Atorvastatin Calcium

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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium vs. 7311 placebo; age range 10-93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin calcium 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 2 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Adverse Reaction % Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755 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 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. Treating to New Targets Study (TNT) In TNT, [see Clinical Studies ( 14.1 )] 10,001 patients (age range 29-78 years, 19% women; 94% White, 3% Black, 1% Asian, 2% other) with clinically evident CHD were treated with Atorvastatin calcium 10 mg daily (n=5006) or Atorvastatin calcium 80 mg daily (n=4995). In the high-dose Atorvastatin calcium group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4-10 days) occurred in 1.3% of individuals with Atorvastatin calcium 80 mg and in 0.2% of individuals with atorvastatin calcium 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin calcium group (0.3%) compared to the low-dose atorvastatin calcium group (0.1%). Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4731 patients (age range 21-92 years, 40% women; 93% White, 3% Black, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with Atorvastatin calcium 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4-10 days) in the Atorvastatin calcium group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the Atorvastatin calcium group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the Atorvastatin calcium group and 3.8% of subjects in the placebo group. In a post-hoc analysis, Atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 Atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the Atorvastatin calcium group (38 nonfatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% Atorvastatin calcium vs. 4% placebo). Adverse Reactions from Clinical Studies of Atorvastatin Calcium in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 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 apo B levels, was generally similar to that of placebo [see Use in Specific Populations ( 8.4 ) and Clinical Studies ( 14.6 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atorvastatin calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: pancreatitis General disorders: fatigue Hepatobiliary Disorders: fatal and non-fatal hepatic failure Immune system disorders: anaphylaxis Injury: tendon rupture Musculoskeletal and connective tissue disorders: rhabdomyolysis, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use . Nervous system disorders: dizziness, peripheral neuropathy. There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric disorders: depression Respiratory disorders : interstitial lung disease Skin and subcutaneous tissue disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

4 CONTRAINDICATIONS Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )] Hypersensitivity to atorvastatin or any excipients in Atorvastatin calcium. 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 ).

11 DESCRIPTION Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Atorvastatin calcium is1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-calcium salt (2:1), trihydrate [R-(R*,R*)]-. The empirical formula of atorvastatin calcium is C 66 H 68 CaF 2 N 4 O 10 .3H 2 O and its molecular weight is 1209.42. Its structural formula is: Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4.5 and below. Atorvastatin calcium is very slightly soluble in distilled water and pH 7.5 phosphate buffer; sparingly soluble in methanol. Atorvastatin calcium tablets, USP for oral administration contain 10, 20, 40, or 80 mg of atorvastatin and the following inactive ingredients: anhydrous lactose, calcium carbonate, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry AMB OY-B-28920 White (lecithin, polyvinyl alcohol, talc, titanium dioxide, xanthan gum) and sodium lauryl sulphate. Atorvastatin calcium tablets, USP meet USP Dissolution Test 6. image-01

2 DOSAGE AND 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, and adjust dosage if necessary ( 2.1 ). Adults ( 2.2 ): о Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. о 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 dosage modifications due to drug interactions ( 2.5 ). 2.1 Important Dosage Information Take atorvastatin calcium tablet 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, and adjust the dosage if necessary 2.2 Recommended Dosage in Adult Patients The recommended starting dosage of atorvastatin calcium is 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 Years of Age and Older with HeFH The recommended starting dosage of atorvastatin calcium is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. 2.4 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of atorvastatin calcium is 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 with the following drugs requires dosage modification of atorvastatin calcium [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 20 mg once daily. • In patients taking nelfinavir, do not exceed atorvastatin calcium 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics • In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium 20 mg once daily. For additional recommendations regarding concomitant use of Atorvastatin calcium with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions ( 7.1 )] .

1 INDICATIONS AND USAGE Atorvastatin calcium is indicated: 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 cholesterol (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, 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: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Atorvastatin calcium is an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): To reduce the risk of о Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD о MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD о 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: о Adults with primary hyperlipidemia о 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: о Primary dysbetaliproteinemia о Hypertriglyceridemia

10 OVERDOSAGE No specific antidotes for atorvastatin calcium 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 clearance.

7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of Atorvastatin calcium 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 ( 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 Atorvastatin calcium is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium plasma levels can be significantly increased with concomitant administration of inhibitors of CYP 3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin calcium 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 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium 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. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium 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. Intervention: • Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium is 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 20 mg. • In patients taking nelfinavir, do not exceed atorvastatin calcium 40 mg [see Dosage and Administration ( 2.5 )]. • Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium. • 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 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 calcium 20 mg [see Dosage and Administration ( 2.5 )]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin calcium. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin calcium. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin calcium. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin calcium outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin calcium. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin calcium. 7.2 Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Table 4 presents drug interactions that may decrease exposure to atorvastatin calcium and instructions for preventing or managing them. Table 4: Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Rifampin Clinical Impact: Concomitant administration of atorvastatin calcium with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin calcium and rifampin simultaneously. 7.3 Atorvastatin calcium Effects on Other Drugs Table 5 presents atorvastatin calcium's effect on other drugs and instructions for preventing or managing them. Table 5: Atorvastatin Calcium Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin calcium and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology ( 12.3 )]. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin calcium. Digoxin Clinical Impact: When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor patients taking digoxin appropriately.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration ( 2 ) ]. 12.3 Pharmacokinetics 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 Cmax 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 Cmax 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 . 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. Elimination 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. Specific Populations Geriatric: Plasma concentrations of atorvastatin calcium are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender: Plasma concentrations of atorvastatin calcium in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between men and women. Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Use in Specific Populations ( 8.6 )] . While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations ( 8.7) ]. Drug Interaction: Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 6: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin & Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Ratio based on a 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. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dose d Three times daily e Four times daily f Every 8 hours Co-administered drug and dosing regimen Atorvastatin Dose (mg) Ratio of AUC & Ratio of Cmax & # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66 # Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg, SD c 9.36 8.58 # Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00 # Telaprevir 750 mg q8h f , 10 days 20 mg, SD c 7.88 10.60 #,‡ Saquinavir 400 mg BID b / ritonavir 400 mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31 # Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34 # Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70 # Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38 # Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25 # Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20 #Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17 # Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84 # Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04 # Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22 # Grapefruit Juice, 240 mL QD a,* 40 mg, SD c 1.37 1.16 Diltiazem 240 mg QD a , 28 days 40 mg, SD c 1.51 1.00 Erythromycin 500 mg QID e , 7 days 10 mg, SD c 1.33 1.38 Amlodipine 10 mg, single dose 80 mg, SD c 1.18 0.91 Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89 Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74** Maalox TC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67 Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01 # Rifampin 600 mg QD a , 7 days (co-administered) † 40 mg SD c 1.12 2.90 # Rifampin 600 mg QD a , 5 days (doses separated) † 40 mg SD c 0.20 0.60 # Gemfibrozil 600 mg BID b , 7 days 40 mg SD c 1.35 1.00 # Fenofibrate 160 mg QD a , 7 days 40 mg SD c 1.03 1.02 Boceprevir 800 mg TID d , 7 days 40 mg SD c 2.32 2.66 Table 7: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs # See Section 7 for clinical significance. a Once daily b Twice daily c Single dose Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of Cmax 80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89 80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20 40 mg QD a for 22 days Oral contraceptive QD a , 2 months - norethindrone 1mg - ethinyl estradiol 35 mcg 1.28 1.19 1.23 1.30 10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96 10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82 10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 0.99 0.94 Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment

12.1 Mechanism of Action 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.

12.2 Pharmacodynamics Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration ( 2 ) ].

12.3 Pharmacokinetics 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 Cmax 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 Cmax 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 . 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. Elimination 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. Specific Populations Geriatric: Plasma concentrations of atorvastatin calcium are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender: Plasma concentrations of atorvastatin calcium in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between men and women. Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Use in Specific Populations ( 8.6 )] . While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations ( 8.7) ]. Drug Interaction: Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 6: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin & Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Ratio based on a 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. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dose d Three times daily e Four times daily f Every 8 hours Co-administered drug and dosing regimen Atorvastatin Dose (mg) Ratio of AUC & Ratio of Cmax & # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66 # Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg, SD c 9.36 8.58 # Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00 # Telaprevir 750 mg q8h f , 10 days 20 mg, SD c 7.88 10.60 #,‡ Saquinavir 400 mg BID b / ritonavir 400 mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31 # Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34 # Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70 # Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38 # Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25 # Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20 #Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17 # Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84 # Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04 # Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22 # Grapefruit Juice, 240 mL QD a,* 40 mg, SD c 1.37 1.16 Diltiazem 240 mg QD a , 28 days 40 mg, SD c 1.51 1.00 Erythromycin 500 mg QID e , 7 days 10 mg, SD c 1.33 1.38 Amlodipine 10 mg, single dose 80 mg, SD c 1.18 0.91 Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89 Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74** Maalox TC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67 Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01 # Rifampin 600 mg QD a , 7 days (co-administered) † 40 mg SD c 1.12 2.90 # Rifampin 600 mg QD a , 5 days (doses separated) † 40 mg SD c 0.20 0.60 # Gemfibrozil 600 mg BID b , 7 days 40 mg SD c 1.35 1.00 # Fenofibrate 160 mg QD a , 7 days 40 mg SD c 1.03 1.02 Boceprevir 800 mg TID d , 7 days 40 mg SD c 2.32 2.66 Table 7: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs # See Section 7 for clinical significance. a Once daily b Twice daily c Single dose Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of Cmax 80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89 80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20 40 mg QD a for 22 days Oral contraceptive QD a , 2 months - norethindrone 1mg - ethinyl estradiol 35 mcg 1.28 1.19 1.23 1.30 10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96 10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82 10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 0.99 0.94 Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment

20230206

3

3 DOSAGE FORMS AND STRENGTHS Atorvastatin calcium tablets, USP are white to off white, elliptical, film-coated, and are available in four strengths (see Table 1). Table 1: Atorvastatin Calcium Tablet, USP Strengths and Identifying Features Tablet Strength Identifying Features 10 mg of atorvastatin "LU" on one side and "A16" on the other 20 mg of atorvastatin "LU" on one side and "A17" on the other 40 mg of atorvastatin "LU" on one side and "A18" on the other 80 mg of atorvastatin "LU" on one side and "A19" on the other Tablets: 10, 20, 40, and 80 mg of atorvastatin ( 3 ).

Atorvastatin Calcium Atorvastatin Calcium ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN ANHYDROUS LACTOSE CALCIUM CARBONATE MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE (1600000 WAMW) LECITHIN, SOYBEAN MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED SILICON DIOXIDE SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE XANTHAN GUM white to white off Elliptical LU;A16

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. 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 aspermia 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 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/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 2 years.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. 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 aspermia 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 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/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 2 years.

ANDA204991

Atorvastatin Calcium

Atorvastatin Calcium

50090-5636

HUMAN PRESCRIPTION DRUG

ORAL

ATORVASTATIN CALCIUM Label Image

RECENT MAJOR CHANGES Contraindications, Pregnancy and Lactation ( 4 ) Removed 12/2022 Warnings and Precautions, CNS Toxicity ( 5.5 ) Removed 12/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that atorvastatin calcium may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )]. Hepatic Dysfunction Inform patients that atorvastatin calcium may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions ( 5.3 )]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with atorvastatin calcium. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions ( 5.4 )] . Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if atorvastatin calcium should be discontinued [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium tablets [see Contraindications ( 4 ) and Use in Specific Populations ( 8.2 )]. The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Nagpur 441 108 INDIA Revised: January 2023

14 CLINICAL STUDIES Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40 to 80 years of age (mean of 63 years, 19% women; 95% White, 3% Black, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age >55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for patients without diabetes; <130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of atorvastatin calcium on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels. Figure 1: Effect of atorvastatin calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% White, 2% Black, 2% South Asian, 1% other; 68% male), ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and triglycerides (TG) ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the trial. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of atorvastatin calcium 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels. Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p=0.059) In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs. atorvastatin calcium 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium. Treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 8). The overall risk reduction was consistent regardless of age (<65, ≥65) or sex. a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint Endpoint Atorvastatin 10 mg (N=5006) Atorvastatin 80 mg (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) Components of the Primary Endpoint 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) SECONDARY ENDPOINTS * 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 b 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpoint b 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) Components of All-Cause Mortality 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) Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 8). Of the predefined secondary endpoints, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF. There was no significant difference between the treatment groups for all-cause mortality (Table 8). 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. Primary Hyperlipidemia in Adults Atorvastatin calcium reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. In two multicenter, placebo-controlled, dose-response trails in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 9.) a Results are pooled from 2 dose-response trials Dose N TC LDL-C Apo B TG HDL-C N Placebo 21 4 4 3 10 -3 Placebo 10 22 -29 -39 -32 -19 6 10 20 20 -33 -43 -35 -26 9 20 40 21 -37 -50 -42 -29 6 40 80 23 -45 -60 -50 -37 5 80 In three multicenter, double-blind trails in patients with hyperlipidemia, atorvastatin calcium was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 10). 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 Treatment (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Trial 1 Atorvastatin Calcium 10 mg 707 -27 a -36 a -28 a -17 a +7 Lovastatin 20 mg 191 -19 -27 -20 -6 +7 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 Trial 2 Atorvastatin Calcium 10 mg 222 -25b -35 b -27 b -17 b +6 Pravastatin 20 mg 77 -17 -23 -17 -9 +8 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 Trial 3 Atorvastatin Calcium 10 mg 132 -29 c -37 c -34 c -23 c +7 Simvastatin 10 mg 45 -24 -30 -30 -15 +7 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 Table 10 does not contain data comparing the effects of atorvastatin calcium 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily interchangeable. Hypertriglyceridemia in Adults The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 11). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267 to 1502). Placebo (N=12) Atorvastatin Calcium 10 mg (N=37) Atorvastatin Calcium 20 mg (N=13) Atorvastatin Calcium 80 mg (N=14) 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) 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) Dysbetalipoproteinemia in Adults The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 12). Median % Change (min, max) Median (min, max) at Baseline (mg/dL) Atorvastatin Calcium 10 mg Atorvastatin Calcium 80 mg 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) HoFH in Adults and Pediatric Patients In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% ˂18 years) with HoFH received maximum daily doses of 20 to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this trial 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%. HeFH in Pediatric Patients In a double-blind, placebo-controlled trial followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years, 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other) 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 trial 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 219 mg/dL (range: 139 to 385 mg/dL) in the atorvastatin calcium group compared to 230 mg/dL (range: 160 to 325 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 (56%). Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 13). 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 The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0 to 242.0 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152.0 to 385.0 mg/dL) in the placebo group during the 26-week double-blind phase. Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of <130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical studies in both adult and pediatric placebo-controlled trials. Figure 1: Effect of atorvastatin calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Figure 2: Effect of atorvastatin calcium 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) Figure 3: Effect of atorvastatin calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)

8.5 Geriatric Use Of the total number of atorvastatin calcium -treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients Advanced age (≥65 years) is a risk factor for atorvastatin calcium -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving Atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] .

8.4 Pediatric Use The safety and effectiveness of Atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of Atorvastatin calcium for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of Atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of Atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies ( 14 )] . The safety and effectiveness of Atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

8.1 Pregnancy Risk Summary Discontinue Atorvastatin calcium when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, Atorvastatin calcium 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 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 1152 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 increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/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 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotarod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ). Lactation: Breastfeeding not recommended during treatment with Atorvastatin calcium ( 8.2 ). 8.1 Pregnancy Risk Summary Discontinue Atorvastatin calcium when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, Atorvastatin calcium 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 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 1152 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 increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/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 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotarod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. 8.2 Lactation Risk Summary There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data) . Statins, including Atorvastatin calcium, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with Atorvastatin calcium [see Use in Specific Populations ( 8.1 ), Clinical Pharmacology ( 12.1 )] . Data Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma). 8.4 Pediatric Use The safety and effectiveness of Atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of Atorvastatin calcium for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of Atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of Atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies ( 14 )] . The safety and effectiveness of Atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH). 8.5 Geriatric Use Of the total number of atorvastatin calcium -treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients Advanced age (≥65 years) is a risk factor for atorvastatin calcium -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving Atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of Atorvastatin calcium, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. 8.7 Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of Atorvastatin calcium are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. Atorvastatin calcium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-5636 NDC: 50090-5636-0 30 TABLET in a BOTTLE NDC: 50090-5636-1 90 TABLET in a BOTTLE