Atorvastatin Calcium

Therapy with lipid-alteringagents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular diseasedue 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 non-pharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, LIPITOR can be started simultaneously with diet.

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, LIPITOR is 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, LIPITOR is indicated to:

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

In adult patients with clinically evident coronary heart disease, LIPITOR is indicated to:

• Reduce the risk of non-fatalmyocardial 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

Hyperlipidemia

LIPITOR is indicated:

• As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TGlevels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and non familial) 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-Cin 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:

1. LDL-C remains ≥ 190 mg/dL or
2. 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

Limitations Of Use

LIPITOR has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons(Fredrickson Types I and V).

Antilipemic agent; hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin).1 18

Prevention of Cardiovascular Events

ACC/AHA cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults; extensive evidence demonstrates that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients).336 337 338 350 Relative reduction in ASCVD risk is correlated with degree of LDL-cholesterol lowering; therefore, use maximum tolerated statin intensity to achieve optimum ASCVD benefits.350 According to ACC/AHA, atorvastatin may be used for primary or secondary prevention in adults when moderate- or high-intensity statin therapy is indicated.350 (See Prevention of Cardiovascular Events under Dosage and Administration.)

Adjunct to nondrug therapies (lifestyle modifications) in patients without clinical evidence of CHD who have multiple risk factors (e.g., age, smoking, hypertension, low HDL-cholesterol concentrations, family history of early CHD) to reduce the risk of MI, stroke, or angina and the risk of undergoing revascularization procedures.1 350 Consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy for primary prevention.350

Adjunct to nondrug therapies (i.e., lifestyle modifications350 ) in patients without clinical evidence of CHD who have type 2 diabetes mellitus and multiple risk factors (e.g., retinopathy, albuminuria, smoking, hypertension) to reduce the risk of MI or stroke.1 Consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy for primary prevention in such patients.350 Addition of a nonstatin drug (i.e., fenofibrate) to statin therapy in patients with type 2 diabetes mellitus not shown to provide incremental ASCVD risk reduction benefit beyond that provided by statin monotherapy.350 353

Adjunct to nondrug therapies (i.e., lifestyle modifications350 ) in patients with clinical evidence of CHD to reduce the risk of nonfatal MI, fatal and nonfatal stroke, angina, or hospitalization for CHF, and the risk of undergoing revascularization procedures.1 Unless contraindicated, statins are considered first-line therapy in patients 21–75 years of age with clinical ASCVD (i.e., acute coronary syndromes; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin).350 Addition of a nonstatin drug (i.e., niacin) to statin-based therapy (i.e., simvastatin with or without ezetimibe) in patients with established cardiovascular disease not shown to provide incremental ASCVD risk reduction benefit beyond that provided by statin monotherapy.350 354

Has been used in patients with CHD to slow the progression of coronary atherosclerosis†.67

Intensive antilipemic therapy (atorvastatin 80 mg daily) shown to be more effective than moderate antilipemic therapy (pravastatin 40 mg daily) in reducing the risk of cardiovascular events in patients hospitalized for acute coronary syndrome (16% reduction in composite risk of death or major cardiovascular events for atorvastatin compared with pravastatin regimen).66 Intensive antilipemic therapy also more effective in slowing progression of coronary atherosclerosis† in patients with CHD.67

May use in fixed combination with amlodipine when treatment with both atorvastatin (for prevention of cardiovascular events) and amlodipine (for hypertension and/or CAD) is appropriate.65

Current recommendations from ACC/AHA regarding prevention of ASCVD and lifestyle modifications to reduce cardiovascular risk are available at or ).352

Dyslipidemias

Adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIa or IIb).1 May use in combination with ezetimibe for additive antilipemic effects.64 Also used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are on optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that provided by statin monotherapy.78 79

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in boys and postmenarchal girls 10–17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of ≥190 mg/dL or a serum LDL-cholesterol concentration of ≥160 mg/dL and either a family history of premature cardiovascular disease or ≥2 other cardiovascular risk factors.1

Adjunct to nondrug therapies (e.g., dietary management) for the management of primary dysbetalipoproteinemia (Fredrickson type III).1

Adjunct to nondrug therapies (e.g., dietary management) for the management of elevated serum triglyceride concentrations (Fredrickson type IV).1 However, fibric acid derivatives provide greater benefit in patients with elevated triglyceride concentrations compared with statins.356

Reduction of elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1 May use in combination with ezetimibe for additive antilipemic effects.64

Has reduced total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by renal transplantation† 8 38 39 undergoing use of protease inhibitors†.21 37

Has reduced total and LDL-cholesterol concentrations in hypercholesterolemic patients undergoing peritoneal dialysis†.34

May use in fixed combination with amlodipine when treatment with both atorvastatin (for dyslipidemias) and amlodipine (for hypertension and/or CAD) is appropriate.65

Metabolized by CYP3A4; does not inhibit CYP3A4.1

When used in fixed combination with amlodipine, consider interactions associated with amlodipine.65 No formal drug interaction studies to date with fixed-combination preparation.65

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (variable increases in plasma atorvastatin concentrations); increased risk of myopathy or rhabdomyolysis.1 Carefully monitor for unexplained muscle pain, tenderness, or weakness, particularly following initiation of atorvastatin therapy or an increase in dosage of either drug.1 (See Specific Drugs and Foods under Interactions.)

Inducers of CYP3A4: Potential pharmacokinetic interaction (variable reductions in plasma atorvastatin concentrations).1 (See Specific Drugs and Foods under Interactions.)

Drugs Transported by Organic Anion Transport Polypeptide 1B1

Inhibitors of organic anion transport polypeptide (OATP) 1B1: Potential pharmacokinetic interaction (increased bioavailability of atorvastatin).1

Specific Drugs and Foods

Absorption

Bioavailability

Rapidly absorbed following oral administration; undergoes extensive first-pass metabolism in the liver.1

Peak plasma concentrations attained at 1–2 hours.1

Absolute bioavailability is approximately 14%.1

Evening administration associated with a decrease in the extent of absorption;1 however, antilipemic activity remains unchanged.1

Onset

Therapeutic response usually is apparent within 2 weeks; maximal response occurs within 4 weeks.1

Food

Food decreases rate and extent of absorption but does not alter antilipemic effects.1

Special Populations

Hepatic impairment (Child-Pugh class A and B) or alcoholic liver disease: Substantially increased concentrations.1

Geriatric patients: Peak plasma concentration and AUC are 40 and 30% higher, respectively, in geriatric individuals (≥65 years of age) compared with younger adults.1

Distribution

Extent

Statins are distributed mainly to the liver.129 130

Distributes into milk in rats; may distribute into human milk.1

Plasma Protein Binding

≥98% (principally albumin).1 129 130 131 132 133 134 135 136

Elimination

Metabolism

Extensively metabolized in the liver,1 mainly by CYP3A4,1 131 136 137 138 139 to active metabolites.1 129 130 131 140

Elimination Route

Excreted principally in feces; <2% of a dose excreted in urine.1

Half-life

Approximately 14 hours.1

You should not take atorvastatin if you are allergic to it, if you are pregnant or breast-feeding, or if you have liver disease.

To make sure you can safely take atorvastatin, tell your doctor if you have any of these other conditions:

• history of liver disease;
• history of kidney disease;
• muscle pain or weakness;
• a thyroid disorder; or
• if you drink more than 2 alcoholic beverages daily.

In rare cases, atorvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).

Tell your doctor about all other medications you use. Certain other drugs can increase your risk of serious muscle problems, and it is very important that your doctor knows if you are using any of them:

• diltiazem (Cardizem, Cartia, Dilacor, Diltia, Diltzac, Taztia, Tiazac);
• gemfibrozil (Lopid), fenofibric acid (Fibricor, Trilipix), or fenofibrate (Antara, Fenoglide, Lipofen, Lofibra, Tricor, Triglide);
• telaprevir (Incivek);
• antibiotics such as clarithromycin (Biaxin) or erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole);
• antifungal medicines such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);
• HIV medications such as darunavir (Prexista), fosamprenavir (Lexiva), ritonavir (Norvir), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept), saquinavir (Invirase), or tipranavir (Aptivus);
• medicines that contain niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others); or
• drugs that weaken your immune system, such as steroids, cancer medicine, or medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune), or tacrolimus (Prograf).

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not take atorvastatin if you are pregnant.Stop taking this medication and tell your doctor right away if you become pregnant. Use effective birth control to avoid pregnancy while you are taking atorvastatin.

Atorvastatin may pass into breast milk and could harm a nursing baby. Do not breast-feed while you are taking atorvastatin.

Avoid eating foods that are high in fat or cholesterol. Atorvastatin will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

Grapefruit and grapefruit juice may interact with atorvastatin and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Your pharmacist can provide more information about atorvastatin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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