Atorvastatin Calcium

1 INDICATIONS & USAGE Atorvastatin Calcium tablets are indicated: •To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD •As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). •As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). •As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia o Hypertriglyceridemia Atorvastatin calcium tablets are an HMG-CoA reductase inhibitor (statin) indicated (1): • To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. • As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. • As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia.

2 DOSAGE & ADMINISTRATION • Take orally once daily with or without food (2.1). • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating Atorvastatin Calcium tablets, and adjust dosage if necessary ( 2.1 ). • Adults ( 2.2 ): o Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. o Patients requiring LDL-C reduction >45% may start at 40 mg once daily. • Pediatric Patients Aged 10 Years of Age and Older with HeFH : Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily ( 2.3 ). • Pediatric Patients Aged 10 Years of Age and Older with HoFH : Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily ( 2.4 ). • See full prescribing information for Atorvastatin Calcium tablets dosage modifications due to drug interactions ( 2.5 ). 2.1 Important Dosage Information • Take Atorvastatin Calcium tablets orally once daily at any time of the day, with or without food. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating Atorvastatin Calcium tablets, and adjust the dosage if necessary. • If a dose is missed, advise patients not to take the missed dose and resume with the next scheduled dose. 2.2 Recommended Dosage in Adult Patients The recommended starting dosage of Atorvastatin Calcium tablets are 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 10 Yearsof Age and Older with HeFH The recommended starting dosage of Atorvastatin Calcium tablets are 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. 2.4 Recommended Dosage in Pediatric Patients 10 Yearsof Age and Older with HoFH The recommended starting dosage of Atorvastatin Calcium tablets are 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of Atorvastatin Calcium tablets with the following drugs requires dosage modification of Atorvastatin Calcium tablets [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )] . Anti-Viral Medications • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed Atorvastatin Calcium tablets 20 mg once daily. • In patients taking nelfinavir, do not exceed Atorvastatin Calcium tablets 40 mg once daily . Select Azole Antifungals or Macrolide Antibiotics •In patients taking clarithromycin or itraconazole, do not exceed Atorvastatin Calcium tablets 20 mg once daily. For additional recommendations regarding concomitant use of Atorvastatin Calcium tablets with other anti-viral medications, azole antifungals or macrolide antibiotics, see Drug Interactions ( 7.1 ).

3 DOSAGE FORMS & STRENGTHS Tablets: • 10 mg of Atorvastatin: White to off-white, oval, bioconvex film coated tablets, debossed with “C15” on one side and plain on other side. • 20 mg of Atorvastatin: White to off-white, oval, bioconvex film coated tablets, debossed with “C16” on one side and plain on other side. • 40 mg of Atorvastatin: White to off-white, oval, bioconvex film coated tablets, debossed with “C23” on one side and plain on other side. • 80 mg of Atorvastatin: White to off-white, oval, bioconvex film coated tablets, debossed with “C24” on one side and plain on other side. Tablets: 10, 20, 40, and 80 mg of atorvastatin (3).

4 CONTRAINDICATIONS • Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )] • Hypersensitivity to atorvastatin or any excipients in Atorvastatin Calcium tablets. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions ( 6.2 )]. • Acute liver failure or decompensated cirrhosis ( 4 ). • Hypersensitivity to atorvastatin or any excipient in Atorvastatin Calcium tablets ( 4 ).

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥ 5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection (6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cadila Pharmaceuticals Limited at 1-202-355-9785 (fax 1-202-355-9784) or www.cadilapharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the atorvastatin calcium tablets placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin calcium tablets vs. 7,311 placebo; age range 10 to 93 years, 39% female, 91% White, 3% Black or African American, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin calcium tablets that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium tablets(n=8,755), from seventeen placebo-controlled trials. Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin Calcium Tablets -Treated with any Dose and Greater than Placebo Adverse Reaction %Placebo N=7,311 % 10 mg N=3,908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4,055 % Any dose N=8,755 Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3 Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9 Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8 Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0 Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4.0 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 2.9 2.8 1.1 5.3 2.8 3.0 Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3 Other adverse reactions reported in placebo-controlled trials include: 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. Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received Atorvastatin Calcium tablets in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of Atorvastatin Calcium tablets. Treating to Ne …

7 DRUG INTERACTIONS • See full prescribing information for details regarding concomitant use of Atorvastatin Calcium tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2.5 , 7.1 ). • Rifampin : May reduce atorvastatin plasma concentrations. Administer simultaneously with Atorvastatin Calcium tablets ( 7.2 ). • Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( 7.3 ). • Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.3 ). 7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets Atorvastatin calcium tablets are a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium tablets plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin calcium tablets and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology ( 12.3 )] . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium tablets. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium tablets are not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology ( 12.3 )] . Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium tablets. Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium tablets are not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium tablets 20 mg. In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg [ see Dosage and Administration ( 2.5 ) ]. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium tablets. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology ( 12.3 )] . Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin cal …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm. (8.1). • Lactation: Breastfeeding not recommended during treatment with Atorvastatin Calcium tablets (8.2). See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. 8.1 Pregnancy Risk Summary Discontinue Atorvastatin Calcium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin Calcium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, Atorvastatin Calcium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with Atorvastatin Calcium tablets use in pregnant women are insufficient to determine if there is a drug associated risk of miscarriage (see Data) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in 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 delay were 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 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/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 300 mg/kg resulted in inc …

12.1 Mechanism of Action Atorvastatin calcium tablets are 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 tablets 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 tablets also reduces LDL production and the number of LDL particles.

11 DESCRIPTION Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Atorvastatin calcium, USP 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) trihydrate. The empirical formula of atorvastatin calcium is (C 33 H 34 FN 2 O 5 )2Ca•3H2O and its molecular weight is 1209.42. Its structural formula is: Atorvastatin calcium USP, is a white to off-white crystalline powder that is freely soluble in methanol, slightly soluble in ethanol (96 %), very slightly soluble in water, phosphate buffer (pH: 7.4) and acetonitrile. Practically insoluble in methylene chloride and aqueous solution at pH: 4.0. Atorvastatin calcium tablets, USP for oral use contain atorvastatin 10, 20, 40, or 80 mg (equivalent to 10.34 mg, 20.68 mg, 41.36 mg or 82.72 mg atorvastatin calcium anhydrous) and the following inactive ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, opadry white, and polysorbate 80. Opadry white contains hypromellose, polyethylene glycol, titanium dioxide, and talc. atorvastatin-spl-strc

10 OVERDOSAGE No specific antidotes for Atorvastatin Calcium tablets are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance Atorvastatin Calcium tablets clearance.

16 HOW SUPPLIED/STORAGE AND HANDLING Atorvastatin Calcium Tablets, are supplied as follows: Strength How Supplied NDC Tablet Description 10 mg of atorvastatin bottles of 90 71209-090-04 white to off-white, oval, biconvex film coated tablets, debossed with “C15” on one side and plain on other side. 20 mg of atorvastatin bottles of 90 71209-091-04 white to off-white, oval, biconvex film coated tablets, debossed with “C16” on one side and plain on other side. 40 mg of atorvastatin bottles of 90 71209-092-04 white to off-white, oval, biconvex film coated tablets, debossed with “C23” on one side and plain on other side. bottles of 500 71209-092-10 80 mg of atorvastatin bottles of 90 71209-093-04 white to off-white, oval, biconvex film coated tablets, debossed with “C24” on one side and plain on other side. bottles of 500 71209-093-10 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].