&C Red No. 7.
1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and
FD&C Yellow No. 6.
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
This product’s label may have been revised after this insert was
used in production. For further product information and current
package insert, please visit www.wyeth.com or call our medical
communications department toll-free at 1-800-934-5556.
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
[Insert new component number here]
[Insert new component number here]
Revised August 2004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.044065 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/04782s137lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 137} |
10,668 | NDA 04-782/S-136
Page 3
Premarin
(conjugated estrogens tablets, USP)
Rx only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the
use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose.
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke,
invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to
79 years of age) during 5 years of treatment with conjugated estrogens (0.625 mg) combined with
medroxyprogesterone acetate (2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY,
Clinical Studies.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk
of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of
treatment with conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is
unknown whether this finding applies to younger postmenopausal women or to women taking estrogen
alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and
dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the
absence of comparable data, these risks should be assumed to be similar. Because of these risks,
estrogens with or without progestins should be prescribed at the lowest effective doses and for the
shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated
estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble
estrogen sulfates blended to represent the average composition of material derived from pregnant
mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as
concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and
17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg,
0.9 mg, and 1.25 mg strengths of conjugated estrogens.
Premarin tablets contain the following inactive ingredients: calcium phosphate tribasic, calcium
sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose,
pharmaceutical glaze, polyethylene glycol, stearic acid (not present in 0.45 mg tablet), sucrose, and
titanium dioxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 4
— 0.3 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C
Yellow No. 6; these tablets comply with USP Drug Release Test 1.
— 0.45 mg tablets also contain: FD&C Blue No. 2; these tablets comply with USP Drug Release Test
1.
— 0.625 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40; these
tablets comply with USP Drug Release Test 1.
— 0.9 mg tablets also contain: D&C Red No. 6, D&C Red No. 7; these tablets comply with USP Drug
Release Test 2.
— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10, FD&C Yellow No. 6; these
tablets comply with USP Drug Release Test 3.
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the female
reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human
estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes
70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause,
most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal
cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate,
are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH)
and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to
reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after
release from the drug formulation. The Premarin tablet releases conjugated estrogens slowly over
several hours. Table 1 summarizes the mean pharmacokinetic parameters for unconjugated and
conjugated estrogens following administration of 2 x 0.3 mg, 2 x 0.45 mg, and 2 x 0.625 mg tablets to
healthy postmenopausal women.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 5
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
82 (33)
7.8 (27)
54.7 (42)
5390 (50)
Baseline-adjusted estrone
58 (42)
7.8 (27)
21.1 (45)
1467 (41)
Equilin
31 (47)
7.2 (28)
18.3 (110)
652 (68)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Estrone
2.5 (32)
6.5 (29)
25.4 (22)
61.0 (43)
Baseline-adjusted total estrone
2.4 (32)
6.5 (29)
16.2 (34)
40.8 (36)
Equilin
1.6 (40)
5.9 (27)
11.8 (21)
22.4 (42)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
92 (32)
8.7 (28)
56.4 (68)
6344 (56)
Baseline-adjusted estrone
65 (40)
8.7 (28)
20.3 (38)
1940 (40)
Equilin
35 (49)
7.6 (33)
21.9 (113)
849 (60)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
2.8 (46)
7.1 (27)
27.6 (35)
77 (34)
Baseline-adjusted total estrone
2.6 (46)
7.1 (27)
14.7 (42)
48 (38)
Total equilin
1.9 (53)
5.9 (32)
11.8 (32)
29 (55)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
139 (37)
8.8 (20)
28.0 (30)
5016 (34)
Baseline-adjusted estrone
120 (41)
8.8 (20)
17.4 (37)
2956 (39)
Equilin
66 (42)
7.9 (19)
13.6 (52)
1210 (37)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
7.3 (41)
7.3 (24)
15.0 (25)
134 (42)
Baseline-adjusted total estrone
7.1 (41)
7.3 (24)
13.6 (23)
122 (38)
Total equilin
5.0 (42)
6.2 (26)
10.1 (26)
65 (44)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 6
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex hormone
target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG)
and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take
place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to
estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via
sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and
hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of
the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a
circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or
hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been
conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450
3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a
decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4
such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may
increase plasma concentrations of estrogens and may result in side effects.
Clinical Studies
Effects on vasomotor symptoms.
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805
postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight
treatment groups, receiving either placebo or conjugated estrogens with or without
medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first
12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least 7 moderate to
severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before
randomization. Premarin (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better
than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe
vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the Premarin 0.3 mg,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 7
0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.
TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY–
MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS
AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE
FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF
Treatment
(No. of Patients)
--------------- No. of Hot Flushes/Day ------------------
Time Period
(week)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change ± SD
p-Values
vs. Placeboa
0.625 mg CE
(n = 27)
4
12.29 ± 3.89
1.95 ± 2.77
-10.34 ± 4.73
<0.001
12
12.29 ± 3.89
0.75 ± 1.82
-11.54 ± 4.62
<0.001
0.45 mg CE
(n = 32)
4
12.25 ± 5.04
5.04 ± 5.31
-7.21 ± 4.75
<0.001
12
12.25 ± 5.04
2.32 ± 3.32
-9.93 ± 4.64
<0.001
0.3 mg CE
(n = 30)
4
13.77 ± 4.78
4.65 ± 3.71
-9.12 ± 4.71
<0.001
12
13.77 ± 4.78
2.52 ± 3.23
-11.25 ± 4.60
<0.001
Placebo
(n = 28)
4
11.69 ± 3.87
7.89 ± 5.28
-3.80 ± 4.71
-
12
11.69 ± 3.87
5.71 ± 5.22
-5.98 ± 4.60
-
a: Based on analysis of covariance with treatment as factor and baseline as covariate.
Effects on vulvar and vaginal atrophy.
Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo
were statistically significant (p<0.001) for all treatment groups (conjugated estrogens alone and
conjugated estrogens/medroxyprogesterone acetate treatment groups).
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NDA 04-782/S-136
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Effects on bone mineral density.
Health and Osteoporosis, Progestin and Estrogen (HOPE) Study
The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of
healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ±
0.9 years, on average, since menopause, and took one 600-mg tablet of elemental calcium (Caltrate)
daily. Subjects were not given vitamin D supplements. They were treated with Premarin 0.625 mg,
0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral
density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD
measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin,
urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and
26.
Intent-to-treat subjects
All active treatment groups showed significant differences from placebo in each of the 4 BMD
endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L2
to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available
evaluation for those who discontinued early) were 2.46% with 0.625 mg, 2.26% with 0.45 mg, and
1.13% with 0.3 mg. The placebo group showed a mean percent decrease from baseline at the final
evaluation of 2.45%. These results show that the lower dosages of Premarin were effective in
increasing L2 to L4 BMD compared with placebo and, therefore, support the efficacy of the lower
doses.
The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral
trochanter that were generally larger than those seen for L2 to L4 and changes in femoral neck and total
body that were generally smaller than those seen for L2 to L4. Significant differences between groups
indicated that each of the Premarin treatments was more effective than placebo for all 3 of these
additional BMD endpoints. With regard to femoral neck and total body, the active treatment groups all
showed mean percent increases in BMD while placebo treatment was accompanied by mean percent
decreases. For femoral trochanter, each of the Premarin dose groups showed a mean percent increase
that was significantly greater than the small increase seen in the placebo group. The percent changes
from baseline to final evaluation are shown in Table 3.
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TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN
ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION,
LAST OBSERVATION CARRIED FORWARD
Region Evaluated
Treatment Groupa
No. of
Subjects
Baseline (g/cm2)
Mean ± SD
Change from Baseline (%)
Adjusted Mean ± SE
p-Value vs
Placebo
L2 to L4 BMD
0.625
83
1.17 ± 0.15
2.46 ± 0.37
<0.001
0.45
91
1.13 ± 0.15
2.26 ± 0.35
<0.001
0.3
87
1.14 ± 0.15
1.13 ± 0.36
<0.001
Placebo
85
1.14 ± 0.14
-2.45 ± 0.36
Total Body BMD
0.625
84
1.15 ± 0.08
0.68 ± 0.17
<0.001
0.45
91
1.14 ± 0.08
0.74 ± 0.16
<0.001
0.3
87
1.14 ± 0.07
0.40 ± 0.17
<0.001
Placebo
85
1.13 ± 0.08
-1.50 ± 0.17
Femoral Neck BMD
0.625
84
0.91 ± 0.14
1.82 ± 0.45
<0.001
0.45
91
0.89 ± 0.13
1.84 ± 0.44
<0.001
0.3
87
0.86 ± 0.11
0.62 ± 0.45
<0.001
Placebo
85
0.88 ± 0.14
-1.72 ± 0.45
Femoral Trochanter BMD
0.625
84
0.78 ± 0.13
3.82 ± 0.58
<0.001
0.45
91
0.76 ± 0.12
3.16 ± 0.56
0.003
0.3
87
0.75 ± 0.10
3.05 ± 0.57
0.005
Placebo
85
0.75 ± 0.12
0.81 ± 0.58
a: Identified by dosage (mg) of Premarin or placebo.
Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater
than the value shown on the x-axis.
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Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN
SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND PLACEBO GROUPS
The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density
study are shown with standard error bars by treatment group in Figure 2. Significant differences
between each of the Premarin dosage groups and placebo were found at cycles 6, 13, 19, and 26.
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Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN
SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBO
The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased
(p<0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group.
Larger mean decreases from baseline were seen with the active groups than with the placebo group.
Significant differences from placebo were seen less frequently in urine calcium.
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg
conjugated estrogens per day) alone or the use of PREMPROTM (0.625 mg conjugated estrogens plus
2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic
diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal
myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome
studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke,
pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other
cause. The study did not evaluate the effects of Premarin or PREMPRO on menopausal symptoms.
The Premarin-only substudy results have not been reported. The estrogen plus progestin substudy was
stopped early because, according to the predefined stopping rule, the increased risk of breast cancer
and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the
estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to
79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in
Table 4 below.
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TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000
Women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than
the events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosisd
2.07 (1.49-2.87)
13
26
Vertebral fracturesd
0.66 (0.44-0.98)
15
9
Other osteoporotic fracturesd
0.77 (0.69-0.86)
170
131
a: adapted from JAMA, 2002; 288:321-333
b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
d: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years
in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8 more PEs, and 8
more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer
colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global
index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-
cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Women’s Health Initiative Memory Study.
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled
4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age
65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the
effects of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on
the incidence of probable dementia (primary outcome) compared with placebo.
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After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with
probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05
(95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first
year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See
BOXED WARNING and WARNINGS, Dementia.)
INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the
menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy,
topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with
metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant risk of
osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise,
adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy.
Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when
not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary
intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate
daily intake in postmenopausal women.
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast except in appropriately selected patients being
treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial
infarction).
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6. Liver dysfunction or disease.
7. Premarin tablets should not be used in patients with known hypersensitivity to their ingredients.
8. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There appears to
be little or no increased risk of birth defects in children born to women who have used estrogen and
progestins from oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS.)
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated with an
increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous
thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these
occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
a. Coronary heart disease and stroke. In the Premarin progestin substudy of the Women’s Health
Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been
observed in women receiving Premarin compared to placebo. These observations are preliminary.
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease (CHD)
events (defined as nonfatal myocardial infarction and CHD death) was observed in women
receiving PREMPRO compared to women receiving placebo (37 vs 30 per 10,000 women-years).
The increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving
PREMPRO compared to women receiving placebo (29 vs 21 per 10,000 women-years). The
increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated
estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the
overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1,
but not during the subsequent years. Two thousand three hundred and twenty one women from the
original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average
follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD
events were comparable among women in the PREMPRO group and the placebo group in HERS,
HERS II, and overall.
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Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism (VTE). In the Premarin progestin substudy of the Women’s Health
Initiative (WHI), an increase in VTE has been observed in women receiving Premarin compared to
placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO
compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the
PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in
VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users with an intact uterus is about 2- to 12-fold greater than in non-
users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no
significant increased risk associated with the use of estrogens for less than one year. The greatest
risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten
years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen
therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule
out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal
estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a
precursor to endometrial cancer.
b. Breast cancer. The use of estrogens and progestins by postmenopausal women has been reported
to increase the risk of breast cancer. The most important randomized clinical trial providing
information about this issue is the Women’s Health Initiative (WHI) trial of estrogen plus progestin
(see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies
are generally consistent with those of the WHI clinical trial.
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After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in
women who took estrogen plus progestin. Observational studies have also reported an increased
risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone
therapy, after several years of use. For both findings, the excess risk increased with duration of use,
and appeared to return to baseline over about five years after stopping treatment (only the
observational studies have substantial data on risk after stopping). In these studies, the risk of
breast cancer was greater, and became apparent earlier, with estrogen/progestin combination
therapy as compared to estrogen alone therapy. However, these studies have not found significant
variation in the risk of breast cancer among different estrogens or among different
estrogen/progestin combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen alone
and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years
during the clinical trial, the overall relative risk of invasive breast cancer was 1.24
(95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000
women-years, for estrogen plus progestin compared with placebo. Among women who reported
prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute
risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin compared with
placebo. Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years
for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were
larger and diagnosed at a more advanced stage in the estrogen plus progestin group compared with
the placebo group. Metastatic disease was rare with no apparent difference between the two groups.
Other prognostic factors such as histologic subtype, grade and hormone receptor status did not
differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality due to
breast cancer among current users of estrogens alone or estrogens plus progestins compared to
never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast cancer
mortality with a mean follow-up of 5.6 years.
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast examinations
by a healthcare provider and perform monthly breast self-examinations. In addition, mammography
examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
3. Dementia. In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy
postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years
of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated
with PREMPRO (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received
diagnoses of probable dementia. The relative risk for PREMPRO versus placebo was 2.05 (95%
confidence interval 1.21 – 3.48), and was similar for women with and without histories of
menopausal hormone use before WHIMS. The absolute risk of probable dementia for PREMPRO
versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for
PREMPRO was 23 cases per 10,000 women-years. It is unknown whether these findings apply to
younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and
PRECAUTIONS, Geriatric Use.)
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The results of the estrogen alone sub-study of the Women’s Health Initiative Memory Study have
not been reported. It is unknown whether these findings apply to estrogen alone therapy.
4. Gallbladder Disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in
postmenopausal women receiving estrogens has been reported.
5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast
cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and
appropriate measures taken to reduce the serum calcium level.
6. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is sudden partial or complete loss
of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema
or retinal vascular lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or
daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a
precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens
compared to estrogen-alone regimens. These include: a possible increased risk of breast cancer,
adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of
glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals during estrogen use.
3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE
study, the mean percent increase from baseline in serum triglycerides after one year of treatment
with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and
10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0,
and 5.5, respectively.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should
be exercised and in the case of recurrence, medication should be discontinued.
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5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid hormone,
thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on
thyroid hormone replacement therapy who are also receiving estrogens may require increased
doses of their thyroid replacement therapy. These patients should have their thyroid function
monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer.
The estrogen plus progestin substudy of WHI reported that after an average follow-up of 5.6 years,
the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95%
confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk of estrogen
plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some
epidemiologic studies, the use of estrogen-only products, in particular for ten or more years, has
been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not
found these associations.
9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual
endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in patients with these conditions.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients
for whom they prescribe Premarin.
C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose for the treatment of postmenopausal
moderate to severe vasomotor symptoms and moderate to severe symptoms of postmenopausal vulvar
and vaginal atrophy and then guided by clinical response rather than by serum hormone levels (e.g.,
estradiol, FSH). Laboratory parameters may be useful in guiding dosage for the treatment of
hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
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D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII,
VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa
and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the
elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement
therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex
hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex
steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may
be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol
concentrations, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the
milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.
Caution should be exercised when Premarin is administered to a nursing woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal
delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to accelerate
epiphyseal closure, which could result in short stature if treatment is initiated before the completion of
physiologic puberty in normally developing children. If estrogen is administered to patients whose
bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers
is recommended during estrogen administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 20
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal
pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I. Geriatric Use
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health
Initiative study, 44% (n=7,320) were 65 years and over, while 6.6% (n=1,095) were 75 years and over
(see CLINICAL PHARMACOLOGY, Clinical Studies). There was a higher relative risk
(PREMPRO vs placebo) of stroke and invasive breast cancer in women 75 and over compared to
women less than 75 years of age.
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older,
followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and
over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens
plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing
probable dementia. Alzheimer’s disease was the most common classification of probable dementia in
both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety
percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See
WARNINGS, Dementia.)
The estrogen alone substudy of the Women’s Health Initiative Memory Study is currently ongoing. No
data are available. It is unknown whether these findings apply to estrogen alone therapy.
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric
patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ
from younger subjects in their response to Premarin.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. The adverse reaction information from clinical trials
does, however, provide a basis for identifying the adverse events that appear to be related to drug use
and for approximating rates.
During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65
years of age (88% Caucasian), 1012 women were treated with conjugated estrogens and 332 were
treated with placebo. Table 5 summarizes adverse events that occurred at a rate of ≥ 5%.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 21
TABLE 5. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Any adverse event
323 (93%)
305 (90%)
292 (90%)
281 (85%)
Body as a Whole
Abdominal pain
56 (16%)
50 (15%)
54 (17%)
37 (11%)
Accidental injury
21 (6%)
41 (12%)
20 (6%)
29 (9%)
Asthenia
25 (7%)
23 (7%)
25 (8%)
16 (5%)
Back pain
49 (14%)
43 (13%)
43 (13%)
39 (12%)
Flu syndrome
37 (11%)
38 (11%)
33 (10%)
35 (11%)
Headache
90 (26%)
109 (32%)
96 (29%)
93 (28%)
Infection
61 (18%)
75 (22%)
74 (23%)
74 (22%)
Pain
58 (17%)
61 (18%)
66 (20%)
61 (18%)
Digestive System
Diarrhea
21 (6%)
25 (7%)
19 (6%)
21 (6%)
Dyspepsia
33 (9%)
32 (9%)
36 (11%)
46 (14%)
Flatulence
24 (7%)
23 (7%)
18 (6%)
9 (3%)
Nausea
32 (9%)
21 (6%)
21 (6%)
30 (9%)
Musculoskeletal System
Arthralgia
47 (14%)
42 (12%)
22 (7%)
39 (12%)
Leg cramps
19 (5%)
23 (7%)
11 (3%)
7 (2%)
Myalgia
18 (5%)
18 (5%)
29 (9%)
25 (8%)
Nervous System
Depression
25 (7%)
27 (8%)
17 (5%)
22 (7%)
Dizziness
19 (5%)
20 (6%)
12 (4%)
17 (5%)
Insomnia
21 (6%)
25 (7%)
24 (7%)
33 (10%)
Nervousness
12 (3%)
17 (5%)
6 (2%)
7 (2%)
Respiratory System
Cough increased
13 (4%)
22 (7%)
14 (4%)
14 (4%)
Pharyngitis
35 (10%)
35 (10%)
40 (12%)
38 (11%)
Rhinitis
21 (6%)
30 (9%)
31 (10%)
42 (13%)
Sinusitis
22 (6%)
36 (11%)
24 (7%)
24 (7%)
Upper respiratory infection
42 (12%)
34 (10%)
28 (9%)
35 (11%)
Skin and Appendages
Pruritus
14 (4%)
17 (5%)
16 (5%)
7 (2%)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 22
TABLE 5. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Urogenital System
Breast pain
38 (11%)
41 (12%)
24 (7%)
29 (9%)
Leukorrhea
18 (5%)
22 (7%)
13 (4%)
9 (3%)
Vaginal hemorrhage
47 (14%)
14 (4%)
7 (2%)
0
Vaginal moniliasis
20 (6%)
18 (5%)
17 (5%)
6 (2%)
Vaginitis
24 (7%)
20 (6%)
16 (5%)
4 (1%)
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
1. Genitourinary system
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough
bleeding, spotting, dysmenorrhea
Increase in size of uterine leiomyomata
Vaginitis, including vaginal candidiasis
Change in amount of cervical secretion
Change in cervical ectropion
Ovarian cancer
Endometrial hyperplasia
Endometrial cancer
2. Breasts
Tenderness, enlargement, pain, discharge, galactorrhea
Fibrocystic breast changes
Breast cancer
3. Cardiovascular
Deep and superficial venous thrombosis
Pulmonary embolism
Thrombophlebitis
Myocardial infarction
Stroke
Increase in blood pressure
4. Gastrointestinal
Nausea, vomiting
Abdominal cramps, bloating
Cholestatic jaundice
Increased incidence of gallbladder disease
Pancreatitis
Enlargement of hepatic hemangiomas
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 23
5. Skin
Chloasma or melasma that may persist when drug is discontinued
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Loss of scalp hair
Hirsutism
Pruritus, rash
6. Eyes
Retinal vascular thrombosis
Intolerance to contact lenses
7. Central Nervous System
Headache
Migraine
Dizziness
Mental depression
Chorea
Nervousness
Mood disturbances
Irritability
Exacerbation of epilepsy
Dementia
8. Miscellaneous
Increase or decrease in weight
Reduced carbohydrate tolerance
Aggravation of porphyria
Edema
Arthralgias
Leg cramps
Changes in libido
Urticaria, angioedema, anaphylactoid/anaphylactic reactions
Hypocalcemia
Exacerbation of asthma
Increased triglycerides
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and
vomiting, and withdrawal bleeding may occur in females.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 24
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin.
Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and
for the shortest duration consistent with treatment goals and risks for the individual woman. Patients
should be re-evaluated periodically as clinically appropriate (e.g., at 3-month to 6-month intervals) to
determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women
with a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be
undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal
bleeding.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of
vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the
treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products
should be considered.
Patients should be treated with the lowest effective dose. Generally women should be started at
0.3 mg Premarin daily. Subsequent dosage adjustment may be made based upon the individual
patient response. This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
2. For prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be
considered only for women at significant risk of osteoporosis and for whom non-estrogen
medications are not considered to be appropriate. Patients should be treated with the lowest
effective dose. Generally women should be started at 0.3 mg Premarin daily. Subsequent dosage
adjustment may be made based upon the individual clinical and bone mineral density responses.
This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian
failure:
Female hypogonadism0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on
and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness
of the endometrium.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 25
In clinical studies of delayed puberty due to female hypogonadism, breast development was
induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12 month
intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure.
Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios
of bone age advancement to chronological age progression (∆BA/∆CA) of 1.1, 1.5, and 2.1,
respectively. (Premarin in the dose strength of 0.15 mg is not available commercially). Available
data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with
sequential progestin treatment and to maintain bone mineral density after skeletal maturity is
achieved.
Female castration or primary ovarian failure1.25 mg daily, cyclically. Adjust dosage, upward or
downward, according to severity of symptoms and response of the patient. For maintenance, adjust
dosage to lowest level that will provide effective control.
4. For treatment of breast cancer, for palliation only, in appropriately selected women and men with
metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by
phosphatase determinations as well as by symptomatic improvement of the patient.
HOW SUPPLIED
Premarin (conjugated estrogens tablets, USP)
— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-0866-81); and
1,000 (NDC 0046-0866-91).
— Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-0864-81).
— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-0867-81);
1,000 (NDC 0046-0867-91); and Unit-Dose Packages of 100 (NDC 0046-0867-99).
— Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-0936-81).
— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-0868-81) and
1,000 (NDC 0046-0868-91).
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
Store at 20-25° C (68-77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled
Room Temperature].
Dispense in a well-closed container as defined in the USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 26
PATIENT INFORMATION
Premarin
(conjugated estrogens tablets, USP)
Read this PATIENT INFORMATION before you start taking Premarin and read what you get each
time you refill Premarin. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or
strokes.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may
increase your risk of dementia, based on a study of women age 65 years or older. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin.
What is Premarin?
Premarin is a medicine that contains a mixture of estrogen hormones.
Premarin is used after menopause to:
• reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The
ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop
in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual
periods). Sometimes both ovaries are removed during an operation before natural menopause takes
place. The sudden drop in estrogen levels causes “surgical menopause.”
When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as
feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating
(“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need to
take estrogens. In other women, symptoms can be more severe. You and your healthcare provider
should talk regularly about whether you still need treatment with Premarin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 27
• treat moderate to severe dryness, itching, and burning, in and around the vagina. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin to control these problems. If you use Premarin only to treat your dryness, itching, and
burning in and around your vagina, talk with your healthcare provider about whether a topical
vaginal product would be better for you.
• help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from
menopause is a thinning of the bones that makes them weaker and easier to break. If you use
Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider about
whether a different treatment or medicine without estrogens might be better for you. You and your
healthcare provider should talk regularly about whether you should continue with Premarin.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements
may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about
exercise and supplements with your healthcare provider before starting them.
Premarin is also used to:
• treat certain conditions in women before menopause if their ovaries do not make enough
estrogen naturally.
• ease symptoms of certain cancers that have spread through the body, in men and women.
Who should not take Premarin?
Do not start taking Premarin if you:
• have unusual vaginal bleeding.
• currently have or have had certain cancers. Estrogens may increase the chances of getting
certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer,
talk with your healthcare provider about whether you should take Premarin.
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have liver problems.
• are allergic to Premarin tablets or any of its ingredients. See the end of this leaflet for a list of
all the ingredients in Premarin.
• think you may be pregnant.
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin can pass into your milk.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 28
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine,
endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels
in your blood.
• about all the medicines you take, including prescription and nonprescription medicines, vitamins,
and herbal supplements. Some medicines may affect how Premarin works. Premarin may also
affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop taking estrogens.
How should I take Premarin?
• Take one Premarin tablet at the same time each day.
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the
missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• Estrogens should be used at the lowest dose possible for your treatment only as long as needed.
You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about
the dose you are taking and whether you still need treatment with Premarin.
What are the possible side effects of Premarin?
Less common but serious side effects include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 29
Call your healthcare provider right away if you get any of these warning signs, or any other unusual
symptom that concerns you.
Common side effects include:
• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin?
• Talk with your healthcare provider regularly about whether you should continue taking Premarin.
• If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is
right for you.
• See your healthcare provider right away if you get vaginal bleeding while taking Premarin.
• Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider
tells you something else. If members of your family have had breast cancer or if you have ever had
breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if
you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare
provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take Premarin for conditions for which it was not prescribed. Do not give Premarin to
other people, even if they have the same symptoms you have. It may harm them.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-136
Page 30
Keep Premarin out of the reach of children.
This leaflet provides a summary of the most important information about Premarin. If you would like
more information, talk with your healthcare provider or pharmacist. You can ask for information about
Premarin that is written for health professionals. You can get more information by calling the toll free
number 800-934-5556.
What are the ingredients in Premarin?
Premarin contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate
and sodium equilin sulfate and other components including sodium sulfate conjugates,
17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin also contains calcium
phosphate tribasic, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium
stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, and titanium
dioxide. The tablets come in different strengths and each strength tablet is a different color. The color
ingredients are:
0.3 mg tablet (green color): D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, and
FD&C Yellow No. 6.
0.45 mg tablet (blue color): FD&C Blue No. 2.
0.625 mg tablet (maroon color): FD&C Blue No. 2, D&C Red No. 27, and FD&C Red No. 40.
0.9 mg tablet (white color): D&C Red No. 6 and D&C Red No. 7.
1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow No. 6.
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
This product’s label may have been revised after this insert was used in
production. For further product information and current package insert,
please visit www.wyeth.com or call our medical communications
department toll-free at 1-800-934-5556.
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
W10405C008
ET04
Revised July 16, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.147933 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/04782slr133,136_premarin_lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 133} |
10,671 | NDA 04-782/S-138, S-139
Page 3
Premarin
(conjugated estrogens tablets, USP)
] only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the
use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or
dementia. (See WARNINGS, Cardiovascular disorders and Dementia.)
The Women’s Health Initiative (WHI) study reported increased risks of stroke and deep vein
thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with
conjugated estrogens (0.625 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical
Studies and WARNINGS, Cardiovascular disorders.)
The WHI study reported increased risks of myocardial infarction, stroke, invasive breast cancer,
pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during
5 years of treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone
acetate (2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies and
WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk
of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years
of treatment with conjugated estrogens alone and during 4 years of treatment with conjugated
estrogens combined with medroxyprogesterone acetate, relative to placebo. It is unknown whether this
finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical
Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and
dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the
absence of comparable data, these risks should be assumed to be similar. Because of these risks,
estrogens with or without progestins should be prescribed at the lowest effective doses and for the
shortest duration consistent with treatment goals and risks for the individual woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 4
DESCRIPTION
Premarin (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated
estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble
estrogen sulfates blended to represent the average composition of material derived from pregnant
mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as
concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and
17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg,
0.9 mg, and 1.25 mg strengths of conjugated estrogens.
Premarin 0.3 mg, 0.45 mg, 0.625 mg, and 0.9 mg tablets contain the following inactive ingredients:
calcium phosphate tribasic, calcium sulfate, carnauba wax, microcrystalline cellulose, powdered
cellulose, glyceryl monooleate, lactose monohydrate, magnesium stearate, methylcellulose,
pharmaceutical glaze, polyethylene glycol, stearic acid (not present in 0.45 mg tablet), sucrose, and
titanium dioxide.
Premarin 1.25 mg tablets contain the following inactive ingredients: calcium phosphate tribasic,
hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose
monohydrate, magnesium stearate, polyethylene glycol, sucrose, and titanium dioxide.
— 0.3 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C
Yellow No. 6.
— 0.45 mg tablets also contain: FD&C Blue No. 2.
— 0.625 mg tablets also contain: FD&C Blue No. 2, D&C Red No. 27, FD&C Red No. 40.
— 0.9 mg tablets also contain: D&C Red No. 6, D&C Red No. 7.
— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10, FD&C Yellow No. 6.
Premarin tablets comply with USP Drug Release Test criteria as outlined below:
Premarin 0.3 mg, 0.45 mg,
and 0.625 mg tablets
Test 1
Premarin 0.9 mg tablets
Test 2
Premarin 1.25 mg tablets
USP Drug Release Test pending
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the female
reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human
estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes
70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause,
most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal
cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate,
are the most abundant circulating estrogens in postmenopausal women.
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Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH)
and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to
reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after
release from the drug formulation. The Premarin tablet releases conjugated estrogens slowly over
several hours. Table 1 summarizes the mean pharmacokinetic parameters for unconjugated and
conjugated estrogens following administration of 2 x 0.3 mg, 2 x 0.45 mg, and 2 x 0.625 mg tablets to
healthy postmenopausal women.
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
82 (33)
7.8 (27)
54.7 (42)
5390 (50)
Baseline-adjusted estrone
58 (42)
7.8 (27)
21.1 (45)
1467 (41)
Equilin
31 (47)
7.2 (28)
18.3 (110)
652 (68)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.3 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Estrone
2.5 (32)
6.5 (29)
25.4 (22)
61.0 (43)
Baseline-adjusted total estrone
2.4 (32)
6.5 (29)
16.2 (34)
40.8 (36)
Equilin
1.6 (40)
5.9 (27)
11.8 (21)
22.4 (42)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
92 (32)
8.7 (28)
56.4 (68)
6344 (56)
Baseline-adjusted estrone
65 (40)
8.7 (28)
20.3 (38)
1940 (40)
Equilin
35 (49)
7.6 (33)
21.9 (113)
849 (60)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.45 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
2.8 (46)
7.1 (27)
27.6 (35)
77 (34)
Baseline-adjusted total estrone
2.6 (46)
7.1 (27)
14.7 (42)
48 (38)
Total equilin
1.9 (53)
5.9 (32)
11.8 (32)
29 (55)
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TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
139 (37)
8.8 (20)
28.0 (30)
5016 (34)
Baseline-adjusted estrone
120 (41)
8.8 (20)
17.4 (37)
2956 (39)
Equilin
66 (42)
7.9 (19)
13.6 (52)
1210 (37)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 2 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
7.3 (41)
7.3 (24)
15.0 (25)
134 (42)
Baseline-adjusted total estrone
7.1 (41)
7.3 (24)
13.6 (23)
122 (38)
Total equilin
5.0 (42)
6.2 (26)
10.1 (26)
65 (44)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
124 (30)
10.0 (32)
38.1 (37)
6332 (44)
Baseline-adjusted estrone
102 (35)
10.0 (32)
19.7 (48)
3159 (53)
Equilin
59 (43)
8.8 (36)
10.9 (47)
1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total Estrone
4.5 (39)
8.2 (58)
26.5 (40)
109 (46)
Baseline-adjusted total estrone
4.3 (41)
8.2 (58)
17.5 (41)
87 (44)
Total equilin
2.9 (42)
6.8 (49)
12.5 (34)
48 (51)
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex hormone
target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG)
and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take
place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to
estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via
sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and
hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of
the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a
circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
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Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or
hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been
conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450
3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a
decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4
such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may
increase plasma concentrations of estrogens and may result in side effects.
Clinical Studies
Effects on vasomotor symptoms.
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805
postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight
treatment groups, receiving either placebo or conjugated estrogens with or without
medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first
12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least 7 moderate to
severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before
randomization. Premarin (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better
than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe
vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the Premarin 0.3 mg,
0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.
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TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY–
MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS
AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE
FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF
Treatment
(No. of Patients)
--------------- No. of Hot Flushes/Day ------------------
Time Period
(week)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change ± SD
p-Values
vs. Placeboa
0.625 mg CE
(n = 27)
4
12.29 ± 3.89
1.95 ± 2.77
-10.34 ± 4.73
<0.001
12
12.29 ± 3.89
0.75 ± 1.82
-11.54 ± 4.62
<0.001
0.45 mg CE
(n = 32)
4
12.25 ± 5.04
5.04 ± 5.31
-7.21 ± 4.75
<0.001
12
12.25 ± 5.04
2.32 ± 3.32
-9.93 ± 4.64
<0.001
0.3 mg CE
(n = 30)
4
13.77 ± 4.78
4.65 ± 3.71
-9.12 ± 4.71
<0.001
12
13.77 ± 4.78
2.52 ± 3.23
-11.25 ± 4.60
<0.001
Placebo
(n = 28)
4
11.69 ± 3.87
7.89 ± 5.28
-3.80 ± 4.71
-
12
11.69 ± 3.87
5.71 ± 5.22
-5.98 ± 4.60
-
a: Based on analysis of covariance with treatment as factor and baseline as covariate.
Effects on vulvar and vaginal atrophy.
Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo
were statistically significant (p<0.001) for all treatment groups (conjugated estrogens alone and
conjugated estrogens/medroxyprogesterone acetate treatment groups).
Effects on bone mineral density.
Health and Osteoporosis, Progestin and Estrogen (HOPE) Study
The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of
healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ±
0.9 years, on average, since menopause, and took one 600-mg tablet of elemental calcium (Caltrate)
daily. Subjects were not given vitamin D supplements. They were treated with Premarin 0.625 mg,
0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral
density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD
measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin,
urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and
26.
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Intent-to-treat subjects
All active treatment groups showed significant differences from placebo in each of the 4 BMD
endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L2
to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available
evaluation for those who discontinued early) were 2.46% with 0.625 mg, 2.26% with 0.45 mg, and
1.13% with 0.3 mg. The placebo group showed a mean percent decrease from baseline at the final
evaluation of 2.45%. These results show that the lower dosages of Premarin were effective in
increasing L2 to L4 BMD compared with placebo and, therefore, support the efficacy of the lower
doses.
The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral
trochanter that were generally larger than those seen for L2 to L4 and changes in femoral neck and total
body that were generally smaller than those seen for L2 to L4. Significant differences between groups
indicated that each of the Premarin treatments was more effective than placebo for all 3 of these
additional BMD endpoints. With regard to femoral neck and total body, the active treatment groups all
showed mean percent increases in BMD while placebo treatment was accompanied by mean percent
decreases. For femoral trochanter, each of the Premarin dose groups showed a mean percent increase
that was significantly greater than the small increase seen in the placebo group. The percent changes
from baseline to final evaluation are shown in Table 3.
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TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN
ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION,
LAST OBSERVATION CARRIED FORWARD
Region Evaluated
Treatment Groupa
No. of
Subjects
Baseline (g/cm2)
Mean ± SD
Change from Baseline (%)
Adjusted Mean ± SE
p-Value vs
Placebo
L2 to L4 BMD
0.625
83
1.17 ± 0.15
2.46 ± 0.37
<0.001
0.45
91
1.13 ± 0.15
2.26 ± 0.35
<0.001
0.3
87
1.14 ± 0.15
1.13 ± 0.36
<0.001
Placebo
85
1.14 ± 0.14
-2.45 ± 0.36
Total Body BMD
0.625
84
1.15 ± 0.08
0.68 ± 0.17
<0.001
0.45
91
1.14 ± 0.08
0.74 ± 0.16
<0.001
0.3
87
1.14 ± 0.07
0.40 ± 0.17
<0.001
Placebo
85
1.13 ± 0.08
-1.50 ± 0.17
Femoral Neck BMD
0.625
84
0.91 ± 0.14
1.82 ± 0.45
<0.001
0.45
91
0.89 ± 0.13
1.84 ± 0.44
<0.001
0.3
87
0.86 ± 0.11
0.62 ± 0.45
<0.001
Placebo
85
0.88 ± 0.14
-1.72 ± 0.45
Femoral Trochanter BMD
0.625
84
0.78 ± 0.13
3.82 ± 0.58
<0.001
0.45
91
0.76 ± 0.12
3.16 ± 0.56
0.003
0.3
87
0.75 ± 0.10
3.05 ± 0.57
0.005
Placebo
85
0.75 ± 0.12
0.81 ± 0.58
a: Identified by dosage (mg) of Premarin or placebo.
Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater
than the value shown on the x-axis.
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Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN
SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND PLACEBO GROUPS
The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density
study are shown with standard error bars by treatment group in Figure 2. Significant differences
between each of the Premarin dosage groups and placebo were found at cycles 6, 13, 19, and 26.
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Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN
SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBO
The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased
(p<0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group.
Larger mean decreases from baseline were seen with the active groups than with the placebo group.
Significant differences from placebo were seen less frequently in urine calcium.
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg
conjugated estrogens per day) alone or the use of PREMPRO (0.625 mg conjugated estrogens plus
2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic
diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal
myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome
studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke,
pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other
cause. The study did not evaluate the effects of Premarin or PREMPRO on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed and it
was deemed that no further information would be obtained regarding the risks and benefits of estrogen
alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included
10,739 women (average age of 63 years, range 50 to 79; 75.3% White, 15% Black, 6.1% Hispanic),
after an average follow-up of 6.8 years are presented in Table 4 below.
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TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE
SUBSTUDY OF WHIa
Placebo
n = 5429
Premarin
n = 5310
Eventc
Relative Risk*
Premarin vs Placebo
at 6.8 Years
(95% CI)
Absolute Risk per 10,000
Women-years
CHD events
0.91 (0.75-1.12)
54
49
Non-fatal MI
0.89 (0.70-1.12)
41
37
CHD death
0.94 (0.65-1.36)
16
15
Invasive breast cancer
0.77 (0.59-1.01)
33
26
Stroke
1.39 (1.10-1.77)
32
44
Pulmonary embolism
1.34 (0.87-2.06)
10
13
Colorectal cancer
1.08 (0.75-1.55)
16
17
Hip fracture
0.61 (0.41-0.91)
17
11
Death due to other causes than
the events above
1.08 (0.88-1.32)
50
53
Global Indexb
1.01 (0.91-1.12)
190
192
Deep vein thrombosisc
1.47 (1.04-2.08)
15
21
Vertebral fracturesc
0.62 (0.42-0.93)
17
11
Total fracturesc
0.70 (0.63-0.79)
195
139
a: adapted from JAMA, 2004; 291:1701-1712
b: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
c: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with Premarin alone were 12 more
strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The
absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000
women-years. There was no difference between the groups in terms of all-cause mortality. (See
BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
The estrogen plus progestin substudy was also stopped early because, according to the predefined
stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified
benefits included in the “global index.” Results of the estrogen plus progestin substudy, which
included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black,
5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below.
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TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000
Women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than
the events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosisd
2.07 (1.49-2.87)
13
26
Vertebral fracturesd
0.66 (0.44-0.98)
15
9
Other osteoporotic fracturesd
0.77 (0.69-0.86)
170
131
a: adapted from JAMA, 2002; 288:321-333
b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
d: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI “global index,” the absolute excess risks per
10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8
more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-
years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events
included in the “global index” was 19 per 10,000 women-years. There was no difference between the
groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and
PRECAUTIONS.)
Women’s Health Initiative Memory Study.
The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled
2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were age
65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the
effects of Premarin (0.625 mg conjugated estrogens) on the incidence of probable dementia (primary
outcome) compared with placebo.
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After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-
years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable
dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95% CI, 0.83 to
2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal
women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric
Use.)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal
women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18%
were 75 years of age and older) to evaluate the effects of PREMPRO (0.625 mg conjugated estrogens
plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome)
compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with
probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05
(95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first
year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See
BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the
menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy,
topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with
metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant risk of
osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise,
adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy.
Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when
not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary
intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate
daily intake in postmenopausal women.
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CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast except in appropriately selected patients being
treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial
infarction).
6. Liver dysfunction or disease.
7. Premarin tablets should not be used in patients with known hypersensitivity to their ingredients.
8. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There appears to
be little or no increased risk of birth defects in children born to women who have used estrogen and
progestins from oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS.)
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated with an
increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous
thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these
occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
a. Coronary heart disease and stroke. In the estrogen alone substudy of the Women’s Health
Initiative (WHI) study, an increased risk of stroke was observed in women receiving Premarin
(0.625 mg conjugated estrogens) per day compared to women receiving placebo (44 vs 32 per
10,000 women-years). The increase in risk was observed in year one and persisted. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease (CHD)
events (defined as nonfatal myocardial infarction and CHD death) was observed in women
receiving PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate)
per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in
risk was observed in year one and persisted.
In the same estrogen plus progestin substudy of WHI, an increased risk of stroke was observed in
women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000
women-years). The increase in risk was observed after the first year and persisted.
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In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated
estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the
overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1,
but not during the subsequent years. Two thousand three hundred and twenty one women from the
original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average
follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD
events were comparable among women in the PREMPRO group and the placebo group in HERS,
HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism (VTE). In the estrogen alone substudy of the Women’s Health Initiative
(WHI) study, an increased risk of deep vein thrombosis was observed in women receiving
Premarin compared to placebo (21 vs 15 per 10,000 women-years). The increase in VTE risk was
observed during the first year. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO
compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the
PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in
VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users with an intact uterus is about 2- to 12-fold greater than in non-
users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no
significant increased risk associated with the use of estrogens for less than one year. The greatest
risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten
years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen
therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule
out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal
estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a
precursor to endometrial cancer.
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b. Breast cancer. In some studies, the use of estrogens and progestins by postmenopausal women has
been reported to increase the risk of breast cancer. The most important randomized clinical trial
providing information about this issue is the Women’s Health Initiative (WHI) trial of estrogen
plus progestin (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from
observational studies are generally consistent with those of the WHI clinical trial.
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in
women who took estrogen plus progestin. Observational studies have also reported an increased
risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone
therapy, after several years of use. For both findings, the excess risk increased with duration of use,
and appeared to return to baseline over about five years after stopping treatment (only the
observational studies have substantial data on risk after stopping). In these studies, the risk of
breast cancer was greater, and became apparent earlier, with estrogen/progestin combination
therapy as compared to estrogen alone therapy. However, these studies have not found significant
variation in the risk of breast cancer among different estrogens or among different
estrogen/progestin combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen alone
and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years
during the clinical trial, the overall relative risk of invasive breast cancer was
1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per
10,000 women-years, for estrogen plus progestin compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the
absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin compared
with placebo. Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years
for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were
larger and diagnosed at a more advanced stage in the estrogen plus progestin group compared with
the placebo group. Metastatic disease was rare with no apparent difference between the two groups.
Other prognostic factors such as histologic subtype, grade and hormone receptor status did not
differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality due to
breast cancer among current users of estrogens alone or estrogens plus progestins compared to
never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast cancer
mortality with a mean follow-up of 5.6 years.
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast examinations
by a healthcare provider and perform monthly breast self-examinations. In addition, mammography
examinations should be scheduled based on patient age, risk factors,
and prior mammogram
results.
3. Dementia. In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy
of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to
Premarin (0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of
4,532 postmenopausal women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/2.5
mg) or placebo.
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Page 19
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen
alone group and 19 women in the placebo group were diagnosed with probable dementia. The
relative risk of probable dementia for Premarin alone versus placebo was 1.49 (95% CI 0.83-2.66).
The absolute risk of probable dementia for Premarin alone versus placebo was 37 versus 25 cases
per 10,000 women-years.
In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the
estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for estrogen plus progestin versus placebo was
2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for PREMPRO versus placebo
was 45 versus 22 cases per 10,000 women-years.
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these
findings apply to younger postmenopausal women. (See BOXED WARNINGS and
PRECAUTIONS, Geriatric Use.)
4. Gallbladder Disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in
postmenopausal women receiving estrogens has been reported.
5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast
cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and
appropriate measures taken to reduce the serum calcium level.
6. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is sudden partial or complete loss
of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema
or retinal vascular lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or
daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a
precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens
compared to estrogen-alone regimens. These include: a possible increased risk of breast cancer,
adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of
glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals during estrogen use.
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3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE
study, the mean percent increase from baseline in serum triglycerides after one year of treatment
with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and
10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0,
and 5.5, respectively.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should
be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid hormone,
thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on
thyroid hormone replacement therapy who are also receiving estrogens may require increased
doses of their thyroid replacement therapy. These patients should have their thyroid function
monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer.
The estrogen plus progestin substudy of WHI reported that after an average follow-up of 5.6 years,
the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95%
confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk of estrogen
plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some
epidemiologic studies, the use of estrogen-only products, in particular for ten or more years, has
been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not
found these associations.
9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual
endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in patients with these conditions.
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Page 21
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients
for whom they prescribe Premarin.
C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose for the treatment of postmenopausal
moderate to severe vasomotor symptoms and moderate to severe symptoms of postmenopausal vulvar
and vaginal atrophy and then guided by clinical response rather than by serum hormone levels (e.g.,
estradiol, FSH). Laboratory parameters may be useful in guiding dosage for the treatment of
hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII,
VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa
and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the
elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement
therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex
hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex
steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may
be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol
concentrations, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).
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G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the
milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.
Caution should be exercised when Premarin is administered to a nursing woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal
delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to accelerate
epiphyseal closure, which could result in short stature if treatment is initiated before the completion of
physiologic puberty in normally developing children. If estrogen is administered to patients whose
bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers
is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal
pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I. Geriatric Use
Of the total number of subjects in the estrogen alone substudy of the Women’s Health Initiative (WHI)
study, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was
a higher relative risk (Premarin vs. placebo) of stroke in women less than 75 years of age compared to
women 75 years and over.
In the estrogen alone substudy of the Women’s Health Initiative Memory Study (WHIMS), a substudy
of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to
Premarin (0.625 mg) or placebo. In the estrogen alone group, after an average follow-up of 5.2 years,
the relative risk (Premarin versus placebo) of probable dementia was 1.49 (95% CI 0.83-2.66).
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health
Initiative study, 44% (n=7,320) were 65 years and over, while 6.6% (n=1,095) were 75 years and over.
There was a higher relative risk (PREMPRO vs placebo) of stroke and invasive breast cancer in
women 75 and over compared to women less than 75 years of age.
In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women,
aged 65 to 79 years, was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. In the estrogen plus
progestin group, after an average follow-up of 4 years, the relative risk (PREMPRO versus placebo) of
probable dementia was 2.05 (95% CI 1.21-3.48).
Pooling the events in women receiving Premarin or PREMPRO in comparison to those in women on
placebo, the overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both
substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply
to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric
patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ
from younger subjects in their response to Premarin.
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ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. The adverse reaction information from clinical trials
does, however, provide a basis for identifying the adverse events that appear to be related to drug use
and for approximating rates.
During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65
years of age (88% Caucasian), 1012 women were treated with conjugated estrogens and 332 were
treated with placebo. Table 6 summarizes adverse events that occurred at a rate of ≥ 5%.
TABLE 6. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Any adverse event
323 (93%)
305 (90%)
292 (90%)
281 (85%)
Body as a Whole
Abdominal pain
56 (16%)
50 (15%)
54 (17%)
37 (11%)
Accidental injury
21 (6%)
41 (12%)
20 (6%)
29 (9%)
Asthenia
25 (7%)
23 (7%)
25 (8%)
16 (5%)
Back pain
49 (14%)
43 (13%)
43 (13%)
39 (12%)
Flu syndrome
37 (11%)
38 (11%)
33 (10%)
35 (11%)
Headache
90 (26%)
109 (32%)
96 (29%)
93 (28%)
Infection
61 (18%)
75 (22%)
74 (23%)
74 (22%)
Pain
58 (17%)
61 (18%)
66 (20%)
61 (18%)
Digestive System
Diarrhea
21 (6%)
25 (7%)
19 (6%)
21 (6%)
Dyspepsia
33 (9%)
32 (9%)
36 (11%)
46 (14%)
Flatulence
24 (7%)
23 (7%)
18 (6%)
9 (3%)
Nausea
32 (9%)
21 (6%)
21 (6%)
30 (9%)
Musculoskeletal System
Arthralgia
47 (14%)
42 (12%)
22 (7%)
39 (12%)
Leg cramps
19 (5%)
23 (7%)
11 (3%)
7 (2%)
Myalgia
18 (5%)
18 (5%)
29 (9%)
25 (8%)
Nervous System
Depression
25 (7%)
27 (8%)
17 (5%)
22 (7%)
Dizziness
19 (5%)
20 (6%)
12 (4%)
17 (5%)
Insomnia
21 (6%)
25 (7%)
24 (7%)
33 (10%)
Nervousness
12 (3%)
17 (5%)
6 (2%)
7 (2%)
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TABLE 6. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Respiratory System
Cough increased
13 (4%)
22 (7%)
14 (4%)
14 (4%)
Pharyngitis
35 (10%)
35 (10%)
40 (12%)
38 (11%)
Rhinitis
21 (6%)
30 (9%)
31 (10%)
42 (13%)
Sinusitis
22 (6%)
36 (11%)
24 (7%)
24 (7%)
Upper respiratory infection
42 (12%)
34 (10%)
28 (9%)
35 (11%)
Skin and Appendages
Pruritus
14 (4%)
17 (5%)
16 (5%)
7 (2%)
Urogenital System
Breast pain
38 (11%)
41 (12%)
24 (7%)
29 (9%)
Leukorrhea
18 (5%)
22 (7%)
13 (4%)
9 (3%)
Vaginal hemorrhage
47 (14%)
14 (4%)
7 (2%)
0
Vaginal moniliasis
20 (6%)
18 (5%)
17 (5%)
6 (2%)
Vaginitis
24 (7%)
20 (6%)
16 (5%)
4 (1%)
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
1. Genitourinary system
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough
bleeding, spotting, dysmenorrhea
Increase in size of uterine leiomyomata
Vaginitis, including vaginal candidiasis
Change in amount of cervical secretion
Change in cervical ectropion
Ovarian cancer
Endometrial hyperplasia
Endometrial cancer
2. Breasts
Tenderness, enlargement, pain, discharge, galactorrhea
Fibrocystic breast changes
Breast cancer
3. Cardiovascular
Deep and superficial venous thrombosis
Pulmonary embolism
Thrombophlebitis
Myocardial infarction
Stroke
Increase in blood pressure
4. Gastrointestinal
Nausea, vomiting
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Page 25
Abdominal cramps, bloating
Cholestatic jaundice
Increased incidence of gallbladder disease
Pancreatitis
Enlargement of hepatic hemangiomas
5. Skin
Chloasma or melasma that may persist when drug is discontinued
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Loss of scalp hair
Hirsutism
Pruritus, rash
6. Eyes
Retinal vascular thrombosis
Intolerance to contact lenses
7. Central Nervous System
Headache
Migraine
Dizziness
Mental depression
Chorea
Nervousness
Mood disturbances
Irritability
Exacerbation of epilepsy
Dementia
8. Miscellaneous
Increase or decrease in weight
Reduced carbohydrate tolerance
Aggravation of porphyria
Edema
Arthralgias
Leg cramps
Changes in libido
Urticaria, angioedema, anaphylactoid/anaphylactic reactions
Hypocalcemia
Exacerbation of asthma
Increased triglycerides
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and
vomiting, and withdrawal bleeding may occur in females.
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DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin.
Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and
for the shortest duration consistent with treatment goals and risks for the individual woman. Patients
should be re-evaluated periodically as clinically appropriate (e.g., at 3-month to 6-month intervals) to
determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women
with a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be
undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal
bleeding.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of
vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the
treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products
should be considered.
Patients should be treated with the lowest effective dose. Generally women should be started at
0.3 mg Premarin daily. Subsequent dosage adjustment may be made based upon the individual
patient response. This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
2. For prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be
considered only for women at significant risk of osteoporosis and for whom non-estrogen
medications are not considered to be appropriate. Patients should be treated with the lowest
effective dose. Generally women should be started at 0.3 mg Premarin daily. Subsequent dosage
adjustment may be made based upon the individual clinical and bone mineral density responses.
This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian
failure:
Female hypogonadism0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on
and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness
of the endometrium.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 27
In clinical studies of delayed puberty due to female hypogonadism, breast development was
induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12 month
intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure.
Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios
of bone age advancement to chronological age progression (∆BA/∆CA) of 1.1, 1.5, and 2.1,
respectively. (Premarin in the dose strength of 0.15 mg is not available commercially). Available
data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with
sequential progestin treatment and to maintain bone mineral density after skeletal maturity is
achieved.
Female castration or primary ovarian failure1.25 mg daily, cyclically. Adjust dosage, upward or
downward, according to severity of symptoms and response of the patient. For maintenance, adjust
dosage to lowest level that will provide effective control.
4. For treatment of breast cancer, for palliation only, in appropriately selected women and men with
metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by
phosphatase determinations as well as by symptomatic improvement of the patient.
HOW SUPPLIED
Premarin (conjugated estrogens tablets, USP)
— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81); and
1,000 (NDC 0046-1104-91).
— Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-0864-81).
— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-0867-81);
1,000 (NDC 0046-0867-91); and Unit-Dose Packages of 100 (NDC 0046-0867-99).
— Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-0936-81).
— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-0868-81) and
1,000 (NDC 0046-0868-91).
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
Store at 20-25° C (68-77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled
Room Temperature].
Dispense in a well-closed container as defined in the USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 28
PATIENT INFORMATION
(Updated March 2005)
Premarin
(conjugated estrogens tablets, USP)
Read this PATIENT INFORMATION before you start taking Premarin and read what you get each
time you refill Premarin. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks,
strokes, or dementia.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without
progestins, may increase your risk of dementia, based on a study of women age 65 years
or older. You and your healthcare provider should talk regularly about whether you still
need treatment with Premarin.
What is Premarin?
Premarin is a medicine that contains a mixture of estrogen hormones.
Premarin is used after menopause to:
• reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The
ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop
in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual
periods). Sometimes both ovaries are removed during an operation before natural menopause takes
place. The sudden drop in estrogen levels causes “surgical menopause.”
When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as
feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating
(“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need to
take estrogens. In other women, symptoms can be more severe. You and your healthcare provider
should talk regularly about whether you still need treatment with Premarin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 29
• treat moderate to severe dryness, itching, and burning, in and around the vagina. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin to control these problems. If you use Premarin only to treat your dryness, itching, and
burning in and around your vagina, talk with your healthcare provider about whether a topical
vaginal product would be better for you.
• help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from
menopause is a thinning of the bones that makes them weaker and easier to break. If you use
Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider about
whether a different treatment or medicine without estrogens might be better for you. You and your
healthcare provider should talk regularly about whether you should continue with Premarin.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements
may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about
exercise and supplements with your healthcare provider before starting them.
Premarin is also used to:
• treat certain conditions in women before menopause if their ovaries do not make enough
estrogen naturally.
• ease symptoms of certain cancers that have spread through the body, in men and women.
Who should not take Premarin?
Do not start taking Premarin if you:
• have unusual vaginal bleeding.
• currently have or have had certain cancers. Estrogens may increase the chances of getting
certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer,
talk with your healthcare provider about whether you should take Premarin.
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have liver problems.
• are allergic to Premarin tablets or any of its ingredients. See the end of this leaflet for a list of
all the ingredients in Premarin.
• think you may be pregnant.
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin can pass into your milk.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 30
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine,
endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels
in your blood.
• about all the medicines you take, including prescription and nonprescription medicines, vitamins,
and herbal supplements. Some medicines may affect how Premarin works. Premarin may also
affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop taking estrogens.
How should I take Premarin?
• Take one Premarin tablet at the same time each day.
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the
missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• Estrogens should be used at the lowest dose possible for your treatment only as long as needed.
You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about
the dose you are taking and whether you still need treatment with Premarin.
What are the possible side effects of Premarin?
Less common but serious side effects include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other unusual
symptom that concerns you.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 31
Common side effects include:
• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin?
• Talk with your healthcare provider regularly about whether you should continue taking Premarin.
• If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is
right for you. In general, the addition of a progestin is recommended for women with a uterus to
reduce the chance of getting cancer of the uterus.
• See your healthcare provider right away if you get vaginal bleeding while taking Premarin.
• Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider
tells you something else. If members of your family have had breast cancer or if you have ever had
breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if
you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare
provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take Premarin for conditions for which it was not prescribed. Do not give Premarin to
other people, even if they have the same symptoms you have. It may harm them.
Keep Premarin out of the reach of children.
This leaflet provides a summary of the most important information about Premarin. If you would like
more information, talk with your healthcare provider or pharmacist. You can ask for information about
Premarin that is written for health professionals. You can get more information by calling the toll free
number 800-934-5556.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 32
What are the ingredients in Premarin?
Premarin contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate
and sodium equilin sulfate and other components including sodium sulfate conjugates,
17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin 0.3 mg, 0.45 mg, 0.625 mg,
and 0.9 mg tablets also contain the following inactive ingredients: calcium phosphate tribasic, calcium
sulfate, carnauba wax, microcrystalline cellulose, powdered cellulose, glyceryl monooleate, lactose
monohydrate, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic
acid (not present in 0.45 mg tablet), sucrose, and titanium dioxide.
Premarin 1.25 mg tablets contain the following inactive ingredients: calcium phosphate tribasic,
hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose
monohydrate, magnesium stearate, polyethylene glycol, sucrose and titanium dioxide.
The tablets come in different strengths and each strength tablet is a different color. The color
ingredients are:
0.3 mg tablet (green color): D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, and
FD&C Yellow No. 6.
0.45 mg tablet (blue color): FD&C Blue No. 2.
0.625 mg tablet (maroon color): FD&C Blue No. 2, D&C Red No. 27, and FD&C Red No. 40.
0.9 mg tablet (white color): D&C Red No. 6 and D&C Red No. 7.
1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow No. 6.
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
This product’s label may have been revised after this insert was
used in production. For further product information and current
package insert, please visit www.wyeth.com or call our medical
communications department toll-free at 1-800-934-5556.
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
W10405C011
ET02
Rev 08/04
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-138, S-139
Page 33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.204206 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/004782s138,139lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 139} |
10,672 | NDA 04-782/S-142
Page 3
Premarin®
(conjugated estrogens tablets, USP)
] only
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the
use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or
dementia. (See WARNINGS, Cardiovascular disorders and Dementia.)
The Women’s Health Initiative (WHI) study reported increased risks of stroke and deep vein
thrombosis in postmenopausal women (50 to 79 years of age) during 6.8 years of treatment with
conjugated estrogens (0.625 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical
Studies and WARNINGS, Cardiovascular disorders.)
The WHI study reported increased risks of myocardial infarction, stroke, invasive breast cancer,
pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during
5 years of treatment with conjugated estrogens (0.625 mg) combined with medroxyprogesterone
acetate (2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies and
WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk
of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years
of treatment with conjugated estrogens alone and during 4 years of treatment with conjugated
estrogens combined with medroxyprogesterone acetate, relative to placebo. It is unknown whether this
finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical
Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and
dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the
absence of comparable data, these risks should be assumed to be similar. Because of these risks,
estrogens with or without progestins should be prescribed at the lowest effective doses and for the
shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
Premarin® (conjugated estrogens tablets, USP) for oral administration contains a mixture of conjugated
estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble
estrogen sulfates blended to represent the average composition of material derived from pregnant
mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 4
concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and
17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625 mg,
0.9 mg, and 1.25 mg strengths of conjugated estrogens.
Premarin 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive
ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered
cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, and
titanium dioxide.
— 0.3 mg tablets also contain: D&C Yellow No. 10 and FD&C Blue No. 2.
— 0.45 mg tablets also contain: FD&C Blue No. 2.
— 0.625 mg tablets also contain: FD&C Blue No. 2 and FD&C Red No. 40.
— 0.9 mg tablets also contain: D&C Red No. 30 and D&C Red No. 7.
— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10 and FD&C Yellow No. 6.
Premarin tablets comply with USP Drug Release Test criteria as outlined below:
Premarin 0.3 mg, 0.45 mg,
0.625 mg, 0.9 mg and
1.25 mg tablets
USP Drug Release Test pending
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the female
reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a
dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human
estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes
70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause,
most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal
cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate,
are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH)
and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to
reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Pharmacokinetics
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after
release from the drug formulation. The Premarin tablet releases conjugated estrogens slowly over
several hours. Table 1 summarizes the mean pharmacokinetic parameters for unconjugated and
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 5
conjugated estrogens following administration of 1 x 0.625 mg and 1 x 1.25 mg tablets to healthy
postmenopausal women.
The pharmacokinetics of Premarin 0.45 mg and 1.25 mg tablets were assessed following a single dose
with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered
approximately 3-13%. The changes to Cmax and AUC are not considered clinically meaningful.
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
87 (33)
9.6 (33)
50.7 (35)
5557 (59)
Baseline-adjusted estrone
64 (42)
9.6 (33)
20.2 (40)
1723 (52)
Equilin
31 (38)
7.9 (32)
12.9 (112)
602 (54)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total estrone
2.7 (43)
6.9 (25)
26.7 (33)
75 (52)
Baseline-adjusted total estrone
2.5 (45)
6.9 (25)
14.8 (35)
46 (48)
Total equilin
1.8 (56)
5.6 (45)
11.4 (31)
27 (56)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(pg/mL)
tmax
(h)
t1/2
(h)
AUC
(pg•h/mL)
Estrone
124 (30)
10.0 (32)
38.1 (37)
6332 (44)
Baseline-adjusted estrone
102 (35)
10.0 (32)
19.7 (48)
3159 (53)
Equilin
59 (43)
8.8 (36)
10.9 (47)
1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Arithmetic Mean (%CV)
Cmax
(ng/mL)
tmax
(h)
t1/2
(h)
AUC
(ng•h/mL)
Total Estrone
4.5 (39)
8.2 (58)
26.5 (40)
109 (46)
Baseline-adjusted total estrone
4.3 (41)
8.2 (58)
17.5 (41)
87 (44)
Total equilin
2.9 (42)
6.8 (49)
12.5 (34)
48 (51)
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex hormone
target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG)
and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take
place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to
estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 6
sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and
hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of
the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a
circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or
hepatic impairment.
Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been
conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450
3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital,
carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a
decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4
such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may
increase plasma concentrations of estrogens and may result in side effects.
Clinical Studies
Effects on vasomotor symptoms.
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805
postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight
treatment groups, receiving either placebo or conjugated estrogens with or without
medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first
12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least 7 moderate to
severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before
randomization. Premarin (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to be statistically better
than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe
vasomotor symptoms. Table 2 shows the adjusted mean number of hot flushes in the Premarin 0.3 mg,
0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.
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NDA 04-782/S-142
Page 7
TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY–
MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE TREATMENT GROUPS
AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE
FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, LOCF
Treatment
(No. of Patients)
--------------- No. of Hot Flushes/Day ------------------
Time Period
(week)
Baseline
Mean ± SD
Observed
Mean ± SD
Mean
Change ± SD
p-Values
vs. Placeboa
0.625 mg CE
(n = 27)
4
12.29 ± 3.89
1.95 ± 2.77
-10.34 ± 4.73
<0.001
12
12.29 ± 3.89
0.75 ± 1.82
-11.54 ± 4.62
<0.001
0.45 mg CE
(n = 32)
4
12.25 ± 5.04
5.04 ± 5.31
-7.21 ± 4.75
<0.001
12
12.25 ± 5.04
2.32 ± 3.32
-9.93 ± 4.64
<0.001
0.3 mg CE
(n = 30)
4
13.77 ± 4.78
4.65 ± 3.71
-9.12 ± 4.71
<0.001
12
13.77 ± 4.78
2.52 ± 3.23
-11.25 ± 4.60
<0.001
Placebo
(n = 28)
4
11.69 ± 3.87
7.89 ± 5.28
-3.80 ± 4.71
-
12
11.69 ± 3.87
5.71 ± 5.22
-5.98 ± 4.60
-
a: Based on analysis of covariance with treatment as factor and baseline as covariate.
Effects on vulvar and vaginal atrophy.
Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo
were statistically significant (p<0.001) for all treatment groups (conjugated estrogens alone and
conjugated estrogens/medroxyprogesterone acetate treatment groups).
Effects on bone mineral density.
Health and Osteoporosis, Progestin and Estrogen (HOPE) Study
The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of
healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ±
0.9 years, on average, since menopause, and took one 600-mg tablet of elemental calcium (Caltrate)
daily. Subjects were not given vitamin D supplements. They were treated with Premarin 0.625 mg,
0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral
density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD
measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin,
urinary calcium, and N-telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and
26.
Intent-to-treat subjects
All active treatment groups showed significant differences from placebo in each of the 4 BMD
endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary efficacy measure (L2
to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available
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NDA 04-782/S-142
Page 8
evaluation for those who discontinued early) were 2.46% with 0.625 mg, 2.26% with 0.45 mg, and
1.13% with 0.3 mg. The placebo group showed a mean percent decrease from baseline at the final
evaluation of 2.45%. These results show that the lower dosages of Premarin were effective in
increasing L2 to L4 BMD compared with placebo and, therefore, support the efficacy of the lower
doses.
The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral
trochanter that were generally larger than those seen for L2 to L4 and changes in femoral neck and total
body that were generally smaller than those seen for L2 to L4. Significant differences between groups
indicated that each of the Premarin treatments was more effective than placebo for all 3 of these
additional BMD endpoints. With regard to femoral neck and total body, the active treatment groups all
showed mean percent increases in BMD while placebo treatment was accompanied by mean percent
decreases. For femoral trochanter, each of the Premarin dose groups showed a mean percent increase
that was significantly greater than the small increase seen in the placebo group. The percent changes
from baseline to final evaluation are shown in Table 3.
TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN
ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION,
LAST OBSERVATION CARRIED FORWARD
Region Evaluated
Treatment Groupa
No. of
Subjects
Baseline (g/cm2)
Mean ± SD
Change from Baseline (%)
Adjusted Mean ± SE
p-Value vs
Placebo
L2 to L4 BMD
0.625
83
1.17 ± 0.15
2.46 ± 0.37
<0.001
0.45
91
1.13 ± 0.15
2.26 ± 0.35
<0.001
0.3
87
1.14 ± 0.15
1.13 ± 0.36
<0.001
Placebo
85
1.14 ± 0.14
-2.45 ± 0.36
Total Body BMD
0.625
84
1.15 ± 0.08
0.68 ± 0.17
<0.001
0.45
91
1.14 ± 0.08
0.74 ± 0.16
<0.001
0.3
87
1.14 ± 0.07
0.40 ± 0.17
<0.001
Placebo
85
1.13 ± 0.08
-1.50 ± 0.17
Femoral Neck BMD
0.625
84
0.91 ± 0.14
1.82 ± 0.45
<0.001
0.45
91
0.89 ± 0.13
1.84 ± 0.44
<0.001
0.3
87
0.86 ± 0.11
0.62 ± 0.45
<0.001
Placebo
85
0.88 ± 0.14
-1.72 ± 0.45
Femoral Trochanter BMD
0.625
84
0.78 ± 0.13
3.82 ± 0.58
<0.001
0.45
91
0.76 ± 0.12
3.16 ± 0.56
0.003
0.3
87
0.75 ± 0.10
3.05 ± 0.57
0.005
Placebo
85
0.75 ± 0.12
0.81 ± 0.58
a: Identified by dosage (mg) of Premarin or placebo.
Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or greater
than the value shown on the x-axis.
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Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM BASELINE IN
SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN AND PLACEBO GROUPS
The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone density
study are shown with standard error bars by treatment group in Figure 2. Significant differences
between each of the Premarin dosage groups and placebo were found at cycles 6, 13, 19, and 26.
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Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH CYCLE IN
SPINE BMD: SUBJECTS COMPLETING IN PREMARIN GROUPS AND PLACEBO
The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased
(p<0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group.
Larger mean decreases from baseline were seen with the active groups than with the placebo group.
Significant differences from placebo were seen less frequently in urine calcium.
Women’s Health Initiative Studies.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy
postmenopausal women to assess the risks and benefits of either the use of Premarin (0.625 mg
conjugated estrogens per day) alone or the use of PREMPRO™ (0.625 mg conjugated estrogens plus
2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic
diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal
myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome
studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke,
pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other
cause. The study did not evaluate the effects of Premarin or PREMPRO on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed and it
was deemed that no further information would be obtained regarding the risks and benefits of estrogen
alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included
10,739 women (average age of 63 years, range 50 to 79; 75.3% White, 15% Black, 6.1% Hispanic),
after an average follow-up of 6.8 years are presented in Table 4 below.
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TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE
SUBSTUDY OF WHIa
Placebo
n = 5429
Premarin
n = 5310
Eventc
Relative Risk*
Premarin vs Placebo
at 6.8 Years
(95% CI)
Absolute Risk per 10,000
Women-years
CHD events
0.91 (0.75-1.12)
54
49
Non-fatal MI
0.89 (0.70-1.12)
41
37
CHD death
0.94 (0.65-1.36)
16
15
Invasive breast cancer
0.77 (0.59-1.01)
33
26
Stroke
1.39 (1.10-1.77)
32
44
Pulmonary embolism
1.34 (0.87-2.06)
10
13
Colorectal cancer
1.08 (0.75-1.55)
16
17
Hip fracture
0.61 (0.41-0.91)
17
11
Death due to other causes than
the events above
1.08 (0.88-1.32)
50
53
Global Indexb
1.01 (0.91-1.12)
190
192
Deep vein thrombosisc
1.47 (1.04-2.08)
15
21
Vertebral fracturesc
0.62 (0.42-0.93)
17
11
Total fracturesc
0.70 (0.63-0.79)
195
139
a: adapted from JAMA, 2004; 291:1701-1712
b: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
c: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with Premarin alone were 12 more
strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The
absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000
women-years. There was no difference between the groups in terms of all-cause mortality. (See
BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
The estrogen plus progestin substudy was also stopped early because, according to the predefined
stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified
benefits included in the “global index.” Results of the estrogen plus progestin substudy, which
included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black,
5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below.
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TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHIa
Placebo
n = 8102
Prempro
n = 8506
Eventc
Relative Risk
Prempro vs Placebo
at 5.2 Years
(95% CI*)
Absolute Risk per 10,000
Women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than
the events above
0.92 (0.74-1.14)
40
37
Global Index c
1.15 (1.03-1.28)
151
170
Deep vein thrombosisd
2.07 (1.49-2.87)
13
26
Vertebral fracturesd
0.66 (0.44-0.98)
15
9
Other osteoporotic fracturesd
0.77 (0.69-0.86)
170
131
a: adapted from JAMA, 2002; 288:321-333
b: includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c: a subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes
d: not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI “global index,” the absolute excess risks per
10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8
more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-
years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events
included in the “global index” was 19 per 10,000 women-years. There was no difference between the
groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and
PRECAUTIONS.)
Women’s Health Initiative Memory Study.
The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled
2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were age
65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the
effects of Premarin (0.625 mg conjugated estrogens) on the incidence of probable dementia (primary
outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-
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years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable
dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95% CI, 0.83 to
2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal
women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric
Use.)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal
women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18%
were 75 years of age and older) to evaluate the effects of PREMPRO (0.625 mg conjugated estrogens
plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome)
compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per
10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with
probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05
(95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first
year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See
BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
INDICATIONS AND USAGE
Premarin therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the
menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy,
topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with
metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant risk of
osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise,
adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy.
Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when
not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary
intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate
daily intake in postmenopausal women.
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CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast except in appropriately selected patients being
treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (e.g., within past year) arterial thromboembolic disease (e.g., stroke, myocardial
infarction).
6. Liver dysfunction or disease.
7. Premarin tablets should not be used in patients with known hypersensitivity to their ingredients.
8. Known or suspected pregnancy. There is no indication for Premarin in pregnancy. There appears to
be little or no increased risk of birth defects in children born to women who have used estrogen and
progestins from oral contraceptives inadvertently during pregnancy. (See PRECAUTIONS.)
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular disorders. Estrogen and estrogen/progestin therapy have been associated with an
increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous
thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these
occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
appropriately.
a. Coronary heart disease and stroke. In the estrogen alone substudy of the Women’s Health
Initiative (WHI) study, an increased risk of stroke was observed in women receiving Premarin
(0.625 mg conjugated estrogens) per day compared to women receiving placebo (44 vs 32 per
10,000 women-years). The increase in risk was observed in year one and persisted. (See
CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, an increased risk of coronary heart disease (CHD)
events (defined as nonfatal myocardial infarction and CHD death) was observed in women
receiving PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate)
per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in
risk was observed in year one and persisted.
In the same estrogen plus progestin substudy of WHI, an increased risk of stroke was observed in
women receiving PREMPRO compared to women receiving placebo (29 vs 21 per 10,000
women-years). The increase in risk was observed after the first year and persisted.
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In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/progestin Replacement Study; HERS) treatment with PREMPRO (0.625 mg conjugated
estrogen plus 2.5 mg medroxyprogesterone acetate per day) demonstrated no cardiovascular
benefit. During an average follow-up of 4.1 years, treatment with PREMPRO did not reduce the
overall rate of CHD events in postmenopausal women with established coronary heart disease.
There were more CHD events in the PREMPRO-treated group than in the placebo group in year 1,
but not during the subsequent years. Two thousand three hundred and twenty one women from the
original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average
follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD
events were comparable among women in the PREMPRO group and the placebo group in HERS,
HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
b. Venous thromboembolism (VTE). In the estrogen alone substudy of the Women’s Health Initiative
(WHI) study, an increased risk of deep vein thrombosis was observed in women receiving
Premarin compared to placebo (21 vs 15 per 10,000 women-years). The increase in VTE risk was
observed during the first year. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the estrogen plus progestin substudy of WHI, a 2-fold greater rate of VTE, including deep
venous thrombosis and pulmonary embolism, was observed in women receiving PREMPRO
compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the
PREMPRO group compared to 16 per 10,000 women-years in the placebo group. The increase in
VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant neoplasms.
a. Endometrial cancer. The use of unopposed estrogens in women with intact uteri has been
associated with an increased risk of endometrial cancer. The reported endometrial cancer risk
among unopposed estrogen users with an intact uterus is about 2- to 12-fold greater than in non-
users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no
significant increased risk associated with the use of estrogens for less than one year. The greatest
risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten
years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen
therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule
out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile
than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal
estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a
precursor to endometrial cancer.
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b. Breast cancer. In some studies, the use of estrogens and progestins by postmenopausal women has
been reported to increase the risk of breast cancer. The most important randomized clinical trial
providing information about this issue is the Women’s Health Initiative (WHI) trial of estrogen
plus progestin (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from
observational studies are generally consistent with those of the WHI clinical trial.
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in
women who took estrogen plus progestin. Observational studies have also reported an increased
risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone
therapy, after several years of use. For both findings, the excess risk increased with duration of use,
and appeared to return to baseline over about five years after stopping treatment (only the
observational studies have substantial data on risk after stopping). In these studies, the risk of
breast cancer was greater, and became apparent earlier, with estrogen/progestin combination
therapy as compared to estrogen alone therapy. However, these studies have not found significant
variation in the risk of breast cancer among different estrogens or among different
estrogen/progestin combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestin, 26% of the women reported prior use of estrogen alone
and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years
during the clinical trial, the overall relative risk of invasive breast cancer was
1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per
10,000 women-years, for estrogen plus progestin compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the
absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen plus progestin compared
with placebo. Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years
for estrogen plus progestin compared with placebo. In the WHI trial, invasive breast cancers were
larger and diagnosed at a more advanced stage in the estrogen plus progestin group compared with
the placebo group. Metastatic disease was rare with no apparent difference between the two groups.
Other prognostic factors such as histologic subtype, grade and hormone receptor status did not
differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality due to
breast cancer among current users of estrogens alone or estrogens plus progestins compared to
never users, while the estrogen plus progestin sub-study of WHI showed no effect on breast cancer
mortality with a mean follow-up of 5.6 years.
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast examinations
by a healthcare provider and perform monthly breast self-examinations. In addition, mammography
examinations should be scheduled based on patient age, risk factors,
and prior mammogram
results.
3. Dementia. In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy
of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to
Premarin (0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of
4,532 postmenopausal women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/2.5
mg) or placebo.
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen
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alone group and 19 women in the placebo group were diagnosed with probable dementia. The
relative risk of probable dementia for Premarin alone versus placebo was 1.49 (95% CI 0.83-2.66).
The absolute risk of probable dementia for Premarin alone versus placebo was 37 versus 25 cases
per 10,000 women-years.
In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the
estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable
dementia. The relative risk of probable dementia for estrogen plus progestin versus placebo was
2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for PREMPRO versus placebo
was 45 versus 22 cases per 10,000 women-years.
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these
findings apply to younger postmenopausal women. (See BOXED WARNINGS and
PRECAUTIONS, Geriatric Use.)
4. Gallbladder Disease. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in
postmenopausal women receiving estrogens has been reported.
5. Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in patients with breast
cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and
appropriate measures taken to reduce the serum calcium level.
6. Visual abnormalities. Retinal vascular thrombosis has been reported in patients receiving
estrogens. Discontinue medication pending examination if there is sudden partial or complete loss
of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema
or retinal vascular lesions, estrogens should be discontinued.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or
daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a
precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens
compared to estrogen-alone regimens. These include: a possible increased risk of breast cancer,
adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL) and impairment of
glucose tolerance.
2. Elevated blood pressure.
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be
monitored at regular intervals during estrogen use.
3. Hypertriglyceridemia.
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis and other complications. In the HOPE
study, the mean percent increase from baseline in serum triglycerides after one year of treatment
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with Premarin 0.625 mg, 0.45 mg, and 0.3 mg compared with placebo were 34.3, 30.2, 25.1, and
10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0,
and 5.5, respectively.
4. Impaired liver function and past history of cholestatic jaundice.
Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should
be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism.
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with
normal thyroid function can compensate for the increased TBG by making more thyroid hormone,
thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on
thyroid hormone replacement therapy who are also receiving estrogens may require increased
doses of their thyroid replacement therapy. These patients should have their thyroid function
monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention.
Because estrogens may cause some degree of fluid retention, patients with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogens are prescribed.
7. Hypocalcemia.
Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer.
The estrogen plus progestin substudy of WHI reported that after an average follow-up of 5.6 years,
the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95%
confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk of estrogen
plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some
epidemiologic studies, the use of estrogen-only products, in particular for ten or more years, has
been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not
found these associations.
9. Exacerbation of endometriosis.
Endometriosis may be exacerbated with administration of estrogen therapy.
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual
endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions.
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in patients with these conditions.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients
for whom they prescribe Premarin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 19
C. Laboratory Tests
Estrogen administration should be initiated at the lowest dose for the treatment of postmenopausal
moderate to severe vasomotor symptoms and moderate to severe symptoms of postmenopausal vulvar
and vaginal atrophy and then guided by clinical response rather than by serum hormone levels (e.g.,
estradiol, FSH). Laboratory parameters may be useful in guiding dosage for the treatment of
hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
D. Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII,
VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa
and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and
fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the
elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement
therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex
hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex
steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may
be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol
concentrations, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
Premarin should not be used during pregnancy. (See CONTRAINDICATIONS).
G. Nursing Mothers
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the
milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.
Caution should be exercised when Premarin is administered to a nursing woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal
delay. Safety and effectiveness in pediatric patients have not otherwise been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 20
Large and repeated doses of estrogen over an extended time period have been shown to accelerate
epiphyseal closure, which could result in short stature if treatment is initiated before the completion of
physiologic puberty in normally developing children. If estrogen is administered to patients whose
bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers
is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal
pubertal process and induce gynecomastia. See INDICATIONS and DOSAGE AND
ADMINISTRATION sections.
I. Geriatric Use
Of the total number of subjects in the estrogen alone substudy of the Women’s Health Initiative (WHI)
study, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was
a higher relative risk (Premarin vs. placebo) of stroke in women less than 75 years of age compared to
women 75 years and over.
In the estrogen alone substudy of the Women’s Health Initiative Memory Study (WHIMS), a substudy
of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to
Premarin (0.625 mg) or placebo. In the estrogen alone group, after an average follow-up of 5.2 years,
the relative risk (Premarin versus placebo) of probable dementia was 1.49 (95% CI 0.83-2.66).
Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health
Initiative study, 44% (n=7,320) were 65 years and over, while 6.6% (n=1,095) were 75 years and over.
There was a higher relative risk (PREMPRO vs placebo) of stroke and invasive breast cancer in
women 75 and over compared to women less than 75 years of age.
In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women,
aged 65 to 79 years, was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. In the estrogen plus
progestin group, after an average follow-up of 4 years, the relative risk (PREMPRO versus placebo) of
probable dementia was 2.05 (95% CI 1.21-3.48).
Pooling the events in women receiving Premarin or PREMPRO in comparison to those in women on
placebo, the overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both
substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply
to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric
patients involved in studies utilizing Premarin to determine whether those over 65 years of age differ
from younger subjects in their response to Premarin.
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. The adverse reaction information from clinical trials
does, however, provide a basis for identifying the adverse events that appear to be related to drug use
and for approximating rates.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 21
During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65
years of age (88% Caucasian), 1012 women were treated with conjugated estrogens and 332 were
treated with placebo. Table 6 summarizes adverse events that occurred at a rate of ≥ 5%.
TABLE 6. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Any adverse event
323 (93%)
305 (90%)
292 (90%)
281 (85%)
Body as a Whole
Abdominal pain
56 (16%)
50 (15%)
54 (17%)
37 (11%)
Accidental injury
21 (6%)
41 (12%)
20 (6%)
29 (9%)
Asthenia
25 (7%)
23 (7%)
25 (8%)
16 (5%)
Back pain
49 (14%)
43 (13%)
43 (13%)
39 (12%)
Flu syndrome
37 (11%)
38 (11%)
33 (10%)
35 (11%)
Headache
90 (26%)
109 (32%)
96 (29%)
93 (28%)
Infection
61 (18%)
75 (22%)
74 (23%)
74 (22%)
Pain
58 (17%)
61 (18%)
66 (20%)
61 (18%)
Digestive System
Diarrhea
21 (6%)
25 (7%)
19 (6%)
21 (6%)
Dyspepsia
33 (9%)
32 (9%)
36 (11%)
46 (14%)
Flatulence
24 (7%)
23 (7%)
18 (6%)
9 (3%)
Nausea
32 (9%)
21 (6%)
21 (6%)
30 (9%)
Musculoskeletal System
Arthralgia
47 (14%)
42 (12%)
22 (7%)
39 (12%)
Leg cramps
19 (5%)
23 (7%)
11 (3%)
7 (2%)
Myalgia
18 (5%)
18 (5%)
29 (9%)
25 (8%)
Nervous System
Depression
25 (7%)
27 (8%)
17 (5%)
22 (7%)
Dizziness
19 (5%)
20 (6%)
12 (4%)
17 (5%)
Insomnia
21 (6%)
25 (7%)
24 (7%)
33 (10%)
Nervousness
12 (3%)
17 (5%)
6 (2%)
7 (2%)
Respiratory System
Cough increased
13 (4%)
22 (7%)
14 (4%)
14 (4%)
Pharyngitis
35 (10%)
35 (10%)
40 (12%)
38 (11%)
Rhinitis
21 (6%)
30 (9%)
31 (10%)
42 (13%)
Sinusitis
22 (6%)
36 (11%)
24 (7%)
24 (7%)
Upper respiratory infection
42 (12%)
34 (10%)
28 (9%)
35 (11%)
Skin and Appendages
Pruritus
14 (4%)
17 (5%)
16 (5%)
7 (2%)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 22
TABLE 6. NUMBER (%) OF PATIENTS REPORTING ≥ 5% TREATMENT EMERGENT
ADVERSE EVENTS
--Conjugated Estrogens Treatment Group--
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Urogenital System
Breast pain
38 (11%)
41 (12%)
24 (7%)
29 (9%)
Leukorrhea
18 (5%)
22 (7%)
13 (4%)
9 (3%)
Vaginal hemorrhage
47 (14%)
14 (4%)
7 (2%)
0
Vaginal moniliasis
20 (6%)
18 (5%)
17 (5%)
6 (2%)
Vaginitis
24 (7%)
20 (6%)
16 (5%)
4 (1%)
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
1. Genitourinary system
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough
bleeding, spotting, dysmenorrhea
Increase in size of uterine leiomyomata
Vaginitis, including vaginal candidiasis
Change in amount of cervical secretion
Change in cervical ectropion
Ovarian cancer
Endometrial hyperplasia
Endometrial cancer
2. Breasts
Tenderness, enlargement, pain, discharge, galactorrhea
Fibrocystic breast changes
Breast cancer
3. Cardiovascular
Deep and superficial venous thrombosis
Pulmonary embolism
Thrombophlebitis
Myocardial infarction
Stroke
Increase in blood pressure
4. Gastrointestinal
Nausea, vomiting
Abdominal cramps, bloating
Cholestatic jaundice
Increased incidence of gallbladder disease
Pancreatitis
Enlargement of hepatic hemangiomas
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 23
5. Skin
Chloasma or melasma that may persist when drug is discontinued
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Loss of scalp hair
Hirsutism
Pruritus, rash
6. Eyes
Retinal vascular thrombosis
Intolerance to contact lenses
7. Central Nervous System
Headache
Migraine
Dizziness
Mental depression
Chorea
Nervousness
Mood disturbances
Irritability
Exacerbation of epilepsy
Dementia
8. Miscellaneous
Increase or decrease in weight
Reduced carbohydrate tolerance
Aggravation of porphyria
Edema
Arthralgias
Leg cramps
Changes in libido
Urticaria, angioedema, anaphylactoid/anaphylactic reactions
Hypocalcemia
Exacerbation of asthma
Increased triglycerides
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and
vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION
When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be
initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin.
Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and
for the shortest duration consistent with treatment goals and risks for the individual woman. Patients
should be re-evaluated periodically as clinically appropriate (e.g., at 3-month to 6-month intervals) to
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 24
determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women
with a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be
undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal
bleeding.
Premarin may be taken without regard to meals.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe symptoms of
vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the
treatment of moderate to severe symptoms of vulvar and vaginal atrophy, topical vaginal products
should be considered.
Patients should be treated with the lowest effective dose. Generally women should be started at
0.3 mg Premarin daily. Subsequent dosage adjustment may be made based upon the individual
patient response. This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
2. For prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be
considered only for women at significant risk of osteoporosis and for whom non-estrogen
medications are not considered to be appropriate. Patients should be treated with the lowest
effective dose. Generally women should be started at 0.3 mg Premarin daily. Subsequent dosage
adjustment may be made based upon the individual clinical and bone mineral density responses.
This dose should be periodically reassessed by the healthcare provider.
Premarin therapy may be given continuously with no interruption in therapy, or in cyclical
regimens (regimens such as 25 days on drug followed by five days off drug) as is medically
appropriate on an individualized basis.
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian
failure:
Female hypogonadism⎯0.3 mg or 0.625 mg daily, administered cyclically (e.g., three weeks on
and one week off). Doses are adjusted depending on the severity of symptoms and responsiveness
of the endometrium.
In clinical studies of delayed puberty due to female hypogonadism, breast development was
induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12 month
intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure.
Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and 0.6 mg are associated with mean ratios
of bone age advancement to chronological age progression (∆BA/∆CA) of 1.1, 1.5, and 2.1,
respectively. (Premarin in the dose strength of 0.15 mg is not available commercially). Available
data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with
sequential progestin treatment and to maintain bone mineral density after skeletal maturity is
achieved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 25
Female castration or primary ovarian failure⎯1.25 mg daily, cyclically. Adjust dosage, upward or
downward, according to severity of symptoms and response of the patient. For maintenance, adjust
dosage to lowest level that will provide effective control.
4. For treatment of breast cancer, for palliation only, in appropriately selected women and men with
metastatic disease:
Suggested dosage is 10 mg three times daily for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only:
1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by
phosphatase determinations as well as by symptomatic improvement of the patient.
HOW SUPPLIED
Premarin (conjugated estrogens tablets, USP)
— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81); and
1,000 (NDC 0046-1104-91).
— Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81).
— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81);
1,000 (NDC 0046-1102-91).
— Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-1101-81).
— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-1100-81) and
1,000 (NDC 0046-1100-91).
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
Store at 20-25° C (68-77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled
Room Temperature].
Dispense in a well-closed container as defined in the USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 26
PATIENT INFORMATION
(Updated April 2005)
Premarin®
(conjugated estrogens tablets, USP)
Read this PATIENT INFORMATION before you start taking Premarin and read what you get each
time you refill Premarin. There may be new information. This information does not take the place of
talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Premarin (an estrogen
mixture)?
• Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking Premarin. Vaginal
bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks,
strokes, or dementia.
Using estrogens with or without progestins may increase your chances of getting heart
attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without
progestins, may increase your risk of dementia, based on a study of women age 65 years
or older. You and your healthcare provider should talk regularly about whether you still
need treatment with Premarin.
What is Premarin?
Premarin is a medicine that contains a mixture of estrogen hormones.
Premarin is used after menopause to:
• reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The
ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop
in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual
periods). Sometimes both ovaries are removed during an operation before natural menopause takes
place. The sudden drop in estrogen levels causes “surgical menopause.”
When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as
feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating
(“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need to
take estrogens. In other women, symptoms can be more severe. You and your healthcare provider
should talk regularly about whether you still need treatment with Premarin.
• treat moderate to severe dryness, itching, and burning, in and around the vagina. You and
your healthcare provider should talk regularly about whether you still need treatment with
Premarin to control these problems. If you use Premarin only to treat your dryness, itching, and
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 27
burning in and around your vagina, talk with your healthcare provider about whether a topical
vaginal product would be better for you.
• help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from
menopause is a thinning of the bones that makes them weaker and easier to break. If you use
Premarin only to prevent osteoporosis from menopause, talk with your healthcare provider about
whether a different treatment or medicine without estrogens might be better for you. You and your
healthcare provider should talk regularly about whether you should continue with Premarin.
Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements
may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about
exercise and supplements with your healthcare provider before starting them.
Premarin is also used to:
• treat certain conditions in women before menopause if their ovaries do not make enough
estrogen naturally.
• ease symptoms of certain cancers that have spread through the body, in men and women.
Who should not take Premarin?
Do not start taking Premarin if you:
• have unusual vaginal bleeding.
• currently have or have had certain cancers. Estrogens may increase the chances of getting
certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer,
talk with your healthcare provider about whether you should take Premarin.
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have liver problems.
• are allergic to Premarin tablets or any of its ingredients. See the end of this leaflet for a list of
all the ingredients in Premarin.
• think you may be pregnant.
Tell your healthcare provider:
• if you are breast feeding. The hormones in Premarin can pass into your milk.
• about all of your medical problems. Your healthcare provider may need to check you more
carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine,
endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels
in your blood.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 28
• about all the medicines you take, including prescription and nonprescription medicines, vitamins,
and herbal supplements. Some medicines may affect how Premarin works. Premarin may also
affect how your other medicines work.
• if you are going to have surgery or will be on bedrest. You may need to stop taking estrogens.
How should I take Premarin?
• Take one Premarin tablet at the same time each day.
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the
missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• Estrogens should be used at the lowest dose possible for your treatment only as long as needed.
You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about
the dose you are taking and whether you still need treatment with Premarin.
What are the possible side effects of Premarin?
Less common but serious side effects include:
• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer
These are some of the warning signs of serious side effects:
• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting
Call your healthcare provider right away if you get any of these warning signs, or any other unusual
symptom that concerns you.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 29
Common side effects include:
• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
These are not all the possible side effects of Premarin. For more information, ask your healthcare
provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with Premarin?
• Talk with your healthcare provider regularly about whether you should continue taking Premarin.
• If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is
right for you. In general, the addition of a progestin is recommended for women with a uterus to
reduce the chance of getting cancer of the uterus.
• See your healthcare provider right away if you get vaginal bleeding while taking Premarin.
• Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider
tells you something else. If members of your family have had breast cancer or if you have ever had
breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if
you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare
provider for ways to lower your chances for getting heart disease.
General information about the safe and effective use of Premarin
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take Premarin for conditions for which it was not prescribed. Do not give Premarin to
other people, even if they have the same symptoms you have. It may harm them.
Keep Premarin out of the reach of children.
This leaflet provides a summary of the most important information about Premarin. If you would like
more information, talk with your healthcare provider or pharmacist. You can ask for information about
Premarin that is written for health professionals. You can get more information by calling the toll free
number 800-934-5556.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 04-782/S-142
Page 30
What are the ingredients in Premarin?
Premarin contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate
and sodium equilin sulfate and other components including sodium sulfate conjugates,
17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.
Premarin 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following inactive
ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered
cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose and
titanium dioxide.
The tablets come in different strengths and each strength tablet is a different color. The color
ingredients are:
⎯ 0.3 mg tablet (green color): D&C Yellow No. 10 and FD&C Blue No. 2.
⎯ 0.45 mg tablet (blue color): FD&C Blue No. 2.
⎯ 0.625 mg tablet (maroon color): FD&C Blue No. 2 and FD&C Red No. 40.
⎯ 0.9 mg tablet (white color): D&C Red No. 30 and D&C Red No. 7.
⎯ 1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and FD&C Yellow No. 6.
The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.
This product’s label may have been revised after this insert was
used in production. For further product information and current
package insert, please visit www.wyeth.com or call our medical
communications department toll-free at 1-800-934-5556.
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
W10405C012
ET01
Rev 04/05
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.369051 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/004782s142lbl.pdf', 'application_number': 4782, 'submission_type': 'SUPPL ', 'submission_number': 142} |
10,673 |
PREMARIN®
(conjugated estrogens tablets, USP)
Rx only
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST
CANCER and PROBABLE DEMENTIA
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed
estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic
measures, including directed or random endometrial sampling when indicated, should be
undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or
recurring abnormal genital bleeding. (See WARNINGS, Malignant Neoplasms, Endometrial
cancer.)
Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or
dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and
Probable Dementia.)
The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke
and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1
years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to
placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders.)
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an
increased risk of developing probable dementia in postmenopausal women 65 years of age or
older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is
unknown whether this finding applies to younger postmenopausal women. (See CLINICAL
STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of
CE and other dosage forms of estrogens.
Estrogens with or without progestins should be prescribed at the lowest effective doses and for
the shortest duration consistent with treatment goals and risks for the individual woman.
Estrogen Plus Progestin Therapy
1
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Cardiovascular Disorders and Probable Dementia
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease
or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and
Probable Dementia.)
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary
embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years
of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with
medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES
and WARNINGS, Cardiovascular Disorders.)
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of
developing probable dementia in postmenopausal women 65 years of age or older during 4 years
of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is
unknown whether this finding applies to younger postmenopausal women. (See CLINICAL
STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use.)
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast
cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast cancer.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of
CE and MPA, and other combinations and dosage forms of estrogens and progestins.
Estrogens with or without progestins should be prescribed at the lowest effective doses and for
the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
PREMARIN® (conjugated estrogens tablets, USP) for oral administration contains a mixture of
conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of
water-soluble estrogen sulfates blended to represent the average composition of material derived
from pregnant mares’ urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate.
It contains as concomitant components, as sodium sulfate conjugates, 17α-dihydroequilin, 17α
estradiol, and 17β-dihydroequilin. Tablets for oral administration are available in 0.3 mg,
0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg strengths of conjugated estrogens.
PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following
inactive ingredients: calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, powdered cellulose, sucrose, and titanium dioxide.
— 0.3 mg tablets also contain: D&C Yellow No. 10 and FD&C Blue No. 2.
2
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— 0.45 mg tablets also contain: FD&C Blue No. 2.
— 0.625 mg tablets also contain: FD&C Blue No. 2 and FD&C Red No. 40.
— 0.9 mg tablets also contain: D&C Red No. 30 and D&C Red No. 7.
— 1.25 mg tablets also contain: black iron oxide, D&C Yellow No. 10 and FD&C Yellow No. 6.
PREMARIN tablets comply with USP Dissolution Test criteria as outlined below:
PREMARIN 1.25 mg tablets
USP Dissolution Test 4
PREMARIN 0.3 mg, 0.45 mg and
USP Dissolution Test 5
0.625 mg tablets
PREMARIN 0.9 mg tablets
USP Dissolution Test 6
CLINICAL PHARMACOLOGY
Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After
menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted
by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-
conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal
women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two
estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone
(LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism.
Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal
women.
Pharmacokinetics
A. Absorption
Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract
after release from the drug formulation. The PREMARIN tablet releases conjugated estrogens
slowly over several hours. Table 1 summarizes the mean pharmacokinetic parameters for
unconjugated and conjugated estrogens following administration of 1 x 0.625 mg and
1 x 1.25 mg tablets to healthy postmenopausal women.
The pharmacokinetics of PREMARIN 0.45 mg and 1.25 mg tablets were assessed following a
single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of
3
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estrogens were altered approximately 3 to 13 percent. The changes to Cmax and AUC are not
considered clinically meaningful.
TABLE 1. PHARMACOKINETIC PARAMETERS FOR PREMARIN®
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter
Cmax
tmax
t1/2
AUC
Arithmetic Mean
(pg/mL)
(h)
(h)
(pg•h/mL)
(%CV)
Estrone
87 (33)
9.6 (33)
50.7 (35) 5557 (59)
Baseline-adjusted
64 (42)
9.6 (33)
20.2 (40) 1723 (52)
estrone
Equilin
31 (38)
7.9 (32)
12.9 (112) 602 (54)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 0.625 mg
PK Parameter
Cmax
tmax
t1/2
AUC
Arithmetic Mean
(ng/mL)
(h)
(h)
(ng•h/mL)
(%CV)
Total Estrone
2.7 (43)
6.9 (25)
26.7 (33)
75 (52)
Baseline-adjusted
2.5 (45)
6.9 (25)
14.8 (35)
46 (48)
total estrone
Total Equilin
1.8 (56)
5.6 (45)
11.4 (31)
27 (56)
Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Cmax
tmax
t1/2
AUC
Arithmetic Mean
(pg/mL)
(h)
(h)
(pg•h/mL)
(%CV)
Estrone
124 (30)
10.0 (32)
38.1 (37) 6332 (44)
Baseline-adjusted
102 (35)
10.0 (32)
19.7 (48) 3159 (53)
estrone
Equilin
59 (43)
8.8 (36)
10.9 (47) 1182 (42)
Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg
PK Parameter
Cmax
tmax
t1/2
AUC
Arithmetic Mean
(ng/mL)
(h)
(h)
(ng•h/mL)
(%CV)
Total Estrone
4.5 (39)
8.2 (58)
26.5 (40)
109 (46)
Baseline-adjusted
4.3 (41)
8.2 (58)
17.5 (41)
87 (44)
total estrone
Total equilin
2.9 (42)
6.8 (49)
12.5 (34)
48 (51)
B. Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
widely distributed in the body and are generally found in higher concentration in the sex
hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding
globulin (SHBG) and albumin.
C. Metabolism
4
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Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating
estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations
take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be
converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic
recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates
into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal
women a significant proportion of the circulating estrogens exist as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate
conjugates.
E. Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal
or hepatic impairment.
F. Drug Interactions
Data from a single-dose drug-drug interaction study involving conjugated estrogens and
medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not
altered when the drugs are coadministered. No other clinical drug-drug interaction studies have
been conducted with conjugated estrogens.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome
P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations,
phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in
side effects.
CLINICAL STUDIES
Effects on vasomotor symptoms
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of
2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of
eight treatment groups, receiving either placebo or conjugated estrogens, with or without
medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first
12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven
moderate to severe hot flushes daily, or at least 50 moderate to severe hot flushes during the
week before randomization. PREMARIN (0.3 mg, 0.45 mg, and 0.625 mg tablets) was shown to
be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity
of moderate to severe vasomotor symptoms. Table 2 shows the adjusted mean number of hot
flushes in the PREMARIN 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over
the initial 12-week period.
5
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TABLE 2. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER
DAY – MEAN VALUES AND COMPARISONS BETWEEN THE ACTIVE
TREATMENT GROUPS AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST
7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT
BASELINE, LAST OBSERVATION CARRIED FORWARD (LOCF)
Treatment
(No. of Patients)
-------------------No. of Hot Flushes/Day-----------------
Time Period
(week)
0.625 mg CE
(n = 27)
4
12
0.45 mg CE
(n = 32)
4
12
0.3 mg CE
(n = 30)
4
12
Placebo
(n = 28)
4
12
Baseline
Mean ± SD
12.29 ± 3.89
12.29 ± 3.89
12.25 ± 5.04
12.25 ± 5.04
13.77 ± 4.78
13.77 ± 4.78
11.69 ± 3.87
11.69 ± 3.87
Observed
Mean ± SD
1.95 ± 2.77
0.75 ± 1.82
5.04 ± 5.31
2.32 ± 3.32
4.65 ± 3.71
2.52 ± 3.23
7.89 ± 5.28
5.71 ± 5.22
Mean
Change ± SD
-10.34 ± 4.73
-11.54 ± 4.62
-7.21 ± 4.75
-9.93 ± 4.64
-9.12 ± 4.71
-11.25 ± 4.60
-3.80 ± 4.71
-5.98 ± 4.60
p-Values
vs. Placeboa
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
-
-
a: Based on analysis of covariance with treatment as factor and baseline as covariate.
Effects on vulvar and vaginal atrophy
Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from
placebo were statistically significant (p < 0.001) for all treatment groups (conjugated estrogens
alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).
Effects on bone mineral density
Health and Osteoporosis, Progestin and Estrogen (HOPE) Study
The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter
study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9
years) were 2.3 ± 0.9 years on average since menopause and took one 600-mg tablet of elemental
calcium (Caltrate™) daily. Subjects were not given Vitamin D supplements. They were treated
with PREMARIN 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed
by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine
(L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were
also analyzed. Serum osteocalcin, urinary calcium, and N-telopeptide were used as bone turnover
markers (BTM) at cycles 6, 13, 19, and 26.
6
Reference ID: 3035837
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Intent-to-treat subjects
All active treatment groups showed significant differences from placebo in each of the
four BMD endpoints at cycles 6, 13, 19, and 26. The mean percent increases in the primary
efficacy measure (L2 to L4 BMD) at the final on-therapy evaluation (cycle 26 for those who
completed and the last available evaluation for those who discontinued early) were 2.46 percent
with 0.625 mg, 2.26 percent with 0.45 mg, and 1.13 percent with 0.3 mg. The placebo group
showed a mean percent decrease from baseline at the final evaluation of 2.45 percent. These
results show that the lower dosages of PREMARIN were effective in increasing L2 to L4 BMD
compared with placebo, and therefore support the efficacy of the lower doses.
The analysis for the other three BMD endpoints yielded mean percent changes from baseline in
femoral trochanter that were generally larger than those seen for L2 to L4, and changes in femoral
neck and total body that were generally smaller than those seen for L2 to L4. Significant
differences between groups indicated that each of the PREMARIN treatments was more effective
than placebo for all three of these additional BMD endpoints. With regard to femoral neck and
total body, the active treatment groups all showed mean percent increases in BMD, while
placebo treatment was accompanied by mean percent decreases. For femoral trochanter, each of
the PREMARIN dose groups showed a mean percent increase that was significantly greater than
the small increase seen in the placebo group. The percent changes from baseline to final
evaluation are shown in Table 3.
7
Reference ID: 3035837
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TABLE 3. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON
BETWEEN ACTIVE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT
POPULATION, LOCF
Change from Baseline
Region Evaluated
No. of
Baseline
(g/cm2)
(%)
Adjusted
p-Value vs
Treatment Groupa
Subjects
Mean ± SD
Mean ± SE
Placebo
L2 to L4 BMD
0.625
83
1.17 ± 0.15
2.46 ± 0.37
<0.001
0.45
91
1.13 ± 0.15
2.26 ± 0.35
<0.001
0.3
87
1.14 ± 0.15
1.13 ± 0.36
<0.001
Placebo
85
1.14 ± 0.14
-2.45 ± 0.36
Total Body BMD
0.625
84
1.15 ± 0.08
0.68 ± 0.17
<0.001
0.45
91
1.14 ± 0.08
0.74 ± 0.16
<0.001
0.3
87
1.14 ± 0.07
0.40 ± 0.17
<0.001
Placebo
85
1.13 ± 0.08
-1.50 ± 0.17
Femoral Neck BMD
0.625
84
0.91 ± 0.14
1.82 ± 0.45
<0.001
0.45
91
0.89 ± 0.13
1.84 ± 0.44
<0.001
0.3
87
0.86 ± 0.11
0.62 ± 0.45
<0.001
Placebo
85
0.88 ± 0.14
-1.72 ± 0.45
Femoral Trochanter
BMD
0.625
84
0.78 ± 0.13
3.82 ± 0.58
<0.001
0.45
91
0.76 ± 0.12
3.16 ± 0.56
0.003
0.3
87
0.75 ± 0.10
3.05 ± 0.57
0.005
Placebo
85
0.75 ± 0.12
0.81 ± 0.58
a: Identified by dosage (mg) of PREMARIN or placebo.
Figure 1 shows the cumulative percentage of subjects with changes from baseline equal to or
greater than the value shown on the x-axis.
8
Reference ID: 3035837
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Figure 1. CUMULATIVE PERCENT OF SUBJECTS WITH CHANGES FROM
BASELINE IN SPINE BMD OF GIVEN MAGNITUDE OR GREATER IN PREMARIN®
AND PLACEBO GROUPS
The mean percent changes from baseline in L2 to L4 BMD for women who completed the bone
density study are shown with standard error bars by treatment group in Figure 2. Significant
differences between each of the PREMARIN dosage groups and placebo were found at cycles
6, 13, 19, and 26.
9
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graph
Figure 2. ADJUSTED MEAN (SE) PERCENT CHANGE FROM BASELINE AT EACH
CYCLE IN SPINE BMD: SUBJECTS COMPLETING IN PREMARIN® GROUPS
AND PLACEBO
The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased
(p < 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo
group. Larger mean decreases from baseline were seen with the active groups than with the
placebo group. Significant differences from placebo were seen less frequently in urine calcium.
Women’s Health Initiative Studies
The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy
postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625
mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of
certain chronic diseases. The primary endpoint was the incidence of coronary heart disease
[(CHD) defined as nonfatal MI, silent MI and CHD death], with invasive breast cancer as the
primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive
breast cancer, stroke, PE, endometrial cancer (only in CE plus MPA substudy), colorectal cancer,
hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-
alone or CE plus MPA on menopausal symptoms.
10
Reference ID: 3035837
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WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was
observed, and it was deemed that no further information would be obtained regarding the risks
and benefits of estrogen-alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age,
range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other)
after an average follow-up of 7.1 years, are presented in Table 4.
11
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TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE
SUBSTUDY OF WHIa
CE
Placebo
Relative Risk
n = 5,310
n = 5,429
Event
CE vs. Placebo
(95% nCIb)
Absolute Risk per 10,000
Women-Years
CHD eventsc
0.95 (0.78-1.16)
54
57
Non-fatal MIc
0.91 (0.73-1.14)
40
43
CHD deathc
1.01 (0.71-1.43)
16
16
All Strokec
1.33 (1.05-1.68)
45
33
Ischemic strokec
Deep vein thrombosisc,d
1.55 (1.19-2.01)
1.47 (1.06-2.06)
38
23
25
15
Pulmonary embolismc
1.37 (0.90-2.07)
14
10
Invasive breast cancerc
0.80 (0.62-1.04)
28
34
Colorectal cancere
1.08 (0.75-1.55)
17
16
Hip fracturec
0.65 (0.45-0.94)
12
19
Vertebral fracturesc,d
Lower arm/wrist fracturesc,d
Total fracturesc,d
Death due to other causese,f
Overall mortalityc,d
0.64 (0.44-0.93)
0.58 (0.47-0.72)
0.71 (0.64-0.80)
1.08 (0.88-1.32)
1.04 (0.88-1.22)
11
35
144
53
79
18
59
197
50
75
Global Indexg
1.02 (0.92-1.13)
206
201
a Adapted from numerous WHI publications. WHI publications can be viewed at
www.nhlbi.nih.gov/whi.
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
d Not included in Global Index.
e Results are based on an average follow-up of 6.8 years.
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or
cerebrovascular disease.
g A subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture,
or death due to other causes.
For those outcomes included in the WHI “global index” that reached statistical significance, the
absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more
strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The
absolute excess risk of events included in the “global index” was a nonsignificant 5 events per
10,000 women-years. There was no difference between the groups in terms of all-cause
mortality.
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and
invasive breast cancer incidence in women receiving CE-alone compared with placebo was
12
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reported in final centrally adjudicated results from the estrogen-alone substudy, after an average
follow-up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average
follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or
severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-
alone increased the risk for ischemic stroke, and this excess was present in all subgroups of
women examined.
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect
the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in
women 50 to 59 years of age, a non-significant trend toward reduced risk for CHD [hazard ratio
(HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined
stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive
breast cancer and cardiovascular events exceeded the specified benefits included in the “global
index.” The absolute excess risk of events included in the “global index” was 19 per 10,000
women-years.
For those outcomes included in the WHI “global index” that reached statistical significance after
5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated
with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive
breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer
colorectal cancers and 5 fewer hip fractures.
Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years
of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent
Other) are presented in Table 5. These results reflect centrally adjudicated data after an average
follow-up of 5.6 years.
13
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TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS
PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa,b
CE/MPA
Placebo
Relative Risk
n = 8,506
n = 8,102
Event
CE/MPA vs. Placebo
(95% nCIc)
Absolute Risk per 10,000
Women-Years
CHD events
1.23 (0.99-1.53)
41
34
Non-fatal MI
1.28 (1.00-1.63)
31
25
CHD death
1.10 (0.70-1.75)
8
8
All strokes
1.31 (1.03-1.68)
33
25
Ischemic Stroke
Deep vein thrombosisd
1.44 (1.09-1.90)
1.95 (1.43-2.67)
26
26
18
13
Pulmonary embolism
2.13 (1.45-3.11)
18
8
Invasive breast cancere
1.24 (1.01-1.54)
41
33
Colorectal cancer
Endometrial cancerd
Cervical cancerd
0.61 (0.42-0.87)
0.81 (0.48-1.36)
1.44 (0.47-4.42)
10
6
2
16
7
1
Hip fracture
Vertebral fracturesd
Lower arm/wrist fracturesd
Total fracturesd
Overall mortalityf
0.67 (0.47-0.96)
0.65 (0.46-0.92)
0.71 (0.59-0.85)
0.76 (0.69-0.83)
1.00 (0.83-1.19)
11
11
44
152
52
16
17
62
199
52
Global Indexg
1.13 (1.02-1.25)
184
165
a Adapted from numerous WHI publications. WHI publications can be viewed at
www.nhlbi.nih.gov/whi.
b Results are based on centrally adjudicated data.
c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index”.
e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or
cerebrovascular disease.
g A subset of the events was combined in a “global index,” defined as the earliest occurrence of
CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture,
or death due to other causes.
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may
affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age
showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall
mortality [HR 0.69 (95 percent CI, 0.44-1.07)].
14
Reference ID: 3035837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Women’s Health Initiative Memory Study
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy
hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of
age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to
evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone
versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for
CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as
defined in this study included Alzheimer disease (AD), vascular dementia (VaD) and mixed type
(having features of both AD and VaD). The most common classification of probable dementia in
the treatment group and the placebo group was AD. Since the ancillary study was conducted in
women 65 to 79 years of age, it is unknown whether these findings apply to younger
postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS,
Geriatric Use.)
The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy
postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35
percent were 70 to 74 years of age; 18 percent were 75 years of age and older) to evaluate the
effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA
was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA
versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this
study included AD, VaD and mixed type (having features of both AD and VaD). The most
common classification of probable dementia in the treatment group and the placebo group was
AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown
whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable
Dementia and PRECAUTIONS, Geriatric Use.)
When data from the two populations were pooled as planned in the WHIMS protocol, the
reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60).
Differences between groups became apparent in the first year of treatment. It is unknown
whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable
Dementia and PRECAUTIONS, Geriatric Use.)
INDICATIONS AND USAGE
PREMARIN therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms due to menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to
menopause. When prescribing solely for the treatment of symptoms of vulvar and
vaginal atrophy, topical vaginal products should be considered.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian
failure.
15
Reference ID: 3035837
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Treatment of breast cancer (for palliation only) in appropriately selected women and
men with metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation
only).
6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention
of postmenopausal osteoporosis, therapy should only be considered for women at
significant risk of osteoporosis and non-estrogen medications should be carefully
considered.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-
bearing exercise, adequate calcium and vitamin D intake, and when indicated,
pharmacologic therapy. Postmenopausal women require an average of 1500 mg per day
of elemental calcium. Therefore, when not contraindicated, calcium supplementation
may be helpful for women with suboptimal dietary intake. Vitamin D supplementation
of 400-800 IU per day may also be required to ensure adequate daily intake in
postmenopausal women.
CONTRAINDICATIONS
PREMARIN therapy should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of breast cancer except in appropriately selected patients
being treated for metastatic disease.
3. Known or suspected estrogen-dependent neoplasia.
4. Active DVT, PE, or a history of these conditions.
5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of
these conditions.
6. Known anaphylactic reaction or angioedema to PREMARIN tablets.
7. Known liver dysfunction or disease.
8. Known protein C, protein S, or antithrombin deficiency or other known thrombophilic
disorders.
9. Known or suspected pregnancy.
WARNINGS
See BOXED WARNINGS.
1. Cardiovascular Disorders
An increased risk of stroke and DVT has been reported with estrogen-alone therapy.
An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin
therapy.
Should any of these events occur or be suspected, estrogen with or without progestin therapy
should be discontinued immediately.
16
Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco
use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example,
personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be
managed appropriately.
a. Stroke
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was
reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to
women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). (See
CLINICAL STUDIES.) The increase in risk was demonstrated in year 1 and persisted. Should a
stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those
women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000
women-years).
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke
was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-
years). (See CLINICAL STUDIES.) The increase in risk was demonstrated after the first year
and persisted. Should a stroke occur or be suspected, estrogen plus progestin therapy should be
discontinued immediately.
b. Coronary heart disease
In the WHI estrogen-alone substudy, no overall effect on CHD events (defined as nonfatal MI,
silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo.
(See CLINICAL STUDIES.)
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant
reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women less than 10
years since menopause (8 versus 16 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased
risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg)
compared to women receiving placebo (41 versus 34 per 10,000 women years). An increase in
relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported
in years 2 through 5.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in
a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus
MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1
years, treatment with CE plus MPA did not reduce the overall rate of CHD events in
postmenopausal women with established coronary heart disease. There were more CHD events
in the CE plus MPA-treated group than in the placebo group in year 1, but not during the
subsequent years. Two thousand three hundred and twenty one (2,321) women from the original
HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow
17
Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events
were comparable among women in the CE plus MPA group and the placebo group in the HERS,
the HERS II, and overall.
c. Venous thromboembolism
In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women
receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-
years), although only the increased risk of DVT reached statistical significance (23 versus 15 per
10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. (See
CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogen-alone therapy should be
discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE
was reported in women receiving daily CE(0.625 mg) plus MPA (2.5 mg) compared to women
receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in
risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000
women years) were also demonstrated. The increase in VTE risk was demonstrated during the
first year and persisted. (See CLINICAL STUDIES.) Should a VTE occur or be suspected,
estrogen plus progestin therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
immobilization.
2. Malignant Neoplasms
a. Endometrial cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen
therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed
estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on
duration of treatment and on estrogen dose. Most studies show no significant increased risk
associated with the use of estrogens for less than 1 year. The greatest risk appears associated
with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk
has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is
important. Adequate diagnostic measures, including directed or random endometrial sampling
when indicated, should be undertaken to rule out malignancy in postmenopausal women with
undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use
of natural estrogens results in a different endometrial risk profile than synthetic estrogens of
equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has been
shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial
cancer.
b. Breast cancer
The most important randomized clinical trial providing information about breast cancer in
estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-
alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not
18
Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) (See
CLINICAL STUDIES).
The most important randomized clinical trial providing information about breast cancer in
estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).
After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased
risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use
of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.
The relative risk of invasive breast cancer was 1.24 and the absolute risk was 41 versus 33 cases
per 10,000 women-years, for CE plus MPA compared with placebo. Among women who
reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and
the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared
with placebo. Among women who reported no prior use of hormone therapy, the relative risk of
invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-
years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers
were larger, were more likely to be node positive, and were diagnosed at a more advanced stage
in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic
disease was rare, with no apparent difference between the two groups. Other prognostic factors,
such as histologic subtype, grade and hormone receptor status did not differ between the groups.
(See CLINICAL STUDIES.)
Consistent with the WHI clinical trial, observational studies have also reported an increased risk
of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-
alone therapy, after several years of use. The risk increased with duration of use, and appeared to
return to baseline over about 5 years after stopping treatment (only the observational studies have
substantial data on risk after stopping). Observational studies also suggest that the risk of breast
cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as
compared to estrogen-alone therapy. However, these studies have not found significant variation
in the risk of breast cancer among different estrogen plus progestin combinations, doses, or
routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase
in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform
monthly breast self-examinations. In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.
c. Ovarian cancer
The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk
of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for
CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 – 3.24). The absolute risk for CE
plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic
studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more
years, has been associated with an increased risk of ovarian cancer. However, the duration of
exposure associated with increased risk is not consistent across all epidemiologic studies and
some report no association.
19
Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Probable Dementia
In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized
women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in
the placebo group were diagnosed with probable dementia. The relative risk of probable
dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of
probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years.
(See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)
In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532
postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA
(2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA
group and 21 women in the placebo group were diagnosed with probable dementia. The relative
risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48).
The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases
per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin
ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative
risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were
conducted in women 65 to 79 years of age, it is unknown whether these findings apply to
younger postmenopausal women. (See PRECAUTIONS, Geriatric Use.)
4. Gallbladder Disease
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving estrogens has been reported.
5. Hypercalcemia
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and
bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate
measures taken to reduce the serum calcium level.
6. Visual Abnormalities
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is sudden partial or complete loss of vision, or a sudden
onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be permanently discontinued.
7. Anaphylactic Reaction and Angioedema
Cases of anaphylaxis, which developed within minutes to hours after taking PREMARIN and
require emergency medical management, have been reported in the postmarketing setting. Skin
(hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or
gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.
Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention
has occurred postmarketing in patients taking PREMARIN. If angioedema involves the tongue,
glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction
20
Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
with or without angioedema after treatment with PREMARIN should not receive PREMARIN
again.
8. Hereditary Angioedema
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary
angioedema.
PRECAUTIONS
A. General
1. Addition of a progestin when a woman has not had a hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration,
or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial
hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be
a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with
estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
2. Elevated blood pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to
idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a
generalized effect of estrogen therapy on blood pressure was not seen.
3. Hypertriglyceridemia
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with
elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment
if pancreatitis occurs.
4. Hepatic impairment and/or past history of cholestatic jaundice
Estrogens may be poorly metabolized in patients with impaired liver function. For women with a
history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution
should be exercised, and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with
normal thyroid function can compensate for the increased TBG by making more thyroid
hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women
dependent on thyroid hormone replacement therapy who are also receiving estrogens may
require increased doses of their thyroid replacement therapy. These women should have their
thyroid function monitored in order to maintain their free thyroid hormone levels in an
acceptable range.
6. Fluid retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be
influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when
estrogens are prescribed.
7. Hypocalcemia
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Reference ID: 3035837
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Estrogen therapy should be used with caution in individuals with hypoparathyroidism as
estrogen-induced hypocalcemia may occur.
8. Exacerbation of endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in
women treated post-hysterectomy with estrogen-alone therapy. For women known to have
residual endometriosis post-hysterectomy, the addition of progestin should be considered.
9. Exacerbation of other conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine,
porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with
caution in women with these conditions.
B. Patient Information
Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with
patients for whom they prescribe PREMARIN.
C. Laboratory Tests
Serum FSH and estradiol levels have not been shown to be useful in the management of
moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and
vaginal atrophy.
Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism
due to hypogonadism, castration and primary ovarian failure.
D. Drug-Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant
activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin;
decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III
activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen
antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total
thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column
or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on
thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, for example, corticosteroid binding
globulin (CBG), SHBG, leading to increased total circulating corticosteroids and sex
steroids, respectively. Free hormone concentrations, such as testosterone and estradiol,
may be decreased. Other plasma proteins may be increased (angiotensinogen/renin
substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction
concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations,
increased triglyceride levels.
5. Impaired glucose tolerance.
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Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
E. Carcinogenesis, Mutagenesis, Impairment of Fertility
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Long-term continuous administration of natural and synthetic estrogens in certain animal species
increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
F. Pregnancy
PREMARIN should not be used during pregnancy. (See CONTRAINDICATIONS.) There
appears to be little or no increased risk of birth defects in children born to women who have used
estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
G. Nursing Mothers
PREMARIN should not be used during lactation. Estrogen administration to nursing women has
been shown to decrease the quantity and quality of the breast milk. Detectable amounts of
estrogens have been identified in the breast milk of women receiving estrogens. Caution should
be exercised when PREMARIN is administered to a nursing woman.
H. Pediatric Use
Estrogen therapy has been used for the induction of puberty in adolescents with some forms of
pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to
accelerate epiphyseal closure, which could result in short stature if treatment is initiated before
the completion of physiologic puberty in normally developing children. If estrogen is
administered to patients whose bone growth is not complete, periodic monitoring of bone
maturation and effects on epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal
cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the
normal pubertal process and induce gynecomastia. (See INDICATIONS AND USAGE and
DOSAGE AND ADMINISTRATION.)
I. Geriatric Use
There have not been sufficient numbers of geriatric patients involved in studies utilizing
PREMARIN to determine whether those over 65 years of age differ from younger subjects in
their response to PREMARIN.
The Women’s Health Initiative Study
In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a
higher relative risk of stroke in women greater than 65 years of age. (See CLINICAL
STUDIES.)
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus
placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women
greater than 65 years of age. (See CLINICAL STUDIES.)
The Women’s Health Initiative Memory Study
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Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an
increased risk of developing probable dementia in women receiving estrogen-alone or estrogen
plus progestin when compared to placebo. (See CLINICAL STUDIES and WARNINGS,
Probable Dementia.)
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown
whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES
and WARNINGS, Probable Dementia.)
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
During the first year of a 2-year clinical trial with 2,333 postmenopausal women between 40 and
65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens
and 332 were treated with placebo. Table 6 summarizes adverse events that occurred at a rate of
≥ 5 percent.
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Reference ID: 3035837
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For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 6. NUMBER (%) OF PATIENTS REPORTING ≥ 5 PERCENT TREATMENT
EMERGENT ADVERSE EVENTS
--Conjugated Estrogens Treatment Group-
Body System
0.625 mg
0.45 mg
0.3 mg
Placebo
Adverse event
(n = 348)
(n = 338)
(n = 326)
(n = 332)
Any adverse event
323 (93%)
305 (90%)
292 (90%)
281 (85%)
Body as a Whole
Abdominal pain
56 (16%)
50 (15%)
54 (17%)
37 (11%)
Accidental injury
21 (6%)
41 (12%)
20 (6%)
29 (9%)
Asthenia
25 (7%)
23 (7%)
25 (8%)
16 (5%)
Back pain
49 (14%)
43 (13%)
43 (13%)
39 (12%)
Flu syndrome
37 (11%)
38 (11%)
33 (10%)
35 (11%)
Headache
90 (26%)
109 (32%)
96 (29%)
93 (28%)
Infection
61 (18%)
75 (22%)
74 (23%)
74 (22%)
Pain
58 (17%)
61 (18%)
66 (20%)
61 (18%)
Digestive System
Diarrhea
21 (6%)
25 (7%)
19 (6%)
21 (6%)
Dyspepsia
33 (9%)
32 (9%)
36 (11%)
46 (14%)
Flatulence
24 (7%)
23 (7%)
18 (6%)
9 (3%)
Nausea
32 (9%)
21 (6%)
21 (6%)
30 (9%)
Musculoskeletal System
Arthralgia
47 (14%)
42 (12%)
22 (7%)
39 (12%)
Leg cramps
19 (5%)
23 (7%)
11 (3%)
7 (2%)
Myalgia
18 (5%)
18 (5%)
29 (9%)
25 (8%)
Nervous System
Depression
25 (7%)
27 (8%)
17 (5%)
22 (7%)
Dizziness
19 (5%)
20 (6%)
12 (4%)
17 (5%)
Insomnia
21 (6%)
25 (7%)
24 (7%)
33 (10%)
Nervousness
12 (3%)
17 (5%)
6 (2%)
7 (2%)
Respiratory System
Cough increased
13 (4%)
22 (7%)
14 (4%)
14 (4%)
Pharyngitis
35 (10%)
35 (10%)
40 (12%)
38 (11%)
Rhinitis
21 (6%)
30 (9%)
31 (10%)
42 (13%)
Sinusitis
22 (6%)
36 (11%)
24 (7%)
24 (7%)
Upper respiratory infection
42 (12%)
34 (10%)
28 (9%)
35 (11%)
Skin and Appendages
Pruritus
14 (4%)
17 (5%)
16 (5%)
7 (2%)
Urogenital System
Breast pain
38 (11%)
41 (12%)
24 (7%)
29 (9%)
Leukorrhea
18 (5%)
22 (7%)
13 (4%)
9 (3%)
Vaginal hemorrhage
47 (14%)
14 (4%)
7 (2%)
0
Vaginal moniliasis
20 (6%)
18 (5%)
17 (5%)
6 (2%)
Vaginitis
24 (7%)
20 (6%)
16 (5%)
4 (1%)
25
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Postmarketing Experience
The following additional adverse reactions have been identified during post approval use of
PREMARIN. Because these reactions are reported voluntarily from a population of uncertain
size, it is not possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Genitourinary System
Abnormal uterine bleeding, dysmenorrhea or pelvic pain, increase in size of uterine
leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian
cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.
Breast
Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer,
gynecomastia in males.
Cardiovascular
Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial
infarction, stroke, increase in blood pressure.
Gastrointestinal
Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of
gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.
Skin
Chloasma or melasma that may persist when drug is discontinued, erythema multiforme,
erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.
Eyes
Retinal vascular thrombosis, intolerance to contact lenses.
Central Nervous System
Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability,
exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.
Miscellaneous
Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias,
leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides,
hypersensitivity.
Additional postmarketing adverse reactions have been reported in patients receiving other forms
of hormone therapy.
OVERDOSAGE
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain,
drowsiness and fatigue and withdrawal bleeding may occur in women. Treatment of overdose
consists of discontinuation of PREMARIN therapy with institution of appropriate symptomatic
care.
26
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DOSAGE AND ADMINISTRATION
When estrogen therapy is prescribed for a postmenopausal woman with a uterus, progestin
should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does
not need progestin. Use of estrogen-alone, or in combination with a progestin, should be with the
lowest effective dose and for the shortest duration consistent with treatment goals and risks for
the individual woman. Patients should be reevaluated periodically as clinically appropriate (for
example at 3-month to 6-month intervals) to determine if treatment is still necessary. Adequate
diagnostic measures, such as directed or random endometrial sampling, when indicated, should
be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or
recurring abnormal genital bleeding.
PREMARIN may be taken without regard to meals.
1. For treatment of moderate to severe vasomotor symptoms and/or moderate to severe
symptoms of vulvar and vaginal atrophy due to menopause:
When prescribing solely for the treatment of moderate to severe symptoms of vulvar and
vaginal atrophy, topical vaginal products should be considered.
Patients should be treated with the lowest effective dose. Generally, women should be
started at 0.3 mg PREMARIN daily. Subsequent dosage adjustment may be made based
upon the individual patient response. This dose should be periodically reassessed by the
healthcare provider.
PREMARIN therapy may be given continuously, with no interruption in therapy, or in
cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is
medically appropriate on an individualized basis.
2. For prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy
should be considered only for women at significant risk of osteoporosis and non-estrogen
medications should be carefully considered. Patients should be treated with the lowest
effective dose. Generally, women should be started at 0.3 mg PREMARIN daily.
Subsequent dosage adjustment may be made based upon the individual clinical and bone
mineral density responses. This dose should be periodically reassessed by the healthcare
provider.
PREMARIN therapy may be given continuously, with no interruption in therapy, or in
cyclical regimens (regimens such as 25 days on drug followed by five days off drug), as is
medically appropriate on an individualized basis.
3. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary
ovarian failure:
Female hypogonadism — 0.3 mg or 0.625 mg daily, administered cyclically (e.g., three
weeks on and one week off). Doses are adjusted depending on the severity of symptoms
and responsiveness of the endometrium.
In clinical studies of delayed puberty due to female hypogonadism, breast development
was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward
at 6-to-12 month intervals as needed to achieve appropriate bone age advancement and
eventual epiphyseal closure. Clinical studies suggest that doses of 0.15 mg, 0.3 mg, and
0.6 mg are associated with mean ratios of bone age advancement to chronological age
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progression (ΔBA/ΔCA) of 1.1, 1.5, and 2.1, respectively. (PREMARIN in the dose
strength of 0.15 mg is not available commercially). Available data suggest that chronic
dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential
progestin treatment and to maintain bone mineral density after skeletal maturity is
achieved.
Female castration or primary ovarian failure — 1.25 mg daily, cyclically. Adjust dosage,
upward or downward, according to severity of symptoms and response of the patient. For
maintenance, adjust dosage to lowest level that will provide effective control.
4. For treatment of breast cancer, for palliation only, in appropriately selected women and
men with metastatic disease:
Suggested dosage is 10 mg three times daily, for a period of at least three months.
5. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation
only:
1.25 mg to 2 x 1.25 mg three times daily. The effectiveness of therapy can be judged by
phosphatase determinations as well as by symptomatic improvement of the patient.
HOW SUPPLIED
PREMARIN® (conjugated estrogens tablets, USP)
— Each oval green tablet contains 0.3 mg, in bottles of 100 (NDC 0046-1100-81) and
1,000 (NDC 0046-1100-91).
— Each oval blue tablet contains 0.45 mg, in bottles of 100 (NDC 0046-1101-81).
— Each oval maroon tablet contains 0.625 mg, in bottles of 100 (NDC 0046-1102-81) and
1,000 (NDC 0046-1102-91).
— Each oval white tablet contains 0.9 mg, in bottles of 100 (NDC 0046-1103-81).
— Each oval yellow tablet contains 1.25 mg, in bottles of 100 (NDC 0046-1104-81) and
1,000 (NDC 0046-1104-91).
The appearance of these tablets is a trademark of Wyeth LLC.
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see
USP Controlled Room Temperature].
Dispense in a well-closed container, as defined in the USP.
LAB-0467-3.0
Rev 06/2011
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PATIENT INFORMATION
PREMARIN®
(conjugated estrogens tablets, USP)
Read this PATIENT INFORMATION before you start taking PREMARIN and read what you
get each time you refill your PREMARIN prescription. There may be new information. This
information does not take the place of talking to your healthcare provider about your medical
condition or your treatment.
What is the most important information I should know about PREMARIN (an estrogen
mixture)?
Using estrogen-alone increases your chance of getting cancer of the uterus (womb)
Report any unusual vaginal bleeding right away while you are taking PREMARIN.
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
Your healthcare provider should check any unusual vaginal bleeding to find out the cause
Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia
(decline of brain function)
Using estrogen-alone may increase your chances of getting strokes or blood clots
Using estrogen-alone may increase your chance of getting dementia, based on a study of
women 65 years of age or older
Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or
dementia
Using estrogens with progestins may increase your chances of getting heart attacks,
strokes, breast cancer, or blood clots
Using estrogens with progestins may increase your chance of getting dementia, based on
a study of women 65 years of age or older
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN
What is PREMARIN?
PREMARIN is a medicine that contains a mixture of estrogen hormones.
What is PREMARIN used for?
PREMARIN is used after menopause to:
Reduce moderate to severe hot flashes
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Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making
estrogens when a woman is between 45 and 55 years old. This drop in body estrogen
levels causes the “change of life” or menopause (the end of monthly menstrual periods).
Sometimes, both ovaries are removed during an operation before natural menopause takes
place. The sudden drop in estrogen levels causes “surgical menopause.”
When the estrogen levels begin dropping, some women get very uncomfortable
symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong
feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women the
symptoms are mild, and they will not need to take estrogens. In other women, symptoms
can be more severe.
Treat menopausal changes in and around the vagina
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN to control these problems. If you use PREMARIN only to
treat your menopausal changes in and around your vagina, talk with your healthcare
provider about whether a topical vaginal product would be better for you.
Help reduce your chances of getting osteoporosis (thin weak bones)
Osteoporosis from menopause is a thinning of the bones that makes them weaker and
easier to break. If you use PREMARIN only to prevent osteoporosis due to menopause,
talk with your healthcare provider about whether a different treatment or medicine without
estrogens might be better for you.
Weight-bearing exercise, like walking or running, and taking calcium (1500 mg per day of
elemental calcium) and vitamin D (400-800 IU per day) supplements may also lower your
chances for getting postmenopausal osteoporosis. It is important to talk about exercise and
supplements with your healthcare provider before starting them.
You and your healthcare provider should talk regularly about whether you still need
treatment with PREMARIN.
PREMARIN is also used to:
Treat certain conditions in women before menopause if their ovaries do not make
enough estrogen naturally
Ease symptoms of certain cancers that have spread through the body, in men and
women
Who should not take PREMARIN?
Do not start taking PREMARIN if you:
Have unusual vaginal bleeding
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Reference ID: 3035837
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Currently have or have had certain cancers
Estrogens may increase the chance of getting certain types of cancers, including cancer of
the breast or uterus. If you have or have had cancer, talk with your healthcare provider
about whether you should take PREMARIN.
Had a stroke or heart attack
Currently have or have had blood clots
Currently have or have had liver problems
Have been diagnosed with a bleeding disorder
Are allergic to PREMARIN tablets or any of its ingredients
See the list of ingredients in PREMARIN at the end of this leaflet.
Think you may be pregnant
Tell your healthcare provider:
If you have any unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
Your healthcare provider should check any unusual vaginal bleeding to find out the cause
About all of your medical problems
Your healthcare provider may need to check you more carefully if you have certain
conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine,
endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high
calcium levels in your blood.
About all the medicines you take
This includes prescription and nonprescription medicines, vitamins, and herbal
supplements. Some medicines may affect how PREMARIN works. PREMARIN may also
affect how your other medicines work.
If you are going to have surgery or will be on bedrest
You may need to stop taking PREMARIN.
If you are breast feeding
The hormones in PREMARIN can pass into your breast milk.
How should I take PREMARIN?
Take one PREMARIN tablet at the same time each day
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If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip
the missed dose and go back to your normal schedule. Do not take 2 doses at the same
time
Estrogens should be used at the lowest dose possible for your treatment only as long as
needed. You and your healthcare provider should talk regularly (for example, every
3 to 6 months) about the dose you are taking and whether you still need treatment with
PREMARIN
If you see something that resembles a tablet in your stool, talk to your healthcare
provider.
What are the possible side effects of PREMARIN?
Side effects are grouped by how serious they are and how often they happen when you are
treated.
Serious, but less common side effects include:
Heart attack
Stroke
Blood clots
Dementia
Breast cancer
Cancer of the lining of the uterus (womb)
Cancer of the ovary
High blood pressure
High blood sugar
Gallbladder disease
Liver problems
Enlargement of benign tumors of the uterus (“fibroids”)
Severe allergic reactions
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Call your healthcare provider right away if you get any of the following warning signs or
any other unusual symptoms that concern you:
New breast lumps
Unusual vaginal bleeding
Changes in vision or speech
Sudden new severe headaches
Severe pains in your chest or legs with or without shortness of breath, weakness and
fatigue
Swollen lips, tongue and face
Less serious, but common side effects include:
Headache
Breast pain
Irregular vaginal bleeding or spotting
Stomach or abdominal cramps, bloating
Nausea and vomiting
Hair loss
Fluid retention
Vaginal yeast infection
These are not all the possible side effects of PREMARIN. For more information, ask your
healthcare provider or pharmacist for advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
What can I do to lower my chances of getting a serious side effect with PREMARIN?
Talk with your healthcare provider regularly about whether you should continue taking
PREMARIN
If you have a uterus, talk to your healthcare provider about whether the addition of a
progestin is right for you. The addition of a progestin is generally recommended for a
woman with a uterus to reduce the chance of getting cancer of the uterus (womb)
See your healthcare provider right away if you get vaginal bleeding while taking
PREMARIN
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Reference ID: 3035837
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Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your
healthcare provider tells you something else. If members of your family have had breast
cancer or if you have ever had breast lumps or an abnormal mammogram, you may need
to have breast exams more often
If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are
overweight, or if you use tobacco, you may have higher chances for getting heart disease.
Ask your healthcare provider for ways to lower your chances for getting heart disease
General information about the safe and effective use of PREMARIN
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take PREMARIN for conditions for which it was not prescribed. Do not give
PREMARIN to other people, even if they have the same symptoms you have. It may harm them.
Keep PREMARIN out of the reach of children.
This leaflet provides a summary of the most important information about PREMARIN. If you
would like more information, talk with your healthcare provider or pharmacist. You can ask for
information about PREMARIN that is written for health professionals. You can get more
information by calling the toll free number 1-800-438-1985.
What are the ingredients in PREMARIN?
PREMARIN contains a mixture of conjugated estrogens, which are a mixture of sodium estrone
sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates,
17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.
PREMARIN 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets also contain the following
inactive ingredients: calcium phosphate tribasic, carnauba wax, hydroxypropyl cellulose,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, powdered cellulose, sucrose and titanium dioxide.
The tablets come in different strengths and each strength tablet is a different color. The color
ingredients are:
— 0.3 mg tablet (green color): D&C Yellow No. 10 and FD&C Blue No. 2.
— 0.45 mg tablet (blue color): FD&C Blue No. 2.
— 0.625 mg tablet (maroon color): FD&C Blue No. 2 and FD&C Red No. 40.
— 0.9 mg tablet (white color): D&C Red No. 30 and D&C Red No. 7.
— 1.25 mg tablet (yellow color): black iron oxide, D&C Yellow No. 10, and
FD&C Yellow No. 6.
The appearance of these tablets is a trademark of Wyeth LLC.
Store at Controlled Room Temperature 20° to 25°C (68° to 77°F).
34
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This product’s label may have been updated. For current package insert and
further product information, please visit www.pfizerpro.com or call our
medical communications department toll-free at 1-800-438-1985. company logo
LAB-0515-2.0
Rev 06/2011
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10,675 |
CII
Demerol® (meperidine hydrochloride, USP)
WARNING: May be habit forming
DESCRIPTION
Meperidine hydrochloride, is a white crystalline substance with a melting point of 186° C to
189° C. It is readily soluble in water and has a neutral reaction and a slightly bitter taste. The
solution is not decomposed by a short period of boiling.
The tablets contain 50 mg or 100 mg of DEMEROL brand of meperidine hydrochloride.
Inactive Ingredients: Calcium Sulfate, Dibasic Calcium Phosphate, Starch, Stearic Acid, Talc.
Chemically, DEMEROL is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-, ethyl ester,
hydrochloride and has the following structure: structural
CLINICAL PHARMACOLOGY
Meperidine hydrochloride is a narcotic analgesic with multiple actions qualitatively similar to
those of morphine; the most prominent of these involve the central nervous system and organs
composed of smooth muscle. The principal actions of therapeutic value are analgesia and
sedation.
There is some evidence which suggests that meperidine may produce less smooth muscle spasm,
constipation, and depression of the cough reflex than equianalgesic doses of morphine.
INDICATIONS AND USAGE
DEMEROL is indicated for the relief of moderate to severe pain.
CONTRAINDICATIONS
DEMEROL is contraindicated in patients with hypersensitivity to meperidine.
Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO)
inhibitors or those who have recently received such agents. Therapeutic doses of meperidine
have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients
who have received such agents within 14 days. The mechanism of these reactions is unclear, but
may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma,
severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of
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Reference ID: 2931372
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For current labeling information, please visit https://www.fda.gov/drugsatfda
acute narcotic overdose. In other reactions the predominant manifestations have been hyper
excitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Although it is not known
that other narcotics are free of the risk of such reactions, virtually all of the reported reactions
have occurred with meperidine. If a narcotic is needed in such patients, a sensitivity test should
be performed in which repeated, small, incremental doses of morphine are administered over the
course of several hours while the patient’s condition and vital signs are under careful
observation. (Intravenous hydrocortisone or prednisolone have been used to treat severe
reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension
and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these
reactions is unknown.)
WARNINGS
Meperidine should not be used for treatment of chronic pain. Meperidine should only be used in
the treatment of acute episodes of moderate to severe pain Prolonged meperidine use may
increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite,
normeperidine.
DEMEROL is an opioid agonist and a Schedule II controlled substance with an abuse
liability similar to morphine.
DEMEROL can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing DEMEROL in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Misuse, Abuse, and Diversion of Opioids
Meperidine is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers
and people with addiction disorders and are subject to criminal diversion.
Meperidine can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing DEMEROL in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
DEMEROL has been reported as being abused by crushing, chewing, snorting, or injecting the
dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose
a significant risk to the abuser that could result in overdose or death (see WARNINGS and
DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction, and diversion should not prevent the proper management of
pain.
Healthcare professionals should contact their State Professional Licensing Board or State
Controlled Substances Authority for information on how to prevent and detect abuse or diversion
of this product.
Interactions with Alcohol and Drugs of Abuse
Meperidine may be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression.
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Reference ID: 2931372
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Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of
meperidine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated
in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial
pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical
course of patients with head injuries. In such patients, meperidine must be used with extreme
caution and only if its use is deemed essential.
Asthma and Other Respiratory Conditions: Meperidine should be used with extreme caution
in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease
or cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with
preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even usual
therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing
airway resistance to the point of apnea.
Hypotensive Effect: The administration of meperidine may result in severe hypotension in the
postoperative patient or any individual whose ability to maintain blood pressure has been
compromised by a depleted blood volume or the administration of drugs such as the
phenothiazines or certain anesthetics.
Usage in Ambulatory Patients: Meperidine may impair the mental and/or physical abilities
required for the performance of potentially hazardous tasks such as driving a car or operating
machinery. The patient should be cautioned accordingly.
Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients.
Usage in Pregnancy: Meperidine should not be used in pregnant women prior to the labor
period, unless in the judgment of the physician the potential benefits outweigh the possible risks,
because safe use in pregnancy prior to labor has not been established relative to possible adverse
effects on fetal development.
Labor and Delivery: Meperidine crosses the placental barrier and can produce depression of
respiration and psychophysiologic functions in the newborn. Resuscitation may be required (See
OVERDOSAGE). Therefore meperidine is not recommended during labor. Nursing Mothers:
Meperidine appears in the milk of nursing mothers receiving the drug. Due to the potential for
serious adverse reactions in nursing infants, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the potential benefits of the drug to the
nursing woman.
PRECAUTIONS
General
Opioid analgesics can have a narrow therapeutic index in certain patient populations, particularly
when combined with CNS depressant drugs. The use of these products should be reserved for
cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression,
altered mental state, and postural hypotension.
Use of DEMEROL may be associated with increased potential risks and should be used with
caution in the following conditions: sickle cell anemia, pheochromocytoma, acute alcoholism;
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Reference ID: 2931372
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For current labeling information, please visit https://www.fda.gov/drugsatfda
adrenocortical insufficiency (e.g., Addison’s disease); CNS depression or coma; delirium
tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema
or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic,
pulmonary, or renal function; and toxic psychosis .
The administration of meperidine may obscure the diagnosis or clinical course in patients with
acute abdominal conditions. All opioids may induce or aggravate seizures in some clinical
settings.
Interactions with other CNS Depressants
DEMEROL should be used with caution and consideration should be given to starting with a
reduced dosage in patients who are concurrently receiving other central nervous system
depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other
tranquilizers, and alcohol. Drug-drug interactions may result in respiratory depression,
hypotension, profound sedation, or coma if these drugs are taken in combination with the usual
doses of DEMEROL.
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine)
should be administered with caution to a patient who has received or is receiving a course of
therapy with a pure opioid agonist analgesic such as meperidine. In this situation, mixed
agonist/antagonist analgesics may reduce the analgesic effect of meperidine and/or may
precipitate withdrawal symptoms in these patients.
Supraventricular Tachycardias: Meperidine should be used with caution in patients with atrial
flutter and other supraventricular tachycardias because of a possible vagolytic action which may
produce a significant increase in the ventricular response rate.
Convulsions: Meperidine may aggravate preexisting convulsions in patients with convulsive
disorders. If dosage is escalated substantially above recommended levels because of tolerance
development, convulsions may occur in individuals without a history of convulsive disorders.
Acute Abdominal Conditions: The administration of meperidine or other narcotics may
obscure the diagnosis or clinical course in patients with acute abdominal conditions.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as
analgesia (in the absence of disease progression or other external factors). Physical dependence
is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon
administration of an antagonist. Physical dependence and tolerance are not unusual during
chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other
symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate.
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In general, opioids used regularly should not be abruptly discontinued.
Use in Drug and Alcohol Addiction
DEMEROL is an opioid with no approved use in the management of addictive disorders. Its
proper usage in individuals with drug or alcohol dependence, either active or in remission, is for
the management of pain requiring opioid analgesia. DEMEROL should be used with caution in
patients with alcoholism and other drug dependencies due to the increased frequency of narcotic
tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of
DEMEROL in combination with other CNS depressant drugs can result in serious risk to the
patient.
Information for Patients/Caregivers
If clinically advisable, patients receiving DEMEROL (meperidine hydrochloride) tablets or their
caregivers should be given the following information by the physician, nurse, pharmacist, or
caregiver:
1. Patients should be aware that DEMEROL tablets contain meperidine, which is a morphine-
like substance.
2. Patients should be advised to report pain and adverse experiences occurring during therapy.
Individualization of dosage is essential to make optimal use of this medication.
3. Patients should be advised not to adjust the dose of DEMEROL without consulting the
prescribing professional.
4. Patients should be advised that DEMEROL may impair mental and/or physical ability
required for the performance of potentially hazardous tasks (e.g., driving, operating heavy
machinery).
5. Patients should not combine DEMEROL with alcohol or other central nervous system
depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because
dangerous additive effects may occur, resulting in serious injury or death.
6. Women of childbearing potential who become, or are planning to become pregnant should be
advised to consult their physician regarding the effects of analgesics and other drug use during
pregnancy on themselves and their unborn child.
7. Patients should be advised that DEMEROL is a potential drug of abuse. They should protect
it from theft, and it should never be given to anyone other than the individual for whom it was
prescribed.
8. Patients should be advised that if they have been receiving treatment with DEMEROL for
more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the
DEMEROL dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal
symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation
of the medication.
9. Patients should be instructed to keep DEMEROL in a secure place out of the reach of
children. When DEMEROL is no longer needed, the unused tablets should be destroyed by
flushing down the toilet.
5
Reference ID: 2931372
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Interactions: Also see WARNINGS.
Acyclovir: Plasma concentrations of meperidine and its metabolite, normeperidine, may be
increased by acyclovir, thus caution should be used with concomitant administration.
Cimetidine: Cimetidine reduced the clearance and volume of distribution of meperidine and also
the formation of the metabolite, normeperidine, in healthy subjects and thus, caution should be
used with concomitant administration.
Phenytoin: The hepatic metabolism of meperidine may be enhanced by Phenytoin. Concomitant
administration resulted in reduced half-life and bioavailability with increased clearance of
meperidine in healthy subjects, however, blood concentrations of normeperidine were increased.
Ritonavir: Plasma concentrations of the active metabolite normeperidine may be increased by
ritonavir, thus concomitant administration should be avoided.
Opioid analgesics, including DEMEROL, may enhance the neuromuscular blocking action of
skeletal muscle relaxants and produce an increased degree of respiratory depression.
Special Risk Patients: Meperidine should be given with caution and the initial dose should be
reduced in certain patients such as the elderly or debilitated, and those with severe impairment of
hepatic or renal function, Sickle Cell Anemia, hypothyroidism, Addison’s disease,
Pheochromocytoma and prostatic hypertrophy or urethral stricture. In patients with
pheochromocytoma, meperidine has been reported to provoke hypertension. Usage in
Hepatically Impaired Patients: Accumulation of meperidine and/or its active metabolite,
normeperidine, can occur in patients with hepatic impairment. Meperidine should therefore be
used with caution in patients with hepatic impairment.
Usage in Renally Impaired Patients: Accumulation of meperidine and/or its active metabolite,
normeperidine, can also occur in patients with renal impairment. Meperidine should therefore be
used with caution in patients with renal impairment.
Carcinogenesis, mutagenesis, impairment of fertility: Studies to assess the
carcinogenic or mutagenic potential of meperidine have not been conducted. Studies to
determine the effect of meperidine on fertility have not been conducted.
Pregnancy: Teratogenic effects. Pregnancy Category C: Animal reproduction studies
have not been conducted with meperidine. It is also not known whether DEMEROL can cause
fetal harm when administered to a pregnant woman or can affect reproduction capacity.
DEMEROL should be given to a pregnant woman only if clearly needed.
Labor and Delivery: See WARNINGS.
Nursing Mothers: See WARNINGS.
Pediatric Use: The safety and effectiveness of meperidine in pediatric patients has not been
established. Literature reports indicate that meperidine has a slower elimination rate in neonates
and young infants compared to older children and adults. Neonates and young infants may also
6
Reference ID: 2931372
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For current labeling information, please visit https://www.fda.gov/drugsatfda
be more susceptible to the effects, especially the respiratory depressant effects. If meperidine
use is contemplated in neonates or young infants, any potential benefits of the drug need to be
weighed against the relative risk to the patient.
Geriatric Use: Clinical studies of DEMEROL during product development did not include
sufficient numbers of subjects aged 65 and over to evaluate age-related differences in safety or
efficacy. Literature reports indicate that geriatric patients have a slower elimination rate
compared to young patients and they may be more susceptible to the effects of meperidine. A
reduction in the total daily dose of meperidine may be required in elderly patients, and the
potential benefits of the drug weighed against the relative risk to a geriatric patient.
ADVERSE REACTIONS
The major hazards of meperidine, as with other narcotic analgesics, are respiratory depression
and, to a lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have
occurred.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation,
nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory
patients and in those who are not experiencing severe pain. In such individuals, lower doses are
advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies
down.
Other adverse reactions include:
Nervous System: Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated
muscle movements (e.g. muscle twitches, myoclonus), severe convulsions, transient
hallucinations and disorientation, visual disturbances.
Gastrointestinal: Dry mouth, constipation, biliary tract spasm.
Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension (see
WARNINGS), syncope. Genitourinary: Urinary retention.
Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous
injection. Hypersensitivity reactions, anaphylaxis, shock.
Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus.
DRUG ABUSE AND ADDICTION
DEMEROL contains meperidine, a mu-agonist opioid with an abuse liability similar to
morphine and is a Schedule II controlled substance. Meperidine, like morphine and other
opioids used in analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued
use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi
disciplinary approach, but relapse is common.
7
Reference ID: 2931372
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For current labeling information, please visit https://www.fda.gov/drugsatfda
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics
include emergency calls or visits near the end of office hours, refusal to undergo appropriate
examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions
and reluctance to provide prior medical records or contact information for other treating
physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug
abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance.
Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the
absence of true addiction and is characterized by misuse for non-medical purposes, often in
combination with other psychoactive substances. DEMEROL, like other opioids, has been
diverted for non-medical use. Careful record-keeping of prescribing information, including
quantity, frequency, and renewal requests is strongly advised.
Abuse of DEMEROL poses a risk of overdose and death. This risk is increased with concurrent
abuse of DEMEROL with alcohol and other substances. Due to the presence of talc as one of the
excipients in tablets, parenteral abuse of crushed tablets can be expected to result in local tissue
necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart
disease. In addition, parenteral drug abuse is commonly associated with transmission of
infectious diseases such as hepatitis and HIV.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
and proper dispensing and storage are appropriate measures that help to limit abuse of opioid
drugs.
OVERDOSAGE
Symptoms: Serious overdosage with meperidine is characterized by respiratory depression (a
decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme
somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and
sometimes bradycardia and hypotension. In severe overdosage, particularly by the intravenous
route, apnea, circulatory collapse, cardiac arrest, and death may occur.
Treatment: Primary attention should be given to the reestablishment of adequate respiratory
exchange through provision of a patent airway and institution of assisted or controlled
ventilation. The narcotic antagonist, naloxone hydrochloride, is a specific antidote against
respiratory depression which may result from overdosage or unusual sensitivity to narcotics,
including meperidine. Therefore, an appropriate dose of this antagonist should be administered,
preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation.
An antagonist should not be administered in the absence of clinically significant respiratory or
cardiovascular depression.
Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as
indicated.
In cases of overdosage with DEMEROL tablets, the stomach should be evacuated by emesis or
gastric lavage.
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Reference ID: 2931372
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE: In an individual physically dependent on narcotics, the administration of the usual dose
of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this
syndrome will depend on the degree of physical dependence and the dose of antagonist
administered. The use of narcotic antagonists in such individuals should be avoided if possible.
If a narcotic antagonist must be used to treat serious respiratory depression in the physically
dependent patient, the antagonist should be administered with extreme care and only one-fifth to
one-tenth the usual initial dose administered.
DOSAGE AND ADMINISTRATION
For Relief of Pain
Dosage should be adjusted according to the severity of the pain and the response of the patient.
Meperidine is less effective orally than on parenteral administration. The dose of DEMEROL
should be proportionately reduced (usually by 25 to 50 percent) when administered
concomitantly with phenothiazines and many other tranquilizers since they potentiate the action
of DEMEROL.
Adults: The usual dosage is 50 mg to 150 mg orally, every 3 or 4 hours as necessary.
Pediatric Patients: The usual dosage is 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose,
every 3 or 4 hours as necessary.
SAFETY AND HANDLING
DEMEROL (meperidine HCl) tablets contain meperidine hydrochloride which is a controlled
substance. Like morphine, meperidine is controlled under Schedule II of the Controlled
Substances Act. Meperidine, like all opioids, is liable to diversion and misuse and should be
handled accordingly. Patients and their families should be instructed to flush DEMEROL tablets
that are no longer needed.
DEMEROL has been targeted for theft and diversion by criminals. Healthcare professionals
should contact their State Professional Licensing Board or State Controlled Substance Authority
for information on how to prevent and detect abuse or diversion of this product.
HOW SUPPLIED
For Oral Use
Tablets are white, round and convex. The 50 mg tablet has a stylized “W” on one side and “M”
score “35” on the other side. The 100 mg tablet has a stylized “W” on one side and “D” score
“37” on the other side.
Tablets of 50 mg, bottles of 100 (NDC 0024-0335-04) and 100 mg, bottles of 100 (NDC 0024
0337-04).
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [See USP Controlled
Room Temperature].
Rx only
9
Reference ID: 2931372
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Revised September 2010
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2010 sanofi-aventis U.S. LLC
Reference ID: 2931372
10
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For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.585894 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/005010s050lbl.pdf', 'application_number': 5010, 'submission_type': 'SUPPL ', 'submission_number': 50} |
10,674 |
CII
Demerol® (meperidine hydrochloride, USP)
WARNING: May be habit forming
DESCRIPTION
Meperidine hydrochloride, a white crystalline substance with a melting point of 186° C to 189°
C. It is readily soluble in water and has a neutral reaction and a slightly bitter taste. The solution
is not decomposed by a short period of boiling.
The oral solution is a pleasant-tasting, nonalcoholic, banana-flavored solution containing 50 mg
of DEMEROL, brand of meperidine hydrochloride, per 5 mL teaspoon (25 drops contain 13 mg
of DEMEROL). The tablets contain 50 mg or 100 mg of the analgesic.
Inactive Ingredients - TABLETS: Calcium Sulfate, Dibasic Calcium Phosphate, Starch, Stearic
Acid, Talc. ORAL SOLUTION: Benzoic Acid, Flavor, Liquid Glucose, Purified Water,
Saccharin Sodium.
Chemically, DEMEROL is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-, ethyl ester,
hydrochloride and has the following structure: Chemical Structure
CLINICAL PHARMACOLOGY
Meperidine hydrochloride is a narcotic analgesic with multiple actions qualitatively similar to
those of morphine; the most prominent of these involve the central nervous system and organs
composed of smooth muscle. The principal actions of therapeutic value are analgesia and
sedation.
There is some evidence which suggests that meperidine may produce less smooth muscle spasm,
constipation, and depression of the cough reflex than equianalgesic doses of morphine.
Meperidine, in 60 mg to 80 mg parenteral doses, is approximately equivalent in analgesic effect
to 10 mg of morphine. The onset of action is slightly more rapid than with morphine, and the
duration of action is slightly shorter. Meperidine is significantly less effective by the oral than
by the parenteral route, but the exact ratio of oral to parenteral effectiveness is unknown.
INDICATIONS AND USAGE
DEMEROL is indicated for the relief of moderate to severe pain.
1
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CONTRAINDICATIONS
DEMEROL is contraindicated in patients with hypersensitivity to meperidine.
Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO)
inhibitors or those who have recently received such agents. Therapeutic doses of meperidine
have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients
who have received such agents within 14 days. The mechanism of these reactions is unclear, but
may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma,
severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of
acute narcotic overdose. In other reactions the predominant manifestations have been hyper
excitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Although it is not known
that other narcotics are free of the risk of such reactions, virtually all of the reported reactions
have occurred with meperidine. If a narcotic is needed in such patients, a sensitivity test should
be performed in which repeated, small, incremental doses of morphine are administered over the
course of several hours while the patient’s condition and vital signs are under careful
observation. (Intravenous hydrocortisone or prednisolone have been used to treat severe
reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension
and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these
reactions is unknown.)
WARNINGS
DEMEROL is an opioid agonist and a Schedule II controlled substance with an abuse
liability similar to morphine.
DEMEROL can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing DEMEROL in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Misuse, Abuse, and Diversion of Opioids
Meperidine is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers
and people with addiction disorders and are subject to criminal diversion.
Meperidine can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing DEMEROL in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
DEMEROL has been reported as being abused by crushing, chewing, snorting, or injecting the
dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose
a significant risk to the abuser that could result in overdose or death (see WARNINGS and
DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction, and diversion should not prevent the proper management of
pain.
Healthcare professionals should contact their State Professional Licensing Board or State
Controlled Substances Authority for information on how to prevent and detect abuse or diversion
of this product.
2
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Interactions with Alcohol and Drugs of Abuse
Meperidine may be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression.
Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of
meperidine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated
in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial
pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical
course of patients with head injuries. In such patients, meperidine must be used with extreme
caution and only if its use is deemed essential.
Asthma and Other Respiratory Conditions: Meperidine should be used with extreme caution in
patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or
cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with
preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even usual
therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing
airway resistance to the point of apnea.
Hypotensive Effect: The administration of meperidine may result in severe hypotension in the
postoperative patient or any individual whose ability to maintain blood pressure has been
compromised by a depleted blood volume or the administration of drugs such as the
phenothiazines or certain anesthetics.
Usage in Ambulatory Patients: Meperidine may impair the mental and/or physical abilities
required for the performance of potentially hazardous tasks such as driving a car or operating
machinery. The patient should be cautioned accordingly.
Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients.
Usage in Pregnancy: Meperidine should not be used in pregnant women prior to the labor
period, unless in the judgment of the physician the potential benefits outweigh the possible risks,
because safe use in pregnancy prior to labor has not been established relative to possible adverse
effects on fetal development.
Labor and Delivery: Meperidine crosses the placental barrier and can produce depression of
respiration and psychophysiologic functions in the newborn. Resuscitation may be required (See
OVERDOSAGE).
Nursing Mothers: Meperidine appears in the milk of nursing mothers receiving the drug. Due to
the potential for serious adverse reactions in nursing infants, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the potential benefits of the
drug to the nursing woman.
3
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PRECAUTIONS
General
Opioid analgesics can have a narrow therapeutic index in certain patient populations, particularly
when combined with CNS depressant drugs. The use of these products should be reserved for
cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression,
altered mental state, and postural hypotension.
Use of DEMEROL may be associated with increased potential risks and should be used with
caution in the following conditions: sickle cell anemia, pheochromocytoma, acute alcoholism;
adrenocortical insufficiency (e.g., Addison’s disease); CNS depression or coma; delirium
tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema
or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic,
pulmonary, or renal function; and toxic psychosis .
The administration of meperidine may obscure the diagnosis or clinical course in patients with
acute abdominal conditions. All opioids may induce or aggravate seizures in some clinical
settings.
Interactions with other CNS Depressants
DEMEROL should be used with caution and consideration should be given to starting with a
reduced dosage in patients who are concurrently receiving other central nervous system
depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other
tranquilizers, and alcohol. Drug-drug interactions may result in respiratory depression,
hypotension, profound sedation, or coma if these drugs are taken in combination with the usual
doses of DEMEROL.
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine)
should be administered with caution to a patient who has received or is receiving a course of
therapy with a pure opioid agonist analgesic such as meperidine. In this situation, mixed
agonist/antagonist analgesics may reduce the analgesic effect of meperidine and/or may
precipitate withdrawal symptoms in these patients.
Supraventricular Tachycardias: Meperidine should be used with caution in patients with atrial
flutter and other supraventricular tachycardias because of a possible vagolytic action which may
produce a significant increase in the ventricular response rate.
Convulsions: Meperidine may aggravate preexisting convulsions in patients with convulsive
disorders. If dosage is escalated substantially above recommended levels because of tolerance
development, convulsions may occur in individuals without a history of convulsive disorders.
Acute Abdominal Conditions: The administration of meperidine or other narcotics may
obscure the diagnosis or clinical course in patients with acute abdominal conditions.
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as
analgesia (in the absence of disease progression or other external factors). Physical dependence
is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon
administration of an antagonist. Physical dependence and tolerance are not unusual during
chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other
symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate.
In general, opioids used regularly should not be abruptly discontinued.
Use in Drug and Alcohol Addiction
DEMEROL is an opioid with no approved use in the management of addictive disorders. Its
proper usage in individuals with drug or alcohol dependence, either active or in remission, is for
the management of pain requiring opioid analgesia. DEMEROL should be used with caution in
patients with alcoholism and other drug dependencies due to the increased frequency of narcotic
tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of
DEMEROL in combination with other CNS depressant drugs can result in serious risk to the
patient.
Information for Patients/Caregivers
If clinically advisable, patients receiving DEMEROL (meperidine hydrochloride) tablets or their
caregivers should be given the following information by the physician, nurse, pharmacist, or
caregiver:
1. Patients should be aware that DEMEROL tablets contain meperidine, which is a morphine-
like substance.
2. Patients should be advised to report pain and adverse experiences occurring during therapy.
Individualization of dosage is essential to make optimal use of this medication.
3. Patients should be advised not to adjust the dose of DEMEROL without consulting the
prescribing professional.
4. Patients should be advised that DEMEROL may impair mental and/or physical ability
required for the performance of potentially hazardous tasks (e.g., driving, operating heavy
machinery).
5. Patients should not combine DEMEROL with alcohol or other central nervous system
depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because
dangerous additive effects may occur, resulting in serious injury or death.
6. Women of childbearing potential who become, or are planning to become pregnant should be
advised to consult their physician regarding the effects of analgesics and other drug use during
pregnancy on themselves and their unborn child.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7. Patients should be advised that DEMEROL is a potential drug of abuse. They should protect
it from theft, and it should never be given to anyone other than the individual for whom it was
prescribed.
8. Patients should be advised that if they have been receiving treatment with DEMEROL for
more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the
DEMEROL dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal
symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation
of the medication.
9. Patients should be instructed to keep DEMEROL in a secure place out of the reach of
children. When DEMEROL is no longer needed, the unused tablets should be destroyed by
flushing down the toilet.
Drug Interactions: Also see WARNINGS.
Acyclovir: Plasma concentrations of meperidine and its metabolite, normeperidine, may be
increased by acyclovir, thus caution should be used with concomitant administration.
Cimetidine: Cimetidine reduced the clearance and volume of distribution of meperidine and also
the formation of the metabolite, normeperidine, in healthy subjects and thus, caution should be
used with concomitant administration.
Phenytoin: The hepatic metabolism of meperidine may be enhanced by Phenytoin. Concomitant
administration resulted in reduced half-life and bioavailability with increased clearance of
meperidine in healthy subjects, however, blood concentrations of normeperidine were increased.
Ritonavir: Plasma concentrations of the active metabolite normeperidine may be increased by
ritonavir, thus concomitant administration should be avoided.
Opioid analgesics, including DEMEROL, may enhance the neuromuscular blocking action of
skeletal muscle relaxants and produce an increased degree of respiratory depression.
Special Risk Patients: Meperidine should be given with caution and the initial dose should be
reduced in certain patients such as the elderly or debilitated, and those with severe impairment of
hepatic or renal function, Sickle Cell Anemia, hypothyroidism, Addison’s disease,
Pheochromocytoma and prostatic hypertrophy or urethral stricture. In patients with
pheochromocytoma, meperidine has been reported to provoke hypertension.
Usage in Hepatically Impaired Patients: Accumulation of meperidine and/or its active
metabolite, normeperidine, can occur in patients with hepatic impairment. Meperidine should
therefore be used with caution in patients with hepatic impairment.
Usage in Renally Impaired Patients: Accumulation of meperidine and/or its active metabolite,
normeperidine, can also occur in patients with renal impairment. Meperidine should therefore be
used with caution in patients with renal impairment.
Carcinogensis, mutagenesis, impairment of fertility: Studies to assess the carcinogenic or
mutagenic potential of meperidine have not been conducted. Studies to determine the effect of
meperidine on fertility have not been conducted.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy: Teratogenic effects. Pregnancy Category C: Animal reproduction studies have not
been conducted with meperidine. It is also not known whether DEMEROL can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. DEMEROL should
be given to a pregnant woman only if clearly needed.
Labor and Delivery: See WARNINGS.
Nursing Mothers: See WARNINGS.
Pediatric Use: Literature reports indicate that meperidine has a slower elimination rate in
neonates and young infants compared to older children and adults. Neonates and young infants
may also be more susceptible to the effects, especially the respiratory depressant effects.
Meperidine should therefore be used with caution in neonates and young infants, and any
potential benefits of the drug weighed against the relative risk to a pediatric patient.
Geriatric Use: Clinical studies of DEMEROL during product development did not include
sufficient numbers of subjects aged 65 and over to evaluate age-related differences in safety or
efficacy. Literature reports indicate that geriatric patients have a slower elimination rate
compared to young patients and they may be more susceptible to the effects of meperidine. A
reduction in the total daily dose of meperidine may be required in elderly patients, and the
potential benefits of the drug weighed against the relative risk to a geriatric patient.
ADVERSE REACTIONS
The major hazards of meperidine, as with other narcotic analgesics, are respiratory depression
and, to a lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have
occurred.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation,
nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory
patients and in those who are not experiencing severe pain. In such individuals, lower doses are
advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies
down.
Other adverse reactions include:
Nervous System: Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated
muscle movements (e.g. muscle twitches, myoclonus), severe convulsions, transient
hallucinations and disorientation, visual disturbances.
Gastrointestinal: Dry mouth, constipation, biliary tract spasm.
Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension (see
WARNINGS), syncope.
Genitourinary: Urinary retention.
Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous
injection. Hypersensitivity reactions including anaphylaxis.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
For Relief of Pain
Dosage should be adjusted according to the severity of the pain and the response of the patient.
Meperidine is less effective orally than on parenteral administration. The dose of DEMEROL
should be proportionately reduced (usually by 25 to 50 percent) when administered
concomitantly with phenothiazines and many other tranquilizers since they potentiate the action
of DEMEROL.
Adults: The usual dosage is 50 mg to 150 mg orally, every 3 or 4 hours as necessary.
Pediatric Patients: The usual dosage is 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose,
every 3 or 4 hours as necessary.
Each dose of the oral solution should be taken in one-half glass of water, since if taken undiluted,
it may exert a slight topical anesthetic effect on mucous membranes.
DRUG ABUSE AND ADDICTION
DEMEROL contains meperidine, a mu-agonist opioid with an abuse liability similar to
morphine and is a Schedule II controlled substance. Meperidine, like morphine and other
opioids used in analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued
use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi
disciplinary approach, but relapse is common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics
include emergency calls or visits near the end of office hours, refusal to undergo appropriate
examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions
and reluctance to provide prior medical records or contact information for other treating
physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug
abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance.
Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the
absence of true addiction and is characterized by misuse for non-medical purposes, often in
combination with other psychoactive substances. DEMEROL, like other opioids, has been
diverted for non-medical use. Careful record-keeping of prescribing information, including
quantity, frequency, and renewal requests is strongly advised.
Abuse of DEMEROL poses a risk of overdose and death. This risk is increased with concurrent
abuse of DEMEROL with alcohol and other substances. Due to the presence of talc as one of the
excipients in tablets, parenteral abuse of crushed tablets can be expected to result in local tissue
necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart
disease. In addition, parenteral drug abuse is commonly associated with transmission of
infectious diseases such as hepatitis and HIV.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
and proper dispensing and storage are appropriate measures that help to limit abuse of opioid
drugs.
OVERDOSAGE
Symptoms: Serious overdosage with meperidine is characterized by respiratory depression (a
decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme
somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and
sometimes bradycardia and hypotension. In severe overdosage, particularly by the intravenous
route, apnea, circulatory collapse, cardiac arrest, and death may occur.
Treatment: Primary attention should be given to the reestablishment of adequate respiratory
exchange through provision of a patent airway and institution of assisted or controlled
ventilation. The narcotic antagonist, naloxone hydrochloride, is a specific antidote against
respiratory depression which may result from overdosage or unusual sensitivity to narcotics,
including meperidine. Therefore, an appropriate dose of this antagonist should be administered,
preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation.
An antagonist should not be administered in the absence of clinically significant respiratory or
cardiovascular depression.
Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as
indicated.
In cases of overdosage with DEMEROL tablets, the stomach should be evacuated by emesis or
gastric lavage.
NOTE: In an individual physically dependent on narcotics, the administration of the usual dose
of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this
syndrome will depend on the degree of physical dependence and the dose of antagonist
administered. The use of narcotic antagonists in such individuals should be avoided if possible.
If a narcotic antagonist must be used to treat serious respiratory depression in the physically
dependent patient, the antagonist should be administered with extreme care and only one-fifth to
one-tenth the usual initial dose administered.
SAFETY AND HANDLING
DEMEROL (meperidine HCl) tablets and oral solution are dosage forms that contain meperidine
hydrochloride which is a controlled substance. Like morphine, meperidine is controlled under
Schedule II of the Controlled Substances Act. Meperidine, like all opioids, is liable to diversion
and misuse and should be handled accordingly. Patients and their families should be instructed
to flush any DEMEROL oral solution or DEMEROL tablets that are no longer needed.
DEMEROL has been targeted for theft and diversion by criminals. Healthcare professionals
should contact their State Professional Licensing Board or State Controlled Substance Authority
for information on how to prevent and detect abuse or diversion of this product.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
For Oral Use
Tablets are white, round and convex. The 50 mg tablet has a stylized “W” on one side and “M”
score “35” on the other side. The 100 mg tablet has a stylized “W” on one side and “M” score
“37” on the other side.
Tablets of 50 mg, bottles of 100 (NDC 0024-0335-04) and 100 mg, bottles of 100 (NDC 0024
0337-04).
Oral Solution, nonalcoholic, banana-flavored 50 mg per 5 mL teaspoon, bottles of 16 fl oz
(NDC 0024-0332-06).
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [See USP Controlled
Room Temperature].
Rx Only
Revised July 2008
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2008 sanofi-aventis U.S. LLC
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.608418 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/005010s049lbl.pdf', 'application_number': 5010, 'submission_type': 'SUPPL ', 'submission_number': 49} |
10,676 |
CII
Demerol® (meperidine hydrochloride, USP)
WARNING: May be habit forming
DESCRIPTION
Meperidine hydrochloride is a white crystalline substance with a melting point of 186° C to 189° C. It is readily soluble in water and
has a neutral reaction and a slightly bitter taste. The solution is not decomposed by a short period of boiling.
The tablets contain 50 mg or 100 mg of DEMEROL brand of meperidine hydrochloride.
Inactive Ingredients: Calcium Sulfate, Dibasic Calcium Phosphate, Starch, Stearic Acid, Talc.
Chemically, DEMEROL is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-, ethyl ester, hydrochloride and has the following
structure:
structural formula
CLINICAL PHARMACOLOGY
Meperidine hydrochloride is a narcotic analgesic with multiple actions qualitatively similar to those of morphine; the most prominent
of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are
analgesia and sedation.
There is some evidence which suggests that meperidine may produce less smooth muscle spasm, constipation, and depression of the
cough reflex than equianalgesic doses of morphine.
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Reference ID: 3037140
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INDICATIONS AND USAGE
DEMEROL is indicated for the relief of moderate to severe pain.
CONTRAINDICATIONS
DEMEROL is contraindicated in patients with hypersensitivity to meperidine or to any of its ingredients.
Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently
received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal
reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to
a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and
hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea,
tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have
been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Although it is not known that other narcotics are
free of the risk of such reactions, virtually all of the reported reactions have occurred with meperidine. If a narcotic is needed in such
patients, a sensitivity test should be performed in which repeated, small, incremental doses of morphine are administered over the
course of several hours while the patient’s condition and vital signs are under careful observation. (Intravenous hydrocortisone or
prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting
hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.)
DEMEROL is contraindicated in patients with severe respiratory insufficiency (see WARNINGS, Respiratory Conditions).
WARNINGS
Meperidine should not be used for treatment of chronic pain. Meperidine should only be used in the treatment of acute episodes of
moderate to severe pain. Prolonged meperidine use may increase the risk of toxicity (e.g. seizures) from the accumulation of the
meperidine metabolite, normeperidine.
DEMEROL is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine.
DEMEROL can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or
dispensing DEMEROL in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or
diversion.
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Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Misuse, Abuse, and Diversion of Opioids
Meperidine is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and
are subject to criminal diversion.
Meperidine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or
dispensing DEMEROL in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or
diversion.
DEMEROL has been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will
result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose or death (see
WARNINGS and DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for
information on how to prevent and detect abuse or diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Meperidine may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause
central nervous system depression.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of meperidine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated
in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, narcotics
produce adverse reactions which may obscure the clinical course of patients with head injuries. In such patients, meperidine must be
used with extreme caution and only if its use is deemed essential.
Respiratory Conditions
Meperidine should be used with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive
pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with preexisting
respiratory depression, hypoxia, or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory
drive while simultaneously increasing airway resistance to the point of apnea.
Hypotensive Effect
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Reference ID: 3037140
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The administration of meperidine may result in severe hypotension in the postoperative patient or any individual whose ability to
maintain blood pressure has been compromised by a depleted blood volume or the administration of drugs such as the phenothiazines
or certain anesthetics.
Usage in Ambulatory Patients
Meperidine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving
a car or operating machinery. The patient should be cautioned accordingly.
Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients.
Usage in Pregnancy
Meperidine should not be used in pregnant women prior to the labor period, unless in the judgment of the physician the potential
benefits outweigh the possible risks, because safe use in pregnancy prior to labor has not been established relative to possible adverse
effects on fetal development.
Labor and Delivery
Meperidine crosses the placental barrier and can produce depression of respiration and psychophysiologic functions in the newborn.
Resuscitation may be required (see OVERDOSAGE). Therefore meperidine is not recommended during labor.
Nursing Mothers
Meperidine appears in the milk of nursing mothers receiving the drug. Due to the potential for serious adverse reactions in nursing
infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits
of the drug to the nursing woman.
PRECAUTIONS
General
Opioid analgesics can have a narrow therapeutic index in certain patient populations, particularly when combined with CNS
depressant drugs. The use of these products should be reserved for cases where the benefits of opioid analgesia outweigh the known
risks of respiratory depression, altered mental state, and postural hypotension.
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Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Use of DEMEROL may be associated with increased potential risks and should be used with caution in the following conditions:
sickle cell anemia, pheochromocytoma, acute alcoholism; adrenocortical insufficiency (e.g., Addison’s disease); CNS depression or
coma; delirium tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism;
prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary, or renal function; and toxic psychosis (see
PRECAUTIONS, Special Risk Patients).
The administration of meperidine may obscure the diagnosis or clinical course in patients with acute abdominal conditions. All
opioids may induce or aggravate seizures in some clinical settings.
Interactions with Other CNS Depressants
DEMEROL should be used with caution and consideration should be given to starting with a reduced dosage in patients who are
concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines,
other tranquilizers, and alcohol. Drug-drug interactions may result in respiratory depression, hypotension, profound sedation,coma,
or death if these drugs are taken in combination with the usual doses of DEMEROL.
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to
a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as meperidine. In this
situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of meperidine and/or may precipitate withdrawal
symptoms in these patients due to competitive blocking of receptors.
Supraventricular Tachycardias
Meperidine should be used with caution in patients with atrial flutter and other supraventricular tachycardias because of a possible
vagolytic action which may produce a significant increase in the ventricular response rate.
Convulsions
Meperidine may aggravate preexisting convulsions in patients with convulsive disorders. If dosage is escalated substantially above
recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive
disorders.
Acute Abdominal Conditions
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Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The administration of meperidine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal
conditions.
Tolerance and Physical Dependence
Meperidine has the potential to produce tolerance and drug dependence. Tolerance is the need for increasing doses of opioids to
maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is
manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical
dependence and tolerance are not unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea,
yawning, perspiration, chills, myalgia, mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint
pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or
heart rate.
In general, opioids used regularly should not be abruptly discontinued.
Use in Drug and Alcohol Addiction
DEMEROL is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or
alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia. DEMEROL should be
used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of narcotic tolerance,
dependence, and the risk of addiction observed in these patient populations. Abuse of DEMEROL in combination with other CNS
depressant drugs can result in serious risk to the patient.
Information for Patients/Caregivers
If clinically advisable, patients receiving DEMEROL (meperidine hydrochloride) tablets or their caregivers should be given the
following information by the physician, nurse, pharmacist, or caregiver:
1. Patients should be aware that DEMEROL tablets contain meperidine, which is a morphine-like substance.
2. Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential
to make optimal use of this medication.
3. Patients should be advised not to adjust the dose of DEMEROL without consulting the prescribing professional.
4. Patients should be advised that DEMEROL may impair mental and/or physical ability required for the performance of potentially
hazardous tasks (e.g., driving, operating heavy machinery).
6
Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Patients should not combine DEMEROL with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except
by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
6. Women of childbearing potential who become, or are planning to become pregnant should be advised to consult their physician
regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
7. Patients should be advised that DEMEROL is a potential drug of abuse. They should protect it from theft, and it should never be
given to anyone other than the individual for whom it was prescribed.
8. Patients should be advised that if they have been receiving treatment with DEMEROL for more than a few weeks and cessation of
therapy is indicated, it may be appropriate to taper the DEMEROL dose, rather than abruptly discontinue it, due to the risk of
precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the
medication.
9. Patients should be instructed to keep DEMEROL in a secure place out of the reach of children. When DEMEROL is no longer
needed, the unused tablets should be destroyed by flushing down the toilet.
Drug Interactions
Also see WARNINGS.
Acyclovir: Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir, thus caution
should be used with concomitant administration.
Cimetidine: Cimetidine reduced the clearance and volume of distribution of meperidine and also the formation of the metabolite,
normeperidine, in healthy subjects and thus, caution should be used with concomitant administration.
CNS Depressants: Concomitant use of CNS depressants with usual doses of Demerol may result in respiratory depression,
hypotension, profound sedation, coma or death (see PRECAUTIONS, Interactions with other CNS Depressants).
Phenytoin: The hepatic metabolism of meperidine may be enhanced by phenytoin. Concomitant administration resulted in reduced
half-life and bioavailability with increased clearance of meperidine in healthy subjects, however, blood concentrations of
normeperidine were increased, thus exercise caution when phenytoin is used concomitantly with meperidine.
Ritonavir: Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir, thus concomitant
administration should be avoided.
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Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Opioid analgesics, including DEMEROL, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce
an increased degree of respiratory depression.
Special Risk Patients
Meperidine should be given with caution and the initial dose should be reduced in certain patients such as the elderly or debilitated,
and those with severe impairment of hepatic or renal function, Sickle Cell Anemia, hypothyroidism, Addison’s disease,
Pheochromocytoma and prostatic hypertrophy or urethral stricture. In patients with pheochromocytoma, meperidine has been reported
to provoke hypertension.
Usage in Hepatically Impaired Patients
Accumulation of meperidine and/or its active metabolite, normeperidine, can occur in patients with hepatic impairment. Meperidine
should therefore be used with caution in patients with hepatic impairment.
Usage in Renally Impaired Patients
Accumulation of meperidine and/or its active metabolite, normeperidine, can also occur in patients with renal impairment. Meperidine
should therefore be used with caution in patients with renal impairment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to assess the carcinogenic or mutagenic potential of meperidine have not been conducted. Studies to determine the effect of
meperidine on fertility have not been conducted.
Pregnancy: Teratogenic Effects
Pregnancy Category C: Animal reproduction studies have not been conducted with meperidine. It is also not known whether
DEMEROL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DEMEROL should be
given to a pregnant woman only if clearly needed.
Labor and Delivery
See WARNINGS.
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Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers
See WARNINGS.
Pediatric Use
The safety and effectiveness of meperidine in pediatric patients has not been established. Literature reports indicate that meperidine
has a slower elimination rate in neonates and young infants compared to older children and adults. Neonates and young infants may
also be more susceptible to the effects, especially the respiratory depressant effects. If meperidine use is contemplated in neonates or
young infants, any potential benefits of the drug need to be weighed against the relative risk of the patient.
Geriatric Use
Clinical studies of DEMEROL during product development did not include sufficient numbers of subjects aged 65 and over to
evaluate age-related differences in safety or efficacy. Literature reports indicate that geriatric patients have a slower elimination rate
compared to young patients and they may be more susceptible to the effects of meperidine. Reducing the total daily dose of
meperidine is recommended in elderly patients and the potential benefits of the drug should be weighed against the relative risk to a
geriatric patient.
ADVERSE REACTIONS
The major hazards of meperidine, as with other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory
depression; respiratory arrest, shock, and cardiac arrest have occurred.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These
effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals,
lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.
Other adverse reactions include:
Nervous System: Mood changes (e.g. euphoria, dysphoria), weakness, headache, agitation, tremor, involuntary muscle movements
(e.g. muscle twitches, myoclonus), severe convulsions, transient hallucinations and disorientation, confusion, delirium, visual
disturbances.
Gastrointestinal: Dry mouth, constipation, biliary tract spasm.
9
Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension (see WARNINGS), syncope. Genitourinary:
Urinary retention.
Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection. Hypersensitivity reactions,
anaphylaxis.
Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus.
DRUG ABUSE AND ADDICTION
DEMEROL contains meperidine, a mu-agonist opioid with an abuse liability similar to morphine and is a Schedule II
controlled substance. Meperidine, like morphine and other opioids used in analgesia, can be abused and is subject to criminal
diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm.
Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the
end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with
prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor
shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may
not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can
occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other
psychoactive substances. DEMEROL, like other opioids, has been diverted for non-medical use. Careful record-keeping of
prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Abuse of DEMEROL poses a risk of overdose and death. This risk is increased with concurrent abuse of DEMEROL with alcohol
and other substances. Due to the presence of talc as one of the excipients in tablets, parenteral abuse of crushed tablets can be
expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart
disease. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are
appropriate measures that help to limit abuse of opioid drugs.
10
Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Symptoms
Serious overdosage with meperidine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume,
Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, hypothermia,
cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, particularly by the intravenous route,
apnea, circulatory collapse, cardiac arrest, and death may occur.
Treatment
Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and
institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, is a specific antidote against
respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including meperidine. Therefore, an
appropriate dose of this antagonist should be administered as necessary, preferably by the intravenous route, simultaneously with
efforts at respiratory resuscitation.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.
Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated.
In cases of overdosage with DEMEROL tablets, the stomach should be evacuated by emesis or gastric lavage.
NOTE: In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate
an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of
antagonist administered. The use of narcotic antagonists in such individuals should be avoided if possible. If a narcotic antagonist
must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with
extreme care and only one-fifth to one-tenth the usual initial dose administered.
DOSAGE AND ADMINISTRATION
For Relief of Pain
Dosage should be adjusted according to the severity of the pain and the response of the patient. Meperidine is less effective orally than
on parenteral administration. The dose of DEMEROL should be proportionately reduced (usually by 25 to 50 percent) when
administered concomitantly with phenothiazines and many other tranquilizers since they potentiate the action of DEMEROL.
Adults: The usual dosage is 50 mg to 150 mg orally, every 3 or 4 hours as necessary.
11
Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Patients: The usual dosage is 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as necessary (see
PRECAUTIONS, Pediatric use).
SAFETY AND HANDLING
DEMEROL (meperidine HCl) tablets contain meperidine hydrochloride which is a controlled substance. Like morphine, meperidine
is controlled under Schedule II of the Controlled Substances Act. Meperidine, like all opioids, is liable to diversion and misuse and
should be handled accordingly. Patients and their families should be instructed to flush DEMEROL tablets that are no longer needed.
DEMEROL has been targeted for theft and diversion by criminals. Healthcare professionals should contact their State Professional
Licensing Board or State Controlled Substance Authority for information on how to prevent and detect abuse or diversion of this
product.
HOW SUPPLIED
For Oral Use
Tablets are white, round and convex. The 50 mg is a scored tablet and has a stylized “W” on one side and “D” over “35” on the other
side. The 100 mg is not a scored tablet and has a stylized “W” on one side and “D” over “37” on the other side.
Tablets of 50 mg, HDPE plastic bottles of 100 (NDC 0024-0335-05) and 100 mg, HDPE plastic bottles of 100 (NDC 0024-0337-05).
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [See USP Controlled Room Temperature].
Rx only
Revised October 2011
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2011 sanofi-aventis U.S. LLC
12
Reference ID: 3037140
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.848522 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/005010s051lbl.pdf', 'application_number': 5010, 'submission_type': 'SUPPL ', 'submission_number': 51} |
10,678 | NDA 05-929/S-032, S-033
NDA 09-000/S-022, S-023
NDA 20-148/S-007, S-008
Package Insert
Page 1
DHE 45 (NDA 05-929) and Migranal Nasal Spray (NDA 20-148)
CLINICAL PHARMACOLOGY
Pharmacokinetics: Interactions
Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids
(e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin,
presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin.
Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions.
No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.
WARNINGS
Fibrotic Complications
There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use
of injectable dihydroergotamine mesylate. In addition, prolonged daily use of dihydroergotamine has
been associated, in at least two reports, with cardiac valvular fibrosis. The mitral and tricuspid valves
were affected and both patients required mitral valve replacement. Administration of D.H.E. 45
(dihydroergotamine mesylate) Injection / Migranal (dihydroergotamine) Nasal Spray, USP, should not
exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE
AND ADMINISTRATION).
PRECAUTIONS
Fibrotic Complications: see WARNINGS: Fibrotic Complications.
Information for Patients
Administration of D.H.E. 45 (dihydroergotamine mesylate) Injection / Migranal (dihydroergotamine)
Nasal Spray, USP, should not exceed the dosing guidelines and should not be used for chronic daily
administration (see DOSAGE AND ADMINISTRATION).
CYP 3A4 Inhibitors
[New Section – replaces “Macrolide Antibiotics”]
Although there have been no reports of serious adverse events in connection with the coadministration
of dihydroergotamine and potent CYP 3A4 inhibitors, there is a potential risk for increased blood
levels and serious toxicity including vasospasm when these drugs are used in combination. The use of
potent CYP 3A4 inhibitors with dihydroergotamine should therefore be avoided. Examples of some of
the more potent CYP 3A4 inhibitors include: anti-fungals ketoconazole and itraconazole, the protease
inhibitors ritonavir, nelfinavir, and indinavir, and macrolide antibiotics erythromycin, clarithromycin,
and troleandomycin. Other less potent CYP 3A4 inhibitors should be administered with caution. Less
potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine,
fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should
consider the effects on CYP3A4 of other agents being considered for concomitant use with
dihydroergotamine.
ADVERSE EVENTS
Fibrotic complications have been associated with long term dihydroergotamine use (see WARNINGS:
Fibrotic Complications).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 05-929/S-032, S-033
NDA 09-000/S-022, S-023
NDA 20-148/S-007, S-008
Package Insert
Page 2
DOSAGE AND ADMINISTRATION
D.H.E. 45 (dihydroergotamine mesylate) Injection / Migranal (dihydroergotamine) Nasal Spray,
USP, should not be used for chronic daily administration.
Cafergot Suppositories (NDA 09-000)
CLINICAL PHARMACOLOGY
Pharmacokinetics: Interactions
Pharmacokinetic interactions (increased blood levels of ergotamine) have been reported in patients
treated orally with ergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin,
erythromycin} presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine by the
macrolide. Ergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed
reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.
CONTRAINDICATIONS
Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir,
erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity
(ergotism) characterized by vasospasm and ischemia of the extremities (see PRECAUTIONS: Drug
Interactions), with some cases resulting in amputation. Because of the increased risk for ergotism and
other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other
potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS: CYP 3A4
Inhibitors).
WARNINGS
Fibrotic Complications
There have been a few reports of patients on CAFERGOT (ergotamine tartrate and caffeine) therapy
developing retroperitoneal and/or pleuropulmonary fibrosis. There have also been rare reports of
fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term continuous
use of CAFERGOT (ergotamine tartrate and caffeine). CAFERGOT (ergotamine tartrate) suppositories
should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).
CYP 3A4 Inhibitors
Coadministration of ergotamine with potent CYP 3A4 inhibitors such as protease inhibitors or
macrolide antibiotics has been associated with serious adverse events; for this reason, these drug
should not be given concomitantly with ergotamine (see CONTRAINDICATIONS, and
PRECAUTIONS: Drug Interactions). While these reactions have not been reported with less potent
CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs
are used with ergotamine. Examples of less potent CYP 3A4 inhibitors include: saquinavir,
nefazodone, fluconazole, fluoxetine, grapefruit juice, fluvoxamine, zileuton, metronidazole, and
clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4
of other agents being considered for concomitant use with dihydroergotamine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 05-929/S-032, S-033
NDA 09-000/S-022, S-023
NDA 20-148/S-007, S-008
Package Insert
Page 3
PRECAUTIONS
Drug Interactions
CYP3A4 Inhibitors: see CONTRAINDICATIONS and WARNINGS.
Information for Patients
Administration of CAFERGOT (ergotamine tartrate) suppositories should not exceed the dosing
guidelines and should not be used for chronic daily administration (see DOSAGE AND
ADMINISTRATION).
ADVERSE EVENTS
Fibrotic complications: (see WARNINGS).
DOSAGE AND ADMINISTRATION
CAFERGOT (ergotamine tartrate) suppositories should not be used for chronic daily administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.894876 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/05929s32s33lbl.pdf', 'application_number': 5929, 'submission_type': 'SUPPL ', 'submission_number': 33} |
10,677 |
PHARMACIST: Med Guide PROVIDED SEPARATELY AND
IS TO BE INCLUDED WITH PRESCRIPTION FOR EACH
PATIENT. Also available at www.ovationpbarma.com.
DESOXYN®
Methamphetamine
Hydrochloride
Tablets, USP
only
DESCRIPTION
DESOXYN®
(methamphetamine
hydrochloride
tablets,
USP),
chemically
known
as
(S)-N,α-dimethylbenzeneethanamine
hydrochloride, is a member of the amphetamine group of
sympathomimetic amines. It has the following structural formula:
DESOXYN tablets contain 5 mg of methamphetamine hydrochloride
for oral administration.
Inactive Ingredients:
Corn starch, lactose, sodium paraminobenzoate, stearic acid and talc.
CLINICAL PHARMACOLOGY
Methamphetamine is a sympathomimetic amine with CNS stimulant
activity. Peripheral actions include elevation of systolic and diastolic
blood pressures and weak bronchodilator and respiratory stimulant
action. Drugs of this class used in obesity are commonly known as
“anorectics” or “anorexigenics”. It has not been established, however,
that the action of such drugs in treating obesity is primarily one of
appetite suppression. Other central nervous system actions, or
metabolic effects, may be involved, for example.
Adult obese subjects instructed in dietary management and treated
with “anorectic” drugs, lose more weight on the average than those
treated with placebo and diet, as determined in relatively short-term
clinical trials.
The magnitude of increased weight loss of drug-treated patients over
placebo-treated patients is only a fraction of a pound a week. The rate
of weight loss is greatest in the first weeks of therapy for both drug
and placebo subjects and tends to decrease in succeeding weeks. The
origins of the increased weight loss due to the various possible drug
effects are not established. The amount of weight loss associated with
the use of an “anorectic” drug varies from trial to trial, and the
increased weight loss appears to be related in part to variables other
than the drug prescribed, such as the physician-investigator, the
population treated, and the diet prescribed. Studies do not permit
conclusions as to the relative importance of the drug and non-drug
factors on weight loss.
The natural history of obesity is measured in years, whereas the
studies cited are restricted to a few weeks duration; thus, the total
impact of drug-induced weight loss over that of diet alone must be
considered clinically limited.
The mechanism of action involved in producing the beneficial
behavioral changes seen in hyperkinetic children receiving
methamphetamine is unknown.
In humans, methamphetamine is rapidly absorbed from the
gastrointestinal tract. The primary site of metabolism is in the liver by
aromatic hydroxylation, N-dealkylation and deamination. At least
seven metabolites have been identified in the urine. The biological
half-life has been reported in the range of 4 to 5 hours. Excretion
occurs primarily in the urine and is dependent on urine pH. Alkaline
urine will significantly increase the drug half-life. Approximately
62% of an oral dose is eliminated in the urine within the first 24 hours
with about one-third as intact drug and the remainder as metabolites.
METHAMPHETAMINE HAS A HIGH POTENTIAL FOR
ABUSE. IT SHOULD THUS BE TRIED ONLY IN
WEIGHT REDUCTION PROGRAMS FOR PATIENTS IN
WHOM
ALTERNATIVE
THERAPY
HAS
BEEN
INEFFECTIVE.
ADMINISTRATION
OF
METHAMPHETAMINE FOR PROLONGED PERIODS
OF TIME IN OBESITY MAY LEAD TO DRUG
DEPENDENCE
AND
MUST
BE
AVOIDED.
PARTICULAR ATTENTION SHOULD BE PAID TO THE
POSSIBILITY
OF
SUBJECTS
OBTAINING
METHAMPHETAMINE FOR NON-THERAPEUTIC USE
OR DISTRIBUTION TO OTHERS, AND THE DRUG
SHOULD
BE
PRESCRIBED
OR
DISPENSED
SPARINGLY. MISUSE OF METHAMPHETAMINE MAY
CAUSE
SUDDEN
DEATH
AND
SERIOUS
CARDIOVASCULAR ADVERSE EVENTS.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
Attention Deficit Disorder with Hyperactivity: DESOXYN tablets
are indicated as an integral part of a total treatment program which
typically
includes
other
remedial
measures
(psychological,
educational, social) for a stabilizing effect in children over 6 years of
age with a behavioral syndrome characterized by the following group
of developmentally inappropriate symptoms: moderate to severe
distractibility, short attention span, hyperactivity, emotional lability,
and impulsivity. The diagnosis of this syndrome should not be made
with finality when these symptoms are only of comparatively recent
origin. Nonlocalizing (soft) neurological signs, learning disability,
and abnormal EEG may or may not be present, and a diagnosis of
central nervous system dysfunction may or may not be warranted.
Exogenous Obesity: as a short-term (i.e., a few weeks) adjunct in a
regimen of weight reduction based on caloric restriction, for patients
in whom obesity is refractory to alternative therapy, e.g., repeated
diets, group programs, and other drugs.
The limited usefulness of DESOXYN tablets (see CLINICAL
PHARMACOLOGY) should be weighed against possible risks
inherent in use of the drug, such as those described below.
CONTRAINDICATIONS
DESOXYN tablets are contraindicated during or within 14 days
following the administration of monoamine oxidase inhibitors;
hypertensive crisis may result. It is also contraindicated in patients
with
glaucoma,
advanced
arteriosclerosis,
symptomatic
cardiovascular
disease,
moderate
to
severe
hypertension,
hyperthyroidism or known hypersensitivity or idiosyncrasy to
sympathomimetic amines. Methamphetamine should not be given to
patients who are in an agitated state or who have a history of drug
abuse.
WARNINGS
Tolerance to the anorectic effect usually develops within a few weeks.
When this occurs, the recommended dose should not be exceeded in
an attempt to increase the effect; rather, the drug should be
discontinued (see DRUG ABUSE AND DEPENDENCE).
Serious Cardiovascular Events
Sudden Death and Pre-existing Structural Cardiac Abnormalities
or Other Serious Heart Problems:
· Children and Adolescents: Sudden death has been reported in
association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious
heart problems. Although some serious heart problems alone carry an
increased risk of sudden death, stimulant products generally should
not be used in children or adolescents with known serious structural
cardiac abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or other serious cardiac problems that may place them
at increased vulnerability to the sympathomimetic effects of a
stimulant drug.
· Adults: Sudden deaths, stroke, and myocardial infarction have been
reported in adults taking stimulant drugs at usual doses for ADHD.
Although the role of stimulants in these adult cases is also unknown,
adults have a greater likelihood than children of having serious
structural cardiac abnormalities, cardiomyopathy, serious heart
rhythm abnormalities, coronary artery disease, or other serious
cardiac problems. Adults with such abnormalities should also
generally not be treated with stimulant drugs.
Hypertension and other Cardiovascular Conditions: Stimulant
medications cause a modest increase in average blood pressure (about
2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals
may have larger increases. While the mean changes alone would not
be expected to have short-term consequences, all patients should be
monitored for larger changes in heart rate and blood pressure. Caution
is indicated in treating patients whose underlying medical conditions
might be compromised by increases in blood pressure or heart rate,
e.g., those with pre-existing hypertension, heart failure, recent
myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with
Stimulant Medications: Children, adolescents, or adults who are
being considered for treatment with stimulant medications should
have a careful history (including assessment for a family history of
sudden death or ventricular arrhythmia) and physical exam to assess
for the presence of cardiac disease, and should receive further cardiac
evaluation if findings suggest such disease (e.g., electrocardiogram
and echocardiogram). Patients who develop symptoms such as
exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during stimulant treatment should
undergo a prompt cardiac evaluation.
Psychiatric Adverse Events
Pre-existing Psychosis:
Administration of stimulants may exacerbate symptoms of behavior
disturbance and thought disorder in patients with a pre-existing
psychotic disorder.
Bipolar Illness:
Particular care should be taken in using stimulants to treat ADHD in
patients with comorbid bipolar disorder because of concern for
possible induction of a mixed/manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
depressive symptoms should be adequately screened to determine if
they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide,
bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms: Treatment
emergent psychotic or manic symptoms, e.g., hallucinations,
delusional thinking, or mania in children and adolescents without a
prior history of psychotic illness or mania can be caused by stimulants
at usual doses. If such symptoms occur, consideration should be given
to a possible causal role of the stimulant, and discontinuation of
treatment may be appropriate. In a pooled analysis of multiple short-
term, placebo-controlled studies, such symptoms occurred in about
0.1% (4 patients with events out of 3482 exposed to methylphenidate
or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
Aggression:
Aggressive behavior or hostility is often observed in children and
adolescents with ADHD, and has been reported in clinical trials and
the postmarketing experience of some medications indicated for the
treatment of ADHD. Although there is no systematic evidence that
stimulants cause aggressive behavior or hostility, patients beginning
treatment for ADHD should be monitored for the appearance of or
worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years
who were randomized to either methylphenidate or non-medication
treatment groups over 14 months, as well as in naturalistic subgroups
of newly methylphenidate-treated and non-medication treated
children over 36 months (to the ages of 10 to 13 years), suggests that
consistently medicated children (i.e., treatment for 7 days per week
throughout the year) have a temporary slowing in growth rate (on
average, a total of about 2 cm less growth in height and 2.7 kg less
growth in weight over 3 years), without evidence of growth rebound
during this period of development. Published data are inadequate to
determine whether chronic use of amphetamines may cause a similar
suppression of growth, however, it is anticipated that they likely have
this effect as well. Therefore, growth should be monitored during
treatment with stimulants, and patients who are not growing or
gaining height or weight as expected may need to have their treatment
interrupted.
Seizures
There is some clinical evidence that stimulants may lower the
convulsive threshold in patients with prior history of seizures, in
patients with prior EEG abnormalities in absence of seizures, and,
very rarely, in patients without a history of seizures and no prior EEG
evidence of seizures. In the presence of seizures, the drug should be
discontinued.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been
reported with stimulant treatment.
PRECAUTIONS
General: DESOXYN tablets should be used with caution in patients
with even mild hypertension.
Methamphetamine should not be used to combat fatigue or to replace
rest in normal persons.
Prescribing and dispensing of methamphetamine should be limited to
the smallest amount that is feasible at one time in order to minimize
the possibility of overdosage.
Information for Patients: The patient should be informed that
methamphetamine may impair the ability to engage in potentially
hazardous activities, such as, operating machinery or driving a motor
vehicle.
The patient should be cautioned not to increase dosage, except on
advice of the physician.
Prescribers or other health professionals should inform patients, their
families and their caregivers about the benefits and risks associated
with treatment with methamphetamine and should counsel them it its
appropriate use. A patient Medication Guide is available for
DESOXYN. The prescriber or health professional should instruct
patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients
should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may
have. The complete text of the Medication Guide is available at
www.ovationpharma.com.
Drug Interactions: Insulin requirements in diabetes mellitus may be
altered in association with the use of methamphetamine and the
concomitant dietary regimen.
Methamphetamine
may
decrease
the
hypotensive
effect
of
guanethidine.
DESOXYN should not be used concurrently with monoamine oxidase
inhibitors (see CONTRAINDICATIONS).
Concurrent administration of tricyclic antidepressants and indirect-
acting sympathomimetic amines such as the amphetamines, should be
closely supervised and dosage carefully adjusted.
Phenothiazines are reported in the literature to antagonize the CNS
stimulant action of the amphetamines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug/Laboratory Test Interactions: Literature reports suggest that
amphetamines may be associated with significant elevation of plasma
corticosteroids. This should be considered if determination of plasma
corticosteroid levels is desired in a person receiving amphetamines.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Data are
not available on long-term potential for carcinogenicity, mutagenicity,
or impairment of fertility.
Pregnancy
Teratogenic effects: Pregnancy Category C. Methamphetamine has
been shown to have teratogenic and embryocidal effects in mammals
given high multiples of the human dose. There are no adequate and
well-controlled studies in pregnant women. DESOXYN tablets should
not be used during pregnancy unless the potential benefit justifies the
potential risk to the fetus.
Nonteratogenic effects: Infants born to mothers dependent on
amphetamines have an increased risk of premature delivery and low
birth weight. Also, these infants may experience symptoms of
withdrawal as demonstrated by dysphoria, including agitation and
significant lassitude.
Usage in Nursing Mothers: Amphetamines are excreted in human
milk. Mothers taking amphetamines should be advised to refrain from
nursing.
Pediatric Use: Safety and effectiveness for use as an anorectic agent
in children below the age of 12 years have not been established.
Long-term effects of methamphetamine in children have not been
established (see WARNINGS).
Drug treatment is not indicated in all cases of the behavioral
syndrome characterized by moderate to severe distractibility, short
attention span, hyperactivity, emotional lability and impulsivity. It
should be considered only in light of the complete history and
evaluation of the child. The decision to prescribe DESOXYN tablets
should depend on the physician’s assessment of the chronicity and
severity of the child’s symptoms and their appropriateness for his/her
age. Prescription should not depend solely on the presence of one or
more of the behavioral characteristics.
When these symptoms are associated with acute stress reactions,
treatment with DESOXYN tablets is usually not indicated.
Clinical experience suggests that in psychotic children, administration
of DESOXYN tablets may exacerbate symptoms of behavior
disturbance and thought disorder.
Amphetamines have been reported to exacerbate motor and phonic
tics and Tourette’s syndrome. Therefore, clinical evaluation for tics
and Tourette’s syndrome in children and their families should precede
use of stimulant medications.
Geriatric Use: Clinical Studies of DESOXYN did not include
sufficient numbers of subjects age 65 years and over to determine
whether elderly subjects respond differently from younger subjects.
Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal or cardiac function, and of concomitant
disease or other drug therapy observed in this population.
ADVERSE REACTIONS
The following are adverse reactions in decreasing order of severity
within each category that have been reported:
Cardiovascular: Elevation of blood pressure, tachycardia and
palpitation. Fatal cardiorespiratory arrest has been reported, mostly in
the context of abuse/misuse.
Central Nervous System: Psychotic episodes have been rarely
reported
at
recommended
doses.
Dizziness,
dysphoria,
overstimulation, euphoria, insomnia, tremor, restlessness and
headache. Exacerbation of motor and phonic tics and Tourette’s
syndrome.
Gastrointestinal:
Diarrhea,
constipation,
dryness
of
mouth,
unpleasant taste and other gastrointestinal disturbances.
Hypersensitivity: Urticaria.
Endocrine: Impotence and changes in libido.
Miscellaneous: Suppression of growth has been reported with the
long-term use of stimulants in children (see WARNINGS).
DRUG ABUSE AND DEPENDENCE
Controlled Substance: DESOXYN tablets are subject to control under
DEA schedule II.
Abuse: Methamphetamine has been extensively abused. Tolerance,
extreme psychological dependence, and severe social disability have
occurred. There are reports of patients who have increased the dosage
to many times that recommended. Abrupt cessation following
prolonged high dosage administration results in extreme fatigue and
mental depression; changes are also noted on the sleep EEG.
Manifestations of chronic intoxication with methamphetamine include
severe dermatoses, marked insomnia, irritability, hyperactivity, and
personality changes. The most severe manifestation of chronic
intoxication is psychosis often clinically indistinguishable from
schizophrenia. Abuse and/or misuse of methamphetamine have
resulted in death. Fatal cardiorespiratory arrest has been reported in
the context of abuse and/or misuse of methamphetamine.
OVERDOSAGE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manifestations of acute overdosage with methamphetamine include
restlessness, tremor, hyperreflexia, rapid respiration, confusion,
assaultiveness, hallucinations, panic states, hyperpyrexia, and
rhabdomyolysis. Fatigue and depression usually follow the central
stimulation. Cardiovascular effects include arrhythmias, hypertension
or hypotension, and circulatory collapse. Gastrointestinal symptoms
include nausea, vomiting, diarrhea, and abdominal cramps. Fatal
poisoning usually terminates in convulsions and coma.
Consult with a Certified Poison Control Center regarding treatment
for up to date guidance and advice. Management of acute
methamphetamine intoxication is largely symptomatic and includes
gastric evacuation, administration of activated charcoal, and sedation.
Experience with hemodialysis or peritoneal dialysis is inadequate to
permit recommendations in this regard.
Acidification of urine increases methamphetamine excretion, but is
believed to increase risk of acute renal failure if myoglobinuria is
present. Intravenous phentolamine (Regitine®) has been suggested for
possible
acute,
severe
hypertension,
if
this
complicates
methamphetamine overdosage. Usually a gradual drop in blood
pressure will result when sufficient sedation has been achieved.
Chlorpromazine has been reported to be useful in decreasing CNS
stimulation and sympathomimetic effects.
DOSAGE AND ADMINISTRATION
DESOXYN tablets are given orally.
Methamphetamine should be administered at the lowest effective
dosage, and dosage should be individually adjusted. Late evening
medication should be avoided because of the resulting insomnia.
Attention Deficit Disorder with Hyperactivity: For treatment of
children 6 years or older with a behavioral syndrome characterized
by moderate to severe distractibility, short attention span,
hyperactivity, emotional lability and impulsivity: an initial dose of 5
mg DESOXYN once or twice a day is recommended. Daily dosage
may be raised in increments of 5 mg at weekly intervals until an
optimum clinical response is achieved. The usual effective dose is 20
to 25 mg daily. The total daily dose may be given in two divided
doses daily.
Where
possible,
drug
administration
should
be
interrupted
occasionally to determine if there is a recurrence of behavioral
symptoms sufficient to require continued therapy.
For Obesity: One 5 mg tablet should be taken one-half hour before
each meal. Treatment should not exceed a few weeks in duration.
Methamphetamine is not recommended for use as an anorectic agent
in children under 12 years of age.
HOW SUPPLIED
DESOXYN (methamphetamine hydrochloride tablets, USP) is
supplied as white tablets imprinted with the letters OV on one side
and the number 12 on the opposite side, containing 5 mg
methamphetamine hydrochloride in bottles of 100
(NDC 67386-102-01).
Recommended Storage: Store below 86°F (30°C).
Dispense in a USP tight, light resistant container.
Manufactured by:
Abbott Pharmaceuticals PR Ltd.
Barceloneta, PR 00617
For:
Deerfield, IL 60015, U.S.A.
Revised: March 2007
® Trademark of Ovation Pharmaceuticals. Inc.
03-5554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
DESOXYN®
(Pronounced Dĕ-sŏks-ĭn)
(methamphetamine hydrochloride tablets, USP)
Read the Medication Guide that comes with DESOXYN®
before you or your child
starts taking it and each time you get a refill.
There may be new information. This Medication Guide does not take the place of
talking to your or your child’s doctor about your or your child’s treatment with
DESOXYN.
What is the most important information I should know about DESOXYN?
The following have been reported with use of methamphetamine
hydrochloride and other stimulant medicines.
1. Heart-related problems:
• sudden death in patients who have heart problems or
heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate
Tell your or your child’s doctor if you or your child have any heart problems, heart
defects, high blood pressure, or a family history of these problems.
Your or your child’s doctor should check you or your child carefully for heart
problems before starting DESOXYN.
Your or your child’s doctor should check you or your child’s blood pressure and
heart rate regularly during treatment with DESOXYN.
Call your or your child’s doctor right away if you or your child has any
signs of heart problems such as chest pain, shortness of breath, or fainting
while taking DESOXYN.
2. Mental (Psychiatric) problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing
things that are not true, are suspicious) or new manic
symptoms
Tell your or your child’s doctor about any mental problems you or your child
have, or about a family history of suicide, bipolar illness, or depression.
Call your or your child’s doctor right away if you or your child have any
new or worsening mental symptoms or problems while taking DESOXYN,
especially seeing or hearing things that are not real, believing things that
are not real, or are suspicious.
What is DESOXYN?
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DESOXYN is a central nervous system stimulant prescription medicine. It is
used for the treatment of Attention-Deficit Hyperactivity Disorder; (ADHD).
DESOXYN may help increase attention and decrease impulsiveness and
hyperactivity in patients with ADHD.
DESOXYN should be used as a part of a total treatment program for ADHD that
may include counseling or other therapies.
DESOXYN is also used short-term, along with a low calorie diet, for weight loss
in obese patients who have not been able to lose weight on other therapies.
DESOXYN is a federally controlled substance (CII) because it can be
abused or lead to dependence. Keep DESOXYN in a safe place to prevent
misuse and abuse. Selling or giving away DESOXYN may harm others, and
is against the law.
Tell your or your child’s doctor if you or your child have (or have a family history
of) ever abused or been dependent on alcohol, prescription medicines or street
drugs.
Who should not take DESOXYN?
DESOXYN should not be taken if you or your child:
• have heart disease or hardening of the arteries
• have moderate to severe high blood pressure
• have hyperthyroidism
• have an eye problem called glaucoma
• are agitated
• have a history of drug abuse
• are taking or have taken within the past 14 days an
antidepression medicine called a monoamine oxidase
inhibitor or MAOI.
• are sensitive to, allergic to, or had a reaction to other
stimulant medicines
DESOXYN is not recommended for use in children less than 6 years old in the
treatment of ADHD.
DESOXYN may not be right for you or your child. Before starting DESOXYN
tell your or your child’s doctor about all health conditions (or a family
history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar
illness, or depression
• tics or Tourette’s syndrome
• thyroid problems
• diabetes
• seizures or have had an abnormal brain wave test (EEG)
Tell your or your child’s doctor if you or your child is pregnant, planning to
become pregnant, or breastfeeding.
Can DESOXYN be taken with other medicines?
Tell your or your child’s doctor about all of the medicines that you or your
child take including prescription and nonprescription medicines, vitamins,
and herbal supplements.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DESOXYN and some medicines may interact with each other and cause serious
side effects. Sometimes the doses of other medicines will need to be adjusted
while taking DESOXYN.
Your or your child’s doctor will decide whether DESOXYN can be taken with
other medicines.
(over)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Especially tell your or your child’s doctor if you or your child takes:
• anti-depression medicines including MAOIs
• anti-psychotic medicines
• blood pressure medicines
• insulin
• seizure medicines
Know the medicines that you or your child takes. Keep a list of your medicines
with you to show your doctor and pharmacist.
Do not start any new medicine while taking DESOXYN® without talking to
your or your child’s doctor first.
How should DESOXYN be taken?
• Take DESOXYN exactly as prescribed. Your or your child’s doctor may
adjust the dose until it is right for you or your child.
• DESOXYN is usually taken 1 or 2 times each day.
• From time to time, your or your child’s doctor may stop DESOXYN
treatment for a while to check ADHD symptoms.
• Your or your child’s doctor may do regular checks of the blood, heart,
and blood pressure while taking DESOXYN. Children should have their
height and weight checked often while taking DESOXYN. DESOXYN
treatment may be stopped if a problem is found during these check-ups.
• If you or your child takes too much DESOXYN or overdoses, call
your or your child’s doctor or poison control center right away, or
get emergency treatment.
What are possible side effects of DESOXYN?
See “What is the most important information I should know about
DESOXYN?” for information on reported heart and mental problems.
Other serious side effects include:
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
Common side effects include:
• fast heart beat
• decreased appetite
• tremors
• headache
• trouble sleeping
• dizziness
• stomach upset
• weight loss
• dry mouth
DESOXYN may affect your or your child’s ability to drive or do other dangerous
activities.
Talk to your or your child’s doctor if you or your child has side effects that are
bothersome or do not go away.
This is not a complete list of possible side effects. Ask your or your child’s doctor
or pharmacist for more information.
How should I store DESOXYN?
• Store DESOXYN in a safe place below 86°F (30°C). Protect from light.
• Keep DESOXYN and all medicines out of the reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General information about DESOXYN
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use DESOXYN for a condition for which it was not
prescribed. Do not give DESOXYN to other people, even if they have the same
condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about
DESOXYN. If you would like more information, talk with your or your child’s
doctor. You can ask your or your child’s doctor or pharmacist for information
about DESOXYN that was written for healthcare professionals.
For more information about DESOXYN, contact OVATION Pharmaceuticals at 1-
888-514-5204 or visit www. ovationpharma.com.
What are the ingredients in DESOXYN?
Active Ingredient: methamphetamine hydrochloride
Inactive Ingredients: Corn starch, lactose, sodium paraminobenzoate, stearic
acid and talc
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Deerfield, IL 60015
® Trademark of Ovation Pharmaceuticals, Inc.
Issued: March 2007
03-5554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.926145 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/005378s026lbl.pdf', 'application_number': 5378, 'submission_type': 'SUPPL ', 'submission_number': 26} |
10,679 | NDA 5-939/S-007
Page 3
BAL in Oil Ampules
DIMERCAPROL INJECTION, USP
BAL (2, 3-dimercapto-1-propanol) 10%, Benzyl Benzoate 20%, in Peanut Oil
C3H8OS2 Molecular Weight 124.22
DESCRIPTION
Dimercaprol Injection USP is a colorless or almost colorless liquid chelating agent having a
disagreeable, mercaptan-like odor. Each 1 mL sterile BAL in Oil (Dimercaprol Injection USP)
contains: 100 mg Dimercaprol in 200 mg Benzyl Benzoate and 700 mg Peanut Oil.
CLINICAL PHARMACOLOGY
The sulfhydryl groups of dimercaprol form complexes with certain heavy metals thus preventing or
reversing the metallic binding of sulfhydryl-containing enzymes. The complex is excreted. The
sustained presence of dimercaprol promotes continued excretion of the metallic poisons - arsenic, gold
and mercury. It is also used in combination with Edetate Calcium Disodium Injection USP to promote
the excretion of lead.
INDICATIONS
BAL in Oil (Dimercaprol Injection USP) is indicated in the treatment of arsenic, gold and mercury
poisoning. It is indicated in acute lead poisoning when used concomitantly with Edetate Calcium
Disodium Injection USP.
Dimercaprol Injection USP is effective for use in acute poisoning by mercury salts if therapy is begun
within one or two hours following ingestion. It is not very effective for chronic mercury poisoning.
Dimercaprol Injection USP is of questionable value in poisoning caused by other heavy metals such as
antimony and bismuth. It should not be used in iron, cadmium, or selenium poisoning because the
resulting dimercaprol-metal complexes are more toxic than the metal alone, especially to the kidneys.
CONTRAINDICATIONS
BAL in Oil (Dimercaprol Injection USP) is contraindicated in most instances of hepatic insufficiency
with the exception of postarsenical jaundice. The drug should be discontinued or used only with
extreme caution if acute renal insufficiency develops during therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 5-939/S-007
Page 4
WARNINGS
There may be local pain at the site of the injection. A reaction apparently peculiar to children is fever
which may persist during therapy. It occurs in approximately 30% of children. A transient reduction of
the percentage of polymorphonuclear leukocytes may also be observed.
PRECAUTIONS
Because the dimercaprol-metal complex breaks down easily in an acid medium, production of an
alkaline urine affords protection to the kidney during therapy. Medicinal iron should not be
administered to patients under therapy with BAL in Oil (Dimercaprol Injection USP).
BAL in Oil Ampules is formulated with peanut oil. Peanut oil may cause allergic reactions in some
individuals. Physicians should use caution in prescribing BAL in Oil Ampules for peanut-sensitive
patients. Medication and equipment necessary to treat allergic reactions should be available if the
product is administered to peanut-allergic patients.
Pregnancy Category C
Animal reproduction studies have not been conducted with BAL in Oil. It is also not known whether
BAL in Oil can cause fetal harm when administered to a pregnant woman, or can affect reproduction
capacity. BAL in Oil should be given to a pregnant woman only if clearly needed.
It is not known whether this drug is excreted in human milk. However, because many drugs are
excreted in human milk, caution should be exercised when BAL in Oil is administered to a nursing
woman.
ADVERSE REACTIONS
One of the most consistent responses to Dimercaprol Injection USP is a rise in blood pressure
accompanied by tachycardia. This rise is roughly proportional to the dose administered. Doses larger
than those recommended may cause other transitory signs and symptoms in approximate order of
frequency as follows: (1) nausea and, in some instance, vomiting; (2) headache; (3) a burning sensation
in the lips, mouth and throat; (4) a feeling of constriction, even pain, in the throat, chest, or hands; (5)
conjunctivitis, lacrimation, blepharal spasm, rhinorrhea, and salivation; (6) tingling of the hands; (7) a
burning sensation in the penis; (8) sweating of the forehead, hands and other areas;
(9) abdominal pain; and (10) occasional appearance of painful sterile abscesses. Many of the above
symptoms are accompanied by a feeling of anxiety, weakness, and unrest and often are relieved by
administration of antihistamine.
DRUG ABUSE AND DEPENDENCE
Dimercaprol Injection USP is not a controlled substance listed in any other Drug Enforcement
Administration schedules. Its use is not known to lead to dependence or abuse.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 5-939/S-007
Page 5
OVERDOSE
Dosage exceeding 5 mg/kg will usually be followed by vomiting, convulsions and stupor, beginning
within 30 minutes and subsiding within 6 hours following injection.
AMER. HOSP. FORM. SERV., 64:00, Amer. Soc. Hosp. Pharm., 1977.
DOSAGE AND ADMINISTRATION
By deep intramuscular injection only. For mild arsenic or gold poisoning, 2.5 mg/kg of body weight
four times daily for two days, two times on the third day, and once daily thereafter for ten days; for
severe arsenic or gold poisoning, 3 mg/kg every four hours for two-days, four times on the third day,
then twice daily thereafter for ten days. For mercury poisoning, 5 mg/kg initially, followed by 2.5
mg/kg one or two times daily for ten days. For acute lead encephalopathy, 4 mg/kg body weight is
given alone in the first dose and thereafter at four-hour intervals in combination with Edetate Calcium
Disodium Injection USP administered at a separate site. For less severe poisoning the dose can be
reduced to 3 mg/kg after the first dose. Treatment is maintained for two to seven days depending on
clinical response. Successful treatment depends on beginning injections at the earliest possible moment
and on the use of adequate amounts at frequent intervals. Other supportive measures should always be
used in conjunction with BAL in Oil (Dimercaprol Injection USP) therapy.
BAL in Oil should be inspected visually for particulate matter and discoloration prior to
administration.
HOW SUPPLIED
3 mL (100 mg/mL) ampules, box of 10 (NDC 11098-526-03).
STORAGE: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.]
ANIMAL TOXICOLOGY
The intramuscular LD50 in rats is approximately 105 mg/kg; intraperitoneally 140 mg/kg.
The intraperitoneal LD80 in mice is approximately 125 mg/kg.
JR. PHARM. EXPER. THER. 87, Supplement Aug. 1946.
Manufactured by
[Taylor logo]
Decatur, IL 62522
BL00N
Rev. 10/06
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:34.939356 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/005939s007lbl.pdf', 'application_number': 5939, 'submission_type': 'SUPPL ', 'submission_number': 7} |
10,680 |
Novartis
Methergine®
(methylergonovine maleate)
Tablets, USP
(methylergonovine maleate)
Injection, USP
Rx only
DESCRIPTION
Methergine® (methylergonovine maleate) is a semi-synthetic ergot alkaloid used for the prevention and
control of postpartum hemorrhage.
Methergine is available in sterile ampuls of 1 mL, containing 0.2 mg methylergonovine maleate for
intramuscular or intravenous injection and in tablets for oral ingestion containing 0.2 mg
methylergonovine maleate.
Tablets
Active Ingredient: methylergonovine maleate, USP, 0.2 mg.
Inactive Ingredients: acacia, carnauba wax, D&C Red #7, FD&C Blue #1, gelatin special, lactose,
maleic acid, mixed parabens, povidone, sodium benzoate, sodium hydroxide, starch, stearic acid,
sucrose, talc, and titanium dioxide.
Ampuls: 1 mL, clear, colorless solution.
Active Ingredient: methylergonovine maleate, USP, 0.2 mg.
Inactive Ingredients: maleic acid, 0.10 mg; sodium chloride, 7.0 mg; water for injection, qs to 1 mL.
Chemically, methylergonovine maleate is designated as ergoline-8-carboxamide, 9,10-didehydro-N-[1
(hydroxymethyl)propyl]-6-methyl-, [8β(S)]-, (Z)-2-butenedioate (1:1) (salt).
Its structural formula is
Reference ID: 3150408
structural formula
CLINICAL PHARMACOLOGY
Methergine (methylergonovine maleate) acts directly on the smooth muscle of the uterus and increases
the tone, rate, and amplitude of rhythmic contractions. Thus, it induces a rapid and sustained tetanic
uterotonic effect which shortens the third stage of labor and reduces blood loss. The onset of action after
I.V. administration is immediate; after I.M. administration, 2-5 minutes, and after oral administration, 5
10 minutes.
Pharmacokinetic studies following an I.V. injection have shown that methylergonovine is rapidly
distributed from plasma to peripheral tissues within 2-3 minutes or less. The bioavailability after oral
administration was reported to be about 60% with no accumulation after repeated doses. During
delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly
eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral
administration is probably a result of first-pass metabolism in the liver.
Bioavailability studies conducted in fasting healthy female volunteers have shown that oral absorption
of a 0.2 mg methylergonovine tablet was fairly rapid with a mean peak plasma concentration of 3243 ±
1308 pg/mL observed at 1.12 ± 0.82 hours. For a 0.2 mg intramuscular injection, a mean peak plasma
concentration of 5918 ± 1952 pg/mL was observed at 0.41 ± 0.21 hours. The extent of absorption of the
tablet, based upon methylergonovine plasma concentrations, was found to be equivalent to that of the
I.M. solution given orally, and the extent of oral absorption of the I.M. solution was proportional to the
dose following administration of 0.1, 0.2, and 0.4 mg. When given intramuscularly, the extent of
absorption of Methergine solution was about 25% greater than the tablet. The volume of distribution
(Vdss/F) of methylergonovine was calculated to be 56.1 ± 17.0 liters, and the plasma clearance (CLp/F)
was calculated to be 14.4 ± 4.5 liters per hour. The plasma level decline was biphasic with a mean
elimination half-life of 3.39 hours (range 1.5 to 12.7 hours). A delayed gastrointestinal absorption (Tmax
about 3 hours) of Methergine tablet might be observed in postpartum women during continuous
treatment with this oxytocic agent.
INDICATIONS AND USAGE
Following delivery of the placenta, for routine management of uterine atony, hemorrhage and
subinvolution of the uterus. For control of uterine hemorrhage in the second stage of labor following
delivery of the anterior shoulder.
Reference ID: 3150408
CONTRAINDICATIONS
Hypertension; toxemia; pregnancy; and hypersensitivity.
WARNINGS
General
This drug should not be administered I.V. routinely because of the possibility of inducing sudden
hypertensive and cerebrovascular accidents. If I.V. administration is considered essential as a lifesaving
measure, Methergine (methylergonovine maleate) should be given slowly over a period of no less than
60 seconds with careful monitoring of blood pressure. Intra-arterial or periarterial injection should be
strictly avoided.
Caution should be exercised in the presence of impaired hepatic or renal function.
Breast-feeding
Mothers should not breast-feed during treatment with Methergine. Milk secreted during this period
should be discarded. Methergine may produce adverse effects in the breast-feeding infant. Methergine
may also reduce the yield of breast milk. Mothers should wait at least 12 hours after administration of
the last dose of Methergine before initiating or resuming breast feeding
Coronary artery disease
Patients with coronary artery disease or risk factors for coronary artery disease (e.g., smoking, obesity,
diabetes, high cholesterol) may be more susceptible to developing myocardial ischemia and infarction
associated with methylergonovine-induced vasospasm.
Medication errors
Inadvertent administration of Methergine to newborn infants has been reported. In these cases of
inadvertent neonatal exposure, symptoms such as respiratory depression, convulsions, cyanosis and
oliguria have been reported. Usual treatment is symptomatic. However, in severe cases, respiratory and
cardiovascular support is required.
Methergine has been administered instead of vitamin K and Hepatitis B vaccine, medications which are
routinely administered to the newborn . Due to the potential for accidental neonatal exposure,
Methergine injection should be stored separately from medications intended for neonatal administration.
PRECAUTIONS
General
Caution should be exercised in the presence of sepsis, obliterative vascular disease. Also use with
caution during the second stage of labor. The necessity for manual removal of a retained placenta should
occur only rarely with proper technique and adequate allowance of time for its spontaneous separation.
Reference ID: 3150408
Drug Interactions
CYP 3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors)
There have been rare reports of serious adverse events in connection with the coadministration of certain
ergot alkaloid drugs (e.g., dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting
in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been
no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be
coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors
include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease or reverse
transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g.,
ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with
caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine,
fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should
consider the effects on CYP 3A4 of other agents being considered for concomitant use with
methylergonovine.
CYP3A4 inducers
Drugs (e.g. nevirapine, rifampicin) that are strong inducers of CYP3A4 are likely to decrease the
pharmacological action of Methergine.
Beta-blockers
Caution should be exercised when Methergine is used concurrently with beta-blockers. Concomitant
administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.
Anesthetics
Anesthetics like halothan and methoxyfluran may reduce the oxytocic potency of Methergine.
Glyceryl trinitrate and other antianginal drugs
Methylergonovine maleate produces vasoconstriction and can be expected to reduce the effect of
glyceryl trinitrate and other antianginal drugs.
No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.
Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with
other vasoconstrictors, ergot alkaloids, or prostaglandins.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies have been performed in animals to evaluate carcinogenic potential. The effect of
the drug on mutagenesis or fertility has not been determined.
Pregnancy
Category C. Animal reproductive studies have not been conducted with Methergine. It is also not known
whether methylergonovine maleate can cause fetal harm or can affect reproductive capacity. Use of
Methergine is contraindicated during pregnancy because of its uterotonic effects. (See INDICATIONS
AND USAGE.)
Reference ID: 3150408
Labor and Delivery
The uterotonic effect of Methergine is utilized after delivery to assist involution and decrease
hemorrhage, shortening the third stage of labor.
Nursing Mothers
Mothers should not breast-feed during treatment with Methergine and at least 12 hours after
administration of the last dose. Milk secreted during this period should be discarded.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Methergine did not include sufficient number of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience
has not identified differences in response between the elderly and younger patients. In general dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
ADVERSE REACTIONS
The most common adverse reaction is hypertension associated in several cases with seizure and/or
headache. Hypotension has also been reported. Abdominal pain (caused by uterine contractions), nausea
and vomiting have occurred occasionally. Rarely observed reactions have included: acute myocardial
infarction, transient chest pains, vasoconstriction, vasospasm, coronary arterial spasm, bradycardia,
tachycardia, dyspnea, hematuria, thrombophlebitis, water intoxication, hallucinations, leg cramps,
dizziness, tinnitus, nasal congestion, diarrhea, diaphoresis, palpitation, rash, and foul taste.1
There have been rare isolated reports of anaphylaxis, without a proven causal relationship to the drug
product.
Postmarketing Experience
The following adverse drug reactions have been derived from post-marketing experience with
Methergine via spontaneous case reports. Because these reactions are reported voluntarily from a
population of uncertain size, it is not possible to reliably estimate their frequency which is therefore
categorized as not known.
Nervous system disorders
Cerebrovascular accident, paraesthesia
Cardiac disorders
Ventricular fibrillation, ventricular tachycardia, angina pectoris, atrioventricular block
DRUG ABUSE AND DEPENDENCE
Methergine (methylergonovine maleate) has not been associated with drug abuse or dependence of
either a physical or psychological nature.
Reference ID: 3150408
OVERDOSAGE
Symptoms of acute overdose may include: nausea, vomiting, oliquria, abdominal pain, numbness,
tingling of the extremities, rise in blood pressure, in severe cases followed by hypotension, respiratory
depression, hypothermia, convulsions, and coma.
Because reports of overdosage with Methergine (methylergonovine maleate) are infrequent, the lethal
dose in humans has not been established. The oral LD50 (in mg/kg) for the mouse is 187, the rat 93, and
the rabbit 4.5.2 Several cases of accidental Methergine injection in newborn infants have been reported,
and in such cases 0.2 mg represents an overdose of great magnitude. However, recovery occurred in all
but one case following a period of respiratory depression, hypothermia, hypertonicity with jerking
movements, and convulsions.
Also, several children 1-3 years of age have accidentally ingested up to 10 tablets (2 mg) with no
apparent ill effects. A postpartum patient took 4 tablets at one time in error and reported paresthesias and
clamminess as her only symptoms.
Treatment of acute overdosage is symptomatic and includes the usual procedures of:
1.
removal of offending drug by inducing emesis, gastric lavage, catharsis, and supportive diuresis.
2.
maintenance of adequate pulmonary ventilation, especially if convulsions or coma develop.
3.
correction of hypotension with pressor drugs as needed.
4.
control of convulsions with standard anticonvulsant agents.
5.
control of peripheral vasospasm with warmth to the extremities if needed.3
DOSAGE AND ADMINISTRATION
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Intramuscularly
1 mL, 0.2 mg, after delivery of the anterior shoulder, after delivery of the placenta, or during the
puerperium. May be repeated as required, at intervals of 2-4 hours.
Intravenously
1 mL, 0.2 mg, administered slowly over a period of no less than 60 seconds (See WARNINGS.)
Orally
One tablet, 0.2 mg, 3 or 4 times daily in the puerperium for a maximum of 1 week.
HOW SUPPLIED
Tablets
0.2 mg round, coated, orchid, branded “78-54” one side, “SANDOZ” other side.
Bottles of 100…………………………………………………………..NDC 0078-0054-05
Ampuls
Reference ID: 3150408
1 mL size
Boxes of 20…………………………………………………………….NDC 0078-0053-03
Store and Dispense
Tablets: Store below 25°C (77°F); in tight, light-resistant container.
Ampuls: Store in refrigerator, 2C-8°C (36°F-46°F). Protect from light. Administer only if solution is
clear and colorless. Novartis
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2012-June
Reference ID: 3150408
Novartis
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
IMPORTANT
DRUG
WARNING
RE: MEDICATION ERRORS RELATED TO ACCIDENTAL ADMINISTRATION OF
METHERGINE® (methylergonovine maleate) INJECTION IN NEWBORN INFANTS
June 2012
Dear Healthcare Professional:
Novartis Pharmaceuticals Corporation (“Novartis”) would like to inform you about medication
errors associated with the a c c i d e n t a l administration of Methergine injection in newborn
infants. Methergine is used for the prevention and control of postpartum hemorrhage.
Serious adverse outcomes that have been reported with inadvertent administration of
Methergine to a newborn include respiratory depression, cyanosis, oliguria, and seizures.
Examples of errors are listed below, 1
• Methergine injection intended for the mother has been inadvertently administered to the
newborn in error.
• Methergine injection intended for the mother has been confused with routine injectable
medications intended for the newborns, such as vitamin K injection and Hepatitis B
vaccine.
These errors appear to be 1) due to the mother and newborn both being administered medications
in the same room and/or 2) because the medications can be stored in similar locations such as a
refrigerator attached to an automatic dispensing machine where medications for the mother and
newborn are stored together. Therefore, the following recommendations are suggested:
• Methergine injection should be physically separated from other injectable pediatric
medications, such as Hepatitis B vaccine and vitamin K. Having separate bins in one
refrigerator may not ensure enough separation because there is still a possibility that
Methergine injection, Hepatitis B vaccine or other medication could be placed in the
wrong bin. Separate refrigerators or automated dispensing machines for the mother and
newborn medications may be considered, if feasible.
• Administering medications to newborn in a setting other than in the mother's room. This
could be a separate unit where all routine newborn medications are administered or a
separate room on the Labor and Delivery unit where routine medications for newborns
are administered.
1 Cases have been reported to FDA, Novartis, and Quantros MedMarx
Reference ID: 3150408
Novartis
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
Please note that this presentation of the risk profile for Methergine is not comprehensive. Please
refer to the enclosed Methergine full Prescribing Information for a complete discussion of the
risks associated with Methergine.
To report adverse events potentially associated with Methergine, please call Novartis
Pharmaceuticals Corporation at 1-888-NOW-NOVA (1-888-669-6682).
Alternatively, adverse event information may be reported to FDA’s MedWatch Reporting
System by:
Phone at 1-800-FDA-1088 (1-800-332-1088)
Facsimile at 1-800-FDA-0178 (1-800-332-0178)
Mail using FDA Form 3500 located at http://www.fda.gov/medwatch
Please contact Novartis at 1-888-NOW-NOVA (1-888-669-6682) if you have any questions
about Methergine or this information.
Sincerely,
Enclosure: Methergine – Full Prescribing Information
Page 2 of 2
Reference ID: 3150408
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DOLOPHINE safely and effectively. See full prescribing information for
DOLOPHINE.
DOLOPHINE® (methadone hydrochloride) tablets, for oral use, CII
Initial U.S. Approval: 1947
WARNING: ABUSE POTENTIAL, LIFE-THREATENING
RESPIRATORY DEPRESSION, LIFE-THREATENING QT
PROLONGATION, ACCIDENTAL EXPOSURE, and TREATMENT
FOR OPIOID ADDICTION
See full prescribing information for complete boxed warning
DOLOPHINE contains methadone, a Schedule II controlled
substance. Monitor for signs of misuse, abuse, and addiction during
DOLOPHINE therapy. (5.1, 9)
Fatal respiratory depression may occur, with highest risk at initiation
and with dose increases. Instruct patients on proper administration
of DOLOPHINE to reduce the risk. (5.2)
QT interval prolongation and serious arrhythmia (torsades de
pointes) have occurred during treatment with methadone. (5.3)
Accidental ingestion of DOLOPHINE can result in fatal overdose of
methadone, especially in children. (5.4)
Methadone products, when used for the treatment of opioid addiction
in detoxification or maintenance programs, shall be dispensed only
by certified opioid treatment programs as stipulated in 42 CFR 8.12.
(1)
----------------------------RECENT MAJOR CHANGES--------------------------
Boxed Warning
07/2012
Indications and Usage (1)
07/2012
Dosage and Administration (2)
07/2012
Contraindications (4)
07/2012
Warnings and Precautions (5)
07/2012
----------------------------INDICATIONS AND USAGE--------------------------
DOLOPHINE is an opioid agonist indicated for the:
Management of moderate to severe pain when a continuous, around-the
clock opioid analgesic is needed for an extended period of time,
Detoxification treatment of opioid addiction (heroin or other morphine-
like drugs), and
Maintenance treatment of opioid addiction (heroin or other morphine-
like drugs), in conjunction with appropriate social and medical services.
(1)
----------------------DOSAGE AND ADMINISTRATION----------------------
Management of Pain: Individualize dosing based on patient’s prior
analgesic treatment experience, and titrate as needed to provide adequate
analgesia and minimize adverse reactions. (2.1, 2.2, 2.3). The usual
starting dose in opioid non-tolerant patients is 2.5 to 10 mg every 8 to 12
hours, slowly titrated to effect. (2.1)
Initiation of detoxification and maintenance treatment: A single dose of
20 to 30 mg may be sufficient to suppress withdrawal syndrome. (2.4)
Do not abruptly discontinue DOLOPHINE in a physically dependent
patient. (2.3, 5.12)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Tablets: 5 mg and 10 mg. (3)
-------------------------------CONTRAINDICATIONS-----------------------------
Significant respiratory depression (4)
Acute or severe bronchial asthma (4)
Known or suspected paralytic ileus (4)
Hypersensitivity to methadone (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Respiratory Depression: The peak respiratory depressant effect typically
occurs later, and persists longer than the peak analgesic effect, which
can contribute to iatrogenic overdose. Patients who are tolerant to other
opioids may be incompletely tolerant to DOLOPHINE. (5.2)
May cause QT interval prolongation and serious arrhythmia. (5.3)
Elderly, cachectic, and debilitated patients, and patients with chronic
pulmonary disease: Monitor closely because of increased risk of
respiratory depression. (5.5, 5.6)
Interaction with CNS depressants: Consider dose reduction of one or
both drugs because of additive effects. (5.7, 7.2)
Hypotensive effect: Monitor during dose initiation and titration (5.8)
Patients with head injury or increased intracranial pressure: Monitor for
sedation and respiratory depression. Avoid use of DOLOPHINE in
patients with impaired consciousness or coma susceptible to intracranial
effects of CO2 retention. (5.9)
------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions are: lightheadedness, dizziness, sedation,
nausea, vomiting, and sweating. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Roxane
Laboratories, Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
------------------------------DRUG INTERACTIONS------------------------------
CYP3A4 Inducers: Increased risk of more rapid metabolism and
decreased effects of methadone. (7.1)
CYP3A4 Inhibitors: Increased risk of reduced metabolism and
methadone toxicity. (7.1)
Anti-retroviral Agents: May result in increased clearance and decreased
plasma levels of methadone or in certain cases, increased plasma levels
and risk of toxicity. (7.1)
Potentially Arrhythmogenic Agents: Extreme caution is necessary when
any drug known to have the potential to prolong the QT interval is
prescribed in conjunction with methadone. (7.3)
Opioid antagonists, partial agonists, mixed agonist/antagonist opioid
analgesics: Avoid use with DOLOPHINE because they may reduce
analgesic effect of DOLOPHINE or precipitate withdrawal symptoms.
(5.12, 7.4)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing mothers: Methadone has been detected in human milk. Closely
monitor infants of nursing women receiving DOLOPHINE. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 07/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Initial Dosing for Management of Pain
2.2 Titration and Maintenance of Therapy for Pain
2.3 Discontinuation of DOLOPHINE for Pain
2.4 Induction/Initial Dosing for Detoxification and Maintenance Treatment
of Opioid Addiction
2.5 Titration and Maintenance Treatment of Opioid Dependence
Detoxification
2.6 Medically Supervised Withdrawal After a Period of Maintenance
Treatment for Opioid Addiction
2.7 Risk of Relapse in Patients on Methadone Maintenance Treatment of
Opioid Addiction
2.8 Considerations for Management of Acute Pain During Methadone
Maintenance Treatment
2.9 Dosage Adjustment During Pregnancy
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
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5 WARNINGS AND PRECAUTIONS
5.1 Abuse Potential
5.2 Life-Threatening Respiratory Depression
5.3 Life-Threatening QT Prolongation
5.4 Accidental Exposure
5.5 Elderly, Cachectic, and Debilitated Patients
5.6 Use in Patients with Chronic Pulmonary Disease
5.7 Interactions with CNS Depressants and Illicit Drugs
5.8 Hypotensive Effect
5.9 Use in Patients with Head Injury or Increased Intracranial Pressure
5.10 Use in Patients with Gastrointestinal Conditions
5.11 Use in Patients with Convulsive or Seizure Disorders
5.12 Avoidance of Withdrawal
5.13 Driving and Operating Machinery
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
7.1 Cytochrome P450 Interactions
7.2 CNS Depressants
7.3 Potentially Arrhythmogenic Agents
7.4 Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists
7.5 Antidepressants
7.6 Anticholinergics
7.7 Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
FULL PRESCRIBING INFORMATION
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Neonatal Opioid Withdrawal Syndrome
8.7 Renal Impairment
8.8 Hepatic Impairment
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 Storage and Handling
16. 2 How Supplied
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed
WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE
THREATENING QT PROLONGATION, ACCIDENTAL EXPOSURE, and TREATMENT FOR OPIOID
ADDICTION
Abuse Potential
DOLOPHINE contains methadone, an opioid agonist and Schedule II controlled substance with an abuse
liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions (5.1)]. Assess each
patient’s risk for opioid abuse or addiction prior to prescribing DOLOPHINE. The risk for opioid abuse is
increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or
addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving
DOLOPHINE for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9)].
Life-threatening Respiratory Depression
Respiratory depression, including fatal cases, have been reported during initiation and conversion of patients to
DOLOPHINE, and even when the drug has been used as recommended and not misused or abused [see
Warnings and Precautions (5.2)]. Proper dosing and titration are essential and DOLOPHINE should only be
prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management
of chronic pain. Monitor for respiratory depression, especially during initiation of DOLOPHINE or following a
dose increase. The peak respiratory depressant effect of DOLOPHINE occurs later, and persists longer than
the peak analgesic effect, especially during the initial dosing period.
Life-threatening QT Prolongation
QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with
methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone,
although cases have been reported in patients receiving doses commonly used for maintenance treatment of
opioid addiction. Closely monitor patients for changes in cardiac rhythm during initiation and titration of
DOLOPHINE.
Accidental Exposure
Accidental ingestion of DOLOPHINE, especially in children, can result in a fatal overdose of methadone [see
Warnings and Precautions (5.4)].
Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction
For detoxification and maintenance of opioid dependence, methadone should be administered in accordance
with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration
Reference ID: 3154841
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[see Indications and Usage (1)].
1 INDICATIONS AND USAGE
DOLOPHINE is indicated for the:
Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an
extended period of time.
Detoxification treatment of opioid addiction (heroin or other morphine-like drugs).
Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate
social and medical services.
Limitations of Use
DOLOPHINE is not for use:
As an as-needed (prn) analgesic
For pain that is mild or not expected to persist for an extended period of time
For acute pain
For postoperative pain
Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction
Code of Federal Regulations, Title 42, Sec 8
Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be
dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the
program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the
designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according
to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for
important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment.
Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply,
revocation of the program approval, and injunction precluding operation of the program.
Regulatory Exceptions To The General Requirement For Certification To Provide Opioid Agonist Treatment: During
inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR
1306.07(c)), to facilitate the treatment of the primary admitting diagnosis).
During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an
appropriately licensed facility (pursuant to 21CFR 1306.07(b)).
2 DOSAGE AND ADMINISTRATION
2.1 Initial Dosing for Management of Pain
Consider the following factors when selecting an initial dose of DOLOPHINE:
Total daily dose, potency, and prior opioid the patient has been taking previously;
Patient's degree of opioid experience and opioid tolerance;
General condition and medical status of the patient;
Concurrent medication;
Type and severity of the patient's pain
In addition, consider the following important factors that differentiate methadone from other opioid analgesics:
Reference ID: 3154841
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The peak respiratory depressant effect of methadone occurs later and persists longer than its peak analgesic effect.
A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise.
Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid
agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other
opioid agonists.
There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based
equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.
The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma
elimination half-life is 8 to 59 hours.
With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential
toxicity.
Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of
dosing.
Methadone has a narrow therapeutic index, especially when combined with other drugs.
DOLOPHINE is administered at a frequency of every 8 to 12 hours.
Use of DOLOPHINE as the First Opioid Analgesic
Initiate DOLOPHINE therapy with small doses, no more than 2.5 mg to 10 mg every 8 to 12 hours. To maintain adequate
analgesia, more frequent administration may be required. Monitor patients closely for signs of respiratory and central
nervous system depression.
Conversion from Parenteral Methadone
Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral
methadone).
Conversion from Other Opioids
Published conversion ratios for other opioids to methadone may overestimate the dose of methadone. Deaths have
occurred in opioid-tolerant patients during conversion to methadone.
Conversion ratios in many commonly used equianalgesic dosing tables are based on single-dose comparisons in patients
not tolerant to the effects of opioid and do not apply in the setting of conversion of opioid tolerant patients to methadone
for chronic use. In the case of a single-dose administration, the onset, duration, and potency of analgesic action of
methadone are comparable to those of morphine. Incomplete cross tolerance can result in greater than expected toxicity.
In addition, with repeated dosing, the potency of methadone increases due to systemic accumulation.
The conversion ratio between methadone and other opioids varies dramatically depending on baseline opioid (morphine
equivalent) use as shown in the table below.
The dose conversion scheme below (Table 1) is derived from various consensus guidelines for converting chronic pain
patients to methadone from morphine. Consult published conversion guidelines to determine the equivalent morphine
dose for patients converting from other opioids.
Table 1: Oral Morphine to Oral Methadone Conversion for Chronic Administration
Estimated Daily Oral
Total Daily Baseline
Methadone Requirement
Oral
as Percent of Total Daily
Morphine Dose
Morphine Dose
< 100 mg
20% to 30%
100 to 300 mg
10% to 20%
300 to 600 mg
8% to 12%
600 mg to 1000 mg
5% to 10%
> 1000 mg
< 5 %
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Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for
administration every 8 hours, divide total daily methadone dose by 3).
Equianalgesic methadone dosing varies not only between patients, but also within the same patient, depending on baseline
morphine (or other opioid) dose. Table 1 has been included in order to illustrate this concept and to provide a
recommendation for a starting point for opioid conversion.
In addition to these recommendations, take into consideration the patient’s:
prior opioid exposure
general medical condition
concomitant medication
anticipated breakthrough medication use
2.2 Titration and Maintenance of Therapy for Pain
Individually titrate DOLOPHINE to a dose that provides adequate analgesia and minimizes adverse reactions.
Continually reevaluate patients receiving DOLOPHINE to assess the maintenance of pain control and the relative
incidence of adverse reactions. During chronic therapy, especially for non-cancer-related pain (or pain associated with
other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.
If the level of pain increases, attempt to identify the source of increased pain, while adjusting the DOLOPHINE dose to
decrease the level of pain. Because steady-state plasma concentrations are approximated within 24 to 36 hours,
DOLOPHINE dosage adjustments may be done every 1 to 2 days. Patients who experience breakthrough pain may require
dosage adjustment or rescue medication with a small dose of an immediate-release medication.
If signs of excessive opioid-related adverse reactions are observed, the next dose may be reduced. Adjust the dose to
obtain an appropriate balance between management of pain and opioid-related adverse reactions. The endpoint of titration
is achievement of adequate pain relief, balanced against tolerability of opioid adverse reactions.
If a patient develops intolerable opioid related adverse reactions, the methadone dose, or dosing interval, may need to be
adjusted.
2.3 Discontinuation of DOLOPHINE for Pain
When a patient no longer requires therapy with DOLOPHINE for pain, use a gradual downward titration, of the dose
every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly
discontinue DOLOPHINE.
2.4 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction
For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the
treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.
Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the
patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of DOLOPHINE will often be sufficient to
suppress withdrawal symptoms. The initial dose should not exceed 30 mg.
To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have
been reached. Provide an additional 5 to 10 mg of DOLOPHINE if withdrawal symptoms have not been suppressed or if
symptoms reappear.
The total daily dose of DOLOPHINE on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose
over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to
4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several
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days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will
“hold” for a longer period of time as tissue stores of methadone accumulate.
Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not
taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment
episodes or dollars spent per day on illicit drug use.
Short-term Detoxification
For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total
daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization,
gradually decrease the dose of DOLOPHINE. Decrease the dose of DOLOPHINE on a daily basis or at 2-day intervals,
keeping the amount of DOLOPHINE sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients
may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.
2.5 Titration and Maintenance Treatment of Opioid Dependence Detoxification
Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug
hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is
tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120
mg/day.
2.6 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction
There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised
withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or
maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of
relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
2.7 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction
Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence
(9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in
susceptible patients.
2.8 Considerations for Management of Acute Pain During Methadone Maintenance Treatment
Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain
or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be
administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients
with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance
patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant
patients due to the opioid tolerance induced by methadone.
2.9 Dosage Adjustment During Pregnancy
Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be
increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies
the potential risk to the fetus [see Use in Specific Populations (8.1)].
3 DOSAGE FORMS AND STRENGTHS
DOLOPHINE Tablets are available in 5mg and 10 mg dosage strengths. The 5 mg tablets are round, white and are
debossed with tablet identifier “54 162” on one side and scored on the other side. The 10 mg tablets are round, white and
are debossed with tablet identifier “54 549” on one side and scored on the other side.
4 CONTRAINDICATIONS
DOLOPHINE is contraindicated in patients with:
Significant respiratory depression
Reference ID: 3154841
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Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
Known or suspected paralytic ileus
Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions (6)]
5 WARNINGS AND PRECAUTIONS
5.1 Abuse Potential
DOLOPHINE contains methadone, an opioid agonist and a Schedule II controlled substance. Methadone can be abused in
a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing
DOLOPHINE in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about
abuse, addiction, and diversion should not, however, prevent the proper management of pain.
For each patient prescribed DOLOPHINE for pain management, assess the risk for opioid abuse or addiction prior to
prescribing DOLOPHINE. The risk for opioid abuse is increased in patients with a personal or family history of substance
abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk
may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive
monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse,
abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.
Contact local state professional licensing board or state controlled substances authority for information on how to prevent
and detect abuse or diversion of this product.
5.2 Life-Threatening Respiratory Depression
Respiratory depression is the primary risk of DOLOPHINE. Respiratory depression, if not immediately recognized and
treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to
breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated
by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate
the sedating effects of opioids. Management of respiratory depression may include close observation, supportive
measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)].
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of DOLOPHINE, the
risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of
methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing
period. Closely monitor patients for respiratory depression when initiating therapy with DOLOPHINE and following dose
increases.
Instruct patients against use by individuals other than the patient for whom DOLOPHINE was prescribed and to keep
DOLOPHINE out of the reach of children, as such inappropriate use may result in fatal respiratory depression.
To reduce the risk of respiratory depression, proper dosing and titration of DOLOPHINE are essential [see Dosage and
Administration (2.1, 2.2)]. Overestimating the DOLOPHINE dose when converting patients from another opioid product
can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of methadone when
used as recommended and not misused or abused.
To further reduce the risk of respiratory depression, consider the following:
Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of
particular concern for patients tolerant to other mu-opioid agonists who are being converted to treatment with
methadone, thus making determination of dosing during opioid treatment conversion complex. Deaths have been
reported during conversion from chronic, high-dose treatment with other opioid agonists.
Proper dosing and titration are essential and DOLOPHINE should be prescribed only by healthcare professionals
who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone, especially when converting
patients from other opioids, and in the use of potent opioids for the management of chronic pain.
DOLOPHINE is contraindicated in patients with respiratory depression and in patients with conditions that increase
the risk of life-threatening respiratory depression [see Contraindications (4)].
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5.3 Life-Threatening QT Prolongation
Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with
methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200
mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases
have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most
patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as
hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the
potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been
confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro
studies.
Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy,
concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking
medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history
who have received high doses of methadone.
Evaluate patients developing QT prolongation while on methadone treatment for the presence of modifiable risk factors,
such as concomitant medications with cardiac effects, drugs that might cause electrolyte abnormalities, and drugs that
might act as inhibitors of methadone metabolism.
Only initiate DOLOPHINE therapy for pain in patients for whom the anticipated benefit outweighs the risk of QT
prolongation and development of dysrhythmias that have been reported with high doses of methadone.
The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied.
5.4 Accidental Exposure
Accidental ingestion of DOLOPHINE, especially in children, can result in a fatal overdose of methadone. DOLOPHINE
should be kept out of reach of children to prevent accidental ingestion.
5.5 Elderly, Cachectic, and Debilitated Patients
Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered
pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients.
Therefore, monitor such patients closely, particularly when initiating and titrating DOLOPHINE and when DOLOPHINE
is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].
5.6 Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a
substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory
depression, particularly when initiating therapy and titrating with DOLOPHINE, as in these patients, even usual
therapeutic doses of DOLOPHINE may decrease respiratory drive to the point of apnea [see Warnings and Precautions
(5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible.
5.7 Interactions with CNS Depressants and Illicit Drugs
Hypotension, profound sedation, coma, or respiratory depression may result if DOLOPHINE is used concomitantly with
other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of
DOLOPHINE in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s
response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s
use, if any, of alcohol or illicit drugs that cause CNS depression. If DOLOPHINE therapy is to be initiated in a patient
taking a CNS depressant, start with a lower DOLOPHINE dose than usual and monitor patients for signs of sedation and
respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)].
Deaths associated with illicit use of methadone have frequently involved concomitant benzodiazepine abuse.
5.8 Hypotensive Effect
DOLOPHINE may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There
is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood
volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see
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Drug Interactions (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of
DOLOPHINE.
5.9 Use in Patients with Head Injury or Increased Intracranial Pressure
Monitor patients taking DOLOPHINE who may be susceptible to the intracranial effects of CO2 retention (e.g., those with
evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly
when initiating therapy with DOLOPHINE. DOLOPHINE may reduce respiratory drive, and the resultant CO2 retention
can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.
Avoid the use of DOLOPHINE in patients with impaired consciousness or coma.
5.10 Use in Patients with Gastrointestinal Conditions
DOLOPHINE is contraindicated in patients with paralytic ileus. Avoid the use of DOLOPHINE in patients with other
gastrointestinal obstruction.
The methadone in DOLOPHINE may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease,
including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.
5.11 Use in Patients with Convulsive or Seizure Disorders
The methadone in DOLOPHINE may aggravate convulsions in patients with convulsive disorders, and may induce or
aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure
control during DOLOPHINE therapy.
5.12 Avoidance of Withdrawal
Avoid the use of partial agonists or mixed agonist/antagonist analgesics (i.e., buprenorphine, pentazocine, nalbuphine, and
butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic,
including DOLOPHINE. In these patients, partial agonists or mixed agonists/antagonists analgesics may reduce the
analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.4)].
When discontinuing DOLOPHINE, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly
discontinue DOLOPHINE.
5.13 Driving and Operating Machinery
DOLOPHINE may impair the mental or physical abilities needed to perform potentially hazardous activities such as
driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant
to the effects of DOLOPHINE and know how they will react to the medication.
6 ADVERSE REACTIONS
The following serious adverse reactions and/or conditions are discussed elsewhere in the labeling:
Respiratory Depression [see Warnings and Precautions (5.2)]
QT Prolongation [see Warnings and Precautions (5.3)]
Chronic Pulmonary Disease [see Warnings and Precautions (5.6)]
Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions (5.9)]
Interactions with Other CNS Depressants [see Warnings and Precautions (5.7)]
Hypotensive Effect [see Warnings and Precautions (5.8)]
Gastrointestinal Effects [see Warnings and Precautions (5.10)]
Seizures [see Warnings and Precautions (5.11)]
The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension.
Respiratory arrest, shock, cardiac arrest, and death have occurred.
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The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and
sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain.
In such individuals, lower doses are advisable.
Other adverse reactions include the following:
Body as a Whole: asthenia (weakness), edema, headache
Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles,
flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion,
tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia
Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures,
visual disturbances
Endocrine: hypogonadism
Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis
Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis
Metabolic: hypokalemia, hypomagnesemia, weight gain
Renal: antidiuretic effect, urinary retention or hesitancy
Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal vesicle and prostate
secretions, decreased sperm motility, abnormalities in sperm morphology
Respiratory: pulmonary edema, respiratory depression
Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria
Hypersensitivity: Anaphylaxis has been reported with ingredients contained in DOLOPHINE. Advise patients how to
recognize such a reaction and when to seek medical attention.
Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone maintenance
treatment program, constipation and sweating often persist and hypogonadism, decreased serum testosterone and
reproductive effects are thought to be related to chronic opioid use.
DOLOPHINE for the Detoxification and Maintenance Treatment of Opioid Dependence
During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit opioids and
may have opioid withdrawal symptoms. Monitor patients for signs and symptoms including: lacrimation, rhinorrhea,
sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability,
weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching
and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose
adjustment as indicated.
7 DRUG INTERACTIONS
7.1 Cytochrome P450 Interactions
Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6,
CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6 [see Clinical Pharmacology (12.3)].
Cytochrome P450 Inducers
Concurrent use of DOLOPHINE and drugs that induce cytochrome P450 enzymes (such as rifampicin, phenytoin,
phenobarbital, carbamazepine, and St. John’s Wort) may result in reduced efficacy of DOLOPHINE and could precipitate
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a withdrawal syndrome. Closely monitor patients receiving DOLOPHINE and an enzyme inducer closely for signs of
withdrawal and adjust the DOLOPHINE dose accordingly.
Cytochrome P450 Inhibitors
Coadministration of drugs that inhibit CYP3A4 (such as ketoconazole, itraconazole, voriconazole, clarithromycin,
erythromycin, telithromycin) and/or drugs that inhibit CYP2C9 (such as sertraline and fluvoxamine) may cause decreased
clearance of methadone, which could increase or prolong adverse drug effects and may cause fatal respiratory depression
[see Clinical Pharmacology (12.3)]. Monitor patients closely for signs of respiratory or central nervous system depression
when DOLOPHINE is prescribed with a CYP3A4 inhibitor and reduce the dosage if necessary.
Paradoxical Effects of Antiretroviral Agents on DOLOPHINE
Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as
abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir,
saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of
methadone. This may result in reduced efficacy of DOLOPHINE and could precipitate a withdrawal syndrome. Monitor
methadone-maintained patients receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects
and adjust the methadone dose accordingly.
Effects of DOLOPHINE on Antiretroviral Agents
Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the
concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for
didanosine. Methadone disposition was not substantially altered.
Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in
toxic effects.
7.2 CNS Depressants
Concurrent use of DOLOPHINE and other central nervous system (CNS) depressants (e.g. sedatives, hypnotics, general
anesthetics, antiemetics, phenothiazines, other tranquilizers, alcohol and drugs of abuse) can increase the risk of
respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and
DOLOPHINE for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce
the initial dose of one or both agents. Deaths have been reported when methadone has been abused in conjunction with
benzodiazepines.
7.3 Potentially Arrhythmogenic Agents
Monitor patients closely for cardiac conduction changes when any drug known to have the potential to prolong the QT
interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of
methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic
antidepressants, and calcium channel blockers.
Similarly, monitor patients closely when prescribing methadone concomitantly with drugs capable of inducing electrolyte
disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval, including diuretics, laxatives, and, in rare
cases, mineralocorticoid hormones.
7.4 Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists
As with other mu-agonists, patients maintained on methadone may experience withdrawal symptoms when given opioid
antagonists, mixed agonist/antagonists, and partial agonists. Examples of such agents are naloxone, naltrexone,
pentazocine, nalbuphine, butorphanol, and buprenorphine.
7.5 Antidepressants
Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients
concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar
reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients,
a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the
course of several hours while the patient’s condition and vital signs are carefully observed.
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Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.
7.6 Anticholinergics
Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioids may result in increased
risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of
urinary retention or reduced gastric motility when DOLOPHINE is used concurrently with anticholinergic drugs.
7.7 Laboratory Test Interactions
False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine,
doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies of methadone use in pregnant women. Methadone has been shown to be
teratogenic in the hamster at doses 2 times the human daily oral dose (120 mg/day on a mg/m2 basis) and in mice at doses
equivalent to the human daily oral dose (120 mg/day on a mg/m2 basis). Increased neonatal mortality and significant
differences in behavioral tests have been reported in the offspring of male rodents that were treated with methadone prior
to mating when compared to control animals. Methadone has been detected in human amniotic fluid and cord plasma at
concentrations proportional to maternal plasma and in newborn urine at lower concentrations than corresponding maternal
urine. Methadone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dosage Adjustment during Pregnancy
The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Total
body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non
pregnant opioid-dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The
decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during
pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the
dosing interval decreased in pregnant patients receiving methadone to achieve therapeutic effect [see Dosage and
Administration (2.9)].
Effects on the Neonate
Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of
withdrawal symptoms in infants is usually in the first days after birth. Monitor newborn for withdrawal signs and
symptoms including: irritability and excessive crying, tremors, hyper-active reflexes, increased respiratory rate, increased
stools, sneezing, yawning, vomiting, and fever. The intensity of the neonatal withdrawal syndrome does not always
correlate with the maternal dose or the duration of maternal exposure. The duration of the withdrawal signs may vary
from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal
[see Use in Specific Populations (8.6)].
Human Data
Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs; the
relevance of these findings to pain patients prescribed methadone during pregnancy is unclear. Pregnant women involved
in methadone maintenance programs have been reported to have significantly improved prenatal care leading to
significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared
to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial
circumstances, complicate the interpretation of investigations of the children of women who take methadone during
pregnancy. Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal
exposure appears to occur after the first trimester of pregnancy.
A review of published data on experiences with methadone use during pregnancy by the Teratogen Information System
(TERIS) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is
unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as “limited to fair”). However, the
data are insufficient to state that there is no risk (TERIS, last reviewed October, 2002). A retrospective case series of 101
pregnant, opioid-dependent women who underwent inpatient opioid detoxification with methadone did not demonstrate
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any increased risk of miscarriage in the 2nd trimester or premature delivery in the 3rd trimester. Recent studies suggest an
increased risk of premature delivery in opioid-dependent women exposed to methadone during pregnancy, although the
presence of confounding factors makes it difficult to determine a causal relationship. Several studies have suggested that
infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have
decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. This growth
deficit does not appear to persist into later childhood. Children prenatally exposed to methadone have been reported to
demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. In addition, several studies
suggest that children born to opioid-dependent women exposed to methadone during pregnancy may have an increased
risk of visual development anomalies; however, a causal relationship has not been assigned.
There are conflicting reports on whether Sudden Infant Death Syndrome occurs with an increased incidence in infants
born to women treated with methadone during pregnancy. Abnormal fetal non-stress tests have been reported to occur
more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy
compared to controls.
Animal Data
Methadone did not produce teratogenic effects in rat or rabbit models. Methadone produced teratogenic effects following
large doses, in the guinea pig, hamster and mouse. One published study in pregnant hamsters indicated that a single
subcutaneous dose of methadone ranging from 31 to 185 mg/kg (the 31 mg/kg dose is approximately 2 times a human
daily oral dose of 120 mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease in the number of fetuses per
litter and an increase in the percentage of fetuses exhibiting congenital malformations described as exencephaly,
cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In another
study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated exposure was approximately equivalent to a
human daily oral dose of 120 mg/day on a mg/m2 basis) administered on day 9 of gestation in mice also produced
exencephaly in 11% of the embryos. However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg
(estimated exposure was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m2
basis) administered during days 6 to 15 and 6 to 18, respectively.
Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with
methadone prior to mating. In these studies, the female rodents were not treated with methadone, indicating paternally-
mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-
naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced
thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male
and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that
paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Other animal
studies have reported that perinatal exposure to opioids including methadone alters neuronal development and behavior in
the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity,
thermal regulation, nociceptive responses and sensitivity to drugs.
Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring,
including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems. Studies demonstrated that
methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any
adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental
toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal”
methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported
clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction
and in males receiving chronic intraspinal opioids.
Additional data have been published indicating that methadone treatment of male rats (once a day for three consecutive
days) increased embryolethality and neonatal mortality. Examination of uterine contents of methadone-naïve female mice
bred to methadone-treated mice indicated that methadone treatment produced an increase in the rate of preimplantation
deaths in all post-meiotic states.
8.2 Labor and Delivery
DOLOPHINE is not for use in women during and immediately prior to labor, where shorter acting analgesics or other
analgesic techniques are more appropriate [see Indications and Usage (1)]. Opioid analgesics may prolong labor by
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temporarily reducing the strength, duration and frequency of uterine contractions. However, these effects are not
consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
Opioids with mixed agonist-antagonist properties should not be used for pain control during labor in patients chronically
treated with methadone as they may precipitate acute withdrawal [see Drug Interactions (7.4)].
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Closely
observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid
antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate.
8.3 Nursing Mothers
Methadone is secreted into human milk. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to
570 mcg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug
concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based
on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is
approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some
infants whose mothers were taking methadone. Cases of sedation and respiratory depression in infants exposed to
methadone through breast milk have been reported. Caution should be exercised when methadone is administered to a
nursing woman.
Advise women who are being treated with methadone and who are breastfeeding or express a desire to breastfeed of the
presence of methadone in human milk. Instruct breastfeeding mothers how to identify respiratory depression and sedation
in their babies and when it may be necessary to contact their healthcare provider or seek immediate medical care.
Breastfed infants of mothers using methadone should be weaned gradually to prevent development of withdrawal
symptoms in the infant.
8.4 Pediatric Use
The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not
been established.
8.5 Geriatric Use
Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they
respond differently compared to younger subjects. Other reported clinical experience has not identified differences in
responses between elderly and younger patients. In general, start elderly patients at the low end of the dosing range, taking
into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other
drug therapy in geriatric patients. Closely monitor elderly patients for signs of respiratory and central nervous system
depression.
8.6 Neonatal Opioid Withdrawal Syndrome
Chronic maternal use of methadone during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal
withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting,
diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the
drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid
withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated
according to protocols developed by neonatology experts.
8.7 Renal Impairment
Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Since
unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses
and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous
system depression.
8.8 Hepatic Impairment
Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by
hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone
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after multiple dosing. Start these patients on lower doses and titrate slowly while carefully monitoring for signs of
respiratory and central nervous system depression.
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled
substance. Methadone and other opioids used in analgesia have the potential for being abused and are subject to criminal
diversion [see Warnings and Precautions (5.1)].
9.2 Abuse
All patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since
use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding
psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a
prescription or over-the counter drug to get ”high”, or the use of steroids for performance enhancement and muscle build
up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance
use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful
consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and
sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or
visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost
prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for
other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common
among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can
be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that
addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In
addition, abuse of opioids can occur in the absence of true addiction.
DOLOPHINE, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-
keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is
strongly advised.
Abuse of DOLOPHINE poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone
with alcohol and other substances. Methadone is for oral use only and must not be injected. Parenteral drug abuse is
commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper
dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit
respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.6)].
9.3 Dependence
Both tolerance and physical dependence can develop during chronic opioid therapy.
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Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of
disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and
may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a
drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g.,
naloxone, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical
dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
DOLOPHINE should not be abruptly discontinued [see Dosage and Administration (2.3)]. If DOLOPHINE is abruptly
discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can
characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis.
Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal
cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory
difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.6)].
10 OVERDOSAGE
Clinical Symptoms
Acute overdosage of methadone is manifested by respiratory depression, somnolence progressing to stupor or coma,
maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and sometimes, bradycardia and
hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and
death may occur.
Treatment of Overdose
In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or
controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management
of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support
techniques.
The opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose.
Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression
secondary to methadone overdose. Such agents should be administered cautiously to patients who are known, or suspected
to be, physically dependent on DOLOPHINE. In such cases, an abrupt or complete reversal of opioid effects may
precipitate an acute withdrawal syndrome.
Because the duration of reversal would be expected to be less than the duration of action of methadone in DOLOPHINE,
carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists
is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information.
In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute
withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of
the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent
patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the
antagonist.
11 DESCRIPTION
Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride.
Methadone hydrochloride is a white, crystalline material that is water-soluble. Its molecular formula is C21H27NO• HCl
and it has a molecular weight of 345.91. Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in
water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5
and 6.5.
Reference ID: 3154841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
It has the following structural formula: structural formula
Each DOLOPHINE tablet contains 5 or 10 mg of methadone hydrochloride, USP and the following inactive ingredients:
magnesium stearate, microcrystalline cellulose, and starch.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those
of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle.
The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction.
The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is
slower, the course is more prolonged, and the symptoms are less severe.
Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The
contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have
been shown to produce neurotoxic effects in animals.
12.3 Pharmacokinetics
Absorption
Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma
concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known.
However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations
ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the
bioavailability of methadone has not been evaluated.
Distribution
Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma,
methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk,
amniotic fluid and umbilical cord plasma.
Metabolism
Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3
diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser
extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites,
which are excreted mainly in the urine. Methadone appears to be a substrate for P-glycoprotein but its pharmacokinetics
do not appear to be significantly altered in case of P-glycoprotein polymorphism or inhibition.
Excretion
The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion.
Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged
between 1.4 and 126 L/h, and the terminal half-life (T1/2) was highly variable and ranged between 8 to 59 hours in
different studies. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in
plasma. Also, since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release
from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.
Drug Interactions
Cytochrome P450 Interactions
Reference ID: 3154841
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Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6,
CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers may
result in more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP
inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz,
nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to
reduce the plasma levels of methadone, possibly due to CYP induction activity [see Drug Interactions (7.1)]. Therefore,
drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to
evaluate individual response to drug therapy.
Cytochrome P450 Inducers
The following drug interactions were reported following coadministration of methadone with known inducers of
cytochrome P450 enzymes:
Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked
reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.
Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250
mg twice daily initially for 1 day followed by 300 mg daily for 3 to 4 days) resulted in an approximately 50% reduction in
methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence
of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin
administration.
St. John’s Wort, Phenobarbital, Carbamazepine: Administration of methadone with other CYP3A4 inducers may result in
withdrawal symptoms.
Cytochrome P450 Inhibitors
Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit
CYP3A4 activity may cause decreased clearance of methadone.
Voriconazole: Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12
hours for 4 days) increased the peak plasma concentration (Cmax) and AUC of (R)-methadone by 31% and 47%,
respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg daily. The Cmax and AUC of (S)
methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been
associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to
methadone is recommended during coadministration. Dose reduction of methadone may be needed [see Drug Interactions
(7.1)].
Antiretroviral drugs:
Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir
combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to
CYP induction activity.
Abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir,
saquinavir+ritonavir,tipranvir+ritonavir combination: Coadministration of these anti-retroviral agents resulted in
increased clearance or decreased plasma levels of methadone [see Drug Interactions (7.1)].
Didanosine and Stavudine: Methadone decreased the AUC and peak levels for didanosine and stavudine, with a more
significant decrease for didanosine. Methadone disposition was not substantially altered [see Drug Interactions (7.1)].
Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions
(7.1)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Reference ID: 3154841
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats following dietary administration of two
doses of methadone HCl have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day methadone for two years.
These doses were approximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a body surface area basis
(mg/m2). There was a significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60
mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence
of neoplasms in male rats. Due to decreased food consumption in males at the high dose, male rats consumed 16
mg/kg/day and 28 mg/kg/day of methadone for two years. These doses were approximately 1.3 and 2.3 times a human
daily oral dose of 120 mg/day, based on body surface area comparison. In contrast, female rats consumed 46 mg/kg/day or
88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day,
based on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a treatment-
related increase in the incidence of neoplasms in either male or female rats.
Mutagenesis
There are several published reports on the potential genetic toxicity of methadone. Methadone tested positive in the in
vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally,
methadone tested positive in the E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward
mutation assays. In contrast, methadone tested negative in tests for chromosome breakage and disjunction and sex-linked
recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures.
Fertility
Published animal studies show that methadone treatment of males can alter reproductive function. Methadone produces a
significant regression of sex accessory organs and testes of male mice and rats.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 Storage and Handling
DOLOPHINE contains methadone which is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone,
and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. DOLOPHINE
may be targeted for theft and diversion by criminals [see Warnings and Precautions (5.1)].
Dispense in a tight, light-resistant container as defined in the USP/NF.
Store at 25ºC (77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
16. 2 How Supplied
DOLOPHINE Tablets, USP
5 mg Tablets: round, white tablets debossed with tablet identifier 54 162 on one side and scored on the other side.
NDC 0054-4218-25: Bottles of 100 tablets.
10 mg Tablets: round, white tablet debossed with tablet identifier 54 549 on one side and scored on the other side.
NDC 0054-4219-25: Bottles of 100 tablets.
DEA order form required.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide)
See FDA-approved patient labeling (Medication Guide)
Abuse Potential
Inform patients that DOLOPHINE contains methadone, a Schedule II controlled substance that is subject to abuse.
Instruct patients not to share DOLOPHINE with others and to take steps to protect DOLOPHINE from theft or misuse.
Life-threatening Respiratory Depression
Reference ID: 3154841
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting DOLOPHINE or
when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they
are experiencing breathing difficulties.
Symptoms of Arrhythmia
Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as
palpitations, near syncope, or syncope) when taking methadone.
Accidental Exposure
Instruct patients to take steps to store DOLOPHINE securely. Accidental exposure, especially in children, may result in
serious harm or death. Advise patients to dispose of unused DOLOPHINE by flushing the tablets down the toilet.
Risks from Concomitant Use of Alcohol and other CNS Depressants
Inform patients that the concomitant use of alcohol with DOLOPHINE can increase the risk of life-threatening respiratory
depression. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter drug
products that contain alcohol, during treatment with DOLOPHINE.
Inform patients that potentially serious additive effects may occur if DOLOPHINE is used with other CNS depressants,
and not to use such drugs unless supervised by a health care provider.
Important Administration Instructions
Instruct patients how to properly take DOLOPHINE, including the following:
Using DOLOPHINE exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory
depression)
Not discontinuing DOLOPHINE without first discussing the need for a tapering regimen with the prescriber
Hypotension
Inform patients that DOLOPHINE may cause orthostatic hypotension and syncope. Instruct patients how to recognize
symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or
lie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery
Inform patients that DOLOPHINE may impair the ability to perform potentially hazardous activities such as driving a car
or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the
medication.
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical
attention.
Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained in DOLOPHINE. Advise patients how to
recognize such a reaction and when to seek medical attention.
Pregnancy
Advise female patients that DOLOPHINE can cause fetal harm and to inform the prescriber if they are pregnant or plan to
become pregnant.
Breastfeeding
Instruct nursing mothers using DOLOPHINE to watch for signs of methadone toxicity in their infants, which include
increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing
mothers to talk to the baby’s healthcare provider immediately if they notice these signs. If they cannot reach the
healthcare provider right away, instruct them to take the baby to the emergency room or call 911 (or local emergency
services).
Roxane Laboratories, Inc.
Reference ID: 3154841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Columbus, Ohio 43216
4077444//04
© RLI, 2012
Reference ID: 3154841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
DOLOPHINE® (DOL-o-feen), (Methadone hydrochloride) Tablets, CII
DOLOPHINE is:
A strong prescription pain medicine that contains methadone, an opioid (narcotic) that is used to
treat moderate to severe around-the-clock pain.
Used to manage drug addiction.
Important info
rmation about DOLOPHINE:
Get emerge
ncy help right away if you take too much DOLOPHINE (overdose). DOLOPHINE overdose
can cause life threateni
ng breathing problems that can lead to death.
Never gi ve anyone else your DOLOPHINE. They could die from taking it. Store DOLOPHINE away from
children and in a sa
fe place to prevent stealing or abuse. Selling or giving away DOLOPHINE is against
the law.
Do not take DOLOPHINE if you have:
Severe asthma, trouble breathing, or other lung problems.
A bowel blockage or have narrowing of the stomach or intestines.
Before tak ing DOLOPHINE, tell your healthcare provider if you have a history of:
head inju ry, seizures
● heart, liver, kidney, thyroid problems
problems u
rinating
● pancreas or gallbladder problems
abuse of street or prescription drugs, alcohol addiction, or mental health problems.
Tell your healthcare provider if you are:
pregnant or planning to become pregnant. DOLOPHINE may harm your unborn baby.
breastfeeding. DOLOPHINE passes into breast milk and may harm your baby.
taking prescription or over-the-counter medicines, vitamins, or herbal supplements.
When taking DOLOPHINE:
Do not change your dose. Take DOLOPHINE exactly as prescribed by your healthcare provider.
Do not ta
ke more than your prescribed dose in 24 hours. If you take DOLOPHINE for pain and miss
a dose, take DOLOPHINE as soon as possible and then take your next dose 8 or 12 hours later as
directed by your healthcare provider. If it is almost time for your next dose, skip the missed dose
and go back to your regular dosing schedule.
If you take DOLOPHINE for opioid addiction, take your next dose the following day as scheduled.
Do not ta
ke extra doses. Taking more than the prescribed dose may cause you to overdose
because DO
LOPHINE builds up in your body over time.
Call your h
ealthcare provider if the dose you are taking does not control your pain.
Do not st
op taking DOLOPHINE without talking to your healthcare p
rovider.
After yo u stop taking DOLOPHINE, flush any unused tablets down the toilet.
While taking DOLOPHINE Do Not:
Drive or operate heavy machinery, until you know how DOLOPHINE affects you. DOLOPHINE can
make you sleepy, dizzy, or lightheaded.
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.
The possible side effects of DOLOPHINE are:
● constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness. Call your healthcare provider
if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or
throat, extreme drowsiness, or you are feeling faint.
These are not all the possible side effects of DOLOPHINE. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to
dailymed.nlm.nih.gov
Manufactured by: Roxane Laboratories, Inc., Columbus, Ohio 43216, www.Roxane.com, or call 1-800-962-8364 company logo
This Medication Guide has been approved by the U.S. FDA. Issue: July 2012
Reference ID: 3154841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
| custom-source | 2025-02-12T13:43:35.322421 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/006134s031lbl.pdf', 'application_number': 6134, 'submission_type': 'SUPPL ', 'submission_number': 31} |
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