Atorvastatin Calcium: Package Insert and Label Information

ATORVASTATIN CALCIUM- atorvastatin calcium trihydrate tablet, film coated
Lannett Company, Inc.

1 INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet.

1.1 Prevention of Cardiovascular Disease in Adults

In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to:

  • Reduce the risk of myocardial infarction
  • Reduce the risk of stroke
  • Reduce the risk for revascularization procedures and angina

In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:

  • Reduce the risk of myocardial infarction
  • Reduce the risk of stroke

In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:

  • Reduce the risk of non-fatal myocardial infarction
  • Reduce the risk of fatal and non-fatal stroke
  • Reduce the risk for revascularization procedures
  • Reduce the risk of hospitalization for CHF
  • Reduce the risk of angina

1.2 Hyperlipidemia

Atorvastatin calcium tablets are indicated:

  • As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb);
  • As an adjunct to diet for the treatment of adult patients with elevated serum TG levels (Fredrickson Type IV);
  • For the treatment of adult patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
  • To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable;
  • As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present:

    a. LDL-C remains ≥ 190 mg/dL or

    b. LDL-C remains ≥ 160 mg/dL and:

    • there is a positive family history of premature cardiovascular disease or
    • two or more other CVD risk factors are present in the pediatric patient

1.3 Limitations of Use

Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

2 DOSAGE AND ADMINISTRATION

2.1 Hyperlipidemia and Mixed Dyslipidemia

The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 Years to 17 Years of Age)

The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies (14.6)].Doses should be individualized according to the recommended goal of therapy [see Indications and Usage (1.2) and Clinical Pharmacolog y (12) ]. Adjustments should be made at intervals of 4 weeks or more.

2.3 Homozygous Familial Hypercholesterolemia

The dosage of atorvastatin calcium tablets in patients with HoFH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

2.4 Concomitant Lipid-Lowering Therapy

Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions (5.1) and Drug Interactions ( 7) ].

2.5 Dosage in Patients with Renal Impairment

Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ].

2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors

In patients taking cyclosporine or the HIV protease inhibitor tipranavir plus ritonavir or the hepatitis C virus (HCV) protease inhibitor glecaprevir plus pibrentasvir or letermovir when co-administered with cyclosporine, therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin calcium tablets. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir or letermovir therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin calcium tablets should be limited to 40 mg [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS

White, round, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium.

Table 1: Atorvastatin Calcium Tablet Strengths and Identifying Features

Tablet Strength

Identifying Features

10 mg of atorvastatin

Debossed with “1” on one side and plain on the other

20 mg of atorvastatin

Debossed with “2” on one side and plain on the other

40 mg of atorvastatin

Debossed with “40” on one side and plain on the other

80 mg of atorvastatin

Debossed with “80” on one side and plain on the other

4 CONTRAINDICATIONS

  • Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels

  • Hypersensitivity to Any Component of This Medication

  • Pregnancy [see Use in Specific Populations (8.1, 8.3)].

  • Lactation [see Use in Specific Populations (8.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

Atorvastatin calcium tablets may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including atorvastatin calcium tablets.

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin calcium tablets dosage [see Drug Interactions (7.1)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

Atorvastatin calcium tablets exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin calcium tablets is not recommended. Atorvastatin calcium tablets dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2.6)]. Cases of myopathy/rhabdomyolysis have been reported with atorvastatin coadministered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interaction s (7.1)].

Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin calcium tablets [see Drug Interactions (7.1)].

Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if atorvastatin calcium tablets is discontinued. Temporarily discontinue atorvastatin calcium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the atorvastatin calcium tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 Liver Dysfunction

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases 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 function tests (LFT) 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 LFT elevations continued treatment with a reduced dose of atorvastatin calcium tablets.

It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium tablets and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium tablets, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin calcium tablets.

Atorvastatin calcium tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin calcium tablets [see Contraindications ( 4) ].

5.4 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin calcium tablets.

Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin calcium tablets does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

5.5 CNS Toxicity

Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum recommended human dose of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

5.6 Use in Patients with Recent Stroke or TIA

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium tablets 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium tablets 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)].

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