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atorvastatin 40 mg tablet (generic lipitor)

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Uses

Atorvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) for prevention of cardiovascular events and for the management of dyslipidemias.

Prevention of Cardiovascular Events

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, atorvastatin may be used for primary or secondary prevention in adults when moderate- or high-intensity statin therapy is indicated.(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.) Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Primary Prevention

The ACC/AHA cholesterol management guideline states that, before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.

Patients without Clinical Evidence of CHD

Atorvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without clinical evidence of coronary heart disease (CHD) who have multiple risk factors (e.g., age, smoking, hypertension, low high-density lipoprotein [HDL]-cholesterol concentrations, family history of early CHD) to reduce the risk of myocardial infarction (MI), stroke, or angina, and to reduce the risk of undergoing revascularization procedures. Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent (i.e., amlodipine) is appropriate.

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater) and in patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher.

Safety and efficacy of atorvastatin for primary prevention of cardiovascular disease have been established in several randomized, double-blind, placebo-controlled studies in patients without clinical evidence of CHD. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) in 10,305 hypertensive, hypercholesterolemic (total cholesterol 251 mg/dL or less) patients with no history of MI who had multiple risk factors for CHD, therapy with atorvastatin (10 mg daily) for a median of 3.3 years reduced the risk of coronary events (i.e., fatal CHD or nonfatal MI) by 36% and the risk of undergoing revascularization procedures by 42%. Lipoprotein concentrations were lowered to levels similar to those observed with atorvastatin 10 mg daily in previous clinical studies. The risk of fatal and nonfatal stroke was reduced by 26%, although this was not statistically significant. Treatment with atorvastatin did not reduce the risk of death from cardiovascular or noncardiovascular causes.

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in hypercholesterolemic patients (LDL-cholesterol concentrations of 100-190 mg/dL) who had a stroke or transient ischemic attack (TIA) within the past 1-6 months, therapy with high-dose atorvastatin (80 mg daily) for a median of 4.9 years reduced the risk of subsequent nonfatal or fatal stroke and of major cardiovascular events by approximately 16 and 20%, respectively, compared with placebo. However, atorvastatin therapy did not reduce overall mortality. In addition, hemorrhagic stroke and elevated aminotransferase (transaminase) concentrations (to at least 3 times the upper limit of normal) were reported in more patients receiving atorvastatin than in those receiving placebo.(See Use in Patients with Recent Stroke or Transient Ischemic Attack under Cautions: Precautions/Contraindications.) Some clinicians state that the results of this study should be interpreted with caution due to the heterogeneity of enrolled patients (i.e., with respect to stroke etiology and vascular risk). Furthermore, because patients with atrial fibrillation or other cardiac sources of embolism were excluded from the study, it is not known whether the observed benefits of atorvastatin apply to ischemic strokes of cardioembolic origin.

Patients with Diabetes Mellitus

Atorvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without clinical evidence of CHD who have type 2 diabetes mellitus and multiple risk factors for CHD (e.g., retinopathy, albuminuria, smoking, hypertension) to reduce the risk of MI or stroke. Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent (i.e., amlodipine) is appropriate.

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 40-75 years of age with type 1 or 2 diabetes mellitus. In patients with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

Safety and efficacy of atorvastatin for prevention of cardiovascular disease in patients with type 2 diabetes mellitus have been established in a randomized, double-blind, placebo-controlled study. In the Collaborative Atorvastatin Diabetes Study (CARDS) in 2838 hypercholesterolemic patients (median total cholesterol concentration of 207 mg/dL, LDL-cholesterol concentration of 120 mg/dL, triglyceride concentration of 151 mg/dL) with type 2 diabetes mellitus (mean hemoglobin A1c [HbA1c] of 7.7%) and one or more other risk factors (e.g., smoking, hypertension, retinopathy, microalbuminuria, macroalbuminuria), therapy with atorvastatin (10 mg daily) for a median of 3.9 years reduced the risk of stroke by 48% and the risk of MI by 42% compared with placebo. Lipoprotein concentrations were lowered to levels similar to those observed with atorvastatin 10 mg daily in previous clinical studies. Treatment with atorvastatin did not reduce the risk of unstable angina, revascularization procedures, or acute CHD death.

The addition of fenofibrate to statin therapy has not been shown to provide an incremental ASCVD risk reduction benefit beyond that already established with statin monotherapy. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD Lipid) study in patients with type 2 diabetes mellitus, addition of fenofibrate (160 mg once daily) to simvastatin therapy (up to 40 mg once daily) did not further reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.

Secondary Prevention

Patients with Clinical Evidence of CHD

Atorvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with clinical evidence of CHD to reduce the risk of nonfatal MI, fatal and nonfatal stroke, angina, or hospitalization for congestive heart failure (CHF), and to reduce the risk of undergoing revascularization procedures. Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent (i.e., amlodipine) is appropriate.

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for secondary prevention in patients 21-75 years of age who have 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) unless contraindicated.

Safety and efficacy of atorvastatin for secondary prevention of cardiovascular disease were established in several randomized studies in patients with clinically evident CHD. In one randomized, double-blind study (Treating to New Targets [TNT]) in 10,001 patients with clinically evident CHD (i.e., history of MI, history of or current angina with objective evidence of atherosclerotic CHD, history of coronary revascularization) and LDL-cholesterol concentrations less than 130 mg/dL, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (atorvastatin 10 mg daily) for a median of 4.9 years reduced LDL-cholesterol concentrations to a mean of 77 or 101 mg/dL, respectively. Compared with the moderate regimen, treatment with the intensive regimen resulted in a 22% relative reduction in the risk of the primary composite end point (i.e., death from CHD, nonfatal non-procedure-related MI, resuscitated cardiac arrest, and fatal or nonfatal stroke). Of the events that comprised the primary composite end point, treatment with the intensive regimen substantially reduced the rate of nonfatal non-procedure-related MI and fatal and nonfatal stroke, but not death from CHD or resuscitated cardiac arrest. Of the predefined secondary end points, treatment with the intensive regimen reduced the rate of coronary revascularization, angina, and hospitalization for CHF, but not peripheral vascular disease. The intensive regimen did not reduce overall mortality and was associated with a slightly (but not statistically significant) increased risk of death from noncardiovascular causes. In addition, severe adverse effects (e.g., increases in concentrations of aminotransferase or creatine kinase [CK, creatine phosphokinase, CPK] to at least 3 or 10 times greater than the upper limit of normal, respectively) and discontinuance of therapy due to adverse effects were more common in patients receiving the intensive regimen compared with the moderate regimen. In a post hoc analysis in 5584 patients with CHD and the metabolic syndrome, treatment with the intensive regimen was associated with a lower incidence of major cardiovascular events than treatment with the moderate regimen (9.5 versus 13%); this represented a 29% relative reduction in the risk of major cardiovascular events in favor of the intensive regimen. However, consistent with the overall population, the intensive regimen did not reduce overall mortality compared with the moderate regimen.

In a randomized, comparative study (Incremental Decrease in Endpoints through Aggressive Lipid Lowering [IDEAL]) in 8888 patients with a history of CHD and an average LDL-cholesterol concentration of approximately 122 mg/dL, treatment with atorvastatin (80 mg daily) or simvastatin (20-40 mg daily) for a median of 4.8 years resulted in similar reduction in the risk of the primary composite end point (i.e., fatal CHD, nonfatal MI, and resuscitated cardiac arrest). In addition, no difference in overall mortality was observed between atorvastatin- or simvastatin-treated patients, and the rates of death from cardiovascular or noncardiovascular causes were similar in both treatment groups.

In a multicenter, randomized, open-label study comparing the incidence of ischemic events in CHD patients undergoing angioplasty or receiving aggressive lipid-lowering therapy with atorvastatin 80 mg daily (Atorvastatin Versus Revascularization Treatments [AVERT] trial), atorvastatin was as effective as angioplasty in reducing the incidence of ischemic events (defined as death from cardiac causes, resuscitation after cardiac arrest, nonfatal MI, cerebrovascular accident, coronary artery bypass grafting, angioplasty, or worsening angina with objective evidence resulting in hospitalization) and delaying the onset of the first ischemic event. However, atorvastatin-treated patients had smaller increases in quality of life scores and were more likely to report worsening of angina (12 versus 7%) compared with patients in the angioplasty group.

High-intensity Statin Therapy

Early and intensive antilipemic therapy with a high dosage of atorvastatin has been shown to be more effective than a moderate dosage of a statin in reducing the risk of cardiovascular events in patients with acute coronary syndrome (ACS).

In a randomized, double-blind, placebo-controlled study (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering [MIRACL]) in patients with unstable angina or non-ST-segment elevation (e.g., non-Q-wave) acute MI, therapy with atorvastatin (80 mg daily), initiated within 24-96 hours after admittance to the hospital, was associated with a lower incidence of recurrent ischemic events (particularly symptomatic ischemia requiring rehospitalization) in the subsequent 16 weeks; however, the validity of these results has been questioned due to the large number of atorvastatin-treated patients lost during follow-up.

In a randomized, double-blind, study (Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT]) in over 4000 patients hospitalized for ACS within the preceding 10 days, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin 40 mg daily) for 2 years reduced LDL-cholesterol concentrations to a median of 62 or 95 mg/dL, respectively. Compared with the moderate regimen, treatment with the intensive regimen resulted in a 16% reduction in the composite risk of primary endpoints, including a 14% reduction in the need for revascularization procedures and a 29% reduction in the risk of recurrent unstable angina. Atorvastatin therapy also was associated with reductions in the rates of death from any cause (28%) and of death or MI (18%) compared with pravastatin therapy, but these differences were not statistically significant. Results of this study suggest that, among patients who have recently had an acute coronary syndrome, an intensive antilipemic regimen provides greater protection against death or major cardiovascular events than does a standard regimen.

Reducing Progression of Coronary Atherosclerosis

Intensive antilipemic therapy with atorvastatin has been shown to slow the progression of coronary atherosclerosis in patients with CHD. In a randomized, double-blind, active-control study (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) in 654 patients with CHD, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin 40 mg daily) for 18 months reduced LDL-cholesterol concentrations to a mean of 79 or 110 mg/dL, respectively; concentrations of C-reactive protein were reduced by 36.4% in atorvastatin-treated patients and by 5.2% in pravastatin-treated patients. Treatment with the intensive regimen was associated with a substantially lower progression rate (measured by percent change in atheroma volume) compared with treatment with the moderate regimen. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. It has been suggested that the differences in atherosclerosis progression between atorvastatin and pravastatin may be related to the greater reduction in atherogenic lipoproteins and C-reactive protein concentrations in patients treated with atorvastatin.

Intensity of Statin Therapy

The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers atorvastatin 10-20 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%) and atorvastatin 40-80 mg daily to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%). Individual patient response may vary in clinical practice.

Combination Antilipemic Therapy

The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.

Patients with Chronic Kidney Disease

The potential benefits of atorvastatin in patients with chronic kidney disease, a population at high risk of cardiovascular disease, were evaluated in the Deutsche Diabetes Dialyse Studie (4D), a randomized, double-blind, placebo-controlled study in 1255 patients with type 2 diabetes mellitus on maintenance hemodialysis. After a median follow-up of 4 years, therapy with atorvastatin 20 mg daily had no substantial effect on the primary composite end point of cardiovascular death, nonfatal MI, and stroke compared with placebo. Although atorvastatin reduced the rate of all cardiac events (a secondary end point in the study) relative to placebo, the difference was only nominally significant.

Dyslipidemias

Atorvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the management of primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa or IIb), hypertriglyceridemia (Fredrickson type IV), primary dysbetalipoproteinemia (Fredrickson type III), and/or homozygous familial hypercholesterolemia. Atorvastatin has not been studied in conditions where the principal lipoprotein abnormality is elevated chylomicrons (Fredrickson types I and V). Atorvastatin in fixed combination with amlodipine is used in patients for whom treatment with both atorvastatin and a calcium-channel blocking agent (i.e., amlodipine) is appropriate.

Primary Hypercholesterolemia or Mixed Dyslipidemia

Adults

Atorvastatin, alone or in combination with ezetimibe, is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and 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). Statins such as atorvastatin also are 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 receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.(See Patients with Diabetes Mellitus under Prevention of Cardiovascular Events: Primary Prevention, under Uses.)

Reductions in total and LDL-cholesterol concentrations produced by usual dosages of atorvastatin substantially exceed those of placebo. Mean reductions of 29-45% in total cholesterol, 39-60% in LDL-cholesterol, 32-50% in apo B, and 19-37% in triglyceride concentrations, and increases of 5-9% in HDL-cholesterol concentrations have been reported in 2 controlled studies in 107 patients with primary hypercholesterolemia who received atorvastatin 10-80 mg daily for 6 weeks. Increases in HDL-cholesterol concentrations also have been observed in other studies in patients with primary hypercholesterolemia or mixed dyslipidemia; pooled data from 24 controlled studies indicate median increases of 5-9% in HDL-cholesterol concentrations in patients receiving atorvastatin 10-80 mg daily. Analysis of pooled data demonstrated consistent and substantial decreases in total cholesterol, LDL-cholesterol, triglyceride, total-cholesterol/HDL-cholesterol ratio, and LDL-cholesterol/HDL-cholesterol ratio in patients receiving atorvastatin. In patients with dyslipidemia and hypertension who received atorvastatin (10-80 mg daily) in combination with amlodipine (5-10 mg daily), LDL-cholesterol concentrations were reduced by 36-48% following 8 weeks of therapy.

Data from comparative studies indicate that therapy with atorvastatin may produce greater reductions in total and LDL-cholesterol concentrations than certain other statins. In 3 multicenter, double-blind, comparative studies, patients with hypercholesterolemia who received atorvastatin 10 mg daily for 16 weeks experienced greater reductions in total and LDL-cholesterol concentrations (25-29 and 35-37%, respectively) than those receiving lovastatin 20 mg daily (19 and 27%, respectively), pravastatin 20 mg daily (17 and 23%, respectively), or simvastatin 10 mg daily (24 and 30%, respectively). In other multicenter, randomized, open-label, comparative studies, patients with hypercholesterolemia who received atorvastatin 10-40 mg daily experienced greater reductions in total and LDL-cholesterol concentrations (25-40 and 35-51%, respectively) than those receiving fluvastatin 20-40 mg daily (13-19 and 17-23%, respectively), lovastatin 20-40 mg daily (21-23 and 29-31%, respectively), pravastatin 10-40 mg daily (13-24 and 19-34%, respectively), or simvastatin 10-40 mg daily (21-31 and 28-41%, respectively). The impact of differences in antilipemic effects between various statins on clinical outcomes is not known.

Compared with certain other statins, the effects of atorvastatin on HDL-cholesterol concentrations may be less pronounced, particularly with higher doses of atorvastatin. In several studies designed to evaluate the effects of atorvastatin (20-80 mg daily) and simvastatin (40-80 mg) on HDL-cholesterol and apolipoprotein (apo) A-I concentrations, increases in HDL-cholesterol and apo A-I concentrations were greater with simvastatin therapy (7-9 and 3-6%, respectively) than with atorvastatin (0-7 and 0-5%, respectively). The mechanisms of these effects have not been fully elucidated but may be related to differences in the 2 drugs' plasma elimination half-lives (approximately 20 and 2 hours for atorvastatin and simvastatin, respectively) and/or differential effects of the drugs on lipolytic enzymes (e.g., lipoprotein lipase, hepatic lipase).

Limited data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by atorvastatin may exceed those produced by fibric acid derivatives. In an open-label study in patients with mixed dyslipidemia, treatment with atorvastatin (10 mg daily) was associated with greater reductions in serum total and LDL-cholesterol concentrations compared with fenofibrate therapy (200 mg daily); however, fenofibrate-treated patients had greater reductions in triglyceride concentrations and larger increases of HDL-cholesterol and apo A-I concentrations than those who received atorvastatin.

The combination of atorvastatin and other antilipemic agents (e.g., bile acid sequestrants, ezetimibe) generally results in additive antilipemic effects; however, the risk of myopathy and rhabdomyolysis may be increased.(See Combination Antilipemic Therapy under Uses: Prevention of Cardiovascular Events.) The addition of a bile acid sequestrant (e.g., colestipol 20 g daily) to atorvastatin therapy (10 mg daily) further reduced LDL-cholesterol by 10%, resulting in an overall LDL-cholesterol reduction of 45% in patients receiving the combination; however, frequent adverse effects (e.g., GI effects such as constipation) reported with this combination regimen may discourage adherence to therapy. The addition of ezetimibe (10 mg daily) to atorvastatin therapy (10-80 mg daily) further reduced LDL-cholesterol by 7-16%, resulting in an overall LDL-cholesterol reduction of 53-61%.

Pediatric Patients

Atorvastatin is used as an 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 greater or a serum LDL-cholesterol concentration of 160 mg/dL or greater and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. The long-term effect of atorvastatin therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has not been established. For additional details on management of dyslipidemias in pediatric patients, and also consult the most recent Integrated Guideline for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).

In a double-blind, placebo-controlled study (followed by an open-label phase), 187 boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia or severe hypercholesterolemia (mean baseline LDL-cholesterol concentration of 219-230 mg/dL) were randomized to receive either atorvastatin (10 mg daily for the first 4 weeks, increased to 20 mg daily if LDL-cholesterol concentration exceeded 130 mg/dL) or placebo for 26 weeks; after 26 weeks of the double-blind phase, all patients entered an open-label phase and received atorvastatin for an additional 26 weeks. During the 26-week double-blind phase, treatment with atorvastatin 10-20 mg daily resulted in mean reductions of 31% in total cholesterol, 40% in LDL-cholesterol, 34% in apo B, and 12% in triglyceride concentrations, while concentrations of these lipoprotein fractions in placebo recipients changed minimally. HDL-cholesterol concentrations increased by 2.8% in atorvastatin-treated patients and decreased by 1.9% in placebo recipients. The mean LDL-cholesterol concentration achieved with atorvastatin therapy was 130.7 mg/dL compared with 228.5 mg/dL achieved with placebo during the 26-week double-blind phase.

Hypertriglyceridemia

Atorvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in the treatment of elevated serum triglyceride concentrations (Fredrickson type IV). AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations.

While statins are effective in reducing LDL-cholesterol concentrations, most statins generally have a limited effect on serum triglyceride concentrations. However, limited data suggest that triglyceride reductions produced by usual dosages of atorvastatin substantially exceed those of placebo and appear to be similar to those reported with usual dosages of fibrates or niacin. In several clinical studies in 64 patients with isolated hypertriglyceridemia, treatment with atorvastatin (10-80 mg daily) resulted in median reductions of 39-52% in triglyceride, 28-44% in total cholesterol, 27-41% in LDL-cholesterol, 45-62% in very low-density lipoprotein (VLDL)-cholesterol, and 33-52% in non-HDL-cholesterol concentrations, and a median increase of 8-14% in HDL-cholesterol concentrations; however, no patient achieved normal triglyceride concentrations as a result of treatment.

Atorvastatin 10 mg daily reportedly has produced greater reductions in LDL-cholesterol than niacin 3 g daily or fenofibrate 300 mg daily in patients with combined hyperlipidemia or isolated hypertriglyceridemia. However, reductions in triglyceride concentrations and increases in HDL-cholesterol concentrations were less than those reported with usual dosages of niacin or fenofibrate.

Primary Dysbetalipoproteinemia

Atorvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the treatment of primary dysbetalipoproteinemia (Fredrickson type III) in patients who do not respond adequately to diet.

In an open-label, crossover study in 16 patients with primary dysbetalipoproteinemia (genotypes 14 apo E2/E2 and 2 apo E3/E2), treatment with atorvastatin (10 or 80 mg daily) for at least 8 weeks resulted in substantial reductions in total cholesterol (37 or 58%, respectively), triglyceride (39 or 53%, respectively), combined intermediate-density lipoprotein (IDL)- and VLDL-cholesterol (32 or 63%, respectively), and non-HDL-cholesterol concentrations (43 or 64%, respectively).

Homozygous Familial Hypercholesterolemia

Atorvastatin is used alone or in combination with ezetimibe to decrease 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. Patients with homozygous familial hypercholesterolemia usually respond poorly to combined dietary management and drug therapy, including regimens containing a statin, in part because these patients have poorly functioning, few, or no LDL receptors. In an uncontrolled study in 29 patients 6-37 years of age with homozygous familial hypercholesterolemia, LDL-cholesterol concentrations were reduced by 7-53% (mean reduction of 20%) in 25 of 29 patients (86%) and increased by 7-24% in 4 of 29 patients (14%) who received atorvastatin dosages of 20-80 mg daily; 5 of the 29 patients had absent LDL-receptor function (of these, 2 patients also had a portacaval shunt and had no substantial reduction in LDL-cholesterol concentrations, and the remaining 3 receptor-negative patients had a mean LDL-cholesterol reduction of 22%). Similar reductions (17-28%) were observed in another open-label study in which patients received atorvastatin dosages of 40-80 mg daily for at least 4 weeks. In a limited number of patients undergoing plasma LDL-apheresis to lower cholesterol concentrations, addition of atorvastatin (80 mg daily) for 8 weeks reduced plasma total and LDL-cholesterol concentrations by an additional 29 and 31%, respectively. Limited evidence indicates that treatment with atorvastatin also may slow the progression of atherosclerosis in these patients.

In a randomized, double-blind study of 12 weeks' duration in a limited number of patients with a clinical and/or genotypic diagnosis of homozygous familial hypercholesterolemia, the addition of ezetimibe (10 mg daily) to atorvastatin or simvastatin therapy (40 or 80 mg daily) was more effective in reducing LDL-cholesterol concentrations (21% additional reduction based on pooled data from 40-mg and 80-mg statin groups) than increasing the dosage of atorvastatin or simvastatin monotherapy from 40 to 80 mg daily (7% additional reduction based on pooled data from 40-mg and 80-mg statin groups). In patients receiving ezetimibe (10 mg daily) in combination with higher dosages (80 mg daily) of atorvastatin or simvastatin, LDL-cholesterol concentrations were reduced by an additional 27% compared with LDL-cholesterol reductions achieved with the 40-mg daily statin dosage.

Other Uses

Atorvastatin has reduced total and LDL-cholesterol concentrations in a few patients with renal transplantation. In addition, the drug has reduced total and LDL-cholesterol concentrations in hypercholesterolemic patients on peritoneal dialysis. Atorvastatin, alone or in combination with gemfibrozil, also has been shown to reduce cholesterol and triglyceride concentrations in patients with hypercholesterolemia associated with the use of protease inhibitors.

For additional information on the role of atorvastatin or other statins in the treatment of lipoprotein disorders, prevention of cardiovascular events, or other uses, see General Principles of Antilipemic Therapy and see Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08. For additional information on the use of amlodipine, see Uses in Amlodipine Besylate 24:28.08.

Dosage and Administration

General

Patients should be placed on a standard cholesterol-lowering diet before initiation of atorvastatin therapy and should remain on this diet during treatment with the drug. In patients with coronary heart disease (CHD) or multiple risk factors for CHD, atorvastatin may be initiated simultaneously with dietary therapy. For recommendations on dietary and other nondrug therapies (i.e., lifestyle modifications), consult the most recent American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

The manufacturer states that lipoprotein concentrations should be determined within 2-4 weeks following initiation and/or titration of atorvastatin, and that dosage should be adjusted accordingly. The ACC/AHA cholesterol management guideline states that lipoprotein concentrations should be determined within 4-12 weeks following initiation of statin therapy (to determine the patient's response to therapy and adherence) and monitored every 3-12 months thereafter as clinically indicated.

Adherence to lifestyle modifications and to statin therapy are required for atherosclerotic cardiovascular disease (ASCVD) risk reduction and, thus, should be reinforced periodically.

Administration

Atorvastatin is administered orally once daily. While food can reduce the systemic bioavailability of atorvastatin, such reduction does not appear to affect the drug's antilipemic activity, and atorvastatin may be taken without regard to meals. Although the manufacturer suggests that atorvastatin can be administered without regard to the time of day, the drug was given in the evening or at bedtime in most studies, when maximum HMG-CoA reductase inhibition occurs.

Dosage

Dosage of atorvastatin calcium is expressed in terms of atorvastatin and must be carefully adjusted according to individual requirements (i.e., percent reduction in low-density lipoprotein [LDL]-cholesterol concentrations) and response.

Prevention of Cardiovascular Events

The ACC/AHA cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk in patients most likely to benefit. Giving a maximally tolerated statin intensity should be emphasized over giving lower statin dosages and adding nonstatin drugs to address low high-density lipoprotein (HDL)-cholesterol or high triglyceride concentrations, a strategy that has not yet been shown to reduce ASCVD risk. It should be noted that although 20 mg once daily is an FDA-labeled dosage of atorvastatin, this dosage was not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.

Primary Prevention

For primary prevention of cardiovascular disease in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater), the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (e.g., atorvastatin 80 mg once daily, or, if not tolerated, atorvastatin 40 mg once daily) be initiated unless contraindicated. In patients who are unable to tolerate high-intensity statin therapy, the maximally tolerated statin intensity should be used. The ACC/AHA cholesterol management guideline states that it is reasonable to intensify statin therapy to achieve at least a 50% reduction in LDL-cholesterol concentrations. In patients currently receiving the maximum intensity of statin therapy, addition of a nonstatin drug may be considered to achieve further reductions in LDL-cholesterol concentrations; however, the potential benefits and risks (e.g., adverse effects, drug interactions) of such combined therapy, along with patient preferences, should be considered.

For primary prevention of cardiovascular disease in patients 40-75 years of age with type 1 or 2 diabetes mellitus and LDL-cholesterol concentrations of 70-189 mg/dL, the ACC/AHA cholesterol management guideline recommends that moderate-intensity statin therapy (e.g., atorvastatin 10-20 mg once daily) be initiated or continued. In those with an estimated 10-year ASCVD risk of 7.5% or higher, it is reasonable to consider high-intensity statin therapy (e.g., atorvastatin 80 mg once daily, or, if not tolerated, atorvastatin 40 mg once daily) unless contraindicated. In patients with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

For primary prevention of cardiovascular disease in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher, the ACC/AHA cholesterol management guideline recommends that moderate- (e.g., atorvastatin 10-20 mg once daily) to high-intensity statin therapy (e.g., atorvastatin 80 mg once daily, or, if not tolerated, atorvastatin 40 mg once daily) be initiated or continued. In those with an estimated 10-year ASCVD risk of 5 to less than 7.5%, it is reasonable to offer treatment with moderate-intensity statin therapy. Before initiating statin therapy for primary prevention of ASCVD in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL, it is reasonable for clinicians and patients to discuss the potential benefits, adverse effects, drug interactions, and patient preferences for such therapy.

Secondary Prevention

For secondary prevention of cardiovascular disease in patients 21-75 years of age with clinical ASCVD, the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (e.g., atorvastatin 80 mg once daily, or, if not tolerated, atorvastatin 40 mg once daily) be initiated or continued unless contraindicated; in patients currently receiving atorvastatin 40 mg once daily, the decision to increase the dosage to 80 mg once daily should be based on the potential for an ASCVD risk reduction benefit, adverse effects, drug interactions, as well as patient preferences. In patients 21-75 years of age with clinical ASCVD who are at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, moderate-intensity statin therapy (e.g., atorvastatin 10-20 mg once daily) should be given if tolerated. In patients older than 75 years of age with clinical ASCVD, use of statin therapy should be individualized based on the potential benefits, adverse effects, drug interactions, and patient preferences; it is reasonable to consider initiating or continuing moderate-intensity statin therapy in such patients if tolerated.

Dyslipidemias

Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) or Mixed Dyslipidemia

The recommended initial oral dosage of atorvastatin in adults for the management of primary hypercholesterolemia (heterozygous familial or nonfamilial) or mixed dyslipidemia is 10 or 20 mg once daily. The manufacturer states that patients requiring reductions in LDL-cholesterol of more than 45% may be started on an atorvastatin dosage of 40 mg daily. The usual maintenance dosage of atorvastatin in adults is 10-80 mg once daily.

The recommended initial dosage of atorvastatin for the management of heterozygous familial hypercholesterolemia in boys and postmenarchal girls 10-17 years of age is 10 mg once daily. Dosage adjustments should be made at intervals of 4 weeks or longer. The maximum recommended dosage of atorvastatin is 20 mg daily. Safety and efficacy of atorvastatin dosages exceeding 20 mg daily have not been evaluated in controlled trials in this patient population.

Homozygous Familial Hypercholesterolemia

The usual oral dosage of atorvastatin for the management of homozygous familial hypercholesterolemia is 10-80 mg once daily; the drug should be used as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.

Atorvastatin/Amlodipine Combination Therapy

The fixed-combination preparation containing atorvastatin and amlodipine (Caduet) may be used as a substitute for individually titrated drugs. In patients currently receiving atorvastatin and amlodipine, the initial dosage of the fixed-combination preparation should be the equivalent of titrated dosages of atorvastatin and amlodipine. Increased amounts of atorvastatin, amlodipine, or both components may be added for additional antilipemic, antianginal, or antihypertensive effects.

The fixed-combination preparation may be used to provide additional therapy for patients currently receiving one component of the preparation. The fixed-combination preparation also may be used to initiate treatment in patients with dyslipidemias and either hypertension or angina. Doses of amlodipine and atorvastatin should be selected independently. For dosage recommendations for amlodipine, The maximum dosage of atorvastatin or amlodipine in the fixed-combination preparation is 80 or 10 mg daily, respectively.

Concomitant Drug Therapy

Atorvastatin may be used in combination with other antilipemic agents (e.g., bile acid sequestrants, certain fibric acid derivatives).For specific recommendations for concomitant use of atorvastatin with other antilipemic agents, see Drug Interactions.

Because concomitant use of atorvastatin with certain drugs (e.g., inhibitors or inducers of cytochrome P-450 [CYP] isoenzyme 3A4) may increase the risk of myopathy, such concomitant use should be avoided or employed with caution.For specific recommendations (including dosage recommendations) for such concomitant use, see Drug Interactions.

Dosage Modification

The ACC/AHA cholesterol management guideline states that decreasing the statin dosage in adults may be considered when LDL-cholesterol concentrations are less than 40 mg/dL on 2 consecutive measurements; however, there are no data to suggest that LDL-cholesterol concentrations below 40 mg/dL would increase the risk of adverse effects.

Special Populations

Atorvastatin is metabolized predominantly in the liver and potentially may accumulate in the plasma of patients with hepatic impairment; however, the manufacturer makes no specific recommendations for dosage adjustment in patients with hepatic impairment. (See Cautions: Contraindications and also see Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Because renal impairment does not affect plasma concentrations or antilipemic effects of atorvastatin, the manufacturer states that dosage modification in patients with renal impairment is not necessary.

Although there are no specific dosage recommendations for geriatric patients, caution is recommended when atorvastatin is used in these patients.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

Contraindications

Active liver disease, including unexplained, persistent elevations in hepatic aminotransferase (transaminase) concentrations.

Women who are or may become pregnant.(See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Nursing women.(See Lactation under Warnings/Precautions: Specific Populations, in Cautions.)

Known hypersensitivity to atorvastatin or any ingredient in the formulation.

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Serum cholesterol and triglyceride concentrations increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development; therefore, suppression of cholesterol biosynthesis by atorvastatin during pregnancy may cause fetal harm. Atherosclerosis is a chronic process, and discontinuance of antilipemic drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There is no known clinical benefit for continued use of antilipemic drugs during pregnancy.

Congenital anomalies following intrauterine exposure to statins have been reported rarely.

Atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards.(See Advice to Patients.) If the patient becomes pregnant while taking the drug, atorvastatin should be immediately discontinued and the patient apprised of the potential fetal hazard and the lack of known clinical benefit with continued use during pregnancy.

Musculoskeletal Effects

Myopathy (defined as muscle aches or weakness in conjunction with increases in creatine kinase [CK, creatine phosphokinase, CPK] concentrations exceeding 10 times the upper limit of normal [ULN]) has been reported occasionally in patients receiving statins, including atorvastatin. Rhabdomyolysis with acute renal failure secondary to myoglobinuria also has been reported rarely in patients receiving statins, including atorvastatin.

The risk of myopathy or rhabdomyolysis is increased in geriatric patients (65 years of age or older) and in patients with uncontrolled hypothyroidism or renal impairment. Patients with renal impairment should be more closely monitored for adverse musculoskeletal effects. The risk of myopathy and/or rhabdomyolysis also is increased when atorvastatin is used concomitantly with cyclosporine, fibric acid derivatives, antilipemic dosages (1 g daily or higher) of niacin, or potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., azole antifungals, certain macrolide antibiotics, certain HIV protease inhibitors or ritonavir-boosted protease inhibitor regimens, certain hepatitis C virus [HCV] protease inhibitors).(See Drug Interactions.) Myopathy, including rhabdomyolysis, has been reported following concomitant use of atorvastatin and colchicine.

Although periodic monitoring of CK concentrations may be considered, there is no assurance that such monitoring will prevent the occurrence of severe myopathy. The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline does not recommend routine monitoring of CK concentrations in patients receiving statin therapy. However, the guideline states that it is reasonable to obtain baseline CK concentrations in adults at increased risk of developing adverse musculoskeletal effects (e.g., patients with personal or family history of statin intolerance or muscle disease, patients receiving concomitant therapy with myotoxic drugs) before initiating statin therapy. During statin therapy, it is reasonable to measure CK concentrations in adults experiencing muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).

The National Heart, Lung, and Blood Institute (NHLBI)-appointed expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that baseline CK concentrations should be obtained before initiating statin therapy in pediatric patients. In addition, routine monitoring for muscle toxicity is strongly recommended in children and adolescents receiving statin therapy.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked increases in CK concentrations. Atorvastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected. Atorvastatin therapy should be temporarily withheld or discontinued in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).(See Advice to Patients.)

For additional details on management of musculoskeletal effects in adults and pediatric patients, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org.) and the Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).

Hepatic Effects

Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including atorvastatin. Persistent increases (exceeding 3 times the ULN and occurring on 2 or more occasions) in serum aminotransferase concentrations occurred in 0.7% of patients receiving atorvastatin in clinical trials (including in 0.2% of those receiving atorvastatin 10 or 20 mg daily, 0.6% of those receiving 40 mg daily, and 2.3% of those receiving 80 mg daily). Although jaundice occurred in at least one patient in clinical trials, increases in aminotransferase concentrations were not associated with jaundice or other clinical manifestations. Upon dosage reduction or therapy interruption or discontinuance, aminotransferase concentrations returned to pretreatment or near-pretreatment levels without sequelae. Eighteen of 30 patients with persistent aminotransferase elevations continued therapy with a reduced dosage of atorvastatin.

Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including atorvastatin, during postmarketing surveillance.

Liver function tests should be performed prior to initiation of atorvastatin therapy and repeated as clinically indicated (e.g., presence of manifestations suggestive of liver damage). Although the manufacturer previously recommended more frequent monitoring of liver function (i.e., at 12 weeks), FDA concluded that serious statin-related liver injury is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. The ACC/AHA cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera). However, the NHLBI expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that routine monitoring of hepatic function is strongly recommended in children and adolescents receiving statin therapy.

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, atorvastatin therapy should be promptly interrupted. If an alternate etiology is not found, atorvastatin therapy should not be restarted.

Atorvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease. The drug is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum aminotransferase concentrations.

Endocrine Effects

Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including atorvastatin. Data from clinical trials and meta-analyses indicate that statin therapy may increase the risk of developing diabetes mellitus. Despite these findings, FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks. The ACC/AHA cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus according to current diabetes screening guidelines. If diabetes mellitus develops during statin therapy, patients should be encouraged to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of atherosclerotic cardiovascular disease (ASCVD).

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

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) has been reported rarely with all statins during postmarketing surveillance. This adverse CNS effect generally was nonserious and reversible, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks following discontinuance of statin therapy). Following review of available data (i.e., from the Adverse Event Reporting System [AERS] database, randomized clinical trials, observational studies, case reports), FDA concluded that cases of cognitive impairment did not appear to be associated with fixed or progressive dementia (e.g., Alzheimer's disease) or result in clinically important cognitive decline. Development of cognitive impairment did not appear to be associated with any specific statin, age of the patient, statin dosage, or concomitant drug therapy. Therefore, FDA continues to believe that the cardiovascular benefits of statins outweigh this small increased risk of cognitive impairment. The National Lipid Association (NLA) statin safety assessment task force recommends that patients experiencing manifestations consistent with cognitive impairment be evaluated and managed appropriately. The ACC/AHA cholesterol management guideline states that, in patients presenting with confusion or memory impairment, it is reasonable to evaluate the patient for statin as well as nonstatin causes (e.g., exposure to other drugs, systemic or neuropsychiatric causes).

Use in Patients with Recent Stroke or Transient Ischemic Attack

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in hypercholesterolemic patients without clinically evident coronary heart disease (CHD) who had a stroke or transient ischemic attack (TIA) within the past 1-6 months, therapy with high-dose atorvastatin (80 mg daily) for a median of 4.9 years was associated with a higher incidence of hemorrhagic stroke (2.3%) compared with placebo (1.4%). The incidence of fatal hemorrhagic stroke was similar between atorvastatin and placebo, while the incidence of nonfatal hemorrhagic stroke was substantially higher with atorvastatin (1.6%) compared with placebo (0.7%). Among patients receiving atorvastatin, those with a history of hemorrhagic or lacunar stroke at study entry were at increased risk of developing hemorrhagic stroke.

Elevated aminotransferase concentrations (to 3 or more times the ULN) were reported more frequently in patients receiving high-dose atorvastatin (0.9%) compared with those receiving placebo (0.1%). Increases in CK concentrations (exceeding 10 times the ULN) were rare but were reported more frequently in patients receiving high-dose atorvastatin (0.1%) compared with those receiving placebo (0%). Diabetes was reported in 6.1% of patients receiving high-dose atorvastatin compared with 3.8% of patients receiving placebo.

Use of Fixed Combination

When atorvastatin is used in fixed combination with amlodipine, the usual cautions, precautions, and contraindications associated with amlodipine must be considered in addition to those associated with atorvastatin.

Specific Populations

Pregnancy

Category X. (See Cautions: Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

Atorvastatin is distributed into milk in rats. It is not known whether atorvastatin is distributed into human milk; however, the drug is probably distributed into human milk because a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from atorvastatin in nursing infants, the drug is contraindicated in nursing women. Women who require atorvastatin therapy should not breast-feed their infants.

Pediatric Use

Safety and efficacy of atorvastatin have not been evaluated in prepubertal children or in children younger than 10 years of age with heterozygous familial hypercholesterolemia. In a randomized, double-blind, placebo-controlled study in boys and postmenarchal girls 10-17 years of age, the adverse effect profile of atorvastatin (10-20 mg daily for 26 weeks) generally was similar to that of placebo; dosages exceeding 20 mg daily have not been evaluated in this population. There were no substantial adverse effects on growth or sexual maturation in adolescent boys or on duration of menstrual cycle in girls. If therapy with atorvastatin is considered, the manufacturer states that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.

The manufacturer states that atorvastatin dosages of up to 80 mg daily for 1 year have been evaluated in an uncontrolled study in 8 pediatric patients (6 years of age or older) with homozygous familial hypercholesterolemia.

Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet) have not been established in pediatric patients.

Geriatric Use

Of the 39,828 patients receiving atorvastatin in clinical studies, 40% were 65 years of age or older, and 7% were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out. Data from a pharmacokinetic study indicate that peak plasma concentration and area under the plasma concentration-time curve (AUC) of atorvastatin were 40 or 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults. In addition, mean reductions in LDL-cholesterol concentrations appear to be higher in geriatric patients receiving any dose of atorvastatin compared with younger patients.

Because advanced age (65 years of age or older) is a predisposing factor for myopathy, atorvastatin should be used with caution in geriatric patients. The ACC/AHA cholesterol management guideline states that initiation of statin therapy for primary prevention of ASCVD in patients older than 75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. Therefore, the potential for an ASCVD risk reduction benefit, adverse effects, and drug interactions, along with patient preferences, must be considered before initiating statin therapy in patients older than 75 years of age.

Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet) have not been established in geriatric patients.

Hepatic Impairment

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Peak plasma concentration and AUC of atorvastatin are increased by fourfold in patients with Child-Pugh class A disease and by approximately 16- and 11-fold, respectively, in patients with Child-Pugh class B disease.

Atorvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease. Atorvastatin is contraindicated in patients with active liver disease, including unexplained, persistent elevations in hepatic aminotransferase concentrations.

Renal Impairment

Renal impairment does not affect plasma concentrations or antilipemic effects of atorvastatin; therefore, dosage modification in patients with renal impairment is not necessary. However, because history of renal impairment may be a risk factor for development of rhabdomyolysis, patients with renal impairment should be monitored more closely for adverse musculoskeletal effects.

Safety and efficacy of atorvastatin have not been established in patients with end-stage renal disease. However, hemodialysis is not expected to substantially enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving atorvastatin in clinical trials that occurred more frequently than with placebo include nasopharyngitis, arthralgia, diarrhea, pain in extremity, urinary tract infection, dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, and pharyngolaryngeal pain.

Drug Interactions

Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.

When atorvastatin is used in fixed combination with amlodipine, interactions associated with amlodipine should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation containing atorvastatin and amlodipine.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Concomitant use of atorvastatin with potent inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, HIV protease inhibitors, grapefruit juice) may result in increased plasma atorvastatin concentrations and increase the risk of myopathy or rhabdomyolysis. The extent of interaction and potentiation of effects depend on the extent of effect on CYP3A4.

Concomitant use of atorvastatin with inducers of CYP3A4 (e.g., efavirenz, rifampin) may result in variable reductions in plasma concentrations of atorvastatin.

Drugs Transported by Organic Anion Transport Polypeptide 1B1

Atorvastatin and its metabolites are substrates of organic anion transport polypeptide (OATP) 1B1. Drugs that inhibit OATP1B1 (e.g., cyclosporine) can increase bioavailability of atorvastatin.

Azole Antifungals

Concomitant use of atorvastatin and azole antifungals (e.g., itraconazole) increases the risk of myopathy or rhabdomyolysis. Following concomitant use of atorvastatin (40 mg as a single dose) and itraconazole (200 mg once daily for 4 days), atorvastatin peak plasma concentration and area under the plasma concentration-time curve (AUC) were increased by 20% and 3.3-fold, respectively.

Clinicians considering concomitant use of atorvastatin and itraconazole or other azole antifungals should weigh the benefits and risks of such concomitant therapy. During concomitant therapy with itraconazole, the lowest necessary dosage of atorvastatin should be employed, and dosage of atorvastatin should not exceed 20 mg daily. Patients receiving concomitant therapy with atorvastatin and azole antifungals should be monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Bile Acid Sequestrants

The cholesterol-lowering effects of atorvastatin and bile acid sequestrants (e.g., cholestyramine) are additive. However, since bile acid sequestrants may decrease absorption of various drugs, some clinicians state that statins (e.g., atorvastatin) generally should be administered one hour before or 4 hours after the bile acid sequestrant.

Colchicine

Myopathy, including rhabdomyolysis, has been reported in patients receiving atorvastatin concomitantly with colchicine. Caution is advised during such concomitant use.

Cyclosporine

Concomitant use of atorvastatin and cyclosporine increases plasma atorvastatin concentrations, which may increase the risk of myopathy or rhabdomyolysis. Following concomitant use of atorvastatin (10 mg daily for 28 days) and cyclosporine (5.2 mg/kg daily), atorvastatin peak plasma concentration and AUC were increased by 10.7- and 8.7-fold, respectively. Concomitant use of atorvastatin and cyclosporine should be avoided.

Digoxin

Concomitant use of atorvastatin (80 mg once daily for 14 days) and digoxin (0.25 mg once daily for 20 days) resulted in 20 and 15% increases in digoxin peak plasma concentration and AUC, respectively. Therefore, patients receiving such concomitant therapy should be monitored appropriately.

Efavirenz

Concomitant use of atorvastatin with efavirenz may result in reductions in plasma concentrations of atorvastatin. Following concomitant use of atorvastatin (10 mg daily for 3 days) and efavirenz (600 mg once daily for 14 days), atorvastatin peak plasma concentration and AUC were decreased by 1 and 41%, respectively.

Fibric Acid Derivatives

Concomitant use of atorvastatin and fibric acid derivatives (e.g., gemfibrozil, fenofibrate) increases the risk of myopathy. Following concomitant use of atorvastatin (40 mg as a single dose) and gemfibrozil (600 mg twice daily for 7 days), atorvastatin AUC was increased by 35%. Following concomitant use of atorvastatin (40 mg as a single dose) and fenofibrate (160 mg once daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 2 and 3%, respectively.

Concomitant use of atorvastatin and gemfibrozil should be avoided. The benefits of concomitant use of atorvastatin and other fibric acid derivatives (e.g., fenofibrate) should be weighed against the possible risk of myopathy. The manufacturer states that caution is advised if such concomitant therapy is employed; lower initial and maintenance dosages of atorvastatin should be considered during such concomitant therapy, and the patient should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug. The ACC/AHA cholesterol management guideline states that the combination of fenofibrate and low- or moderate-intensity statin therapy may be considered only if the benefits from atherosclerotic cardiovascular disease (ASCVD) risk reduction or triglyceride lowering (when triglyceride concentrations exceed 500 mg/dL) outweigh the potential risk of adverse effects.

Grapefruit Juice

Because grapefruit juice contains one or more components that inhibit CYP3A4, ingestion of grapefruit juice may result in increased atorvastatin concentrations. Following concomitant use of atorvastatin (40 mg as a single dose) with grapefruit juice (240 mL once daily), atorvastatin peak plasma concentration and AUC were increased by 16 and 37%, respectively. More substantial increases in atorvastatin peak plasma concentration (up to 71%) and/or AUC (up to 2.5-fold) have been reported following ingestion of large quantities (750-1200 mL daily or more) of grapefruit juice. Ingestion of large quantities (more than one liter daily) of grapefruit juice may increase the risk of myopathy.

HIV Protease Inhibitors

Darunavir

Concomitant use of atorvastatin and ritonavir-boosted darunavir increases the risk of myopathy or rhabdomyolysis. Following concomitant use of atorvastatin (10 mg daily for 4 days) and ritonavir-boosted darunavir (darunavir 300 mg twice daily with ritonavir 100 mg twice daily for 9 days), atorvastatin peak plasma concentration and AUC were increased by 2.25- and 3.4-fold, respectively.

The benefits of concomitant use of atorvastatin and ritonavir-boosted darunavir should be weighed against the possible risk of myopathy or rhabdomyolysis. Caution is advised if such concomitant therapy is employed. During such concomitant therapy, the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should not exceed 20 mg daily. Patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Fosamprenavir

Concomitant use of atorvastatin and fosamprenavir (with or without low-dose ritonavir) increases the risk of myopathy or rhabdomyolysis. Following concomitant use of atorvastatin (10 mg daily for 4 days) and fosamprenavir (1.4 g twice daily for 14 days), atorvastatin peak plasma concentration and AUC were increased by 4.04- and 2.3-fold, respectively, while fosamprenavir peak plasma concentration and AUC were decreased by 18 and 27%, respectively. Following concomitant use of atorvastatin (10 mg daily for 4 days) and ritonavir-boosted fosamprenavir (fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily for 14 days), atorvastatin peak plasma concentration and AUC were increased by 2.84- and 2.53-fold, respectively, while fosamprenavir peak plasma concentration and AUC were unchanged.

The benefits of concomitant use of atorvastatin and fosamprenavir (with or without low-dose ritonavir) should be weighed against the possible risk of myopathy or rhabdomyolysis. Caution is advised if such concomitant therapy is employed. During such concomitant therapy, the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should not exceed 20 mg daily. Patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Lopinavir

Concomitant use of atorvastatin with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) increases the risk of myopathy or rhabdomyolysis.

The benefits of concomitant use of atorvastatin and lopinavir/ritonavir should be weighed against the possible risk of myopathy or rhabdomyolysis. Caution is advised if such concomitant therapy is employed. During such concomitant therapy, the lowest necessary dosage of atorvastatin should be used. Patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Nelfinavir

Following concomitant use of atorvastatin (10 mg daily for 28 days) and nelfinavir (1.25 g twice daily for 14 days), atorvastatin peak plasma concentration and AUC were increased by 2.2-fold and 74%, respectively.

Patients receiving atorvastatin concomitantly with nelfinavir should be closely monitored. During such concomitant therapy, the lowest necessary dosage of atorvastatin should be employed, and dosage of atorvastatin should not exceed 40 mg daily.

Saquinavir

Concomitant use of atorvastatin and ritonavir-boosted saquinavir increases the risk of myopathy or rhabdomyolysis.

The benefits of concomitant use of atorvastatin and ritonavir-boosted saquinavir should be weighed against the possible risk of myopathy or rhabdomyolysis. Caution is advised if such concomitant therapy is employed. During such concomitant therapy, the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should not exceed 20 mg daily. Patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Tipranavir

Concomitant use of atorvastatin and ritonavir-boosted tipranavir increases the risk of myopathy or rhabdomyolysis. Following concomitant use of atorvastatin (10 mg as a single dose) and ritonavir-boosted tipranavir (tipranavir 500 mg twice daily with ritonavir 200 mg twice daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 8.6- and 9.4-fold, respectively, while tipranavir peak plasma concentration and AUC were unchanged.

Concomitant use of atorvastatin and ritonavir-boosted tipranavir should be avoided.

Lomitapide

Following concomitant use of atorvastatin (single 20-mg dose) with lomitapide (10 mg once daily for 7 days), peak plasma concentration and AUC of atorvastatin acid were increased by 19 and 11%, respectively. Following concomitant use of lomitapide (60 mg once daily for 7 days) with atorvastatin (single 20-mg dose), peak plasma concentration and AUC of atorvastatin acid were increased by 63 and 52%, respectively. When lomitapide is used concomitantly with atorvastatin, adjustment of atorvastatin dosage is not required; however, lomitapide dosage should not exceed 30 mg daily.

Macrolide Antibiotics

Concomitant use of atorvastatin and macrolide antibiotics (e.g., clarithromycin, erythromycin) increases the risk of myopathy or rhabdomyolysis. Following concomitant use of atorvastatin (80 mg daily for 8 days) and clarithromycin (500 mg twice daily for 9 days), atorvastatin peak plasma concentration and AUC were increased by 5.4- and 4.4-fold, respectively. Following concomitant use of atorvastatin (10 mg as a single dose) and erythromycin (500 mg 4 times daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 38 and 33%, respectively.

The benefits of concomitant use of atorvastatin and macrolide antibiotics (e.g., clarithromycin, erythromycin) should be weighed against the possible risk of myopathy or rhabdomyolysis. Caution is advised if such concomitant therapy is employed. Lower initial and maintenance dosages of atorvastatin should be considered during such concomitant therapy. During concomitant therapy with clarithromycin, the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should not exceed 20 mg daily. Patients receiving atorvastatin concomitantly with macrolide antibiotics should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Niacin

Concomitant use of atorvastatin and antilipemic dosages (1 g daily or higher) of niacin increases the risk of myopathy. Data from several large randomized studies indicate that concomitant use of niacin (1.5-2 g daily) with another statin (i.e., simvastatin 40-80 mg once daily, with or without ezetimibe) resulted in an increased risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, and bleeding.

The benefits of concomitant use of atorvastatin and antilipemic dosages of niacin should be weighed against the possible risk of myopathy. If concomitant therapy is employed, caution is advised, and lower initial and maintenance dosages of atorvastatin should be considered; in addition, patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Omega-3-acid Ethyl Esters

Concomitant use of atorvastatin (80 mg daily) with omega-3-acid ethyl esters (4 g daily) for 14 days did not affect the rate or extent of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.

Oral Contraceptives

Concomitant use of atorvastatin (40 mg once daily for 22 days) and an oral contraceptive (ethinyl estradiol 35 mcg with norethindrone 1 mg for 2 months) resulted in 30 and 19% increases in ethinyl estradiol peak plasma concentration and AUC, respectively, and 23 and 28% increases in norethindrone peak plasma concentration and AUC, respectively. This interaction should be considered when selecting oral contraceptives for patients receiving atorvastatin.

Rifampin

Administration of rifampin (600 mg once daily for 5 days) followed by delayed administration of atorvastatin (40 mg as a single dose) resulted in 40 and 80% decreases in atorvastatin peak plasma concentration and AUC, respectively, while simultaneous administration of the drugs (rifampin 600 mg once daily for 7 days with atorvastatin 40 mg as a single dose) resulted in 2.7-fold and 30% increases in atorvastatin peak plasma concentration and AUC, respectively. Therefore, if atorvastatin and rifampin are used concomitantly, these drugs should be administered simultaneously.

Warfarin

Atorvastatin had no clinically important effect on prothrombin time (PT) when administered to patients receiving long-term warfarin therapy. Some experts recommend closer monitoring of the international normalized ratio (INR) after initiation of a statin or a change in statin dosage.

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