Atorvastatin: uses, appearance and warnings

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

Atorvastatin calcium tablets, USP: 10 mg of atorvastatin calcium tablets, USP: white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “A10” on the other side. 20 mg of atorvastatin calcium tablets, USP: white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “ATV20” on the other side. 40 mg of atorvastatin calcium tablets, USP: white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “ATV40” on the other side. 80 mg of atorvastatin calcium tablets, USP: white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “ATV80” on the other side. Tablets: 10 mg; 20 mg; 40 mg 80 mg of atorvastatin ( 3 ).

Atorvastatin calcium tablets, USP are supplied as white to off-white, oval, biconvex film-coated tablets of atorvastatin calcium containing 10, 20, 40 and 80 mg atorvastatin. 10 mg tablets Atorvastatin calcium tablets, USP 10 mg, are available for oral administration as white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “A10” on the other side. Bottles of 90 (NDC 60505-2578-9) Bottles of 1,000 (NDC 60505-2578-8) 20 mg tablets Atorvastatin calcium tablets, USP 20 mg, are available for oral administration as white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “ATV20” on the other side. Bottles of 90 (NDC 60505-2579-9) Bottles of 1,000 (NDC 60505-2579-8) 40 mg tablets Atorvastatin calcium tablets, USP 40 mg, are available for oral administration as white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “ATV40” on the other side. Bottles of 90 (NDC 60505-2580-9) Bottles of 1,000 (NDC 60505-2580-8) 80 mg tablets Atorvastatin calcium tablets, USP 80 mg, are available for oral administration as white to off-white, oval, biconvex film-coated tablets, engraved “APO” on one side, “ATV80” on the other side. Bottles of 90 (NDC 60505-2671-9) Bottles of 1,000 (NDC 60505-2671-8) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container [see USP].

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

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin calcium dosage. Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin calcium in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing atorvastatin calcium dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 2.5 , 5.1 , 7.1 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue atorvastatin calcium tablets if IMNM is suspected ( 5.2 ). Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium tablets ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis Atorvastatin calcium may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher atorvastatin calcium dosage [see Drug Interactions (7.1) and Use in Specific Populations ( 8.5 , 8.6)]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Atorvastatin calcium 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 is not recommended. Atorvastatin calcium dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration ( 2. 5)] . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir [see Adverse Reactions ( 6.1 )] . Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions ( 7.1 )] . Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin calcium [see Drug Interactions ( 7.1 )] . Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if atorvastatin calcium tablets are 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 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, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persists 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. Discontinue atorvastatin calcium tablets if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of atorvastatin calcium tablets [see Adverse Reactions ( 6.1 )] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin calcium tablets in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations ( 8.7 )] . Consider liver enzyme testing before atorvastatin calcium tablets initiation and when clinically indicated thereafter. Atorvastatin calcium tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 ) ] . …

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 Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . …

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 ( 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 CYP3A4 and transporters. …