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KADIAN - morphine sulfate capsule, extended release
Physicians Total Care, Inc.

40-9068
KADIAN® C-II
(morphine sulfate extended-release)
Capsules
Revised – January 2008
KADIAN® 10 mg Capsules
KADIAN® 20 mg
Capsules
KADIAN® 30 mg Capsules
KADIAN® 50 mg Capsules
KADIAN® 60 mg
Capsules
KADIAN® 80 mg Capsules
KADIAN® 100 mg Capsules
KADIAN® 200 mg
Capsules

BOXED WARNING SECTION
KADIAN® contains morphine sulfate, an opioid
agonist and a Schedule II controlled substance, with an abuse liability similar
to other opioid analgesics. KADIAN® can be abused in a manner similar to other
opioid agonists, legal or illicit. This should be considered when prescribing or
dispensing KADIAN® in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse or diversion.

KADIAN® capsules are an extended-release oral formulation of
morphine sulfate 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.

KADIAN® Capsules are NOT for use as a prn analgesic.

KADIAN® 100 mg and 200 mg Capsules ARE FOR USE IN
OPIOID-TOLERANT PATIENTS ONLY.  Ingestion of these capsules or of the pellets
within the capsules may cause fatal respiratory depression when administered to
patients not already tolerant to high doses of opioids.  KADIAN® CAPSULES ARE TO
BE SWALLOWED WHOLE OR THE CONTENTS OF THE CAPSULES SPRINKLED ON APPLE SAUCE.
THE PELLETS IN THE CAPSULES ARE NOT TO BE CHEWED, CRUSHED, OR DISSOLVED DUE TO
THE RISK OF RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF
MORPHINE.

DESCRIPTION

KADIAN® (morphine sulfate) capsules are an opioid analgesic
supplied in 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg, and 200 mg
strengths for oral administration.

Chemically, morphine sulfate is 7,8-didehydro-4,5
α-epoxy-17-methyl-morphinan-3,6 α-diol sulfate (2:1) (salt) pentahydrate and has
the following structural formula:

Morphine sulfate is an odorless, white, crystalline powder with a bitter
taste and a molecular weight of 758 (as the sulfate).  It has a solubility of 1
in 21 parts of water and 1 in 1000 parts of alcohol, but is practically
insoluble in chloroform or ether. The octanol: water partition coefficient of
morphine is 1.42 at physiologic pH and the pKb is 7.9 for
the tertiary nitrogen (mostly ionized at pH 7.4).

Each KADIAN® extended-release capsule contains either 10 mg, 20 mg, 30 mg, 50
mg, 60 mg, 80 mg, 100 mg, or 200 mg of Morphine Sulfate USP and the following
inactive ingredients common to all strengths:  hypromellose, ethylcellulose,
methacrylic acid copolymer, polyethylene glycol, diethyl phthalate, talc, corn
starch, and sucrose.  The capsule shells contain gelatin, silicon dioxide,
sodium lauryl sulfate, titanium dioxide, and black ink, D&C red #28,
FD&C blue #1 (10 mg), D&C yellow #10 (20 mg), FD&C red #3, FD&C
blue #1 (30 mg), D&C red #28, FD&C red #40, FD&C blue #1 (50 mg),
D&C red #28, FD&C red #40, FD&C blue #1 (60 mg), FD&C blue #1,
FD&C red #40, FD&C yellow #6 (80 mg), D&C yellow #10, FD&C blue
#1 (100 mg), black iron oxide, yellow iron oxide, red iron oxide (200 mg).

CLINICAL PHARMACOLOGY

Morphine is a natural product that is the prototype for the class
of natural and synthetic opioid analgesics. Opioids produce a wide spectrum of
pharmacologic effects including analgesia, dysphoria, euphoria, somnolence,
respiratory depression, diminished gastrointestinal motility, altered
circulatory dynamics, histamine release and physical dependence.

Morphine produces both its therapeutic and its adverse effects by interaction
with one or more classes of specific opioid receptors located throughout the
body.  Morphine acts as a pure agonist, binding with and activating opioid
receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the
ventro-medial medulla and the spinal cord to produce analgesia.

Effects on the Central Nervous System
The principal actions of therapeutic value of morphine are
analgesia and sedation (i.e., sleepiness and anxiolysis). The precise mechanism
of the analgesic action is unknown.  However, specific CNS opiate receptors and
endogenous compounds with morphine-like activity have been identified throughout
the brain and spinal cord and are likely to play a role in the expression of
analgesic effects.  Morphine produces respiratory depression by direct action on
brainstem respiratory centers.  The mechanism of respiratory depression involves
a reduction in the responsiveness of the brainstem respiratory centers to
increases in carbon dioxide tension, and to electrical stimulation.  Morphine
depresses the cough reflex by direct effect on the cough center in the medulla.
Antitussive effects may occur with doses lower than those usually required for
analgesia.  Morphine causes miosis, even in total darkness, and little tolerance
develops to this effect.  Pinpoint pupils are a sign of opioid overdose but are
not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may
produce similar findings).  Marked mydriasis rather than miosis may be seen with
worsening hypoxia in the setting of KADIAN® overdose (See  OVERDOSAGE).

Effects on the Gastrointestinal Tract and Other Smooth
Muscle
Gastric, biliary and pancreatic secretions are decreased by
morphine.  Morphine causes a reduction in motility associated with an increase
in tone in the antrum of the stomach and duodenum.  Digestion of food in the
small intestine is delayed and propulsive contractions are decreased.
Propulsive peristaltic waves in the colon are decreased, while tone is increased
to the point of spasm. The end result is constipation.  Morphine can cause a
marked increase in biliary tract pressure as a result of spasm of the sphincter
of Oddi.

Effects on the Cardiovascular System
Morphine produces peripheral vasodilation which may result in
orthostatic hypotension or syncope.  Release of histamine may be induced by
morphine and can contribute to opioid-induced hypotension. Manifestations of
histamine release and/or peripheral vasodilation may include pruritus, flushing,
red eyes and sweating.

Pharmacodynamics
Plasma Level-Analgesia Relationships
In any particular
patient, both analgesic effects and plasma morphine concentrations are related
to the morphine dose.

While plasma morphine-efficacy relationships can be demonstrated in
non-tolerant individuals, they are influenced by a wide variety of factors and
are not generally useful as a guide to the clinical use of morphine. The
effective dose in opioid-tolerant patients may be 10-50 times as great (or
greater) than the appropriate dose for opioid-naive individuals.  Dosages of
morphine should be chosen and must be titrated on the basis of clinical
evaluation of the patient and the balance between therapeutic and adverse
effects.

For any fixed dose and dosing interval, KADIAN® will have, at steady-state, a
lower Cmax and a higher Cmin than
conventional morphine.

Pharmacokinetics
KADIAN® capsules contain polymer coated extended-release pellets
of morphine sulfate that release morphine significantly more slowly than from
conventional oral preparations. KADIAN® activity is primarily due to morphine.
One metabolite, morphine-6-glucuronide, has been shown to have analgesic
activity, but does not readily cross the blood-brain barrier.

Following oral administration of morphine, the extent of absorption is
essentially the same for immediate or extended-release formulations, although
the time to peak blood level (Tmax) will be longer and
the Cmax will be lower for formulations that delay the
release of morphine in the gastrointestinal tract.

Elimination of morphine is primarily via hepatic metabolism to glucuronide
metabolites (55 to 65%) which are then renally excreted. The terminal half-life
of morphine is 2 to 4 hours, however, a longer term half-life of about 15 hours
has been reported in studies where blood has been sampled up to 48 hours.

The single-dose pharmacokinetics of KADIAN® are linear over the dosage range
of 30 to 100 mg. The single dose and multiple dose pharmacokinetic parameters of
KADIAN® in normal volunteers are summarized in Table 1.

Table 1: Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose study in normal volunteers and a multiple dose study in patients with cancer pain.

Regimen/
Dosage Form

AUC#,+
(ng.h/mL)

Cmax+
(ng/mL)

Tmax
(h)

Cmin+
(ng/mL)

Fluctuation*

Single Dose (n=24)

KADIAN® Capsule

271.0 (19.4)

15.6 (24.4)

8.6 (41.1)

na^

na

Extended-Release Tablet

304.3 (19.1)

30.5 (32.1)

2.5 (52.6)

na

na

Morphine Solution

362.4 (42.6)

64.4 (38.2)

0.9 (55.8)

na

na

Multiple Dose (n=24)

KADIAN® Capsule q24h

500.9 (38.6)

37.3 (37.7)

10.3 (32.2)

9.9 (52.3)

3.0 (45.5)

Extended-Release Tablet q12h

457.3 (40.2)

36.9 (42.0)

4.4 (53.0)

7.6 (60.3)

4.1 (51.5)

#  For single dose AUC = AUC0-48h, for multiple dose AUC = AUC0-24h at steady state
+  For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to
100 mg per 24 hours
*  Steady-state fluctuation in plasma concentrations = Cmax- Cmin/Cmin
^  Not applicable

Absorption
Following the administration of oral morphine solution,
approximately 50% of the morphine absorbed reaches the systemic circulation
within 30 minutes.  However, following the administration of an equal amount of
KADIAN® to healthy volunteers, this occurs, on average, after 8 hours. As with
most forms of oral morphine, because of pre-systemic elimination, only about 20
to 40% of the administered dose reaches the systemic circulation.

Food Effects: While concurrent administration of
food slows the rate of absorption of KADIAN®, the extent of absorption is not
affected and KADIAN® can be administered without regard to meals.

Steady State: When KADIAN® is given on a fixed
dosing regimen to patients with chronic pain due to malignancy, steady state is
achieved in about two days.  At steady state, KADIAN® will have a significantly
lower Cmax and a higher Cmin than
equivalent doses of oral morphine solution and some other extended-release
preparations (see Graph 1).

Graph 1 (Study # MOB-1/90): Mean steady state plasma
morphine concentrations for KADIAN® (twice a day), extended-release morphine
tablet (twice a day) and oral morphine solution (every 4 hours); plasma
concentrations are normalized to 100 mg every 24 hours, (n=24).

When given once-daily (every 24 hours) to 24 patients with malignancy,
KADIAN® had a similar Cmax and higher Cmin at steady state in clinical usage, when compared to
twice-daily (every 12 hours) extended-release morphine tablets, given at an
equivalent total daily dosage (see Graph 2 and Table 1). Drug-disease
interactions are frequently seen in the older and more gravely ill patients, and
may result in both altered absorption and reduced clearance as compared to
normal volunteers (see Geriatric, Hepatic Failure, and Renal Insufficiency
sections).

Graph 2 (Study # MOR-9/92): Dose normalized mean
steady state plasma morphine concentrations for KADIAN® (once a day), and an
equivalent dose of a 12-hour, extended-release morphine tablet given twice a
day.  Plasma concentrations are normalized to 100 mg every 24 hours, (n=24).

Distribution
Once absorbed, morphine is distributed to skeletal muscle,
kidneys, liver, intestinal tract, lungs, spleen and brain.  The volume of
distribution of morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35%
reversibly bound to plasma proteins.  Although the primary site of action of
morphine is in the CNS, only small quantities pass the blood-brain barrier.
Morphine also crosses the placental membranes (see PRECAUTIONS-Pregnancy) and has
been found in breast milk (see PRECAUTIONS-Nursing
Mothers).

Metabolism
The major pathway of the detoxification of morphine is
conjugation, either with D-glucuronic acid in the liver to produce glucuronides
or with sulfuric acid to give morphine-3-etheral sulfate.  Although a small
fraction (less than 5%) of morphine is demethylated, for all practical purposes,
virtually all morphine is converted to glucuronide metabolites including
morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5
to 15%). Studies in healthy subjects and cancer patients have shown that the
glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar
after both single doses and at steady state for KADIAN®, 12-hour
extended-release morphine sulfate tablets and morphine sulfate solution.

M3G has no significant analgesic activity. M6G has been shown to have opioid
agonist and analgesic activity in humans.

Excretion
Approximately 10% of morphine dose is excreted unchanged in the
urine.  Most of the dose is excreted in the urine as M3G and M6G. A small amount
of the glucuronide metabolites is excreted in the bile and there is some minor
enterohepatic cycling.  Seven to 10% of administered morphine is excreted in the
feces.

The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective
terminal half-life of morphine after IV administration is reported to be
approximately 2.0 hours.  Longer plasma sampling in some studies suggests a
longer terminal half-life of morphine of about 15 hours.

Special PopulationsGeriatric
The elderly may have increased sensitivity to morphine and may
achieve higher and more variable serum levels than younger patients.  In adults,
the duration of analgesia increases progressively with age, though the degree of
analgesia remains unchanged.  KADIAN® pharmacokinetics have not been
investigated in elderly patients (>65 years) although such patients were
included in the clinical studies.

Nursing Mothers
Morphine is excreted in the maternal milk, and the milk to plasma
morphine AUC ratio is about 2.5:1. The amount of morphine received by the infant
depends on the maternal plasma concentration, amount of milk ingested by the
infant, and the extent of first pass metabolism.

Pediatric
Infants under 1 month of age have a prolonged elimination
half-life and decreased clearance relative to older infants and pediatric
patients. The clearance of morphine and its elimination half-life begin to
approach adult values by the second month of life. Pediatric patients old enough
to take capsules should have pharmacokinetic parameters similar to adults, dosed
on a per kilogram basis (see PRECAUTIONS-Pediatric
Use).

Gender
No meaningful differences between male and female patients were
demonstrated in the analysis of the pharmacokinetic data from clinical
studies.

Race
Pharmacokinetic differences due to race may exist.  Chinese
subjects given intravenous morphine in one study had a higher clearance when
compared to caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80
mL/min).

Hepatic Failure
The pharmacokinetics of morphine were found to be significantly
altered in individuals with alcoholic cirrhosis. The clearance was found to
decrease with a corresponding increase in half-life. The M3G and M6G to morphine
plasma AUC ratios also decreased in these patients indicating a decrease in
metabolic activity.

Renal Insufficiency
The pharmacokinetics of morphine are altered in renal failure
patients.  AUC is increased and clearance is decreased.  The metabolites, M3G
and M6G accumulate several fold in renal failure patients compared with healthy
subjects.

Drug-Drug Interactions
The known drug interactions involving morphine are
pharmacodynamic, not pharmacokinetic (see PRECAUTIONS-Drug Interactions).

INDICATIONS AND USAGE

KADIAN® Capsules are an extended-release oral formulation of
morphine sulfate 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 (see CLINICAL
PHARMACOLOGY).

KADIAN® Capsules are NOT intended for use as a prn
analgesic.

KADIAN® is not indicated for pain in the immediate postoperative period (the
first 12-24 hours following surgery), or if the pain is mild or not expected to
persist for an extended period of time. KADIAN® is only indicated for
postoperative use if the patient is already receiving the drug prior to surgery
or if the postoperative pain is expected to be moderate to severe and persist
for an extended period of time. Physicians should individualize treatment,
moving from parenteral to oral analgesics as appropriate. (See American Pain
Society guidelines.)

CONTRAINDICATIONS

KADIAN® is contraindicated in patients with a known
hypersensitivity to morphine, morphine salts or any of the capsule components,
or in any situation where opioids are contraindicated.  This includes in
patients with respiratory depression (in the absence of resuscitative equipment
or in unmonitored settings), and in patients with acute or severe bronchial
asthma or hypercarbia.

KADIAN® is contraindicated in any patient who has or is suspected of having
paralytic ileus.

WARNINGS

KADIAN® Capsules are to be swallowed whole and
are not to be chewed, crushed, or dissolved.  Taking chewed, crushed, or
dissolved KADIAN® Capsules leads to rapid release and absorption of a
potentially fatal dose of morphine.

KADIAN® 100 mg and 200 mg Capsules ARE FOR USE IN
OPIOID-TOLERANT PATIENTS ONLY.  This capsule strength may cause fatal
respiratory depression when ingested or administered to patients who are not
previously exposed to opioids.

Care should be taken in the prescribing of this capsule
strength.  Patients should be instructed against use by individuals other than
the patient for whom it was prescribed, as such inappropriate use may have
severe medical consequences, including death.

Misuse, Abuse and Diversion of Opioids
KADIAN® contains morphine an opioid agonist and a Schedule II
controlled substance.  Opioid agonists have the potential for being abused and
are sought by drug abusers and people with addiction disorders and are subject
to criminal diversion.

Morphine can be abused in a manner similar to other opioid agonists, legal or
illicit.  This should be considered when prescribing or dispensing KADIAN® in
situations where the physician or pharmacist is concerned about an increased
risk of misuse, abuse, or diversion.

Abuse of KADIAN® by crushing, chewing, snorting or injecting the dissolved
product will result in the uncontrolled delivery of the opioid and pose a
significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND DEPENDENCE)

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
KADIAN® may be expected to have additive effects when used in
conjunction with alcohol, other opioids, or illicit drugs that cause central
nervous system depression because respiratory depression, hypotension, and
profound sedation or coma may result.

Impaired Respiration
Respiratory depression is the chief hazard of all morphine
preparations.  Respiratory depression occurs more frequently in elderly and
debilitated patients, and those suffering from conditions accompanied by
hypoxia, hypercapnia, or upper airway obstruction (when even moderate
therapeutic doses may significantly decrease pulmonary ventilation).

KADIAN® should be used with extreme caution in patients with chronic
obstructive pulmonary disease or cor pulmonale, and in patients having a
substantially decreased respiratory reserve (e.g. severe kyphoscoliosis),
hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients,
even usual therapeutic doses of morphine may increase airway resistance and
decrease respiratory drive to the point of apnea.  In these patients,
alternative non-opioid analgesics should be considered, and opioids should be
employed only under careful medical supervision at the lowest effective
dose.

Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of morphine with carbon
dioxide retention and secondary elevation of cerebrospinal fluid pressure may be
markedly exaggerated in the presence of head injury, other intracranial lesions,
or a pre-existing increase in intracranial pressure. KADIAN® produces effects
which may obscure neurologic signs of further increases in pressure in patients
with head injuries.  Morphine should only be administered under such
circumstances when considered essential and then with extreme care.

Hypotensive Effect
KADIAN® may cause severe hypotension.  There is an added risk to
individuals whose ability to maintain blood pressure has already been
compromised by a reduced blood volume, or a concurrent administration of drugs
such as phenothiazines or general anesthetics. (See also PRECAUTIONS-Drug Interactions.)
KADIAN® may produce orthostatic hypotension and syncope in ambulatory
patients.

KADIAN®, like all opioid analgesics, should be administered with caution to
patients in circulatory shock, as vasodilation produced by the drug may further
reduce cardiac output and blood pressure.

Interactions with other CNS Depressants
KADIAN® should be used with great caution and in reduced dosage
in patients who are concurrently receiving other central nervous system
depressants including sedatives or hypnotics, general anesthetics,
phenothiazines, other tranquilizers, and alcohol because respiratory depression,
hypotension, and profound sedation or coma may result.

Gastrointestinal Obstruction
KADIAN® should not be given to patients with gastrointestinal
obstruction, particularly paralytic ileus, as there is a risk of the product
remaining in the stomach for an extended period and the subsequent release of a
bolus of morphine when normal gut motility is restored.  As with other solid
morphine formulations diarrhea may reduce morphine absorption.

Other
Although extremely rare, cases of anaphylaxis have been reported.

PRECAUTIONS

General
KADIAN® is intended for use in patients who require continuous,
around-the-clock opioid analgesia for an extended period of time.  As with any
potent opioid, it is critical to adjust the dosing regimen for KADIAN® for each
patient, taking into account the patient's prior analgesic treatment
experience.  Although it is clearly impossible to enumerate every consideration
that is important to the selection of the initial dose of KADIAN®, attention
should be given to the points under DOSAGE AND ADMINISTRATION.

Opioid analgesics have a narrow therapeutic index in certain patient
populations, especially when combined with CNS depressant drugs, and should be
reserved for cases where the benefits of opioid analgesia outweigh the known
risks of respiratory depression, altered mental state, and postural
hypotension.

Selection of patients for treatment with KADIAN® should be governed by the
same principles that apply to the use of any potent opioid analgesics.
Specifically, the increased risks associated with its use in the following
populations should be considered: the elderly or debilitated and those with
severe impairment of hepatic, pulmonary, or renal function; hypothyroidism;
adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma;
toxic psychosis; prostatic hypertrophy, or urethral stricture; acute alcoholism;
delirium tremens; kyphoscoliosis, or inability to swallow.

The administration of KADIAN® may obscure the diagnosis or clinical course in
patients with acute abdominal conditions.

KADIAN® may aggravate pre-existing convulsions in patients with convulsive
disorders.

Cordotomy
Patients taking KADIAN® who are scheduled for cordotomy or other
interruption of pain transmission pathways should have KADIAN® ceased 24 hours
prior to the procedure and the pain controlled by parenteral short-acting
opioids. In addition, the post-procedure titration of analgesics for such
patients should be individualized to avoid either oversedation or withdrawal
syndromes.

Use in Pancreatic/Biliary Tract Disease
KADIAN® may cause spasm of the sphincter of Oddi and should be
used with caution in patients with biliary tract disease, including acute
pancreatitis. Opioids may cause increases in the serum amylase level.

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, and 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 should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION:
Cessation of Therapy).

Special Risk Groups
KADIAN® should be administered with caution, and in reduced
dosages in elderly or debilitated patients; patients with severe renal or
hepatic insufficiency; patients with Addison's disease; myxedema;
hypothyroidism; prostatic hypertrophy or urethral stricture.

Caution should also be exercised in the administration of KADIAN® to patients
with CNS depression, toxic psychosis, acute alcoholism and delirium tremens, and
convulsive disorders.

Driving and Operating Machinery
KADIAN® may impair the mental and/or physical abilities needed to
perform potentially hazardous activities such as driving a car or operating
machinery.  Patients must be cautioned accordingly.  Patients should also be
warned about the potential combined effects of KADIAN® with other CNS
depressants, including other opioids, phenothiazines, sedative/hypnotics and
alcohol (see Drug
Interactions).

Information for Patients
If clinically advisable, patients receiving KADIAN®, or their
caregivers should be given the following information by the physician, nurse, or
pharmacist:

Patients should be advised that KADIAN® contains morphine and
should be taken only as directed.

Patients should be advised that KADIAN® capsules should be
swallowed whole (not chewed, crushed, or dissolved). Alternately, KADIAN®
capsules may be opened and the entire contents sprinkled on a small amount of
apple sauce immediately prior to ingestion. KADIAN® capsules or the contents of
the capsules must not be chewed or crushed due to a risk of fatal
overdose.

Patients should be advised that KADIAN® 100 mg and 200 mg
Capsules are for use only in opioid-tolerant patients.  Special care must be
taken to avoid accidental ingestion or use by individuals (including children)
other than the patient for whom it was originally prescribed, as such
unsupervised use may have severe, even fatal, consequences.

Patients should be advised that the dose of KADIAN® should not be
adjusted without consulting the prescribing health care provider.

Patients should be advised to report episodes of breakthrough
pain and adverse experiences occurring during therapy.  Individualization of
dosage is essential to make optimal use of this medication.

Patients should be advised that KADIAN® may impair mental and/or
physical ability required for the performance of potentially hazardous tasks
(e.g., driving, operating machinery).  Patients started on KADIAN® or whose dose
has been changed should refrain from dangerous activity until it is established
that they are not adversely affected.

Patients should be advised that KADIAN® should not be taken with
alcohol or other CNS depressants (sleeping medication, tranquilizers) except by
the orders of the prescribing healthcare provider because dangerous additive
effects may occur resulting in serious injury or death.

Women of childbearing potential who become or are planning to
become pregnant, should consult their prescribing healthcare provider prior to
initiating or continuing therapy with KADIAN®.

Patients should be advised that if they have been receiving
treatment with KADIAN® for more than a few weeks and cessation of therapy is
indicated, it may be appropriate to taper the KADIAN® dose, rather than abruptly
discontinue it, due to the risk of precipitating withdrawal symptoms.  Their
prescribing healthcare provider should provide a dose schedule to accomplish a
gradual discontinuation of the medication.

Patients should be advised that KADIAN® 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.

Patients should be advised that severe constipation could occur
as a result of taking KADIAN® and appropriate laxatives, stool softeners and
other appropriate treatments should be initiated from the beginning of opioid
therapy.

Patients should be instructed to keep KADIAN® in a secure place
out of the reach of children.  When KADIAN® is no longer needed, the unused
capsules should be destroyed by flushing down the toilet.

Drug Interactions
CNS Depressants: Morphine should be used with great caution and
in reduced dosage in patients who are concurrently receiving other central
nervous system (CNS) depressants including sedatives, hypnotics, general
anesthetics, antiemetics, phenothiazines, other tranquilizers and alcohol
because of the risk of respiratory depression, hypotension and profound sedation
or coma.  When such combined therapy is contemplated, the initial dose of one or
both agents should be reduced by at least 50%.

Muscle Relaxants: KADIAN® may enhance the neuromuscular blocking action of
skeletal relaxants and produce an increased degree of respiratory
depression.

Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics
(i.e., pentazocine, nalbuphine, and butorphanol) 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 KADIAN®.  In this situation, mixed
agonist/antagonist analgesics may reduce the analgesic effect of KADIAN® and/or
may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs): MAOIs have been reported to intensify
the effects of at least one opioid drug causing anxiety, confusion and
significant depression of respiration or coma.  KADIAN® should not be used in
patients taking MAOIs or within 14 days of stopping such treatment.

Cimetidine:  There is an isolated report of confusion and severe respiratory
depression when a hemodialysis patient was concurrently administered morphine
and cimetidine.

Diuretics:  Morphine can reduce the efficacy of diuretics by inducing the
release of antidiuretic hormone.  Morphine may also lead to acute retention of
urine by causing spasm of the sphincter of the bladder, particularly in men with
prostatism.

Carcinogenicity/Mutagenicity/Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic
potential of morphine have not been conducted. There are no reports of
carcinogenic effects in humans. In vitro studies have
reported that morphine is non-mutagenic in the Ames test with Salmonella, and induces chromosomal aberrations in human
leukocytes and lethal mutation induction in Drosophila.
Morphine was found to be mutagenic in vitro in
human T-cells, increasing the DNA fragmentation. In vivo,
morphine was mutagenic in the mouse micronucleus test and induced
chromosomal aberrations in spermatids and murine lymphocytes. Chronic opioid
abusers (e.g., heroin abusers) and their offspring display higher rates of
chromosomal damage. However, the rates of chromosomal abnormalities were similar
in nonexposed individuals and in heroin users enrolled in long term opioid
maintenance programs.

PregnancyTeratogenic Effects (Pregnancy Category C)
Teratogenic effects of morphine have been reported in the animal
literature. High parental doses during the second trimester were teratogenic in
neurological, soft and skeletal tissue. The abnormalities included
encephalopathy and axial skeletal fusions. These doses were often maternally
toxic and were 0.3 to 3-fold the maximum recommended human dose (MRHD) on a
mg/m2 basis. The relative contribution of
morphine-induced maternal hypoxia and malnutrition, each of which can be
teratogenic, has not been clearly defined. Treatment of male rats with
approximately 3-fold the MRHD for 10 days prior to mating decreased litter size
and viability.

Nonteratogenic Effects
Morphine given subcutaneously, at non-maternally toxic doses, to
rats during the third trimester with approximately 0.15-fold the MRHD caused
reversible reductions in brain and spinal cord volume, and testes size and body
weight in the offspring, and decreased fertility in female offspring.  The
offspring of rats and hamsters treated orally or intraperitoneally throughout
pregnancy with 0.04- to 0.3-fold the MRHD of morphine have demonstrated delayed
growth, motor and sexual maturation and decreased male fertility.  Chronic
morphine exposure of fetal animals resulted in mild withdrawal, altered reflex
and motor skill development, and altered responsiveness to morphine that
persisted into adulthood.

There are no well-controlled studies of chronic in utero
exposure to morphine sulfate in human subjects. However, uncontrolled
retrospective studies of human neonates chronically exposed to other opioids
in utero, demonstrated reduced brain volume which
normalized over the first month of life.  Infants born to opioid-abusing mothers
are more often small for gestational age, have a decreased ventilatory response
to CO2 and increased risk of sudden infant death
syndrome.  KADIAN® should only be used during pregnancy if the need for strong
opioid analgesia justifies the potential risk to the fetus.

Labor and Delivery
KADIAN® is not recommended for use in women during and
immediately prior to labor, where shorter acting analgesics or other analgesic
techniques are more appropriate.  Occasionally, opioid analgesics may prolong
labor through actions which temporarily reduce the strength, duration and
frequency of uterine contractions.  However, this effect is not consistent and
may be offset by an increased rate of cervical dilatation which tends to shorten
labor.  Neonates whose mothers received opioid analgesics during labor should be
observed closely for signs of respiratory depression.  A specific opioid
antagonist, such as naloxone or nalmefene, should be available for reversal of
opioid-induced respiratory depression in the neonate.

Neonatal Withdrawal Syndrome
Chronic maternal use of opiates or opioids during pregnancy
coexposes the fetus. The newborn may experience subsequent neonatal withdrawal
syndrome (NWS).  Manifestations of NWS include irritability, hyperactivity,
abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight
loss, and failure to gain weight.  The onset, duration, and severity of the
disorder differ based on such factors as the addictive drug used, time and
amount of mother's last dose, and rate of elimination of the drug from the
newborn.  Approaches to the treatment of this syndrome have included supportive
care and, when indicated, drugs such as paregoric or phenobarbital.

Nursing Mothers
Low levels of morphine sulfate have been detected in human milk.
Withdrawal symptoms can occur in breast-feeding infants when maternal
administration of morphine sulfate is stopped.  Because of the potential for
adverse reactions in nursing infants from KADIAN®, a decision should be made
whether to discontinue nursing or discontinue the drug, taking into account the
importance of the drug to the mother.

Pediatric Use
The safety of KADIAN®, both the entire capsule and the pellets
sprinkled on apple sauce, have not been directly investigated in pediatric
patients below the age of 18 years.  The range of doses available is not
suitable for the treatment of very young pediatric patients or those who are not
old enough to take capsules safely.  The apple sauce sprinkling method is not an
appropriate alternative for these patients.

Geriatric Use
Clinical studies of KADIAN® did not include sufficient numbers of
subjects aged 65 and over to determine whether they 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.

ADVERSE REACTIONS

Serious adverse reactions that may be associated with KADIAN®
therapy in clinical use are those observed with other opioid analgesics and
include: respiratory depression, respiratory arrest, apnea, circulatory
depression, cardiac arrest, hypotension, and/or shock (see OVERDOSAGE, WARNINGS).

The less severe adverse events seen on initiation of therapy with KADIAN® are
also typical opioid side effects.  These events are dose dependent, and their
frequency depends on the clinical setting, the patient's level of opioid
tolerance, and host factors specific to the individual.  They should be expected
and managed as a part of opioid analgesia.  The most frequent of these include
drowsiness, dizziness, constipation and nausea.  In many cases, the frequency of
these events during initiation of therapy may be minimized by careful
individualization of starting dosage, slow titration, and the avoidance of large
rapid swings in plasma concentrations of the opioid.  Many of these adverse
events, will cease or decrease as KADIAN® therapy is continued and some degree
of tolerance is developed, but others may be expected to remain troublesome
throughout therapy.

Management of Excessive Drowsiness
Most patients receiving KADIAN® will experience initial
drowsiness.  This usually disappears within 3-5 days and is not a cause of
concern unless it is excessive, or accompanied by unsteadiness or confusion.
Dizziness and unsteadiness may be associated with postural hypotension,
particularly in elderly or debilitated patients, and has been associated with
syncope and falls in non-tolerant patients started on opioids.

Excessive or persistent sedation should be investigated.  Factors to be
considered should include: concurrent sedative medications, the presence of
hepatic or renal insufficiency, hypoxia or hypercapnia due to exacerbated
respiratory failure, intolerance to the dose used (especially in older
patients), disease severity and the patient's general condition.

The dosage should be adjusted according to individual needs, but additional
care should be used in the selection of initial doses for the elderly patient,
the cachectic or gravely ill patient, or in patients not already familiar with
opioid analgesic medications to prevent excessive sedation at the onset of
treatment.

Management of Nausea and Vomiting
Nausea and vomiting are common after single doses of KADIAN® or
as an early undesirable effect of chronic opioid therapy.  The prescription of a
suitable antiemetic should be considered, with the awareness that sedation may
result (see Drug
Interactions). The frequency of nausea and vomiting usually decreases within
a week or so but may persist due to opioid-induced gastric stasis.
Metoclopramide is often useful in such patients.

Management of Constipation
Virtually all patients suffer from constipation while taking
opioids, such as KADIAN®, on a chronic basis.  Some patients, particularly
elderly, debilitated or bedridden patients may become impacted.  Tolerance does
not usually develop for the constipating effects of opioids.  Patients must be
cautioned accordingly and laxatives, softeners and other appropriate treatments
should be used prophylactically from the beginning of opioid therapy.

Adverse Events Probably Related to KADIAN®
Administration
In clinical studies in patients with chronic cancer pain the most
common adverse events reported by patients at least once during therapy were
drowsiness (9%), constipation (9%), nausea (7%), dizziness (6%), and anxiety
(6%).  Other less common side effects expected from KADIAN® or seen in less than
3% of patients in the clinical studies were:

Body as a Whole:  Asthenia, accidental injury, fever, pain, chest pain,
headache, diaphoresis, chills, flu syndrome, back pain, malaise, withdrawal
syndrome

Cardiovascular:  Tachycardia, atrial fibrillation, hypotension, hypertension,
pallor, facial flushing, palpitations, bradycardia, syncope

Central Nervous System:  Confusion, dry mouth, anxiety, abnormal thinking,
abnormal dreams, lethargy, depression, tremor, loss of concentration, insomnia,
amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia,
slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures,
myoclonus

Endocrine:  Hyponatremia due to inappropriate ADH secretion, gynecomastia

Gastrointestinal:  Vomiting, anorexia, dysphagia, dyspepsia, diarrhea,
abdominal pain, stomach atony disorder, gastro-esophageal reflux, delayed
gastric emptying, biliary colic

Hemic & Lymphatic:  Anemia, leukopenia, thrombocytopenia

Metabolic & Nutritional:  Peripheral edema, hyponatremia, edema

Musculoskeletal:  Back pain, bone pain, arthralgia

Respiratory:  Hiccup, rhinitis, atelectasis, asthma, hypoxia, dyspnea,
respiratory insufficiency, voice alteration, depressed cough reflex,
non-cardiogenic pulmonary edema

Skin and Appendages:  Rash, decubitus ulcer, pruritus, skin flush

Special Senses:  Amblyopia, conjunctivitis, miosis, blurred vision,
nystagmus, diplopia

Urogenital:  Urinary abnormality, amenorrhea, urinary retention, urinary
hesitancy, reduced libido, reduced potency, prolonged labor

Post-marketing Adverse Events Probably Related to
KADIAN®
The safety of KADIAN® has been evaluated in a randomized,
prospective, open-label, 4-week treatment period, post-marketing study
consisting of 1418 patients ages 18-85 with chronic, non-malignant pain (e.g.,
back pain, osteoarthritis, neuropathic pain).  No control arm was included in
this study.  The most common adverse events reported at least once during
therapy were constipation (12%), nausea (9%) and somnolence (3%).  Other less
common side effects occurring in less than 3% of patients were vomiting,
pruritus, dizziness, sedation, dry mouth, headache, fatigue and rash.

DRUG ABUSE AND DEPENDENCE

KADIAN® is a mu-agonist opioid with an abuse
liability similar to other opioid agonists and is a Schedule II controlled
substance.  KADIAN® and other opioids used in analgesia can be abused and are
subject to criminal diversion.

KADIAN® is an opioid with no approved use in the management of addiction
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.

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-seekingâ€? 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. KADIAN®, 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.

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.

KADIAN® is intended for oral use only.  Abuse of chewed,
crushed, or dissolved capsules or pellets poses a hazard of overdose and death.
This risk is increased with concurrent abuse of alcohol and other substances.
Due to the presence of talc as one of the excipients in capsules, parenteral
abuse can be expected to result in local tissue necrosis, infection, pulmonary
granulomas, and increased risk of endocarditis and valvular heart injury.
Parenteral drug abuse is commonly associated with transmission of infectious
diseases such as hepatitis and HIV.

OVERDOSAGE

Symptoms
Acute overdosage with morphine is manifested by respiratory
depression, somnolence progressing to stupor or coma, skeletal muscle
flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary
edema, bradycardia, hypotension and death.  Marked mydriasis rather than miosis
may be seen due to severe hypoxia in overdose situations.

Treatment
Primary attention should be given to the re-establishment of a
patent airway and institution of assisted or controlled ventilation. Gastric
contents may need to be emptied to remove unabsorbed drug when an
extended-release formulation such as KADIAN® has been taken.  Care should be
taken to secure the airway before attempting treatment by gastric emptying or
activated charcoal.

Supportive measures (including oxygen, vasopressors) should be employed in
the management of circulatory shock and pulmonary edema accompanying overdose as
indicated.  Cardiac arrest or arrhythmias may require cardiac massage or
defibrillation.

The pure opioid antagonists, naloxone or nalmefene, are specific antidotes to
respiratory depression which results from opioid overdose.  Since the duration
of reversal would be expected to be less than the duration of action of KADIAN®,
the patient must be carefully monitored until spontaneous respiration is
reliably re-established.  KADIAN® will continue to release and add to the
morphine load for up to 24 hours after administration and the management of an
overdose should be monitored accordingly. If the response to opioid antagonists
is suboptimal or not sustained, additional antagonist should be given as
directed by the manufacturer of the product.

Opioid antagonists should not be administered in the absence of clinically
significant respiratory or circulatory depression secondary to morphine
overdose.  Such agents should be administered cautiously to persons who are
known, or suspected to be physically dependent on KADIAN®.  In such cases, an
abrupt or complete reversal of opioid effects may precipitate an acute
abstinence syndrome.

Opioid Tolerant Individuals: In an individual
physically dependent on opioids, administration of the usual dose of the
antagonist will 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.  Use of an opioid antagonist should be reserved for
cases where such treatment is clearly needed.  If it is necessary 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.

DOSAGE AND ADMINISTRATION

KADIAN® may be administered once or twice daily.

KADIAN® capsules should be swallowed whole.  The pellets in
KADIAN® capsules should not be chewed, crushed, or dissolved due to the risk of
rapid release and absorption of a potentially fatal dose of morphine.

Alternatively, KADIAN® capsules may be administered as a sprinkle on apple
sauce or through a 16 French gastrostomy tube (see ALTERNATIVE METHODS OF
ADMINISTRATION section).

The 100 mg and 200 mg capsules are for use only in
opioid-tolerant patients.

KADIAN® is not indicated for pre-emptive analgesia
(administration pre-operatively for the management of post-operative pain), or
for pain in the immediate post-operative period (the first 12 to 24 hours
following surgery) for patients not previously taking the drug, because its
safety in these settings have not been established.

KADIAN® is only indicated for post-operative use if the
patient is already receiving the drug prior to surgery or if the postoperative
pain is expected to be moderate to severe and persist for an extended period of
time.

Patients who are already receiving KADIAN® Capsules as part of ongoing
analgesic therapy may be safely continued on the drug if appropriate dosage
adjustments are made considering the procedure, other drugs given, and the
temporary changes in physiology caused by the surgical intervention.

Initiating Therapy with KADIAN® Capsules
Physicians should individualize treatment using a progressive
plan of pain management such as outlined by the World Health Organization, the
American Pain Society and the Federation of State Medical Boards Model
Guidelines.  Health care professionals should follow appropriate pain management
principles of careful assessment and ongoing monitoring.

It is critical to adjust the dosing regimen for each patient individually,
taking into account the patient's prior analgesic treatment experience.  In the
selection of the initial dose of KADIAN®, attention should be given to:

the total daily dose, potency and kind of opioid the patient has
been taking previously;

the reliability of the relative potency estimate used to
calculate the equivalent dose of morphine needed (Note: potency estimates may
vary with the route of administration);

the patient's degree of opioid experience and opioid
tolerance;

the general condition and medical status of the patient;

concurrent medication;

the type and severity of the patient's pain.

Care should be taken to use low initial doses of KADIAN® in
patients who are not already opioid-tolerant, especially those who are receiving
concurrent treatment with muscle relaxants, sedatives, or other CNS active
medications (see PRECAUTIONS).

During periods of changing analgesic requirements including initial
titration, frequent communication is recommended between physician, other
members of the healthcare team, the patient, and the caregiver/family.

The following dosing recommendations, therefore, can only be considered
suggested approaches to what is actually a series of clinical decisions over
time in the management of the pain of an individual patient.

Conversion from Other Oral Morphine Formulations to
KADIAN®
Patients on other oral morphine formulations may be converted to
KADIAN® by administering one-half of the patient's total daily oral morphine
dose as KADIAN® capsules every 12 hours (twice-a-day) or by administering the
total daily oral morphine dose as KADIAN® capsules every 24 hours (once-a-day).
KADIAN® should not be given more frequently than every 12 hours.

Conversion from Parenteral Morphine or Other Parenteral or
Oral Opioids to KADIAN®
KADIAN® can be administered to patients previously receiving
treatment with parenteral morphine or other opioids.  While there are useful
tables of oral and parenteral equivalents in cancer analgesia, there is
substantial interpatient variation in the relative potency of different opioid
drugs and formulations.  For these reasons, it is better to underestimate the
patient's 24-hour oral morphine requirement and provide rescue medication, than
to overestimate and manage an adverse event. The following general points should
be considered:

Parenteral to Oral Morphine Ratio:  It may take anywhere from 2-6
mg of oral morphine to provide analgesia equivalent to 1 mg of parenteral
morphine.  A dose of oral morphine three times the daily parenteral morphine
requirement may be sufficient in chronic use settings.

Other Parenteral or Oral Opioids to Oral Morphine Sulfate:  There
is lack of systematic evidence bearing on these types of analgesic
substitutions.  Therefore, specific recommendations are not possible.
Physicians are advised to refer to published relative potency data, keeping in
mind that such ratios are only approximate.  In general, it is safest to give
half of the estimated daily morphine demand as the initial dose, and to manage
inadequate analgesia by supplementation with immediate-release morphine. (See
discussion which follows.)

The first dose of KADIAN® may be taken with the last dose of any
immediate-release (short-acting) opioid medication due to the long delay until
the peak effect after administration of KADIAN®.

Use of KADIAN® as the First Opioid Analgesic
There has been no evaluation of KADIAN® as an initial opioid
analgesic in the management of pain. Because it may be more difficult to titrate
a patient to adequate analgesia using an extended-release morphine, it is
ordinarily advisable to begin treatment using an immediate-release morphine
formulation.

Individualization of Dosage
The best use of opioid analgesics in the management of chronic
malignant and non-malignant pain is challenging, and is well described in
materials published by the World Health Organization and the Agency for Health
Care Policy and Research which are available from Alpharma Pharmaceuticals LLC
upon request.  KADIAN® is a third step drug which is most useful when the
patient requires a constant level of opioid analgesia as a "floor" or "platform"
from which to manage breakthrough pain.  When a patient has reached the point
where comfort cannot be provided with a combination of non-opioid medications
(NSAIDs and acetaminophen) and intermittent use of moderate or strong opioids,
the patient's total opioid therapy should be converted into a 24 hour oral
morphine equivalent.

KADIAN® should be started by administering one-half of the estimated total
daily oral morphine dose every 12 hours (twice-a-day) or
by administering the total daily oral morphine dose every 24 hours
(once-a-day).  The dose should be titrated no more frequently than
every-other-day to allow the patients to stabilize before escalating the dose.
If breakthrough pain occurs, the dose may be supplemented with a small dose
(less than 20% of the total daily dose) of a short-acting analgesic. Patients
who are excessively sedated after a once-a-day dose or who regularly experience
inadequate analgesia before the next dose should be switched to twice-a-day
dosing.

Patients who do not have a proven tolerance to opioids should be started only
on the 10 mg or 20 mg strength, and usually should be increased at a rate not
greater than 20 mg every-other-day.  Most patients will rapidly develop some
degree of tolerance, requiring dosage adjustment until they have achieved their
individual best balance between baseline analgesia and opioid side effects such
as confusion, sedation and constipation.  No guidance can be given as to the
recommended maximal dose, especially in patients with chronic pain of
malignancy. In such cases the total dose of KADIAN® should be advanced until the
desired therapeutic endpoint is reached or clinically significant opioid-related
adverse reactions intervene.

Alternative Methods of Administration
In a study of healthy volunteers, KADIAN® pellets sprinkled over
apple sauce were found to be bioequivalent to KADIAN® capsules swallowed whole
with apple sauce under fasting conditions. Other foods have not been tested.
Patients who have difficulty swallowing whole capsules or tablets may benefit
from this alternative method of administration.

Sprinkle the pellets onto a small amount of apple sauce. Apple
sauce should be room temperature or cooler.

The patient must be cautioned not to chew the pellets which could
result in the immediate release of a potentially dangerous, even fatal dose of
morphine.

Use immediately.

Rinse mouth to ensure all pellets have been swallowed.

Patients should consume entire portion and should not divide
apple sauce into separate doses.

The entire capsule contents may alternatively be administered through a 16
French gastrostomy tube.

Flush the gastrostomy tube with water to ensure that it is
wet.

Sprinkle the KADIAN® Pellets into 10 mL of water.

Use a swirling motion to pour the pellets and water into the
gastrostomy tube through a funnel.

Rinse the beaker with a further 10 mL of water and pour this into
the funnel.

Repeat rinsing until no pellets remain in the
beaker.

THE ADMINISTRATION OF KADIAN®
PELLETS THROUGH A NASOGASTRIC TUBE SHOULD NOT BE ATTEMPTED.

Considerations in the Adjustment of Dosing Regimens
If signs of excessive opioid effects are observed early in the
dosing interval, the next dose should be reduced.  If this adjustment leads to
inadequate analgesia, that is, if breakthrough pain occurs when KADIAN® is
administered on an every 24 hours dosing regimen, consideration should be given
to dosing every 12 hours.  If breakthrough pain occurs on a 12 hour dosing
regimen a supplemental dose of a short-acting analgesic may be given.  As
experience is gained, adjustments in both dose and dosing interval can be made
to obtain an appropriate balance between pain relief and opioid side effects.
To avoid accumulation the dosing interval of KADIAN® should not be reduced below
12 hours.

Cessation of Therapy
When the patient no longer requires therapy with
KADIAN® capsules, doses should be tapered gradually to prevent signs and
symptoms of withdrawal in the physically dependent patient.

Conversion from KADIAN® to Other Extended-Release Oral
Morphine Formulations
KADIAN® is not bioequivalent to other extended-release morphine
preparations.  Although for a given dose the same total amount of morphine is
available from KADIAN® as from morphine solution or extended-release morphine
tablets, the slower release of morphine from KADIAN® results in reduced maximum
and increased minimum plasma morphine concentrations than with shorter acting
morphine products.  Conversion from KADIAN® to the same total daily dose of
extended-release morphine preparations may lead to either excessive sedation at
peak or inadequate analgesia at trough and close observation and appropriate
dosage adjustments are recommended.

Conversion from KADIAN® to Parenteral Opioids
When converting a patient from KADIAN® to parenteral opioids, it
is best to calculate an equivalent parenteral dose, and then initiate treatment
at half of this calculated value.  For example, to estimate the required 24 hour
dose of parenteral morphine for a patient taking KADIAN®, one would take the 24
hour KADIAN® dose, divide by an oral to parenteral conversion ratio of 3, divide
the estimated 24 hour parenteral dose into six divided doses (for a four hour
dosing interval), then halve this dose as an initial
trial.

For example, to estimate the required parenteral morphine dose for a patient
taking 360 mg of KADIAN® a day, divide the 360 mg daily oral morphine dose by a
conversion ratio of 1 mg of parenteral morphine for every 3 mg of oral
morphine.  The estimated 120 mg daily parenteral requirement is then divided
into six 20 mg doses, and half of this, or 10 mg, is then given every 4 hours as
an initial trial dose.

This approach is likely to require a dosage increase in the first 24 hours
for many patients, but is recommended because it is less likely to cause
overdose than trying to establish an equivalent dose without titration.

Safety and Handling
KADIAN® Capsules contain morphine sulfate which is a controlled
substance under Schedule II of the Controlled Substances Act. Morphine, like all
opioids, is liable to diversion and misuse and should be handled accordingly.
Patients and their families should be instructed to flush any KADIAN® capsules
that are no longer needed.

KADIAN® may be targeted for theft and diversion by criminals.  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.

KADIAN® consists of closed hard gelatin capsules containing polymer coated
morphine sulfate pellets that pose no known handling risk to health care
workers. KADIAN® Capsules are liable to diversion and misuse both by the general
public and health care workers, and should be handled accordingly.

HOW SUPPLIED

KADIAN® capsules contain white to off-white or tan colored
polymer coated extended-release pellets of morphine sulfate and are available in
eight dose strengths:

10 mg size 4 capsule, light blue opaque cap printed with KADIAN and light
blue opaque body printed with 10 mg. Capsules are supplied in:

bottles of 10      (NDC 54868-5964-0)
bottles of 30      (NDC 54868-5964-2)
bottles of 60      (NDC 54868-5964-1).

20 mg size 4 capsule, yellow opaque cap printed with KADIAN and yellow opaque
body printed with 20 mg.  Capsules are supplied in:

bottles of 20      (NDC 54868-4571-1)
bottles of 30      (NDC 54868-4571-2)
bottles of 60      (NDC 54868-4571-0).

30 mg size 4 capsule, blue violet opaque cap printed with KADIAN and blue
violet opaque body printed with 30 mg.  Capsules are supplied in:

bottles of 10      (NDC 54868-4981-1)
bottles of 60      (NDC 54868-4981-0)
bottles of 90      (NDC 54868-4981-2).

50 mg size 2 capsule, blue opaque cap printed with KADIAN and blue opaque
body printed with 50 mg.  Capsules are supplied in:

bottles of 20      (NDC 54868-4572-2)
bottles of 30      (NDC 54868-4572-1)
bottles of 60      (NDC 54868-4572-0).

60 mg size 1 capsule, pink opaque cap printed with KADIAN and pink opaque
body printed with 60 mg.  Capsules are supplied in:

bottles of 20      (NDC 54868-5850-0)
bottles of 30      (NDC 54868-5850-2)
bottles of 60      (NDC 54868-5850-1).

100 mg size 0 capsule, green opaque cap printed with KADIAN and green opaque
body printed with 100 mg.  Capsules are supplied in:

bottles of 10      (NDC 54868-4573-2)
bottles of 30      (NDC 54868-4573-1)
bottles of 60      (NDC 54868-4573-0).

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Protect
from light and moisture.

Dispense in a sealed tamper-evident, childproof, light-resistant
container.

CAUTION: DEA Order Form Required.

Rx Only

KADIAN® is a registered trademark of Alpharma Pharmaceuticals LLC

Manufactured for: Alpharma Pharmaceuticals LLC
One New England Avenue
Piscataway, NJ 08854

by: Actavis
Elizabeth LLC
200 Elmora Avenue
Elizabeth, NJ 07207 USA

40-9068

Revised – January 2008

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK      74146

PRINCIPAL DISPLAY PANEL

KADIAN® capsules

10 mg

20 mg

30 mg

50 mg

60 mg

100 mg

KADIAN

morphine sulfate capsule, extended release

Product Information

Product Type
HUMAN PRESCRIPTION DRUG LABEL
Item Code (Source)
NDC:54868-4571(NDC:63857-322-11)

Route of Administration
ORAL
DEA Schedule
CII

Active Ingredient/Active Moiety

Ingredient Name
Basis of Strength
Strength

MORPHINE SULFATE (MORPHINE)
MORPHINE SULFATE
20 mg

Inactive Ingredients

Ingredient Name
Strength

HYPROMELLOSE

ETHYLCELLULOSE

POLYETHYLENE GLYCOL

DIETHYL PHTHALATE

TALC

STARCH, CORN

SUCROSE

GELATIN

SILICON DIOXIDE

TITANIUM DIOXIDE

D&C YELLOW NO. 10

SODIUM LAURYL SULFATE

Product Characteristics

Color
yellow
Score
no score

Shape
CAPSULE
Size
14mm

Flavor

Imprint Code
KADIAN;20;mg

Contains

Packaging

#
Item Code
Package Description
Marketing Start Date
Marketing End Date

1
NDC:54868-4571-0
60  in 1 BOTTLE

2
NDC:54868-4571-1
20  in 1 BOTTLE

3
NDC:54868-4571-2
30  in 1 BOTTLE

Marketing Information

Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date

NDA
NDA020616
11/07/2001

KADIAN

morphine sulfate capsule, extended release

Product Information

Product Type
HUMAN PRESCRIPTION DRUG LABEL
Item Code (Source)
NDC:54868-4981(NDC:63857-325-11)

Route of Administration
ORAL
DEA Schedule
CII

Active Ingredient/Active Moiety

Ingredient Name
Basis of Strength
Strength

MORPHINE SULFATE (MORPHINE)
MORPHINE SULFATE
30 mg

Inactive Ingredients

Ingredient Name
Strength

HYPROMELLOSE

ETHYLCELLULOSE

POLYETHYLENE GLYCOL

DIETHYL PHTHALATE

TALC

STARCH, CORN

SUCROSE

GELATIN

SILICON DIOXIDE

SODIUM LAURYL SULFATE

TITANIUM DIOXIDE

FD&C RED NO. 3

FD&C BLUE NO. 1

Product Characteristics

Color
blue
Score
no score

Shape
CAPSULE
Size
14mm

Flavor

Imprint Code
KADIAN;30;mg

Contains

Packaging

#
Item Code
Package Description
Marketing Start Date
Marketing End Date

1
NDC:54868-4981-0
60  in 1 BOTTLE

2
NDC:54868-4981-1
10  in 1 BOTTLE

3
NDC:54868-4981-2
90  in 1 BOTTLE

Marketing Information

Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date

NDA
NDA020616
01/16/2004

KADIAN

morphine sulfate capsule, extended release

Product Information

Product Type
HUMAN PRESCRIPTION DRUG LABEL
Item Code (Source)
NDC:54868-4572(NDC:63857-323-11)

Route of Administration
ORAL
DEA Schedule
CII

Active Ingredient/Active Moiety

Ingredient Name
Basis of Strength
Strength

MORPHINE SULFATE (MORPHINE)
MORPHINE SULFATE
50 mg

Inactive Ingredients

Ingredient Name
Strength

HYPROMELLOSE

ETHYLCELLULOSE

POLYETHYLENE GLYCOL

DIETHYL PHTHALATE

TALC

STARCH, CORN

SUCROSE

GELATIN

SILICON DIOXIDE

SODIUM LAURYL SULFATE

TITANIUM DIOXIDE

D&C RED NO. 28

FD&C BLUE NO. 1

FD&C RED NO. 40

Product Characteristics

Color
blue
Score
no score

Shape
CAPSULE
Size
18mm

Flavor

Imprint Code
KADIAN;50;mg

Contains

Packaging

#
Item Code
Package Description
Marketing Start Date
Marketing End Date

1
NDC:54868-4572-0
60  in 1 BOTTLE

2
NDC:54868-4572-1
30  in 1 BOTTLE

3
NDC:54868-4572-2
20  in 1 BOTTLE

Marketing Information

Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date

NDA
NDA020616
11/07/2001

KADIAN

morphine sulfate capsule, extended release

Product Information

Product Type
HUMAN PRESCRIPTION DRUG LABEL
Item Code (Source)
NDC:54868-5850(NDC:63857-326-11)

Route of Administration
ORAL
DEA Schedule
CII

Active Ingredient/Active Moiety

Ingredient Name
Basis of Strength
Strength

MORPHINE SULFATE (MORPHINE)
MORPHINE SULFATE
60 mg

Inactive Ingredients

Ingredient Name
Strength

HYPROMELLOSE

ETHYLCELLULOSE

POLYETHYLENE GLYCOL

DIETHYL PHTHALATE

TALC

STARCH, CORN

SUCROSE

GELATIN

SILICON DIOXIDE

SODIUM LAURYL SULFATE

TITANIUM DIOXIDE

D&C RED NO. 28

FD&C BLUE NO. 1

FD&C RED NO. 40

Product Characteristics

Color
pink
Score
no score

Shape
CAPSULE
Size
19mm

Flavor

Imprint Code
KADIAN;60;mg

Contains

Packaging

#
Item Code
Package Description
Marketing Start Date
Marketing End Date

1
NDC:54868-5850-0
20  in 1 BOTTLE

2
NDC:54868-5850-1
60  in 1 BOTTLE

3
NDC:54868-5850-2
30  in 1 BOTTLE

Marketing Information

Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date

NDA
NDA020616
01/16/2008

KADIAN

morphine sulfate capsule, extended release

Product Information

Product Type
HUMAN PRESCRIPTION DRUG LABEL
Item Code (Source)
NDC:54868-4573(NDC:63857-324-11)

Route of Administration
ORAL
DEA Schedule
CII

Active Ingredient/Active Moiety

Ingredient Name
Basis of Strength
Strength

MORPHINE SULFATE (MORPHINE)
MORPHINE SULFATE
100 mg

Inactive Ingredients

Ingredient Name
Strength

HYPROMELLOSE

ETHYLCELLULOSE

POLYETHYLENE GLYCOL

DIETHYL PHTHALATE

TALC

STARCH, CORN

SUCROSE

GELATIN

SILICON DIOXIDE

SODIUM LAURYL SULFATE

TITANIUM DIOXIDE

D&C YELLOW NO. 10

FD&C BLUE NO. 1

Product Characteristics

Color
green
Score
no score

Shape
CAPSULE
Size
22mm

Flavor

Imprint Code
KADIAN;100;mg

Contains

Packaging

#
Item Code
Package Description
Marketing Start Date
Marketing End Date

1
NDC:54868-4573-0
60  in 1 BOTTLE

2
NDC:54868-4573-1
30  in 1 BOTTLE

3
NDC:54868-4573-2
10  in 1 BOTTLE

Marketing Information

Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date

NDA
NDA020616
11/20/2008

KADIAN

morphine sulfate capsule, extended release

Product Information

Product Type
HUMAN PRESCRIPTION DRUG LABEL
Item Code (Source)
NDC:54868-5964(NDC:63857-410-11)

Route of Administration
ORAL
DEA Schedule
CII

Active Ingredient/Active Moiety

Ingredient Name
Basis of Strength
Strength

MORPHINE SULFATE (MORPHINE)
MORPHINE SULFATE
10 mg

Inactive Ingredients

Ingredient Name
Strength

HYPROMELLOSE

ETHYLCELLULOSE

POLYETHYLENE GLYCOL

DIETHYL PHTHALATE

TALC

STARCH, CORN

SUCROSE

GELATIN

SILICON DIOXIDE

SODIUM LAURYL SULFATE

TITANIUM DIOXIDE

D&C RED NO. 28

FD&C BLUE NO. 1

Product Characteristics

Color
blue (light)
Score
no score

Shape
CAPSULE
Size
14mm

Flavor

Imprint Code
KADIAN;10;mg

Contains

Packaging

#
Item Code
Package Description
Marketing Start Date
Marketing End Date

1
NDC:54868-5964-0
10  in 1 BOTTLE

2
NDC:54868-5964-1
60  in 1 BOTTLE

3
NDC:54868-5964-2
30  in 1 BOTTLE

Marketing Information

Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date

NDA
NDA020616
11/19/2008

Labeler - Physicians Total Care, Inc.
							(194123980)

Establishment

Name
Address
ID/FEI
Business Operations

Physicians Total Care, Inc.

194123980
relabel, repack

Revised: 6/2010

Document Id: 8ea73dd1-dfe3-4628-940f-16587e605fcb

Set id: 6c826b0a-ac87-48cc-a780-9a4a2118e8a8

Version: 1

Effective Time: 20100611

Physicians Total Care, Inc.


text:
/*      $NetBSD: filecomplete.c,v 1.31 2011/09/16 16:13:16 plunky Exp $ */

/*-
 * Copyright (c) 1997 The NetBSD Foundation, Inc.
 * All rights reserved.
 *
 * This code is derived from software contributed to The NetBSD Foundation
 * by Jaromir Dolecek.
 *
 * Redistribution and use in source and binary forms, with or without
 * modification, are permitted provided that the following conditions
 * are met:
 * 1. Redistributions of source code must retain the above copyright
 *    notice, this list of conditions and the following disclaimer.
 * 2. Redistributions in binary form must reproduce the above copyright
 *    notice, this list of conditions and the following disclaimer in the
 *    documentation and/or other materials provided with the distribution.
 *
 * THIS SOFTWARE IS PROVIDED BY THE NETBSD FOUNDATION, INC. AND CONTRIBUTORS
 * ``AS IS'' AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED
 * TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR
 * PURPOSE ARE DISCLAIMED.  IN NO EVENT SHALL THE FOUNDATION OR CONTRIBUTORS
 * BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR
 * CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF
 * SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS
 * INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN
 * CONTRACT, STRICT LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE)
 * ARISING IN ANY WAY OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE
 * POSSIBILITY OF SUCH DAMAGE.
 */

#include "config.h"

#if !defined(lint) && !defined(SCCSID)
__RCSID("$NetBSD: filecomplete.c,v 1.31 2011/09/16 16:13:16 plunky Exp $");
#endif /* not lint && not SCCSID */

#include <sys/types.h>
#include <sys/stat.h>
#include <stdio.h>
#include <dirent.h>
#include <string.h>
#include <pwd.h>
#include <ctype.h>
#include <stdlib.h>
#include <unistd.h>
#include <limits.h>
#include <errno.h>
#include <fcntl.h>
#include <vis.h>

#include "el.h"
#include "fcns.h"               /* for EL_NUM_FCNS */
#include "histedit.h"
#include "filecomplete.h"

/* Lagopus additions. */
#define LAGOPUS
#ifdef LAGOPUS
extern int completion_status;
extern int describe_status;
#endif /* LAGOPUS */

static const Char break_chars[] = { ' ', '\t', '\n', '"', '\\', '\'', '`', '@',
                                    '$', '>', '<', '=', ';', '|', '&', '{', '(', '\0'
                                  };

/********************************/
/* completion functions */

/*
 * does tilde expansion of strings of type ``~user/foo''
 * if ``user'' isn't valid user name or ``txt'' doesn't start
 * w/ '~', returns pointer to strdup()ed copy of ``txt''
 *
 * it's callers's responsibility to free() returned string
 */
char *
fn_tilde_expand(const char *txt) {
#if defined(HAVE_GETPW_R_POSIX) || defined(HAVE_GETPW_R_DRAFT)
  struct passwd pwres;
  char pwbuf[1024];
#endif
  struct passwd *pass;
  char *temp;
  size_t len = 0;

  if (txt[0] != '~') {
    return strdup(txt);
  }

  temp = strchr(txt + 1, '/');
  if (temp == NULL) {
    temp = strdup(txt + 1);
    if (temp == NULL) {
      return NULL;
    }
  } else {
    /* text until string after slash */
    len = (size_t)(temp - txt + 1);
    temp = el_malloc(len * sizeof(*temp));
    if (temp == NULL) {
      return NULL;
    }
    (void)strncpy(temp, txt + 1, len - 2);
    temp[len - 2] = '\0';
  }
  if (temp[0] == 0) {
#ifdef HAVE_GETPW_R_POSIX
    if (getpwuid_r(getuid(), &pwres, pwbuf, sizeof(pwbuf),
                   &pass) != 0) {
      pass = NULL;
    }
#elif HAVE_GETPW_R_DRAFT
    pass = getpwuid_r(getuid(), &pwres, pwbuf, sizeof(pwbuf));
#else
    pass = getpwuid(getuid());
#endif
  } else {
#ifdef HAVE_GETPW_R_POSIX
    if (getpwnam_r(temp, &pwres, pwbuf, sizeof(pwbuf), &pass) != 0) {
      pass = NULL;
    }
#elif HAVE_GETPW_R_DRAFT
    pass = getpwnam_r(temp, &pwres, pwbuf, sizeof(pwbuf));
#else
    pass = getpwnam(temp);
#endif
  }
  el_free(temp);                /* value no more needed */
  if (pass == NULL) {
    return strdup(txt);
  }

  /* update pointer txt to point at string immedially following */
  /* first slash */
  txt += len;

  len = strlen(pass->pw_dir) + 1 + strlen(txt) + 1;
  temp = el_malloc(len * sizeof(*temp));
  if (temp == NULL) {
    return NULL;
  }
  (void)snprintf(temp, len, "%s/%s", pass->pw_dir, txt);

  return temp;
}

/*
 * return first found file name starting by the ``text'' or NULL if no
 * such file can be found
 * value of ``state'' is ignored
 *
 * it's caller's responsibility to free returned string
 */
char *
fn_filename_completion_function(const char *text, int state) {
  static DIR *dir = NULL;
  static char *filename = NULL, *dirname = NULL, *dirpath = NULL;
  static size_t filename_len = 0;
  struct dirent *entry;
  char *temp;
  size_t len;

  if (state == 0 || dir == NULL) {
    temp = strrchr(text, '/');
    if (temp) {
      char *nptr;
      temp++;
      nptr = el_realloc(filename, (strlen(temp) + 1) *
                        sizeof(*nptr));
      if (nptr == NULL) {
        el_free(filename);
        filename = NULL;
        return NULL;
      }
      filename = nptr;
      (void)strcpy(filename, temp);
      len = (size_t)(temp - text);      /* including last slash */

      nptr = el_realloc(dirname, (len + 1) *
                        sizeof(*nptr));
      if (nptr == NULL) {
        el_free(dirname);
        dirname = NULL;
        return NULL;
      }
      dirname = nptr;
      (void)strncpy(dirname, text, len);
      dirname[len] = '\0';
    } else {
      el_free(filename);
      if (*text == 0) {
        filename = NULL;
      } else {
        filename = strdup(text);
        if (filename == NULL) {
          return NULL;
        }
      }
      el_free(dirname);
      dirname = NULL;
    }

    if (dir != NULL) {
      (void)closedir(dir);
      dir = NULL;
    }

    /* support for ``~user'' syntax */

    el_free(dirpath);
    dirpath = NULL;
    if (dirname == NULL) {
      if ((dirname = strdup("")) == NULL) {
        return NULL;
      }
      dirpath = strdup("./");
    } else if (*dirname == '~') {
      dirpath = fn_tilde_expand(dirname);
    } else {
      dirpath = strdup(dirname);
    }

    if (dirpath == NULL) {
      return NULL;
    }

    dir = opendir(dirpath);
    if (!dir) {
      return NULL;  /* cannot open the directory */
    }

    /* will be used in cycle */
    filename_len = filename ? strlen(filename) : 0;
  }

  /* find the match */
  while ((entry = readdir(dir)) != NULL) {
    /* skip . and .. */
    if (entry->d_name[0] == '.' && (!entry->d_name[1]
                                    || (entry->d_name[1] == '.' && !entry->d_name[2]))) {
      continue;
    }
    if (filename_len == 0) {
      break;
    }
    /* otherwise, get first entry where first */
    /* filename_len characters are equal          */
    if (entry->d_name[0] == filename[0]
        /* Some dirents have d_namlen, but it is not portable. */
        && strlen(entry->d_name) >= filename_len
        && strncmp(entry->d_name, filename,
                   filename_len) == 0) {
      break;
    }
  }

  if (entry) {          /* match found */

    /* Some dirents have d_namlen, but it is not portable. */
    len = strlen(entry->d_name);

    len = strlen(dirname) + len + 1;
    temp = el_malloc(len * sizeof(*temp));
    if (temp == NULL) {
      return NULL;
    }
    (void)snprintf(temp, len, "%s%s", dirname, entry->d_name);
  } else {
    (void)closedir(dir);
    dir = NULL;
    temp = NULL;
  }

  return temp;
}

static const char *
append_char_function(const char *name) {
  struct stat stbuf;
  char *expname = *name == '~' ? fn_tilde_expand(name) : NULL;
  const char *rs = " ";

  if (stat(expname ? expname : name, &stbuf) == -1) {
    goto out;
  }
  if (S_ISDIR(stbuf.st_mode)) {
    rs = "/";
  }
out:
  if (expname) {
    el_free(expname);
  }
  return rs;
}
/*
 * returns list of completions for text given
 * non-static for readline.
 */
char **completion_matches(const char *, char *(*)(const char *, int));
char **
completion_matches(const char *text, char *(*genfunc)(const char *, int)) {
  char **match_list = NULL, *retstr, *prevstr;
  size_t match_list_len, max_equal, which, i;
  size_t matches;

  matches = 0;
  match_list_len = 1;
  while ((retstr = (*genfunc) (text, (int)matches)) != NULL) {
    /* allow for list terminator here */
    if (matches + 3 >= match_list_len) {
      char **nmatch_list;
      while (matches + 3 >= match_list_len) {
        match_list_len <<= 1;
      }
      nmatch_list = el_realloc(match_list,
                               match_list_len * sizeof(*nmatch_list));
      if (nmatch_list == NULL) {
        el_free(match_list);
        return NULL;
      }
      match_list = nmatch_list;

    }
    match_list[++matches] = retstr;
  }

  if (!match_list) {
    return NULL;  /* nothing found */
  }

  /* find least denominator and insert it to match_list[0] */
  which = 2;
  prevstr = match_list[1];
  max_equal = strlen(prevstr);
  for (; which <= matches; which++) {
    for (i = 0; i < max_equal &&
         prevstr[i] == match_list[which][i]; i++) {
      continue;
    }
    max_equal = i;
  }

  retstr = el_malloc((max_equal + 1) * sizeof(*retstr));
  if (retstr == NULL) {
    el_free(match_list);
    return NULL;
  }
  (void)strncpy(retstr, match_list[1], max_equal);
  retstr[max_equal] = '\0';
  match_list[0] = retstr;

  /* add NULL as last pointer to the array */
  match_list[matches + 1] = NULL;

  return match_list;
}

/*
 * Sort function for qsort(). Just wrapper around strcasecmp().
 */
static int
_fn_qsort_string_compare(const void *i1, const void *i2) {
  const char *s1 = ((const char *const *)i1)[0];
  const char *s2 = ((const char *const *)i2)[0];

  return strcasecmp(s1, s2);
}

/*
 * Display list of strings in columnar format on readline's output stream.
 * 'matches' is list of strings, 'num' is number of strings in 'matches',
 * 'width' is maximum length of string in 'matches'.
 *
 * matches[0] is not one of the match strings, but it is counted in
 * num, so the strings are matches[1] *through* matches[num-1].
 */
void
fn_display_match_list (EditLine *el, char **matches, size_t num,
                       size_t width) {
  size_t line, lines, col, cols, thisguy;
  int screenwidth = el->el_terminal.t_size.h;

  /* Ignore matches[0]. Avoid 1-based array logic below. */
  matches++;
  num--;

  /*
   * Find out how many entries can be put on one line; count
   * with one space between strings the same way it's printed.
   */
  cols = (size_t)screenwidth / (width + 1);
  if (cols == 0) {
    cols = 1;
  }

  /* how many lines of output, rounded up */
  lines = (num + cols - 1) / cols;

  /* Sort the items. */
  qsort(matches, num, sizeof(char *), _fn_qsort_string_compare);

  /*
   * On the ith line print elements i, i+lines, i+lines*2, etc.
   */
  for (line = 0; line < lines; line++) {
    for (col = 0; col < cols; col++) {
      thisguy = line + col * lines;
      if (thisguy >= num) {
        break;
      }
      (void)fprintf(el->el_outfile, "%s%-*s",
                    col == 0 ? "" : " ", (int)width, matches[thisguy]);
    }
    (void)fprintf(el->el_outfile, "\n");
  }
}

/*
 * Complete the word at or before point,
 * 'what_to_do' says what to do with the completion.
 * \t   means do standard completion.
 * `?' means list the possible completions.
 * `*' means insert all of the possible completions.
 * `!' means to do standard completion, and list all possible completions if
 * there is more than one.
 *
 * Note: '*' support is not implemented
 *       '!' could never be invoked
 */
int
fn_complete(EditLine *el,
            char *(*complet_func)(const char *, int),
            char **(*attempted_completion_function)(const char *, int, int),
            const Char *word_break, const Char *special_prefixes,
            const char *(*app_func)(const char *), size_t query_items,
            int *completion_type, int *over, int *point, int *end) {
  const TYPE(LineInfo) *li;
  Char *temp;
  char **matches;
  const Char *ctemp;
  size_t len;
  int what_to_do = '\t';
  int retval = CC_NORM;

#ifndef LAGOPUS
  if (el->el_state.lastcmd == el->el_state.thiscmd) {
    what_to_do = '?';
  }
#endif /* LAGOPUS */

  /* readline's rl_complete() has to be told what we did... */
  if (completion_type != NULL) {
    *completion_type = what_to_do;
  }

  if (!complet_func) {
    complet_func = fn_filename_completion_function;
  }
  if (!app_func) {
    app_func = append_char_function;
  }

  /* We now look backwards for the start of a filename/variable word */
  li = FUN(el,line)(el);
  ctemp = li->cursor;
  while (ctemp > li->buffer
         && !Strchr(word_break, ctemp[-1])
         && (!special_prefixes || !Strchr(special_prefixes, ctemp[-1]) ) ) {
    ctemp--;
  }

  len = (size_t)(li->cursor - ctemp);
  temp = el_malloc((len + 1) * sizeof(*temp));
  (void)Strncpy(temp, ctemp, len);
  temp[len] = '\0';

  /* these can be used by function called in completion_matches() */
  /* or (*attempted_completion_function)() */
  if (point != 0) {
    *point = (int)(li->cursor - li->buffer);
  }
  if (end != NULL) {
    *end = (int)(li->lastchar - li->buffer);
  }

  if (attempted_completion_function) {
    int cur_off = (int)(li->cursor - li->buffer);
#ifdef LAGOPUS
    {
      /* char *null is for avoid compilation warnings.  */
      char *null;
      null = (char *)&li->buffer[li->lastchar - li->buffer];
      *null = '\0';
    }
#endif /* LAGOPUS */
    matches = (*attempted_completion_function)(
                ct_encode_string(temp, &el->el_scratch),
                cur_off - (int)len, cur_off);
  } else {
    matches = 0;
  }
  if (!attempted_completion_function ||
      (over != NULL && !*over && !matches))
    matches = completion_matches(
                ct_encode_string(temp, &el->el_scratch), complet_func);

  if (over != NULL) {
    *over = 0;
  }

  if (matches) {
    int i;
    size_t matches_num, maxlen, match_len, match_display=1;

    retval = CC_REFRESH;
    /*
     * Only replace the completed string with common part of
     * possible matches if there is possible completion.
     */
    if (matches[0][0] != '\0') {
      el_deletestr(el, (int) len);
      FUN(el,insertstr)(el,
                        ct_decode_string(matches[0], &el->el_scratch));
    }

    if (what_to_do == '?') {
      goto display_matches;
    }

    if (matches[2] == NULL && strcmp(matches[0], matches[1]) == 0
#ifdef LAGOPUS
        && completion_status == 1
#endif /* LAGOPUS */
       ) {
      /*
       * We found exact match. Add a space after
       * it, unless we do filename completion and the
       * object is a directory.
       */
      FUN(el,insertstr)(el,
                        ct_decode_string((*app_func)(matches[0]),
                                         &el->el_scratch));
#ifdef LAGOPUS
    } else if (completion_status == 0) {
#else
    } else if (what_to_do == '!') {
#endif /* LAGOPUS */
    display_matches:
      /*
       * More than one match and requested to list possible
       * matches.
       */

      for (i = 1, maxlen = 0; matches[i]; i++) {
        match_len = strlen(matches[i]);
        if (match_len > maxlen) {
          maxlen = match_len;
        }
      }
      /* matches[1] through matches[i-1] are available */
      matches_num = (size_t)(i - 1);

      /* newline to get on next line from command line */
      (void)fprintf(el->el_outfile, "\n");

      /*
       * If there are too many items, ask user for display
       * confirmation.
       */
      if (matches_num > query_items) {
        (void)fprintf(el->el_outfile,
                      "Display all %zu possibilities? (y or n) ",
                      matches_num);
        (void)fflush(el->el_outfile);
        if (getc(stdin) != 'y') {
          match_display = 0;
        }
        (void)fprintf(el->el_outfile, "\n");
      }

      if (match_display) {
        /*
         * Interface of this function requires the
         * strings be matches[1..num-1] for compat.
         * We have matches_num strings not counting
         * the prefix in matches[0], so we need to
         * add 1 to matches_num for the call.
         */
        fn_display_match_list(el, matches,
                              matches_num+1, maxlen);
      }
      retval = CC_REDISPLAY;
    } else if (matches[0][0]) {
      /*
       * There was some common match, but the name was
       * not complete enough. Next tab will print possible
       * completions.
       */
      el_beep(el);
    } else {
      /* lcd is not a valid object - further specification */
      /* is needed */
      el_beep(el);
      retval = CC_NORM;
    }

    /* free elements of array and the array itself */
    for (i = 0; matches[i]; i++) {
      el_free(matches[i]);
    }
    el_free(matches);
    matches = NULL;
  }
#ifdef LAGOPUS
  if (matches == NULL && describe_status == 1) {
    retval = CC_REDISPLAY;
  }
#endif /* LAGOPUS */

  el_free(temp);
  return retval;
}

/*
 * el-compatible wrapper around rl_complete; needed for key binding
 */
/* ARGSUSED */
unsigned char
_el_fn_complete(EditLine *el, int ch __attribute__((__unused__))) {
  return (unsigned char)fn_complete(el, NULL, NULL,
                                    break_chars, NULL, NULL, (size_t)100,
                                    NULL, NULL, NULL, NULL);
}

redpajama_set_name: RedPajamaGithub


text:
using UnityEngine;
using System.Collections;
using MGSpawn.Spawn;

public class MGAISuperClass : MonoBehaviour {

	//the gameobject that Spawned this
	private MGSpawner mOwner;

	public virtual void SetOwner(MGSpawner owner)
	{
		mOwner = owner;
	}

	public virtual void Remove()
	{
		if(mOwner != null)
		{
			mOwner.RemoveUnit();
		}

		GLOBAL.that.SuperDestroy(this.transform.parent.transform.gameObject);
	}
}


text:
<?php
class sfFlexibleLogger extends sfLogger
{
  /**
   * Returns the sfFlexibleLogger instance.
   *
   * @return  object the sfFlexibleLogger instance
   */
  public static function getInstance()
  {
    // the class exists
    $class = __CLASS__;
    sfFlexibleLogger::$logger = new $class();
    sfFlexibleLogger::$logger->initialize();

    return sfFlexibleLogger::$logger;
  }

  public function getLogger($type)
  {
    if (isset($this->loggers[$type]))
    {
      return $this->loggers[$type];
    }
  }

  /**
   * Registers a logger.
   *
   * @param object Logger
   */
  public function registerLogger($logger)
  {
    $this->loggers[get_class($logger)] = $logger;
  }

  /**
   * Unregisters a logger.
   *
   * @param string Logger class name
   */
  public function unregisterLogger(string $type)
  {
    if (isset($this->loggers[$type]))
    {
      unset($this->loggers[$type]);
    }
  }
}


text:
package org.apache.jmeter.report.gui.action;

import java.awt.event.ActionEvent;
import java.util.HashSet;
import java.util.Set;

import org.apache.jmeter.control.Controller;
import org.apache.jmeter.gui.ReportGuiPackage;
import org.apache.jmeter.report.gui.action.AbstractAction;
import org.apache.jmeter.report.gui.tree.ReportTreeListener;
import org.apache.jmeter.report.gui.tree.ReportTreeNode;
import org.apache.jmeter.samplers.Sampler;
import org.apache.jmeter.testelement.TestElement;
import org.apache.jmeter.testelement.TestPlan;
import org.apache.jmeter.testelement.WorkBench;

public class ReportDragNDrop extends AbstractAction {
    public static final String ADD = "drag_n_drop.add";//$NON-NLS-1$

    public static final String INSERT_BEFORE = "drag_n_drop.insert_before";//$NON-NLS-1$

    public static final String INSERT_AFTER = "drag_n_drop.insert_after";//$NON-NLS-1$

    private static final Set<String> commands = new HashSet<String>();
    static {
        commands.add(ADD);
        commands.add(INSERT_BEFORE);
        commands.add(INSERT_AFTER);
    }

    /**
     * @see org.apache.jmeter.gui.action.Command#doAction(ActionEvent)
     */
    @Override
    public void doAction(ActionEvent e) {
        String action = e.getActionCommand();
        ReportGuiPackage guiPackage = ReportGuiPackage.getInstance();
        ReportTreeNode[] draggedNodes = guiPackage.getTreeListener().getDraggedNodes();
        ReportTreeListener treeListener = guiPackage.getTreeListener();
        ReportTreeNode currentNode = treeListener.getCurrentNode();
        ReportTreeNode parentNode = (ReportTreeNode) currentNode.getParent();
        TestElement te = currentNode.getTestElement();
        if (te instanceof TestPlan || te instanceof WorkBench) {
            parentNode = null; // So elements can only be added as children
        }
        // System.out.println(action+" "+te.getClass().getName());

        if (ADD.equals(action) && canAddTo(currentNode)) {
            removeNodesFromParents(draggedNodes);
            for (int i = 0; i < draggedNodes.length; i++) {
                ReportGuiPackage.getInstance().getTreeModel().insertNodeInto(draggedNodes[i], currentNode,
                        currentNode.getChildCount());
            }
        } else if (INSERT_BEFORE.equals(action) && canAddTo(parentNode)) {
            removeNodesFromParents(draggedNodes);
            for (int i = 0; i < draggedNodes.length; i++) {
                @SuppressWarnings("null")
                int index = parentNode.getIndex(currentNode); // can't be null - this is checked by canAddTo
                ReportGuiPackage.getInstance().getTreeModel().insertNodeInto(draggedNodes[i], parentNode, index);
            }
        } else if (INSERT_AFTER.equals(action) && canAddTo(parentNode)) {
            removeNodesFromParents(draggedNodes);
            for (int i = 0; i < draggedNodes.length; i++) {
                @SuppressWarnings("null")
                int index = parentNode.getIndex(currentNode) + 1; // can't be null - this is checked by canAddTo
                ReportGuiPackage.getInstance().getTreeModel().insertNodeInto(draggedNodes[i], parentNode, index);
            }
        }
        ReportGuiPackage.getInstance().getMainFrame().repaint();
    }

    /**
     * Determine whether or not dragged nodes can be added to this parent. Also
     * used by Paste TODO tighten rules TODO move to MenuFactory?
     *
     * @param parentNode
     * @return whether it is OK to add the dragged nodes to this parent
     */
    static boolean canAddTo(ReportTreeNode parentNode) {
        if (null == parentNode) {
            return false;
        }
        TestElement te = parentNode.getTestElement();
        // System.out.println("Add to: "+te.getClass().getName());
        if (te instanceof Controller) {
            return true;
        }
        if (te instanceof Sampler) {
            return true;
        }
        if (te instanceof WorkBench) {
            return true;
        }
        if (te instanceof TestPlan) {
            return true;
        }
        return false;
    }

    protected void removeNodesFromParents(ReportTreeNode[] nodes) {
        for (int i = 0; i < nodes.length; i++) {
            ReportGuiPackage.getInstance().getTreeModel().removeNodeFromParent(nodes[i]);
        }
    }

    /**
     * @see org.apache.jmeter.gui.action.Command#getActionNames()
     */
    @Override
    public Set<String> getActionNames() {
        return commands;
    }
}


text:
namespace Microsoft.Azure.Management.RecoveryServices.Backup.Models
{
    using Newtonsoft.Json;
    using System.Linq;

    /// <summary>
    /// Azure VM workload-specific protectable item.
    /// </summary>
    public partial class AzureVmWorkloadProtectableItem : WorkloadProtectableItem
    {
        /// <summary>
        /// Initializes a new instance of the AzureVmWorkloadProtectableItem
        /// class.
        /// </summary>
        public AzureVmWorkloadProtectableItem()
        {
            CustomInit();
        }

        /// <summary>
        /// Initializes a new instance of the AzureVmWorkloadProtectableItem
        /// class.
        /// </summary>
        /// <param name="backupManagementType">Type of backup management to
        /// backup an item.</param>
        /// <param name="workloadType">Type of workload for the backup
        /// management</param>
        /// <param name="friendlyName">Friendly name of the backup
        /// item.</param>
        /// <param name="protectionState">State of the back up item. Possible
        /// values include: 'Invalid', 'NotProtected', 'Protecting',
        /// 'Protected', 'ProtectionFailed'</param>
        /// <param name="parentName">Name for instance or AG</param>
        /// <param name="parentUniqueName">Parent Unique Name is added to
        /// provide the service formatted URI Name of the Parent
        /// Only Applicable for data bases where the parent would be either
        /// Instance or a SQL AG.</param>
        /// <param name="serverName">Host/Cluster Name for instance or
        /// AG</param>
        /// <param name="isAutoProtectable">Indicates if protectable item is
        /// auto-protectable</param>
        /// <param name="isAutoProtected">Indicates if protectable item is
        /// auto-protected</param>
        /// <param name="subinquireditemcount">For instance or AG, indicates
        /// number of DBs present</param>
        /// <param name="subprotectableitemcount">For instance or AG, indicates
        /// number of DBs to be protected</param>
        /// <param name="prebackupvalidation">Pre-backup validation for
        /// protectable objects</param>
        public AzureVmWorkloadProtectableItem(string backupManagementType = default(string), string workloadType = default(string), string friendlyName = default(string), string protectionState = default(string), string parentName = default(string), string parentUniqueName = default(string), string serverName = default(string), bool? isAutoProtectable = default(bool?), bool? isAutoProtected = default(bool?), int? subinquireditemcount = default(int?), int? subprotectableitemcount = default(int?), PreBackupValidation prebackupvalidation = default(PreBackupValidation))
            : base(backupManagementType, workloadType, friendlyName, protectionState)
        {
            ParentName = parentName;
            ParentUniqueName = parentUniqueName;
            ServerName = serverName;
            IsAutoProtectable = isAutoProtectable;
            IsAutoProtected = isAutoProtected;
            Subinquireditemcount = subinquireditemcount;
            Subprotectableitemcount = subprotectableitemcount;
            Prebackupvalidation = prebackupvalidation;
            CustomInit();
        }

        /// <summary>
        /// An initialization method that performs custom operations like setting defaults
        /// </summary>
        partial void CustomInit();

        /// <summary>
        /// Gets or sets name for instance or AG
        /// </summary>
        [JsonProperty(PropertyName = "parentName")]
        public string ParentName { get; set; }

        /// <summary>
        /// Gets or sets parent Unique Name is added to provide the service
        /// formatted URI Name of the Parent
        /// Only Applicable for data bases where the parent would be either
        /// Instance or a SQL AG.
        /// </summary>
        [JsonProperty(PropertyName = "parentUniqueName")]
        public string ParentUniqueName { get; set; }

        /// <summary>
        /// Gets or sets host/Cluster Name for instance or AG
        /// </summary>
        [JsonProperty(PropertyName = "serverName")]
        public string ServerName { get; set; }

        /// <summary>
        /// Gets or sets indicates if protectable item is auto-protectable
        /// </summary>
        [JsonProperty(PropertyName = "isAutoProtectable")]
        public bool? IsAutoProtectable { get; set; }

        /// <summary>
        /// Gets or sets indicates if protectable item is auto-protected
        /// </summary>
        [JsonProperty(PropertyName = "isAutoProtected")]
        public bool? IsAutoProtected { get; set; }

        /// <summary>
        /// Gets or sets for instance or AG, indicates number of DBs present
        /// </summary>
        [JsonProperty(PropertyName = "subinquireditemcount")]
        public int? Subinquireditemcount { get; set; }

        /// <summary>
        /// Gets or sets for instance or AG, indicates number of DBs to be
        /// protected
        /// </summary>
        [JsonProperty(PropertyName = "subprotectableitemcount")]
        public int? Subprotectableitemcount { get; set; }

        /// <summary>
        /// Gets or sets pre-backup validation for protectable objects
        /// </summary>
        [JsonProperty(PropertyName = "prebackupvalidation")]
        public PreBackupValidation Prebackupvalidation { get; set; }

    }
}