text:
Label: ATORVASTATIN CALCIUM tablet, film coated
Packager: NuCare Pharmaceuticals,Inc.
This is a repackaged label.
Source NDC Code(s): 69097-944
These highlights do not include all the information needed to use atorvastatin calcium safely and effectively. See full prescribing information for atorvastatin calcium tablets.
Atorvastatin calcium tablet is an HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to:
Reduce the risk of MI, stroke, revascularization procedures, and angina in adult patients without CHD, but with multiple risk factors ( 1.1).
Reduce the risk of MI and stroke in adult patients with type 2 diabetes without CHD, but with multiple risk factors ( 1.1).
Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in adult patients with CHD ( 1.1).
Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( 1.2).
Reduce elevated TG in adult patients with hypertriglyceridemia and primary dysbetalipoproteinemia ( 1.2).
Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) ( 1.2).
Reduce elevated total-C, LDL-C, and apo B levels in pediatric patients 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) after failing an adequate trial of diet therapy ( 1.2).
Atorvastatin calcium tablets has not been studied in Fredrickson Types I and V dyslipidemias ( 1.3).
Dose range: 10 to 80 mg once daily ( 2.1).
Recommended start dose: 10 or 20 mg once daily ( 2.1).
Patients requiring large LDL-C reduction (>45%) may start at 40 mg once daily ( 2.1).
Pediatric patients with HeFH: starting dose: 10 mg once daily; dose range: 10 to 20 mg/day for patients 10 years to 17 years of age ( 2.2).
Tablets: 10, 20, 40, and 80 mg of atorvastatin ( 3).
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4).
Hypersensitivity to any component of this medication ( 4).
Pregnancy ( 4, 8.1, 8.3)
Lactation ( 4, 8.2)
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected ( 5.1, 8.5).
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.2).
A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs. placebo ( 5.5).
The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin calcium in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily
Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin calcium ( 7).
Digoxin: Patients should be monitored appropriately ( 7.8).
Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased ( 7.9).
Rifampin should be simultaneously co-administered with atorvastatin calcium ( 7.7).
Hepatic impairment: Plasma concentrations markedly increased in patients with chronic alcoholic liver disease ( 8.6, 12.3).
Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with atorvastatin calcium ( 8.3).
See 17 for PATIENT COUNSELING INFORMATION.
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors
6.1 Clinical Trials Experiences
7.8 Digoxin
7.9 Oral Contraceptives
In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:
In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:
Atorvastatin calcium tablets are indicated:
As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb);
As an adjunct to diet for the treatment of adult patients with elevated serum TG levels ( Fredrickson Type IV);
For the treatment of adult patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet;
As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present:
a. LDL-C remains ≥ 190 mg/dL or
b. LDL-C remains ≥ 160 mg/dL and:
Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson Types I and V).
The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies (14.6)]. Doses should be individualized according to the recommended goal of therapy [see Indications and Usage (1.2) and Clinical Pharmacology (12)]. Adjustments should be made at intervals of 4 weeks or more.
The dosage of atorvastatin calcium tablets in patients with homozygous HoFH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other Lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium tablets and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin calcium tablets should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Atorvastatin calcium tablets are yellow, oval shape, biconvex, film coated, and are available in four strengths (see Table 1).
Table 1: Atorvastatin Calcium Tablet Strengths and Identifying Features
"SG" on one side and "152" on the other
20 mg of atorvastatin "SG" on one side and "153" on the other
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with atorvastatin calcium and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs [ see Drug Interactions (7)] . Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 2 [see Dosage and Administration (2.6), Drug Interactions (7), and Clinical Pharmacology (12.3)].
Table 2. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
*Use with caution and with the lowest dose necessary (12.3)
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11)].
Table 3. Clinical adverse reactions occurring in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials.
Adverse Reaction* Any dose
N=8755 10 mg
N=188 40 mg
N=4055 Placebo
Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2
Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5
Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3
Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9
Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6
Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3
Nausea 4.0 3.7 3.7 7.1 3.8 3.5
Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6
Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3.0
Myalgia 3.5 3.6 5.9 8.4 2.7 3.1
Insomnia 3.0 2.8 1.1 5.3 2.8 2.9
Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1
*Adverse Reaction > 2% in any dose greater than placebo
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.
In TNT [see Clinical Studies (14.1)] involving 10,001 subjects (age range 29 to 78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin calcium 10 mg daily (n=5006) or atorvastatin calcium 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).
In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to17 years) (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of Atorvastatin calcium 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apoB levels, was generally similar to that of placebo [see Use in Special Populations (8.4) and Clinical Studies(14.6)] .
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)] . Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Dosage and Administration (2.6), and Warnings and Precautions (5.1)].
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)] . Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin calcium should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of atorvastatin calcium should not exceed 20 mg and should be used with caution [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] . In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin calcium should not exceed 40 mg and close clinical monitoring is recommended.
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)] . Therefore, in patients taking itraconazole, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)] . The co-administration of atorvastatin calcium with cyclosporine should be avoided [see Warnings and Precautions (5.1)].
When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Atorvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥ 6 times the MRHD (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300mg/kg/day and 100mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300mg/kg/day or in rabbits at doses up to 100mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2). In rats, the maternally toxic dose of 300mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100mg/kg/day in rabbits, there was increased post-implantation loss, and at 100mg/kg/day fetal body weights were decreased.
In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100mg/kg/dayand acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22times (225 mg/kg) the human exposure at the MRHD, based on AUC.
Atorvastatin calcium use is contraindicated during breastfeeding [see Contraindications (4)] . There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with atorvastatin calcium.
A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls,10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin calcium had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.
Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations (8.1), (8.3)] .
Additional pediatric use information is approved for Pfizer's LIPITOR (atorvastatin calcium) tablets. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled with that pediatric information
Clinical efficacy of atorvastatin calcium with dosages up to 80mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients [see Clinical Studies (14.5)].
Atorvastatin calcium is [R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1).The empirical formula of atorvastatin calcium is C 66H 68 Ca F 2N 4O 10 and its molecular weight is 1155.36. Its structural formula is:
Atorvastatin calcium is a white to off-white colored powder free from visible extraneous matter. Atorvastatin calcium is soluble in dimethyl sulphoxide, slightly soluble in alcohol, very slightly soluble in water, in pH 7.4 phosphate buffer and in acetonitrile and practically insoluble in aqueous solutions of pH 4 and below.
Atorvastatin calcium tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; lecitihin, polyvinyl alcohol part hydrolyzed, talc, titanium dioxide, xanthan gum and iron oxide yellow.
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles.
Absorption: Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].
Distribution: Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.2)].
Metabolism: Atorvastatin calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin calcium and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration.
Geriatric: Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations (8.5)].
Gender: Plasma concentrations of atorvastatin calcium in women differ from those in men (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between men and women.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4)].
Change in AUC &
Change in C max&
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold
#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold
#Telaprevir 750 mg q8h, 10 days 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold
#Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold
#Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold
#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold
#Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20%
#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold
#Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold
#Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold
#Grapefruit Juice, 240 mL QD § 40 mg, SD ↑ 37% ↑ 16%
Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change
Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38%
Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 %
Cimetidine 300 mg QID, 2 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11%
Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26% ¶
Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34%
Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1%
#Rifampin 600 mg QD, 7 days (co-administered) † 40 mg SD ↑ 30% ↑ 2.7 fold
#Rifampin 600 mg QD, 5 days (doses separated) † 40 mg SD ↓ 80% ↓ 40%
#Gemfibrozil 600mg BID, 7 days 40mg SD ↑ 35% ↓ Less than 1%
#Fenofibrate 160mg QD, 7 days 40mg SD ↑ 3% ↑ 2%
Boceprevir 800 mg TID, 7 days 40 mg SD ↑2.30 fold ↑2.66 fold
& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change).
* Greater increases in AUC (up to 2.5 fold) and/or C max (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL - 1.2 liters per day).
** Single sample taken 8 to 16 h post dose.
†Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Change in AUC
Change in Cmax
80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11%
80 mg QD for 14 days #Digoxin 0.25 mg QD, 20 days ↑ 15% ↑ 20 %
40 mg QD for 22 days Oral contraceptive QD,
- ethinyl estradiol 35mcg
10 mg, SD Tipranavir 500mg
BID/ritonavir 200 mg
BID, 7 days No change No change
10 mg QD for 4 days Fosamprenavir 1400
mg BID, 14 days ↓ 27% ↓ 18%
10 mg QD for 4 days Fosamprenavir 700 mg
BID, 14 days No change No change
In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and as permia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80mg dose); testis weights were significantly lower at 30 and 100mg/kg and epididymal weight was lower at 100mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA 1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.
Endpoint Atorvastatin
(N=5006) Atorvastatin
(N=4995) HR a (95%CI)
PRIMARY ENDPOINT n (%) n (%)
First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89)
CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03)
Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93)
Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67)
Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96)
First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94)
First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15)
First CABG or other coronary revascularization procedure ‡ 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80)
First documented angina endpoint ‡ 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99)
All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19)
Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03)
Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57)
Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55)
Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00)
Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82)
a Atorvastatin 80 mg: atorvastatin 10 mg
b Component of other secondary endpoints
HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft
Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
There was no significant difference between the treatment groups for all-cause mortality (Table 6). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group.
Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb). Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.
TABLE 7. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a
Dose N TC LDL-C Apo B TG HDL-C Non-HDL- C/ HDL-C
Placebo 21 4 4 3 10 -3 7
10 22 -29 -39 -32 -19 6 -34
a Results are pooled from 2 dose-response studies.
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25 th and 75 th percentile) percent changes from baseline in HDL-C for atorvastatin calcium 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
(Daily Dose) N Total-C LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C
Atorvastatin 10 mg 707 -27 a -36 a -28 a -17 a +7 -37 a
Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28
95% CI for Diff 1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7, 2.0 -11.1, -7.1
Atorvastatin 10 mg 222 -25 b -35 b -27 b -17 b +6 -36 b
Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28
95% CI for Diff 1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1
Atorvastatin 10 mg 132 -29 c -37 c -34 c -23 c +7 -39 c
Simvastatin 10 mg 45 -24 30 -30 -15 +7 -33
95% CI for Diff 1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9
1 A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a statistically significant difference.
a Significantly different from lovastatin, ANCOVA, p ≤0.05
b Significantly different from pravastatin, ANCOVA, p ≤0.05
c Significantly different from simvastatin, ANCOVA, p ≤0.05
The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia ( Fredrickson Type IV) treated across several clinical trials is shown in the table below (Table 9). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267 to 1502).
(N=12) Atorvastatin Calcium 10 mg
Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3)
Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8)
LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8)
HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2)
VLDL-C -1.0 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62.0 (-88.2, 37.6)
non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3)
The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia ( Fredrickson Type III) are shown in the table below (Table 10).
Median (min, max) at
Baseline (mg/dL) Atorvastatin Calcium
10 mg Atorvastatin Calcium
Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31)
Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30)
IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8)
non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36)
In a study without a concurrent control group, 29 patients ages 6 to 37 years with HoFH received maximum daily doses of 20 to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10 years to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5 to 385.0 mg/dL) in the atorvastatin calcium group compared to 230.0 mg/dL (range: 160.0 to 324.5 mg/dL) in the placebo group. The dosage of atorvastatin calcium (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).
DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B
Placebo 47 -1.5 -0.4 -1.9 1.0 0.7
Atorvastatin Calcium 140 -31.4 -39.6 2.8 -12.0 -34.0
Additional pediatric use information is approved for Pfizer's LIPITOR (atorvastatin calcium) tablets. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
10 mg tablets:
Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 152 on other side.
NDC 68071-4797-9 BOTTLES OF 90
Store at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, child-resistant container.
Advisethe patient to read the FDA-approved patient labeling (Patient Information).
All patients starting therapy with atorvastatin calcium should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.
Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)] .
Advise women not to breastfeed during treatment with atorvastatin calcium [see Contraindications (4) and Use in Specific Populations (8.2)].
Cipla USA, Inc.
1560 Sawgrass Corporate Parkway
Suite 130, Sunrise, FL 33323
ScieGen Pharmaceuticals, Inc.
Hauppauge, NY 11788 USA
Rev: 01/2018
Atorvastatin Calcium Tablets
(a tor″ va stat′ in kal′ see um)
What is Atorvastatin Calcium Tablet?
Atorvastatin calcium tablets is a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C ("bad" cholesterol) and triglycerides in your blood. It can raise your HDL-C ("good" cholesterol) as well. Atorvastatin calcium tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.
Atorvastatin calcium tablets can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as:
Atorvastatin calcium tablets can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as:
are breast feeding. Atorvastatin calcium tablets can pass into your breast milk and may harm your baby.
Atorvastatin calcium tablets can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or atorvastatin calcium tablets are stopped. These serious side effects include:
How do I store Atorvastatin Calcium Tablets
This leaflet summarizes the most important information about atorvastatin calcium tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about atorvastatin calcium tablets that is written for health professionals.
Inactive Ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; lecitihin, polyvinyl alcohol part hydrolyzed, talc, titanium dioxide, xanthan gum and iron oxide yellow.
Package/Label Display Panel
atorvastatin calcium tablet, film coated
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68071-4797(NDC:69097-944)
COPOVIDONE K25-31 (UNII: D9C330MD8B)
MANNITOL (UNII: 3OWL53L36A)
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
SODIUM BICARBONATE (UNII: 8MDF5V39QO)
SODIUM CARBONATE (UNII: 45P3261C7T)
EGG PHOSPHOLIPIDS (UNII: 1Z74184RGV)
FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
Color yellow Score no score
Shape OVAL Size 10mm
Flavor Imprint Code SG;152
NDC:68071-4797-9 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/07/2019
Labeler - NuCare Pharmaceuticals,Inc. (010632300)
NuCare Pharmaceuticals,Inc. 010632300 relabel(68071-4797)
https://dailymed.nlm.nih.gov/dailymed/labelrss.cfm?setid=838a0dfe-dd55-28ce-e053-2a91aa0a801b


Partly cloudy Saturday, temperatures as high as 20°C / 69°F, low temperature around 6°C / 43°F, probability of precipitation 0%, wind out of the E 10 km/h / 6 mph. Barometric pressure 1025 mb / 30.27 in, visibility 19 km / 12 mi, humidity 66%.
Partly cloudy Sunday, temperatures as high as 21°C / 69°F, low temperature around 5°C / 41°F, probability of precipitation 0%, wind out of the ESE 5 km/h / 3 mph. Barometric pressure 1019 mb / 30.09 in, visibility 20 km / 12 mi, humidity 60%.
Partly cloudy Monday, temperatures as high as 20°C / 67°F, low temperature around 6°C / 43°F, probability of precipitation 0%, wind out of the E 9 km/h / 5 mph. Barometric pressure 1007 mb / 29.74 in, visibility 19 km / 12 mi, humidity 65%.
Patchy rain possible Tuesday, temperatures as high as 20°C / 68°F, low temperature around 8°C / 46°F, probability of precipitation 85%, wind out of the SW 10 km/h / 6 mph. Barometric pressure 1000 mb / 29.53 in, visibility 16 km / 10 mi, humidity 64%.
Partly cloudy Wednesday, temperatures as high as 22°C / 71°F, low temperature around 7°C / 45°F, probability of precipitation 0%, wind out of the E 10 km/h / 6 mph. Barometric pressure 1010 mb / 29.83 in, visibility 15 km / 9 mi, humidity 70%.
Moderate or heavy rain shower Thursday, temperatures as high as 22°C / 72°F, low temperature around 8°C / 47°F, probability of precipitation 79%, wind out of the SW 11 km/h / 7 mph. Barometric pressure 1009 mb / 29.8 in, visibility 13 km / 8 mi, humidity 72%.
Light rain Friday, temperatures as high as 10°C / 50°F, low temperature around 7°C / 45°F, probability of precipitation 86%, wind out of the W 9 km/h / 6 mph. Barometric pressure 1019 mb / 30.09 in, visibility 9 km / 6 mi, humidity 87%.
Payerne, Switzerland Weather Forecast - Find local Payerne, Switzerland weather forecast and current conditions. Continually striving to be your best resource for Local Payerne, Switzerland Weather!


text:
using System.Collections.Generic;

namespace Tested
{
    public class Aggregator
    {
        private readonly IDepend _depend;
        private readonly IAnother _another;

        public IService Service { get; set; }

        public int Serial { get; set; }

        public Aggregator(IDepend depend, IAnother another)
        {
            _depend = depend;
            _another = another;
        }

        public Master Aggregate(ISome some)
        {
            return some.Get();
        }

        public IEnumerable<Detail> Aggregate(IService service)
        {
            return service.Details;
        }

        public IEnumerable<Detail> Aggregate()
        {
            return Service.Details;
        }

        public int Aggregate(string intoCalabanga)
        {
            _depend.Caramba(_another);
            return _another.Calabanga(intoCalabanga);
        }

        public Master GetMaster(Detail detail)
        {
            return detail.Master;
        }
    }

    public interface IService
    {
        IEnumerable<Detail> Details { get; set; }
    }

    public interface ISome
    {
        Master Get();
    }

    public class Master
    {
        public int Id { get; set; }

        public string Name { get; set; }

        public bool Flag { get; set; }

        public IList<Detail> Details { get; set; }
    }

    public class Detail
    {
        public int Id { get; set; }

        public string Name { get; set; }

        public Master Master { get; set; }
    }

    public interface IAnother
    {
        int Calabanga(string s);
    }

    public interface IDepend
    {
        void Caramba(IAnother another);
    }
}

redpajama_set_name: RedPajamaGithub


The Buzludzha Project is a design proposal for the conservation of the Buzludzha Memorial House. The project was created by the Bulgarian architect Dora Ivanova, who initially presented and defended it for her 2014 master's thesis in architecture at the Technical University of Berlin. The proposal has since been developed to incorporate feedback gathered during the dozens of public discussions that she organised and chaired between 2015 and 2018.
The Buzludzha Monument is unique in terms of its history, architecture and art. Even in its current decayed condition, thousands of people travel from around the world to visit the site – and many of them are left with unanswered questions: How and why was such a structure built? What was it used for? What do the mosaics represent? How was it destroyed and why? Preserved in the form of a museum, Buzludzha will provide answers to all of those questions.
The Buzludzha Memorial House was built to celebrate the Bulgarian Communist Party – and so any painstaking, loving recreation of the monument in its original form could give the impression of celebrating those same ideologies. We don't want to do that. But neither will this project adapt or repurpose the monument, forgetting or disguising its original intention.
What we want is to preserve this unique work of architecture, while offering a critical and objective explanation of its history and purpose. We believe that traumatic history should never be forgotten… but instead be remembered, explained, discussed, and used as a basis for further education.
The main hall will be used for cultural, historical, educational, arts and music events. The auditorium design, as it currently stands, can host up to 500 people, and by harnessing this space for small to mid-sized events it is believed that the venue can contribute to the national and social significance of the monument.
An objective and critical analysis will be offered for the mosaics decorating this interior space. These will be preserved in their current state, with roughly 80% of the original artwork surviving. The mosaics detail key historical events and personalities from the communist period, and will be used to explain not only the ideas behind communism, but also the propaganda that the system created about itself.
The corridor between the inner and the outer mosaic rings will be dedicated to the political and social repressions under Bulgaria's communist government. Visitors will learn about the prisons, the extensive citizen dossiers and the feared internal security forces, through an exhibition of documents and dissident accounts.
The outer ring of mosaics presents scenes of everyday life during communism. It depicts themes such as industrialisation, military power and domestic life, and here visitors will learn about the reality of life in communist Bulgaria – objectively exploring such ideas as the role of women in communist society, childcare and education, culture and foreign policy.
The monument's basement will be developed to offer a narrative of the monument itself, with a gallery that spans from the history of Buzludzha Peak through to the planning, construction and utilisation of the monument in the 20th century. The gallery will chronicle Buzludzha's decline, and of course, its preservation. The collection will incorporate: original design sketches for the mosaics, the building's blueprints, archive records and photography, in addition to more recent photographs of the monument.
A glass elevator ascending the 70m tower provides visitors with dramatic views over the mountain terrain. It will pass through the chamber between the 12m red stars, with this space being cleared to allow unhindered views from the interior. Roughly 50% of the red glass currently remains, with missing portions to be secured and insulated. This vertical experience also offers a place for visitors to learn about other communist-era monuments in Bulgaria.
The panoramic observation deck at the top of the tower will provide exceptional 360-degree views across the surrounding landscape. A glass 'sky-walk' allows braver visitors to walk out beyond the overhang for a dizzying downward view, while a map of the region points out a number of other nearby attractions which may be viewed through the installed telescope. On a clear day, the view stretches more than 100km – spanning the mountain range, the Danube Plain in the north and the Thracian Valley to the south.
The project chooses to preserve the monument as a spectacular educational experience – rather than restoring it to its original form, and risk honouring the ideologies it was built to celebrate. This proposal will see many of the building's interior spaces frozen in their current, semi-ruined state. Through the use of modern technology however, visitors will be able to see Buzludzha's past glory juxtaposed against its current state of disrepair.
The Buzludzha project will use 3D projection mapping to bring the monument to life. Missing or damaged sections of the mosaic can be projected onto the walls, while also allowing vast scope for educational light shows and seasonal exhibits.
The museum will take advantage of virtual, augmented and mixed reality formats, to create a truly unique visitor experience. Audio guides will be accompanied by specially developed headsets, allowing visitors to experience immersive and unforgettable self-guided tours.


text:
<?php
function _ops_update_score() {
  $OID=max(0,intval($_POST['OID']));
  $CID=max(0,intval($_POST['CID']));
  $msg="";

  loginRequireMgmt();
  if (!loginCheckPermission(USER::MGMT_TEAM)) redirect("errors/401");
  $itemName="Team";
  $urlPrefix="mgmt_team";
  $object=new Team();

  if ($OID)
  {
    $object->retrieve($OID,$CID);
    if (!$object->exists())
    {
      $msg="$itemName not found!";
    }
    else
    {
      transactionBegin();
      if ($object->updateTotalScore() )
      {
      	Event::createEvent(EVENT::TYPE_EDIT, $object, Station::getRegistrationStation(), 0, $_POST); // just put the post data into the event
        transactionCommit();
        $msg="$itemName updated!";
      }
      else
      {
        transactionRollback();
        $msg="$itemName update failed";
      }
    }
  }
  else
  {
    $msg = "attempting to create team from ops_update_score which is not supported";
  }
  redirect("$urlPrefix/manage",$msg);
}


text:
Mom charged with having gun in school parking lot
Diane Turbyfill dturbyfill@gastongazette.com
Police say a woman had a gun and drug paraphernalia with her while she slept in a school parking lot during school hours.
The incident happened around 11 a.m. Monday.
A Dallas police officer walked over to a car in the parking lot of Carr Elementary School because he saw a woman slumped over behind the wheel, according to Capt. R.A. Scott.
The officer woke the woman and asked to see her driver's license. Melissa Ann Acord said her son attended the school, and she reportedly handed over an expired South Carolina license.
Scott says the officer was given permission to search Acord's car where he found a semi-automatic handgun inside a bag and a glass pipe with methamphetamine residue in it.
Acord, 27, of Dallas, was arrested and charged with felony gun on educational property, misdemeanor carrying a concealed weapon and misdemeanor possession of drug paraphernalia.
She was booked into Gaston County Jail around 1 p.m. and released on a $25,000 bond about eight hours later.
Acord was arrested in late February on a charge of failure to appear in court.
You can reach Diane Turbyfill at 704-869-1817 and Twitter.com/GazetteDiane.

redpajama_set_name: RedPajamaCommonCrawl


(Ash) ,x25 (CCITT X.25) .
Shutdown scheduled for Sat 2017-07-01 22:00:00 EDT, use 'shutdown -c' to cancel.
Shutdown scheduled for Sat 2017-07-01 08:54:35 EDT, use 'shutdown -c' to cancel.
[root@localhost ~]# echo "hello linux"
[root@localhost ~]# shutdown +5 "System will shutdown after 5 minutes"


text:
About EV
Our investment criteria
SageRider joins Madison Industries
March 27, 2018 In News
Oil & Gas technology and information services leader SageRider, Inc. has joined the Madison Energy vertical of Madison Industries.
Founded in 2008, SageRider serves its customers from offices throughout the USA, Argentina, and Colombia. SageRider specializes in subsurface surveillance technology, complete with pressure/temperature sensor systems, fiber optics, reservoir evaluation, and a host of innovative data collection methods.
SageRider prides itself on delivering cutting edge technology and critical information to its customers real time. The proprietary technology associated with SageRider's products and services translates into significant cost savings through maximizing production and overall field development optimization.
Madison purchased its ownership stake from EV Private Equity who successfully supported management in growing the business over the last five years.
The Founders and leadership team will continue to build their business as owners in SageRider.
Stan Wall, CEO of SageRider said
"In Madison, we could not have chosen a more dedicated partner to support our future growth and be our permanent home. I would like to thank my partners and our entire employee group for 10 years of extremely hard work and dedication to building a thriving business. I would also like to thank the entire group of EV Private Equity, and, in-particular, Shantanu Agarwal for their incredible support during the last several years."
About Madison Industries
Madison Industries is one of the largest and most successful privately held companies in the world. Madison builds entrepreneurially driven, branded market leaders that are committed to making the world safer, healthier and more productive by creating innovative solutions that deliver outstanding customer value. The team at Madison is committed to building something truly remarkable that long outlasts them while coaching others to reach their highest potential.
www.madison.net
New Promotion Strengthens Investment Team
In the News: Greg Herrera shares his insights into 2019 market trends and 2020 predictions
Q&A with New EV employees: Kaivan Forouzesh and Amy Brownlie
Successful leadership – capabilities, responsibilities and tasks
Embracing the behavioural aspects of leadership
Kongsgaardbakken 1
P +47 51 84 12 95
10777 Westheimer Suite 1175,
P +1 281 768 6721
15 Albert Street Aberdeen
P +44 1224 628 280
EV Private Equity is authorised and regulated by the Financial Conduct Authority.
EV Private Equity is registered as an investment adviser with the Securities and Exchange Commission under the Investment Advisers Act of 1940.


Muncie, Indiana, native Troye Kinnett began playing the piano at the age of eight and spent much of his youth listening to keyboard icons such as Stevie Wonder and Elton John.
In high school, Troye had the opportunity to perform at the Macy's Thanksgiving Day Parade in New York City, which sparked his musical ambition that would lead to future performances there at Radio City Music Hall and Carnegie Hall. Troye studied music composition at Ball State and played in the University's top jazz ensemble. While in college, he immersed himself in a variety of musical styles, including jazz, progressive rock, and classical. It's Troye's Midwestern roots though that would later propel his career.
Early in his career, Troye toured with several rock bands playing in clubs across the Midwest. He increasingly began to work as a studio keyboardist where his talent soon gained him much deserved recognition. Eventually, he began working in Indianapolis as both a composer and as an audio engineer. He had the opportunity to write music for a variety of entities, including the NCAA, the Heartland Film Festival, Eli Lilly, F.C. Tucker, Simon Malls, Subway, Delta Faucet, Kenra, and H.H. Gregg. His compositions have won Addy, Telly, and Silver Microphone Awards, and he has scored independent feature films that have aired on Showtime and The Movie Channel.
Throughout this period, Troye performed on studio recordings while staying active in the live music scene. He performed and recorded with Donovan, The Boxtops, Rare Earth, Eddie Money, and Grammy Award winner, Sandi Patty.
In the fall of 2005, Troye was asked to record with fellow Hoosier and perhaps the most well-known celebrity from Indiana, John Mellencamp. Six months later, Troye began touring with his band, playing keyboards, accordion, harmonica, and singing background vocals. Since that time, Troye has appeared on studio albums with Mellencamp, working with artists such as T Bone Burnett, Joan Baez, and Little Big Town, and has performed live with Keith Urban, Stephen Stills, Sheryl Crow, and Kenny Wayne Shepherd. His musical talent and keyboard and accordion skills, together with his Indiana roots, make him a perfect fit for the band headed by Mellencamp, a member of the Rock and Roll Hall of Fame.
Recent endeavors include appearing on the soundtrack for the feature film Ithaca directed by Meg Ryan, keyboardist and programmer for the Sandi Patty Forever Grateful Tour, musical director for Rock-IN-Roar 500 where he led a 500-piece rock band to celebrate the 100th Running of the Indianapolis 500, and is currently involved in the production of The Ghost Brothers of Darkland County, a musical written by Stephen King with songs by Mellencamp.


text:
Agrilus folognei es una especie de insecto del género Agrilus, familia Buprestidae, orden Coleoptera.

Fue descrita científicamente por Kerremans, 1912.

Referencias

folognei
Insectos descritos en 1912

redpajama_set_name: RedPajamaWikipedia


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