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Uses

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, simvastatin may be used for primary or secondary prevention in adults when moderate-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).

Secondary Prevention

Simvastatin is used as an adjunct to nondrug therapies (e.g., lifestyle modification) in patients with coronary heart disease (CHD) or CHD risk equivalents (i.e., risk factors that confer a risk for major coronary events equal to that of established CHD, such as diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease) to reduce the risk of total mortality by reducing CHD deaths, to reduce the risk of nonfatal myocardial infarction (MI) and stroke, and to reduce the need for coronary and noncoronary revascularization procedures.

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 [ACS]; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack [TIA], or peripheral arterial disease presumed to be of atherosclerotic origin) unless contraindicated.

Several clinical trials designed to evaluate the benefits of simvastatin in patients with established CHD have reported improvements in the risk of cardiovascular events, as evidenced by reductions in the risks of total mortality and nonfatal coronary events. In the Scandinavian Simvastatin Survival Study (4S), therapy with simvastatin in 4444 patients with hypercholesterolemia and angina pectoris or prior MI was associated with reductions in total mortality (30%), CHD mortality (42%), and hospital-verified nonfatal MI (37%) compared with placebo over a median of 5.4 years of follow-up; the risk of undergoing myocardial revascularization procedures also was reduced by 37%. In addition, simvastatin therapy reduced the risk of fatal and nonfatal cerebrovascular events (combined incidence of stroke and TIA) by 28%. The reduction in the combined coronary events (nonfatal MI and revascularization procedures) reported in the 4S trial also was observed in women, geriatric patients (65 years of age and older), and in patients with diabetes mellitus. Unlike some prior studies of cholesterol-lowering therapy, an increased risk of death from noncardiovascular causes was not observed in patients receiving simvastatin therapy in this study.

In the Heart Protection Study (HPS), therapy with simvastatin (40 mg daily) in over 20,000 patients with CHD, history or stroke or other cerebrovascular disease, other occlusive arterial disease (e.g., peripheral arterial disease), hypertension or diabetes mellitus reduced the risk of total mortality (13%), CHD mortality (18%), nonfatal MI (38%), ischemic stroke (25%), coronary revascularization procedures (30%), and peripheral and other noncoronary revascularization procedures (16%) compared with placebo over approximately 5 years of follow-up, irrespective of baseline lipoprotein concentrations.

In another randomized, double-blind study (A to Z trial) in about 4500 patients who had manifestations of ACS within the preceding 5 days, treatment with intensive antilipemic therapy (simvastatin 40 mg daily for 1 month, then simvastatin 80 mg daily thereafter) for 6-24 months resulted in a 25% reduction in the risk of cardiovascular mortality compared with moderate antilipemic therapy (placebo for 4 months, then simvastatin 20 mg daily thereafter); there was a reduction (11%) in the rate of the primary endpoint (a composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke) for the entire study period but this difference failed to reach statistical significance. However, while no difference was evident between the intensive and moderate regimens during the first 4 months of therapy, from 4 months through the end of the study, the primary endpoint was substantially reduced (by 25%) in patients receiving the intensive regimen. Intensive or moderate antilipemic therapy reduced LDL-cholesterol concentrations to a median of 63 or 77 mg/dL, respectively, at 8 months. While a favorable trend toward reduction of major cardiovascular events was observed in this study, it is possible that more intensive therapy is required immediately after the onset of ACS during the period of greatest clinical instability to achieve a more rapid clinical benefit.

Simvastatin has been shown to slow the progression and/or induce regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness. In the Multicenter Anti-Atheroma Study (MAAS) in hypercholesterolemic men and women with clinical evidence of CHD, progression of atherosclerosis at 2-4 years (measured as the mean per-patient changes from baseline in mean and minimal coronary artery lumen diameters, diameter stenosis, and formation of new lesions) was reduced in patients who received simvastatin (20 mg daily) compared with those receiving placebo.

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 simvastatin 10 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and simvastatin 20-40 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 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.

Although early findings from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study demonstrated that combination therapy with simvastatin and ezetimibe was not superior to simvastatin monotherapy in reducing carotid intimal-medial wall thickness (cIMT), a more recent study (the Improved Reduction of Outcomes: Vytorin Efficacy International [IMPROVE-IT]) in 18,144 post-ACS patients with baseline LDL-cholesterol concentrations of 50-125 mg/dL (or 50-100 mg/dL if they were receiving lipid-lowering therapy) showed that the addition of ezetimibe (10 mg daily) to simvastatin (40 mg daily) therapy not only produced a 24% further reduction in LDL-cholesterol concentrations, but also improved cardiovascular outcomes (a composite of cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke) compared with simvastatin (40 mg daily) monotherapy. Treatment with the simvastatin and ezetimibe combination resulted in an absolute risk reduction of 2% over 7 years for the primary composite end point.

The addition of niacin to statin-based therapy has not been shown to provide an incremental benefit in reducing cardiovascular morbidity and mortality beyond that already demonstrated with statin-based therapy. In the Impact on Global Health Outcomes (AIM-HIGH) study, the combination of extended-release niacin (1.5-2 g daily) and statin-based therapy (simvastatin 40-80 mg once daily, with or without ezetimibe 10 mg daily) was compared with statin-based therapy alone in patients with established cardiovascular disease (i.e., documented stable CHD, cerebrovascular or carotid disease, peripheral arterial disease). Despite a favorable effect on serum lipid concentrations (median high-density lipoprotein [HDL]-cholesterol concentration increased from 35 to 42 mg/dL, triglyceride concentration decreased from 164 to 122 mg/dL, and LDL-cholesterol concentration decreased from 74 to 62 mg/dL), the addition of niacin to simvastatin-based therapy did not further reduce the incidence of the primary end point (i.e., composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for more than 23 hours for ACS, or symptom-driven coronary or cerebral revascularization) compared with simvastatin-based therapy alone over a follow-up period of 36 months. The addition of extended-release niacin to existing simvastatin-based therapy, however, did increase the risk of adverse effects (e.g., pruritus, flushing, adverse GI effects, increased blood glucose concentrations). The investigators of this study stated that whether such combination therapy provides incremental benefit in higher-risk patients or in those receiving suboptimal statin therapy remains to be established.

Data from another large randomized, double-blind, multicenter study involving 25,673 adults with cardiovascular disease confirmed findings of the AIM-HIGH study. In the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), the combination of extended-release niacin/laropiprant (2 g/40 mg daily) (no longer commercially available) and statin-based therapy (simvastatin 40 mg once daily, with or without ezetimibe 10 mg daily) was compared with statin-based therapy alone in patients with established cardiovascular disease (i.e., history of MI, cerebrovascular disease, peripheral arterial disease, diabetes mellitus with evidence of symptomatic coronary disease). Despite a favorable effect on serum lipid concentrations (additional 6-mg/dL increase in HDL-cholesterol concentration, 33-mg/dL reduction in triglyceride concentration, and 10-mg/dL reduction in LDL-cholesterol concentration), the addition of niacin/laropiprant to simvastatin-based therapy did not further reduce the incidence of major cardiovascular events (i.e., nonfatal MI, death from coronary causes, stroke of any type, coronary or noncoronary revascularization) compared with simvastatin-based therapy alone over a median follow-up of 3.9 years. The addition of niacin/laropiprant to existing simvastatin-based therapy, however, did increase the risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, and, unexpectedly, infection and bleeding.

Patients with Chronic Kidney Disease

In the Study of Heart and Renal Protection (SHARP), the fixed-combination preparation containing ezetimibe and simvastatin was shown to reduce the risk of major vascular and atherosclerotic events in patients with chronic kidney disease, a population known to be at increased risk of cardiovascular disease. More than 9000 patients with moderate to severe chronic kidney disease (33% receiving dialysis) and no known history of MI or coronary revascularization were initially randomized in a 4:4:1 ratio to receive the fixed-combination preparation containing ezetimibe and simvastatin (10 and 20 mg daily, respectively), placebo, or simvastatin alone (20 mg daily) for 1 year to assess the safety of adding ezetimibe to simvastatin; patients in the simvastatin monotherapy group were then re-randomized to the fixed-combination preparation or placebo. After a median duration of follow-up of 4.9 years, the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or revascularization excluding dialysis access procedures) was reduced by 16% (based on the primary intent-to-treat analysis in patients initially randomized to the fixed-combination preparation or placebo groups) and the risk of a major atherosclerotic event (nonfatal MI or cardiac death, nonhemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was reduced by 17% (based on all patients randomized at any time to the fixed-combination preparation or placebo groups) with the fixed-combination preparation compared with placebo. The treatment effect was largely driven by a substantial reduction in ischemic strokes and arterial revascularization procedures. The subgroup of patients receiving dialysis at baseline experienced a smaller risk reduction benefit compared with those not receiving dialysis. In addition, therapy with the fixed-combination preparation did not appear to slow the progression to end-stage renal disease.

Dyslipidemias

Simvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), triglyceride, and very low-density lipoprotein (VLDL)-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the management of primary hyperlipidemia of primary or mixed dyslipidemia, homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia, and/or hypertriglyceridemia. The efficacy of simvastatin remains to be established in patients with elevated chylomicrons as their primary lipid abnormality (Fredrickson types I and V).

Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake, addition of plant stanols/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.

Primary Hyperlipidemia or Mixed Dyslipidemia

Simvastatin is used alone or in combination with ezetimibe as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apo B, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hyperlipidemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIa or IIb). Simvastatin also is used to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the treatment of heterozygous familial hypercholesterolemia in boys and girls (at least one year postmenarchal) 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 simvastatin therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has not been established. Statins such as simvastatin 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 established with such combination therapy beyond that already established with statin monotherapy.

Reductions in total and LDL-cholesterol produced by usual dosages of simvastatin substantially exceed those of placebo and appear to be similar to or greater than those produced by monotherapy with certain other antilipemic agents. Mean reductions in total cholesterol concentrations of 19-36%, LDL-cholesterol concentrations of 26-47%, apo B concentrations of 31-38%, and triglyceride concentrations of 12-33% have been reported in controlled studies in patients with primary hypercholesterolemia who received 5-80 mg of simvastatin daily for at least 6 weeks. Modest and variable increases in HDL-cholesterol concentrations (5-16%) also were observed in these patients.

Reductions in total and LDL-cholesterol concentrations produced by usual dosages of simvastatin appear to be similar to or greater than those produced by monotherapy with most other statins (e.g., fluvastatin, lovastatin, pravastatin). In several randomized, comparative studies with various statins, patients with hypercholesterolemia who received simvastatin 5-40 mg daily had greater reductions in plasma total and LDL-cholesterol concentrations (16-30 and 21-41%, respectively) than those who received fluvastatin 20-40 mg daily (12-19 and 16-23%, respectively), lovastatin 20-40 mg daily (21-23 and 29-31%, respectively), or pravastatin 10-40 mg daily (13-24 and 19-34%, respectively). However, patients treated with atorvastatin 10-40 mg daily had greater reductions in total and LDL-cholesterol concentrations (28-40 and 38-51%, respectively) than simvastatin-treated patients. Furthermore, atorvastatin (40 mg daily) appears to be more effective than simvastatin (40 mg daily) in the management of patients with severe hypercholesterolemia who require regular plasma LDL-apheresis. Limited data indicate that reductions in LDL-cholesterol concentrations may be similar among patients receiving high-dose simvastatin and atorvastatin (80 mg daily).

Increases in HDL-cholesterol concentrations appear to be greater among simvastatin- than atorvastatin-treated patients. In several studies designed to evaluate the effects of simvastatin (40-80 mg) and atorvastatin (20-80 mg daily) on HDL-cholesterol and apolipoprotein A-I (apo A-I) concentrations, increases in HDL-cholesterol and apo A-I concentrations were more pronounced in simvastatin-treated (7-9 and 3-6%, respectively) patients than in atorvastatin-treated (0-7 and 0-5%, respectively) patients. The mechanisms of these effects have not been fully elucidated but may be related to differences in plasma elimination half-lives (approximately 20 hours for atorvastatin and 2 hours for simvastatin) and differential effects 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 simvastatin may be greater than those of some other antilipemic agents (i.e., bile acid sequestrants, fibric acid derivatives). In several controlled studies comparing 12 weeks of simvastatin therapy (20-40 mg daily) with that of cholestyramine (4-16 g in divided doses) in patients with familial and nonfamilial hypercholesterolemia, simvastatin was more effective than cholestyramine in reducing total and LDL-cholesterol concentrations (26-36 and 32-40% versus 23 and 15-21%, respectively). Simvastatin also was more effective than cholestyramine in improving triglyceride (21% reduction versus 11% increase) and HDL-cholesterol concentrations (16% versus 9% increase). Simvastatin appears to be more effective than fibric acid derivatives (e.g., gemfibrozil) in reducing total and LDL-cholesterol concentrations but less effective than these agents in reducing triglycerides and increasing HDL-cholesterol concentrations. In several randomized, comparative studies in patients with primary hypercholesterolemia, therapy with simvastatin (5-20 mg) produced greater reductions in total and LDL-cholesterol (14-27 and 22-34%, respectively) than treatment with gemfibrozil (600 mg twice daily) (5-14 and 17%, respectively); however, reductions in triglycerides and increases in HDL-cholesterol concentrations were less pronounced among patients treated with simvastatin (7-16% reduction and 6-13% increase) than in those receiving gemfibrozil (30-44% reduction and 16-26% increase). Similar results have been reported with other fibric acid derivatives (e.g., fenofibrate).

The combination of simvastatin and other antilipemic agents (e.g., bile acid sequestrants, fibric acid derivatives, ezetimibe) may produce additive antilipemic effects; however, the risk of myopathy and rhabdomyolysis may be increased with some combinations.(See Combination Antilipemic Therapy under Uses: Prevention of Cardiovascular Events.) The addition of a bile acid sequestrant to simvastatin therapy further reduced LDL-cholesterol by 11%, resulting in an overall LDL-cholesterol reduction of 54% in patients receiving simvastatin 20-40 mg daily and cholestyramine 8-16 g daily. Low-dose simvastatin (10 mg daily) in combination with fenofibrate (300 mg daily) in patients with combined hyperlipidemia further reduced triglyceride concentrations by 32% and increased HDL-cholesterol concentrations by an additional 7%. In a multicenter, double-blind study, the addition of ezetimibe (10 mg daily) to simvastatin therapy (10-80 mg daily) further reduced LDL-cholesterol by 10-19%, resulting in overall LDL-cholesterol reductions of 46-58% with combined therapy. Similar additive antilipemic effects were observed following therapy with the fixed-combination preparation containing simvastatin and ezetimibe; LDL-cholesterol was reduced by 45-60% following therapy with the fixed-combination preparation and by 33-49% following monotherapy with simvastatin (10-80 mg daily). In another multicenter, double-blind study, the fixed-combination preparation containing 10 mg of ezetimibe and 20 mg of simvastatin was substantially more effective than doubling the dose of simvastatin (e.g., from 20 to 40 mg).

The increased risk of adverse muscular effects should be considered when simvastatin is used in combination with certain antilipemic agents (e.g., fibric acid derivatives or niacin at lipid-modifying dosages [at least 1 g daily]).

Homozygous Familial Hypercholesterolemia

Simvastatin 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 several open-label clinical trials in a limited number of patients with homozygous familial hypercholesterolemia receiving simvastatin 40-80 mg daily, LDL-cholesterol concentrations were reduced by 8-46% in most patients; however, at least one patient with homozygous familial hypercholesterolemia experienced increases (15%) in LDL-cholesterol concentrations with simvastatin therapy.

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 simvastatin or atorvastatin 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 simvastatin or atorvastatin 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 simvastatin or atorvastatin, LDL-cholesterol concentrations were reduced by an additional 27% compared with LDL-cholesterol reductions achieved with the 40-mg daily statin dosage.

Primary Dysbetalipoproteinemia

Simvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride and VLDL-cholesterol concentrations in the treatment of primary dysbetalipoproteinemia (Fredrickson type III).

Treatment with simvastatin has resulted in substantial reductions in combined intermediate-density lipoprotein (IDL)- and VLDL-cholesterol, total cholesterol, triglyceride, and non-HDL-cholesterol concentrations. In several studies in a limited number of patients with primary dysbetalipoproteinemia who received simvastatin 20-80 mg daily for at least 6 weeks, combined IDL- and VLDL-cholesterol, total cholesterol, triglyceride, and non-HDL-cholesterol concentrations decreased by 50-60, 39-54, 32-55, and 32-59%, respectively. Simvastatin 20 mg daily reportedly has produced greater reductions in LDL-cholesterol than gemfibrozil 1200 mg daily in patients with primary dysbetalipoproteinemia. However, reductions in triglyceride concentrations and increases in HDL-cholesterol concentrations were less pronounced than those reported with usual dosages of gemfibrozil.

Hypertriglyceridemia

Simvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride concentrations in the treatment of hypertriglyceridemia (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.

Median reductions in total cholesterol concentrations of 25-32%, LDL-cholesterol concentrations of 28-37%, VLDL-cholesterol concentrations of 37-41%, triglyceride concentrations of 29-34%, and non-HDL-cholesterol concentrations of 32-38% have been reported in a subgroup analysis in patients with hypertriglyceridemia who received 40-80 mg daily. Simvastatin 20 mg daily reportedly has produced greater reductions in total and LDL-cholesterol concentrations than gemfibrozil 600 mg twice daily in patients with borderline hypertriglyceridemia; however, reductions in triglyceride concentrations were less pronounced than those reported with usual dosages of gemfibrozil.

Other Uses

Treatment with simvastatin preoperatively to control lipoprotein fractions has been shown to reduce the risk of postoperative thrombocytosis and thrombotic complications following coronary artery bypass grafting (CABG) procedures. Postoperative thrombocytosis (platelet counts exceeding 400,000/ mm) and MI occurred less frequently in simvastatin-treated patients than in those who received placebo (3 and 0%, respectively, versus 81 and 14%, respectively).

Simvastatin has reduced total and LDL-cholesterol concentrations in a few patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia) (see Secondary Prevention under Uses: Prevention of Cardiovascular Events), cardiac or renal transplantation, or nephrotic syndrome.

Simvastatin also has been shown to improve ejection fraction in cardiac transplant recipients. Improvement in renal cholesterol emboli syndrome was reported in at least one patient who received simvastatin (10-40 mg daily) for 3 months. However, the relationship between simvastatin and these effects is unclear.

For additional information on the role of simvastatin 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.

Dosage and Administration

Administration

Simvastatin, alone or in fixed combination with ezetimibe, is administered orally in the evening without regard to meals. GI absorption of the drug does not appear to be affected substantially when simvastatin is administered immediately before a low-fat meal. Patients should be placed on a standard cholesterol-lowering diet before initiation of simvastatin therapy and should remain on this diet during treatment with the drug; in patients with coronary heart disease (CHD) or CHD risk equivalents, simvastatin may be initiated simultaneously with dietary management. 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).

Because administration of simvastatin with grapefruit juice has resulted in substantial increases in plasma concentrations of the antilipemic agent, the manufacturer and some clinicians recommend that concomitant administration of simvastatin with grapefruit juice should be avoided. Because the extent of this interaction may be influenced by the quantity and timing of grapefruit juice consumption, other clinicians suggest that small amounts (e.g., 240 mL) of grapefruit juice may be acceptable.

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

Dosage

Dosage of simvastatin must be carefully adjusted according to individual requirements and response. The manufacturers state that serum lipoprotein concentrations should be determined 4 weeks after initiation of simvastatin monotherapy or 2 or more weeks after initiation or titration of therapy with the fixed-combination preparation (Vytorin), and then periodically thereafter. The ACC/AHA guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults 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.

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 HDL-cholesterol or high triglyceride concentrations, a strategy that has not yet been shown to reduce ASCVD risk. It should be noted that although 10 mg once daily is an FDA-labeled dosage of simvastatin, 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 low-density lipoprotein (LDL)-cholesterol concentration (190 mg/dL or greater), the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated unless contraindicated. ( or .)

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., simvastatin 20-40 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 (i.e., with atorvastatin or rosuvastatin) 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., simvastatin 20-40 mg once daily) to high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) 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 (i.e., with atorvastatin or rosuvastatin) be initiated unless contraindicated. ( or .) 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., simvastatin 20-40 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

The usual initial dosage of simvastatin in adults is 10 or 20 mg once daily in the evening. In patients with CHD or CHD risk equivalents (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease), the recommended initial dosage of simvastatin is 40 mg daily. The usual maintenance dosage of simvastatin is 5-40 mg once daily in the evening; geriatric patients may respond to maintenance dosages of 20 mg or less daily. Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturer states that patients who are unable to achieve the desired percent reduction in LDL-cholesterol concentrations with the 40-mg daily dosage of simvastatin should not be titrated to the 80-mg daily dosage but should be switched to alternative antilipemic agents that provide greater LDL-cholesterol reduction. The manufacturer also states that use of the 80-mg daily dosage of simvastatin should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of adverse muscular effects.(See Cautions.) Patients currently tolerating the 80-mg daily dosage of simvastatin who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin with less drug interaction potential.

The recommended initial dosage of simvastatin for the treatment of heterozygous familial hypercholesterolemia in boys and postmenarchal girls 10-17 years of age is 10 mg once daily in the evening. The recommended dosage range of simvastatin is 10-40 mg daily. Dosage adjustments should be made at intervals of 4 weeks or longer. The maximum recommended dosage of simvastatin in children and adolescents 10-17 years of age is 40 mg daily. Safety and efficacy of simvastatin dosages exceeding 40 mg daily have not been evaluated in this patient population.

In patients with homozygous familial hypercholesterolemia, the recommended dosage of simvastatin is 40 mg daily in the evening. Simvastatin should be used as an adjunct to other lipid-lowering treatment (e.g., LDL apheresis) in these patients or as an alternative if such therapy is unavailable.

Because of an increased risk of myopathy, including rhabdomyolysis, during concomitant therapy, particularly at higher dosages of simvastatin, the manufacturer of simvastatin states that concomitant use of simvastatin with potent inhibitors of cytochrome P-450 isoenzyme 3A4 (CYP3A4) (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, clarithromycin, erythromycin, telithromycin, nefazodone, cobicistat-containing preparations), cyclosporine, danazol, or gemfibrozil is contraindicated. The manufacturer states that consumption of grapefruit juice should be avoided. In patients receiving diltiazem, dronedarone, or verapamil concomitantly with simvastatin, dosage of simvastatin should not exceed 10 mg daily. In patients receiving amiodarone, amlodipine, or ranolazine concomitantly with simvastatin, dosage of simvastatin should not exceed 20 mg daily. In patients with homozygous familial hypercholesterolemia receiving lomitapide, dosage of simvastatin should not exceed 20 mg daily (or 40 mg daily in patients who have been receiving the 80-mg daily dosage of simvastatin for at least 1 year without evidence of adverse muscular effects).

The risk of myopathy appears to be increased among Chinese patients versus non-Chinese patients receiving simvastatin 40 mg daily concomitantly with preparations containing antilipemic dosages (1 g daily or higher) of niacin. The cause of the increased risk of myopathy is not known, and it is not known whether these findings apply to patients of other Asian ancestries. Because of such increased risk, caution is advised when Chinese patients receive simvastatin dosages exceeding 20 mg daily with preparations containing antilipemic dosages of niacin. Because the risk of myopathy is dose related, patients of Chinese descent should avoid concomitant use of simvastatin 80 mg daily with preparations containing antilipemic dosages of niacin.

Combination Oral Therapy

The usual initial dosage of the commercially available fixed-combination preparation (Vytorin) for the management of primary hyperlipidemia or mixed dyslipidemia is 10 or 20 mg of simvastatin and 10 mg of ezetimibe once daily in the evening. Patients requiring reductions in LDL-cholesterol concentrations of more than 55% may receive an initial dosage of 40 mg of simvastatin and 10 mg of ezetimibe once daily in the absence of moderate to severe renal impairment (estimated glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m). Serum lipoprotein concentrations should be determined 2 or more weeks after initiation or titration of therapy, and dosage adjusted as needed. The usual maintenance dosage of simvastatin in fixed combination with ezetimibe is 10-40 mg of simvastatin and 10 mg of ezetimibe daily. Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturer states that patients who have inadequate response to the fixed combination containing 40 mg of simvastatin and 10 mg of ezetimibe should not be titrated to the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe but should be switched to alternative antilipemic agents that provide greater LDL-cholesterol reduction. The manufacturer also states that use of the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of adverse muscular effects.(See Cautions.) Patients currently tolerating the fixed combination containing 80 mg of simvastatin and 10 mg of ezetimibe who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin or statin-based regimen with less drug interaction potential.

The usual dosage of simvastatin in fixed combination with ezetimibe for the management of homozygous familial hypercholesterolemia is 40 mg of simvastatin and 10 mg of ezetimibe once daily in the evening. Simvastatin in fixed combination with ezetimibe should be used as an adjunct to other lipid-lowering treatment (e.g., LDL apheresis) in these patients or as an alternative if such therapy is unavailable.

Because of an increased risk of myopathy, including rhabdomyolysis, during concomitant therapy, particularly at higher dosages of simvastatin, the manufacturer of Vytorin states that concomitant use of this fixed-combination preparation with potent inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, clarithromycin, erythromycin, telithromycin, nefazodone, cobicistat-containing preparations), cyclosporine, danazol, or gemfibrozil is contraindicated. The manufacturer states that consumption of grapefruit juice should be avoided. In patients receiving diltiazem, dronedarone, or verapamil, dosage of the fixed-combination preparation should not exceed 10 mg of simvastatin and 10 mg of ezetimibe daily. In patients receiving amiodarone, amlodipine, or ranolazine, dosage of the fixed-combination preparation should not exceed 20 mg of simvastatin and 10 mg of ezetimibe daily. In patients with homozygous familial hypercholesterolemia receiving lomitapide, dosage of the fixed-combination preparation should not exceed 20 mg of simvastatin and 10 mg of ezetimibe daily (or 40 mg of simvastatin and 10 mg of ezetimibe daily in patients who have been receiving the 80-mg daily dosage of simvastatin for at least 1 year without evidence of adverse muscular effects).

The risk of myopathy appears to be increased among Chinese patients versus non-Chinese patients receiving simvastatin 40 mg daily (alone or in combination with ezetimibe 10 mg daily) concomitantly with preparations containing antilipemic dosages (1 g daily or higher) of niacin. The cause of the increased risk of myopathy is not known, and it is not known whether these findings apply to patients of other Asian ancestries. Because of such increased risk, caution is advised when Chinese patients receive fixed-combinations dosages exceeding 20 mg of simvastatin and 10 mg of ezetimibe daily with preparations containing antilipemic dosages of niacin. Because the risk of myopathy is dose related, patients of Chinese descent should avoid concomitant use of the fixed-combination preparation containing 80 mg of simvastatin and 10 mg of ezetimibe with preparations containing antilipemic dosages of niacin.

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.

Dosage in Renal and Hepatic Impairment

Because simvastatin does not undergo substantial renal excretion, the manufacturer states that modifications of dosage should not be necessary in patients with mild to moderate renal impairment. However, simvastatin should be administered with caution in patients with severe renal impairment, initiating therapy with the drug under close monitoring at a dosage of 5 mg daily. In patients receiving simvastatin in fixed combination with ezetimibe, the manufacturer states that no dosage adjustment is necessary in patients with mild renal impairment (estimated GFR of 60 mL/minute per 1.73 m or greater). However, in patients with chronic kidney disease and an estimated GFR of less than 60 mL/minute per 1.73 m, the dosage of the fixed-combination preparation is 20 mg of simvastatin and 10 mg of ezetimibe once daily in the evening; in such patients, higher dosages should be used with caution and close monitoring.

Because simvastatin is metabolized predominantly in the liver and potentially may accumulate in the plasma of patients with hepatic impairment, the drug should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease. Simvastatin is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Cautions

Simvastatin shares the toxic potentials of other statins, and the usual cautions, precautions, and contraindications associated with these drugs should be observed. Patients should be fully advised about the risks, especially myopathy and rhabdomyolysis, associated with statin therapy alone or combined with other drugs.

Although myopathy, including rhabdomyolysis, is a known adverse effect of all statins, studies have shown that patients receiving higher dosages of simvastatin may be at greater risk of muscle injury than those receiving lower dosages of the drug and possibly other statins. In a clinical trial database of 41,413 patients receiving simvastatin, with approximately 60% of patients enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03 or 0.08% in patients receiving simvastatin 20 or 40 mg daily, respectively. The incidence of myopathy was disproportionately higher in patients receiving simvastatin 80 mg daily (0.61%). In a clinical study (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine [SEARCH]) in which over 12,064 patients with a history of myocardial infarction (MI) were randomized to receive either high- or low-dose simvastatin, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK, creatine phosphokinase, CPK] concentration exceeding 10 times the upper limit of normal [ULN]), after a mean follow-up of 6.7 years, was approximately 0.9 or 0.02% in patients receiving simvastatin 80 or 20 mg daily, respectively. The incidence of rhabdomyolysis (defined as myopathy with a serum CK concentration exceeding 40 times the ULN) was approximately 0.4 or 0% in patients receiving simvastatin 80 or 20 mg daily, respectively. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and notably decreased during subsequent years of treatment. The investigators of the SEARCH trial found a genetic variant (single-nucleotide polymorphism within the SLCOlBl gene on chromosome 12) that was strongly associated with the risk of developing statin-induced myopathy; more than 60% of the cases of myopathy could be attributed to the specific SLCOlBl genetic variant. The SLCO1B1 gene encodes organic anion transporter protein (OATP) 1B1, which has been shown to mediate hepatic uptake of statins.

Because the risk of myopathy, including rhabdomyolysis, is greater with simvastatin 80 mg daily compared with other statin therapies with similar or greater LDL-cholesterol lowering efficacy and compared with lower dosages of simvastatin, the manufacturer states that the 80-mg daily dosage of simvastatin should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of adverse muscular effects.(See Dosage and Administration: Dosage.) Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if adverse muscular effects persist after discontinuance of therapy. If markedly elevated CK concentrations occur or if myopathy is diagnosed or suspected, simvastatin should be discontinued immediately.

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

Pediatric Precautions

Simvastatin has been administered to a limited number of hypercholesterolemic children and adolescents without apparent adverse effects. In a randomized, double-blind, placebo-controlled study in boys and postmenarchal girls 10-17 years of age, the adverse effect profile of simvastatin (10-40 mg daily) generally was similar to that of placebo; dosages exceeding 40 mg daily have not been evaluated in this population. There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. If therapy with simvastatin 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.(See Cautions: Pregnancy, Fertility, and Lactation.) Safety and efficacy of simvastatin have not been evaluated in prepubertal girls or in children younger than 10 years of age.For additional information on the use of statins in pediatric patients,

Use of simvastatin in combination with ezetimibe has been evaluated in a limited number of adolescent boys and girls with heterozygous familial hypercholesterolemia. In a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia, discontinuance of therapy because of adverse effects occurred in more patients receiving simvastatin (10-40 mg daily) in combination with ezetimibe (6%) than in those receiving simvastatin monotherapy (2%); in addition, increases in aminotransferase or CK concentrations also occurred more frequently in patients receiving combination therapy (3 or 2%, respectively) than in those receiving simvastatin monotherapy (2 or 0%, respectively). There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Use of simvastatin dosages exceeding 40 mg daily in combination with ezetimibe has not been evaluated in adolescents; safety and efficacy of simvastatin in fixed combination with ezetimibe have not been evaluated in prepubertal girls or in children younger than 10 years of age.

Geriatric Precautions

Of the 2423 patients receiving simvastatin in phase 3 clinical studies and the 10,269 patients receiving the drug in the Heart Protection Study (HPS), 15 and 52%, respectively, were 65 years of age or older; in HPS, 6% of patients were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients receiving simvastatin alone or in combination with ezetimibe, 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. Results of a pharmacokinetic study in a limited number of patients receiving simvastatin (40 mg daily) indicate that mean plasma levels of HMG-CoA reductase inhibitory activity are approximately 45% higher in geriatric patients (70-78 years of age) than in younger adults (18-30 years of age). In the Scandinavian Simvastatin Survival Study (4S) in which 23% of patients were 65 years of age or older, antilipemic effects of simvastatin in these patients were similar to those in younger patients, and simvastatin substantially reduced total mortality and CHD mortality in geriatric patients with a history of CHD; in this study, there were no overall differences in safety between the 2 groups. In HPS in which 52% of patients were 65 years of age or older, reduction in the risk of CHD death, nonfatal MI, stroke, or coronary or noncoronary revascularization procedures was similar in geriatric patients and in younger patients; of the 7 cases of myopathy/rhabdomyolysis reported among over 10,000 patients randomized to receive simvastatin, 4 occurred in patients 65 years of age or older.

In a clinical trial in which patients received higher dosages (i.e., 80 mg daily) of simvastatin, patients 65 years of age and older had an increased risk of myopathy, including rhabdomyolysis, compared with younger patients. Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be used with caution in geriatric patients. In addition, because geriatric patients frequently have decreased renal function (e.g., glomerular filtration), particular attention should be paid to evaluating renal function prior to initiation of simvastatin and subsequently thereafter in this age group. If evidence of severe renal impairment exists or develops, appropriate adjustments in dosage should be made and the patient closely monitored.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

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.

Mutagenicity and Carcinogenicity

Simvastatin did not exhibit mutagenic potential in vitro in microbial mutagen (Ames) tests with or without rat or mouse liver metabolic activation, the alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, a chromosome aberration study in Chinese hamster ovary cells, or in vivo in a chromosomal aberration assay in mouse bone marrow.

In mice receiving simvastatin dosages of 25, 100, and 400 mg/kg daily (which produced mean plasma drug concentrations approximately equivalent to or 4 and 8 times higher, respectively, than the mean plasma drug concentration observed in humans with a simvastatin dose of 80 mg) for 72 weeks, there was an increased incidence of liver carcinomas in females receiving 400 mg/kg daily and in males receiving 100 and 400 mg/kg daily. The maximum incidence of liver carcinomas was 90% in male mice. An increased incidence of liver adenomas also was observed in female mice receiving 100 and 400 mg/kg daily. The incidence of lung adenomas also was increased in mice receiving 100 and 400 mg/kg daily, regardless of gender, and the incidence of adenomas of the Harderian gland (a gland of the rodent eye) was increased in mice receiving 400 mg/kg daily. A tumorigenic effect was not observed in mice receiving 25 mg/kg daily in this study. In a separate study, no evidence of a tumorigenic effect was observed in mice receiving simvastatin dosages up to 25 mg/kg daily (which produced mean plasma drug concentrations equivalent to those in humans receiving 80 mg daily) for 92 weeks.

An increased incidence of thyroid follicular adenomas was observed in female rats receiving simvastatin for 2 years at dosages that produced plasma drug exposure (as measured by AUC) approximately 11 times higher than that in humans receiving 80 mg daily. Hepatocellular adenomas and carcinomas were observed in female rats receiving simvastatin 50 mg/kg and 100 mg/kg daily (which produced plasma drug exposure [AUC] approximately 22 and 25 times, respectively, those in humans receiving 80 mg daily) and in male rats receiving 100 mg/kg daily (which produced plasma drug exposure approximately 15 times that in humans receiving 80 mg daily) for two years. Rats receiving both dosages also exhibited an increased incidence in thyroid follicular adenomas, regardless of gender, and female rats receiving 100 mg/kg daily exhibited an increased incidence of thyroid follicular cell carcinoma. In male rats, 50 mg/kg daily produced plasma drug exposure approximately 7 times that in humans receiving 80 mg daily.

While early animal studies raised concerns of possible carcinogenic properties of simvastatin, a large body of evidence indicates that long-term statin therapy is not associated with an increased risk of cancer. However, the fixed combination of ezetimibe and simvastatin was reported in one study (Simvastatin and Ezetimibe in Aortic Stenosis [SEAS]) to be possibly associated with an increased risk of cancer. Results of this study in 1873 patients with asymptomatic aortic stenosis revealed a higher incidence of cancer and cancer-related deaths (11.1 and 4.1%, respectively) in patients receiving the fixed-combination preparation compared with those receiving placebo (7.5 and 2.5%, respectively). Findings from the SEAS study prompted FDA to issue an early communication in 2008 about this potential safety risk. However, results of 2 subsequent large randomized studies (the Study of Heart and Renal Protection [SHARP] and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]) found no consistent pattern of increased cancer risk among patients receiving the fixed-combination preparation. Based on the currently available evidence, FDA has concluded that the fixed-combination preparation of ezetimibe and simvastatin (Vytorin) is not likely to increase the risk of cancer.

Pregnancy, Fertility, and Lactation

Pregnancy

Simvastatin was not teratogenic in rats receiving dosages of 25 mg/kg daily (3 times the usual human exposure based on mg/m) or in rabbits receiving dosages up to 10 mg/kg daily (3 times the usual human exposure based on mg/m). However, another structurally related statin has produced skeletal malformations in rats and mice.

There are no adequate and well-controlled studies using simvastatin in pregnant women; however, congenital anomalies have been reported rarely following intrauterine exposure to statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a three- to fourfold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Cholesterol and cholesterol derivatives are essential for normal fetal development. Because statins (e.g., simvastatin) decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, simvastatin may cause fetal harm when administered to a pregnant woman; therefore, the drug is contraindicated in women who are or may become pregnant.

Since atherosclerosis is a chronic process, and discontinuance of antilipemic agents during pregnancy generally should not have a substantial effect on the outcome of long-term therapy for primary hypercholesterolemia, therapy with simvastatin should be immediately discontinued as soon as pregnancy is recognized, and the patient should be informed of the potential hazard to the fetus. Currently, most experts recommend that dyslipidemias in pregnant women be managed with dietary measures; consultation with a lipid specialist is recommended for pregnant women with severe forms of dyslipidemia.

Simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive; these women should be advised to use effective contraception. Women trying to conceive should consider discontinuing simvastatin therapy; if pregnancy occurs, simvastatin should be discontinued immediately, and the patient should be informed of the potential hazard to the fetus.

Fertility

Decreased fertility was observed in male rats receiving simvastatin 25 mg/kg daily (4 times the maximum plasma drug exposure [based on AUC] in humans receiving 80 mg daily) for 34 weeks. This effect was not observed in a subsequent study using the same dosage for 11 weeks (the entire duration of the spermatogenesis cycle in rats, including epididymal maturation). No microscopic changes in the testes were observed in either study. At a simvastatin dosage of 180 mg/kg daily in rats (22 times the plasma drug exposure in humans receiving 80 mg daily on a mg/m basis), seminiferous tubule degeneration was observed. Testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs were observed at a dosage of 10 mg/kg daily (which produced plasma drug exposure approximately 2 times that in humans receiving 80 mg daily). The clinical importance of these effects has not been established.

Lactation

It is not known whether simvastatin is distributed into milk. However, a small amount of another statin is distributed into milk. Because of the potential for serious adverse reactions from simvastatin in nursing infants, the drug is contraindicated in nursing women; women who require simvastatin therapy should not breast-feed their infants. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.