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Introduction ⬇

AHFS Class:

Generic Name(s):

Simvastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statin), is an antilipemic agent.1,2,3,4,5

Uses ⬆ ⬇

[Section Outline]

Reduction in Risk of Cardiovascular Events !!navigator!!

Reducing Progression of Coronary Atherosclerosis (Secondary Prevention)

Simvastatin is used as an adjunct to diet and other lifestyle modifications in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes mellitus, who are at high risk of coronary heart disease (CHD) events; simvastatin is indicated in such patients to reduce the risk of total mortality by reducing CHD deaths, nonfatal myocardial infarction (MI) and stroke, and the need for revascularization procedures.1,132,400

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.1,11,132 In the randomized, multicenter, double-blind, placebo-controlled, Scandinavian Simvastatin Survival Study (4S), therapy with simvastatin (20-40 mg daily) 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%.1,11,68,132 In addition, simvastatin therapy reduced the risk of fatal and nonfatal cerebrovascular events (combined incidence of stroke and TIA) by 28%.1,11,66,68,132 Simvastatin reduced the risk of major coronary events in women by 34% and, compared with younger adults, similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in geriatric patients (≥65 years) were observed.1,132

In the Heart Protection Study (HPS), therapy with simvastatin (40 mg daily) in over 20,000 patients with CHD, history of 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.1,86,132 Substantial risk reductions of 27 and 24% were observed for the composite end points of major coronary events and major vascular events, respectively.1,132 Risk reductions produced by simvastatin were evident irrespective of cardiovascular disease history, gender, age, serum creatinine concentrations, baseline lipoprotein concentrations, concomitant cardiovascular drugs, smoking status, alcohol intake, or obesity.1,132 In addition, patients with diabetes mellitus experienced risk reductions for major coronary events and major vascular events regardless of baseline hemoglobin A1C levels or obesity, with the greatest effects seen for patients without CHD.1,132

In another randomized, double-blind study (A to Z trial) in about 4500 patients who had manifestations of acute coronary syndrome (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.87 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.87 Intensive or moderate antilipemic therapy reduced LDL-cholesterol concentrations to a median of 63 or 77 mg/dL, respectively, at 8 months.87 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.87

Simvastatin has been shown to slow the progression and/or induce regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness.48,51,53 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.51,53

Primary Prevention

Simvastatin also has been used for primary prevention† of atherosclerotic cardiovascular disease (ASCVD).400 When considering whether to initiate statin therapy for primary prevention, the 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400

Chronic kidney disease is a risk-enhancing factor for ASCVD.400 Some studies have found that the cardiovascular risk in patients with chronic kidney disease may be as high as that of patients with diabetes mellitus.400 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.103,308 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.103,308 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 15.2% (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.103,308 The treatment effect was largely driven by a substantial reduction in ischemic strokes and arterial revascularization procedures.308 The subgroup of patients receiving dialysis at baseline experienced a smaller risk reduction (6%) benefit compared with those not receiving dialysis (22%).103,308 In addition, therapy with the fixed-combination preparation did not appear to slow the progression to end-stage renal disease.103,308

Combination Antilipemic Therapy

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),101 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 monotherapy.309 Treatment with the simvastatin and ezetimibe combination resulted in an absolute risk reduction of 2% over 7 years for the primary composite end point.309

Randomized controlled studies do not support the addition of niacin to statin-based therapy.354,400 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).354 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.354 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).371

Clinical Perspective

The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.400,401,402 There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for secondary or primary prevention in high-risk patients.336,337,338,400,401,402

When considering whether to initiate statin therapy for primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk ≥7.5%.400,401

The guideline states that patients with clinical ASCVD (defined as those with ACS, history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack [TIA], or peripheral artery disease [PAD], including those with aortic aneurysm) should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations.400 Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400 The maximum tolerated intensity of a statin should be used to achieve optimum ASCVD benefits.400 AHA/ACC recommends the use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%).400 If high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) may be used.400

Intensity of Statin Therapy

The appropriate intensity of a statin should be used to reduce the risk of ASCVD.400 Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the AHA/ACC guideline panel, simvastatin 20-40 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400 Although simvastatin 80 mg daily was evaluated in randomized controlled studies, this dosage is not recommended by the FDA because of an increased risk of myopathy, including rhabdomyolysis.400

Combination Antilipemic Therapy

The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be useful in patients who experience an inadequate reduction in LDL-cholesterol concentrations despite maximally tolerated statin therapy (e.g., <50% reduction in LDL-cholesterol or LDL-cholesterol concentration ≥55 mg/dL or non-HDL-cholesterol ≥85 mg/dL).400,403 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.400,403

A 2022 consensus decision pathway published by the ACC addresses the use of nonstatin therapies for primary or secondary prevention of ASCVD.403 In patients with primary hypercholesterolemia without ASCVD who require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies due to demonstrated benefits in cardiovascular outcomes.403 If therapeutic goals are not achieved, other nonstatin therapies (e.g., inclisiran, bempedoic acid, evinacumab, lomitapide) may be considered.403

In patients receiving statin therapy as secondary prevention who are at very high risk of ASCVD and require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies.403 In patients receiving statin therapy as secondary prevention who are not at very high risk of ASCVD, ezetimibe is considered the preferred initial nonstatin therapy, followed by addition or replacement with a PCSK9 inhibitor if additional LDL-lowering therapy is needed.403 If therapeutic goals are not achieved in the secondary prevention setting, inclisiran (in place of a PCSK9 inhibitor) or bempedoic acid may be considered.403

A 2022 scientific statement published by the National Lipid Association (NLA) addresses the use of nonstatin therapies for ASCVD risk reduction in patients with statin intolerance.406 Nonstatin LDL-lowering therapy may be considered in patients with complete or partial statin intolerance, including during the course of attempting to identify a tolerable alternate statin regimen in patients with high or very high ASCVD risk.406 When nonstatin therapies are used, agents that have demonstrated cardiovascular outcome benefit in randomized trials are preferred.406

Dyslipidemias !!navigator!!

Simvastatin is used in the management of primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial), mixed (Fredrickson type IIb) dyslipidemia, homozygous familial hypercholesterolemia (HoFH), primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia), and hypertriglyceridemia (Fredrickson type IV hyperlipidemia).1,3,4,132 The efficacy of simvastatin remains to be established in patients with elevated chylomicrons as their primary lipid abnormality (Fredrickson types I and V).132

Primary Hyperlipidemia or Mixed Dyslipidemia

Simvastatin is used alone or in combination with ezetimibe as an adjunct to nondrug therapies (e.g., diet) in adults to decrease elevated serum total and LDL-cholesterol, apo B, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).1,3,4,89,103,132

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.19,20,21,22,23,24,27,28,29,30,31,32,74 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.1,19,20,21,22,23,24,84,132 Modest and variable increases in HDL-cholesterol concentrations (5-16%) also were observed in these patients.1,19,20,22,23,24,132

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).27,28,30,31,72,73 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),72 lovastatin 20-40 mg daily (21-23 and 29-31%, respectively),30 or pravastatin 10-40 mg daily (13-24 and 19-34%, respectively).29,30,32 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.32 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.37 Limited data indicate that reductions in LDL-cholesterol concentrations may be similar among patients receiving high-dose simvastatin and atorvastatin (80 mg daily).82

Increases in HDL-cholesterol concentrations appear to be greater among simvastatin- than atorvastatin-treated patients.65,82,83 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.65,82,83 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).65,83

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).38,39,40,43,44,45 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).43,45 Simvastatin also was more effective than cholestyramine in improving triglyceride (21% reduction versus 11% increase) and HDL-cholesterol concentrations (16% versus 9% increase).43,45 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.38,39,40,41,44 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);38,39,44 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).38,39,44 Similar results have been reported with other fibric acid derivatives (e.g., fenofibrate).40,41,42

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.43,46,89,103,309 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.43 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%.46

Simvastatin/Ezetimibe

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.89 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).103 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).103

Homozygous Familial Hypercholesterolemia

Simvastatin is used alone or in combination with ezetimibe to decrease elevated serum total and LDL-cholesterol concentrations in adult patients with HoFH as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1,89,103,132 In an open-label clinical trial in a limited number of patients with HoFH receiving simvastatin 40-80 mg daily, LDL-cholesterol concentrations were reduced by 8-46% in most patients; however, at least one patient experienced increases (15%) in LDL-cholesterol concentrations with simvastatin therapy.1,70,132

Simvastatin/Ezetimibe

Efficacy and safety of ezetimibe combined with simvastatin or atorvastatin for the management of HoFH were established in a randomized, double-blind study of 12 weeks' duration.89,103,504 The study included a limited number of patients with a clinical and/or genotypic diagnosis of HoFH who were already receiving simvastatin (40 mg daily) or atorvastatin (40 mg daily), with or without concomitant LDL apheresis.89,103,504 Patients were randomized to receive 1 of 3 regimens: simvastatin (80 mg daily) or atorvastatin (80 mg daily) monotherapy; ezetimibe (10 mg daily) with either simvastatin (40 mg daily) or atorvastatin (40 mg daily); or ezetimibe (10 mg daily) with either simvastatin (80 mg daily) or atorvastatin (80 mg daily).504 The addition of ezetimibe (10 mg daily) to simvastatin (40 or 80 mg daily) or atorvastatin (40 or 80 mg daily) was more effective in reducing LDL-cholesterol concentrations (21% additional reduction based on pooled data from 40- and 80-mg 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 groups).89,504

In a subgroup of 14 patients receiving simvastatin 40 mg at baseline, LDL-cholesterol was reduced by 13% from baseline in those who increased to simvastatin 80 mg compared with a reduction of 23% from baseline in those converted to ezetimibe (10 mg) and simvastatin (40 or 80 mg).103 A 29% reduction in LDL-cholesterol from baseline was observed in those converted from simvastatin 40 mg to ezetimibe 10 mg and simvastatin 80 mg (equivalent to Vytorin® 10/80 mg).103

In the group of patients receiving higher dosages (80 mg daily) of either simvastatin or atorvastatin in combination with ezetimibe (10 mg daily), LDL-cholesterol concentrations were reduced by approximately 27% compared with a 7% reduction with statin monotherapy.89,504 Comparable reductions in LDL-cholesterol concentrations were observed in the subgroup of patients with genotype-confirmed HoFH.504

Beneficial effects of ezetimibe combined with simvastatin or atorvastatin in patients with HoFH who currently are undergoing LDL apheresis compared with the effects in patients not undergoing the procedure have not been established.504 Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) also have not been established.504

Primary Dysbetalipoproteinemia

Simvastatin is used as an adjunct to diet to decrease elevated serum triglyceride and VLDL-cholesterol concentrations in adults with primary dysbetalipoproteinemia (Fredrickson type III).1,132

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.1,132 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.1,79,80,81,132 Simvastatin 20 mg daily reportedly has produced greater reductions in LDL-cholesterol than gemfibrozil 1200 mg daily in patients with primary dysbetalipoproteinemia.71 However, reductions in triglyceride concentrations and increases in HDL-cholesterol concentrations were less pronounced than those reported with usual dosages of gemfibrozil.71

Hypertriglyceridemia

Simvastatin is used as an adjunct to diet to decrease elevated serum triglyceride concentrations in the treatment of adults with hypertriglyceridemia (Fredrickson type IV hyperlipidemia).1,132

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 simvastatin 40-80 mg daily.132

In another double-blind, placebo-controlled study, 195 adults with fasting serum triglyceride levels between 300 and 900 mg/dL were randomized to 4 treatment groups (placebo or simvastatin 20-, 40-, or 80 mg/day).383 In this study, triglyceride, LDL-cholesterol, and non-HDL-cholesterol levels were significantly reduced across all doses compared to placebo.383 Approximately 60% of enrolled patients had LDL-cholesterol levels <130 mg/dL and were classified as having type IV hyperlipidemia.383 In this subgroup analysis, triglyceride and LDL-cholesterol levels were reduced by approximately 20-33% and 25-35%, respectively, in patients receiving simvastatin 40-80 mg/day.383

Adolescent Patients with Heterozygous Familial Hypercholesterolemia

Simvastatin also is used alone or in combination with ezetimibe as an adjunct to diet to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the treatment of heterozygous familial hypercholesterolemia (HeFH) 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 ≥190 mg/dL or a serum LDL-cholesterol concentration ≥160 mg/dL and either a family history of premature cardiovascular disease or 2 or more other cardiovascular disease risk factors.1,89,103,132 The long-term effect of simvastatin therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has not been established.1,132

Efficacy and safety of simvastatin for this use have been established in a double-blind, placebo-controlled study.1,132 In this study, 175 pediatric patients ≥10 years of age (girls were post-menarchal) with HeFH were randomized to receive simvastatin or placebo once daily.132 Patients were required to have an elevated LDL-cholesterol (160-400 mg/dL) and at least one parent with an LDL-cholesterol level >189 mg/dL.1,132 Mean baseline LDL-cholesterol was 204 and 212 mg/dL in the simvastatin and placebo groups, respectively.1,132 Simvastatin dosage (administered once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter for 24 weeks.1,132 Simvastatin significantly decreased plasma LDL-cholesterol, total cholesterol, and apo B levels by 37, 27, and 32%, respectively; similar results were observed in the 24-week extension study.1,132 The mean achieved LDL-cholesterol was approximately 125 mg/dL in the simvastatin group compared to 208 mg/dL in the placebo group.132

Simvastatin/Ezetimibe

Efficacy and safety of simvastatin in combination with ezetimibe have been established in a double-blind, controlled study followed by an open-label phase.103 In this study, males and postmenarchal females 10-17 years of age with HeFH were randomized to receive ezetimibe coadministered with simvastatin (ezetimibe/simvastatin ) or simvastatin monotherapy.89,103 Patients were required to have an elevated LDL-cholesterol (160-400 mg/dL) and a medical history and clinical presentation consistent with HeFH.89,103 Mean baseline LDL-cholesterol was 225 and 219 mg/dL in the ezetimibe/simvastatin and simvastatin monotherapy groups, respectively.89,103 Patients received ezetimibe plus simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, followed by ezetimibe plus simvastatin 40 mg or simvastatin 40 mg monotherapy for the next 27 weeks (2nd double-blind phase), followed by open-label ezetimibe plus simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.89,103 Simvastatin with coadministered ezetimibe (all dosages pooled) significantly decreased plasma LDL-cholesterol, total cholesterol, and apo B levels by 15, 12, and 12%, respectively, compared to simvastatin monotherapy (all dosages pooled) at the end of 6 weeks.89,103 At the end of the 2nd double-blind phase (week 33), mean LDL-cholesterol reductions of 54 and 38% were observed in the ezetimibe/simvastatin and simvastatin monotherapy groups, respectively.505

Clinical Perspective

Elevated serum cholesterol, especially the LDL-cholesterol fraction, is a major cause of clinical ASCVD; other major risk factors include cigarette smoking, hypertension, diabetes, age, HeFH, chronic kidney disease (eGFR 15-59 mL/minute per 1.73 m2), history of heart failure, and other lipoprotein abnormalities.400,403 Therefore, the goal of antilipemic therapy in patients with hyperlipidemia is to reduce the risk of ASCVD.400 Clinical studies have demonstrated that simvastatin 20-40 mg daily is considered to be a moderate-intensity statin, producing approximate LDL-cholesterol reductions of 30-49% when used alone.400 The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended.400,402

When considering whether to initiate statin therapy for dyslipidemia in the setting of primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher.400,401

There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for such patients.336,337,338,400,401,402,403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400,401,402

Combination Antilipemic Therapy

An ACC expert committee update on nonstatin drug therapies recommends that adults without clinical ASCVD with baseline LDL-cholesterol concentrations greater than 190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 inhibitor if they have not met certain thresholds of LDL-cholesterol reduction on maximally tolerated statin therapy for primary prevention (e.g., at least 50% reduction in LDL-cholesterol with an LDL-cholesterol <100 mg/dL or a non-HDL-cholesterol concentration <130 mg/dL).403 Individuals with LDL- cholesterol concentrations greater than 190 mg/dL are more likely to have genetic disorders associated with hypercholesterolemia, such as HeFH or HoFH.403 Current treatments for patients with familial hypercholesterolemia include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran) among other options.403

Hypertriglyceridemia

Patients with moderate or severe hypertriglyceridemia (fasting or non-fasting triglyceride levels 175-499 mg/dL or fasting levels ≥500 mg/dL, respectively) generally are at increased risk of ASCVD and pancreatitis (especially in patients with fasting levels ≥500 mg/dL).400,403 The AHA/ACC cholesterol management guideline recommends assessment and modification of lifestyle (obesity and metabolic syndrome), secondary disorders (e.g., diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.400 Initiation or intensification of statin therapy may be considered in adults 40-75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of ≥7.5%.400 Experts state statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes from triggering acute hypertriglyceridemic pancreatitis.400

Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extreme elevations of serum LDL-cholesterol concentrations (often in excess of 400-500 mg/dL).407,408 Such extreme elevations, when left untreated, can lead to premature ASCVD as early as childhood; management of the condition requires referral to a lipid specialist and is focused on the aggressive reduction of LDL-cholesterol concentrations to slow ASCVD development.407,408 The treatment of HoFH often requires the use of multiple therapies, including pharmacologic and non-pharmacologic approaches, to reduce LDL-cholesterol concentrations.408 Current treatments for patients with HoFH include dietary lifestyle modifications with maximally tolerated dosages of high-intensity statins, ezetimibe, and PCSK9 inhibitors.403,408,409 In patients with HoFH who do not achieve target reductions in LDL-cholesterol levels, other options such as evinacumab and lomitapide can be added to therapy with or without lipoprotein apheresis.408,409

Pediatric Patients

In addition to early identification of children with familial hypercholesterolemia (FH), dietary (e.g., caloric restriction, Mediterranean-style diet) and lifestyle modification (e.g., physical activity) are prioritized for the management of hypercholesterolemia in children and adolescents.400,404 Evidence from randomized controlled trials, coupled with the increased risk of cardiovascular disease in untreated severe hypercholesterolemia, support the use of statins in children and adolescents at ages ≥10 years who have FH.400

In children and adolescents ≥10 years of age with an LDL-cholesterol level persistently ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with FH and who do not respond adequately with 3-6 months of lifestyle therapy, experts state it is reasonable to initiate statin therapy.400 Experts state that statins may be considered as early as at 8 years of age in the presence of concerning family history, extremely elevated LDL-cholesterol level, or elevated lipoprotein (a) and in the context of informed shared decision-making and counseling with the patient and family.400,404 Treatment intensity should be based on the severity of the hypercholesterolemia and should incorporate patient/family preference; some experts recommend initiation at the lowest recommended dose and up-titration according to the LDL-cholesterol lowering response and tolerability.400,404 Some experts recommend a target LDL-cholesterol level <130 mg/dL or ≥50% reduction from pre-treatment levels, particularly in those with high-risk conditions or other major risk factors; combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe) may be required.404

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Administration !!navigator!!

Simvastatin is administered orally (as tablets or oral suspension) in the evening.1,2,3,4,132 The tablets may be administered without regard to meals.1 The oral suspension should be administered on an empty stomach.132 The fixed-combination preparation containing simvastatin and ezetimibe is administered orally as tablets in the evening without regard to meals.103

If a dose of simvastatin tablets or the fixed-combination preparation containing simvastatin and ezetimibe is missed, the missed dose may be administered as soon as possible; do not double the next dose.1,103

If the oral suspension is used, shake the bottle well for at least 20 seconds before measuring the dose with an accurate measuring device; do not use a household teaspoon.132 The 8 mg/mL (40 mg/5 mL) preparation is recommended for doses ≥ 40 mg.132

Store simvastatin tablets at 5-30°C.1

Store the commercially available oral suspension at 20-25°C; do not freeze or refrigerate.132 The oral suspension should be protected from heat and used within 30 days of opening.132

Store the fixed-combination preparation containing simvastatin and ezetimibe in well-closed containers at 20-25°C.103

Dosage !!navigator!!

Reduction in Risk of Cardiovascular Events

The manufacturers state that the usual dosage range of simvastatin in adults is 5-40 mg daily.1,132

Some manufacturers state that the recommended usual initial dosage of simvastatin in adults is 10 or 20 mg once daily in the evening.132 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.1,132

Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis,87,95,96 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.1,132 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.1,132 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.1,132

The AHA/ACC cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce the risk of ASCVD.400 The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) should be used.400 The AHA/ACC guideline panel considers simvastatin 20-40 mg daily to be a moderate-intensity statin.400 Although simvastatin 80 mg daily was evaluated in randomized controlled studies, this dosage is not recommended by the FDA because of increased risk of myopathy, including rhabdomyolysis.400

Dyslipidemias

Adult Dosage

The usual dosage range of simvastatin is 5-40 mg once daily in the evening for the treatment of adults with primary hyperlipidemia.1,132 Some manufacturers suggest the usual initial dosage of simvastatin in adults is 10 or 20 mg once daily in the evening.1 In patients with CHD or a high risk for CHD (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease), the recommended initial dosage of simvastatin is 40 mg daily.132 The maximum recommended dosage of simvastatin is 40 mg once daily.1,132 Because higher dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis,87,95,96 particularly during the first year of treatment, the manufacturers state 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 an alternative LDL-lowering treatment.1,132 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 muscle toxicity.1,132 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.1

In patients with homozygous familial hypercholesterolemia (HoFH), the recommended dosage of simvastatin is 40 mg daily in the evening.1,132 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.1,132

The recommended dosage range of the commercially available fixed-combination preparation (Vytorin® and generic equivalents) for the management of primary hyperlipidemia, mixed dyslipidemia, or HoFH in adults is 10-40 mg of simvastatin and 10 mg of ezetimibe daily.103 Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis,87,95,96 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.103 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.103 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.103

Pediatric Dosage

The recommended initial dosage of simvastatin for the treatment of heterozygous familial hypercholesterolemia (HeFH) in boys and postmenarchal girls 10-17 years of age is 10 mg once daily in the evening.132 The recommended dosage range of simvastatin is 10-40 mg daily.1,132 Dosage adjustments should be made at intervals of 4 weeks or longer.132 The maximum recommended dosage of simvastatin in children and adolescents 10-17 years of age is 40 mg daily.132

The recommended dosage range of the commercially available fixed-combination preparation (Vytorin® and generic equivalents) for the treatment of pediatric patients ≥10 years of age with HeFH is 10-40 mg of simvastatin and 10 mg of ezetimibe daily.103

Dosage Modification for Concomitant Therapy

Simvastatin

In patients receiving verapamil, diltiazem, or dronedarone concomitantly with simvastatin, dosage of simvastatin should not exceed 10 mg daily.1,132 In patients receiving amiodarone, amlodipine, or ranolazine concomitantly with simvastatin, dosage of simvastatin should not exceed 20 mg daily.1,132

When lomitapide is being initiated, reduce the simvastatin dosage by 50%.1,132 Simvastatin dosage should not exceed 20 mg daily (or 40 mg daily in patients who have received the 80-mg daily dosage for at least 12 months without evidence of adverse muscular effects).1,132

Simvastatin/Ezetimibe Fixed-Combination

In patients receiving verapamil, diltiazem, or dronedarone concomitantly with simvastatin in fixed combination with ezetimibe, dosage of this preparation should not exceed 10 mg of simvastatin and 10 mg of ezetimibe once daily.103 In patients receiving amiodarone, amlodipine, or ranolazine concomitantly with simvastatin in fixed combination with ezetimibe, dosage of this preparation should not exceed 20 mg of simvastatin and 10 mg of ezetimibe once daily.103

When lomitapide is being initiated, reduce the dosage of simvastatin in fixed combination with ezetimibe by 50%.103 Dosage of this preparation should not exceed 20 mg of simvastatin and 10 mg of ezetimibe once daily (or 40 mg of simvastatin and 10 mg of ezetimibe in patients who have received the 80 mg of simvastatin and 10 mg of ezetimibe dosage for at least 12 months without evidence of adverse muscular effects).103

Special Populations !!navigator!!

Hepatic Impairment

Simvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1,103,132 Simvastatin is contraindicated in patients with active liver disease, acute liver failure, decompensated cirrhosis, or unexplained, persistent increases in serum aminotransferase concentrations.1,16,103,132

Renal 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.1,132 However, simvastatin should be administered with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/minute), initiating therapy with the drug under close monitoring at a dosage of 5 mg daily.1,132

In patients receiving simvastatin in fixed combination with ezetimibe, the manufacturer states that no dosage adjustment is necessary in patients with mild renal impairment.103 However, in patients with moderate to severe renal impairment, 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.103

Geriatric Patients

The manufacturers make no specific simvastatin or simvastatin in fixed combination with ezetimibe dosage recommendations at this time.1,103,132 Dose selection in geriatric patients (≥65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.1,103,132

Monitor geriatric patients for the increased risk of myopathy.1,103,132

Pharmacogenomic Considerations in Dosing

Patients with solute carrier organic anion transporter (SLCO) 1B1 decreased or possible decreased function phenotypes will have increased simvastatin exposure compared to those with normal function, which may increase the risk of statin-associated musculoskeletal symptoms.500 In such patients, limit simvastatin dosage to <20 mg per day; the risk of musculoskeletal symptoms is high with daily dosages of 20 mg or higher500

Patients with SLCO1B1 poor function phenotypes will have increased simvastatin exposure compared to those with normal and decreased function, which may increase the risk of statin-associated musculoskeletal symptoms.500 In such patients, an alternative statin is recommended.500

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Musculoskeletal Effects

Myopathy manifested as muscle pain, tenderness, or weakness associated with elevated creatine kinase and rhabdomyolysis with acute renal injury secondary to myoglobinuria have been reported in patients receiving statins, including simvastatin; rare fatalities have occurred.1,132

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.1,87,95,96,99,132 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.1,103,132 The incidence of myopathy was disproportionately higher in patients receiving simvastatin 80 mg daily (0.61%).1,132 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,95,98,99,100 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.1,132 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.1,103,132 The incidence of myopathy, including rhabdomyolysis, was highest during the first year and notably decreased during subsequent years of treatment.1,103,132 The investigators of the SEARCH trial found a genetic variant (single-nucleotide polymorphism within the SLCO1B1 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 SLCO1B1 genetic variant.97,99 The SLCO1B1 gene encodes organic anion transporter protein (OATP) 1B1, which has been shown to mediate hepatic uptake of statins.97,99,500

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.1,132 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.1,132

In addition to higher simvastatin dosage, other predisposing factors for myopathy include advanced age (≥65 years of age), concomitant use of statins with certain other drugs (including other lipid-lowering drugs), and in patients with renal impairment, and uncontrolled hypothyroidism; Chinese patients receiving simvastatin and concomitant lipid-modifying doses of niacin (≥ 1 g/day) may also be at higher risk.1,132 Simvastatin is contraindicated in patients also receiving concomitant strong CYP3A4 inhibitors (select azole antifungals, macrolide antibiotics, antiviral medications, and nefazodone), cyclosporine, danazol, or gemfibrozil.1,132 Interruption of simvastatin therapy and/or dosage modification may be required when used concomitantly with drugs that may increase simvastatin levels (e.g., macrolide antibiotics, amiodarone, dronedarone, calcium channel blocking agents, ranolazine) and/or increase the risk of myopathy (e.g., colchicine, other fibrates, niacin ≥ 1 g/day); the benefits of concomitant use should be carefully weighed against the potential risks.1,132

The AHA/ACC cholesterol management guideline recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.400

Simvastatin should be discontinued immediately if markedly elevated CK concentrations occur or if myopathy is diagnosed or suspected.1,132 Simvastatin therapy should be temporarily withheld in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, shock or hypotension, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures).1,132

Patients should be fully advised about the risks, especially myopathy and rhabdomyolysis, associated with statin therapy alone or combined with other drugs, especially patients receiving an 80 mg daily dosage of simvastatin.1,91,92,93,132

Patients of Chinese Background

An increased risk of myopathy was observed in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product in an ongoing, double-blind, randomized, cardiovascular outcomes trial.1,132 Concomitant use of simvastatin with lipid-modifying doses of niacin (≥1 g/day) is not recommended in Chinese patients.1

If the benefits of combined use of such drugs outweighs the increased risk of myopathy and rhabdomyolysis, caution should be used when treating Chinese patients with simvastatin in dosages exceeding 20 mg/day coadministered with lipid-modifying doses (≥1 g/day) of niacin-containing products.1,132 Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.132 It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses (≥1 g/day) of niacin-containing products observed in Chinese patients applies to other Asian patients.132

Immune-Mediated Necrotizing Myopathy

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins, including reports of recurrence when the same or a different statin was administered.1,132 The condition is characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement following therapy with immunosuppressive agents.1,132 Additional neuromuscular and serologic testing may be necessary and treatment with immunosuppressive agents may be required in patients who develop IMNM.1,132

Discontinue simvastatin if IMNM is suspected.1 The risk of IMNM should be considered carefully prior to initiating therapy with another statin, and patients should be monitored for signs and symptoms.132

Hepatic Effects

Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including simvastatin.1,132 In most cases, the elevations appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy.1,132 Persistent increases to more than 3 times the ULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical trials.1,132 Marked persistent increases of hepatic transaminases have also occurred with simvastatin.1

Consider liver enzyme tests prior to simvastatin initiation and repeat as clinically indicated.1,132 Serious statin-related liver injury is rare and unpredictable in individual patients, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious statin-related liver injury.200 The AHA/ACC 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, routine monitoring is not recommended.200,400 Because ALT may emanate from muscle, concurrent increases in ALT and CK concentrations may indicate myopathy.132

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin.1,132 If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, simvastatin therapy should be promptly discontinued.1,132 If an alternate etiology is not found, simvastatin therapy should not be restarted.132

Patients who consume substantial amounts of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.1,132 Simvastatin is contraindicated in patients with acute liver failure, active liver disease, including unexplained persistent elevations in hepatic transaminase levels, or decompensated cirrhosis.1,103,132

Hyperglycemic Effects

Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including simvastatin.1,132,200

Data from meta-analyses and clinical trials with other statins indicate that statin therapy may increase the risk of developing diabetes mellitus.200 AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus but because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.400

Use of Fixed Combinations

When used in fixed combination with ezetimibe, consider the cautions, precautions, and contraindications associated with ezetimibe.103

Specific Populations

Pregnancy

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit.405 This determination was based on several factors including safety signals from animal data.405 No evidence of maternal toxicity or embryolethality was seen in pregnant rats orally administered simvastatin from gestation days 6 through lactation day 21 at doses that resulted in 0.6-2.5 times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2); slight decreases in maternal and offspring body weight gain were observed.1 No evidence of maternal toxicity or embryolethality was seen in pregnant rabbits orally administered simvastatin from gestation days 6-18 at doses that resulted in 0.5-2 times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2).1 In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester.400 Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm.405 More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.405 The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.405 While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.400,405 The FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects.405 Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.405 While the FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with HoFH or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits.400,402,405 Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.405

Lactation

It is not known whether simvastatin is distributed into human milk.1,132 However, a small amount of another statin is distributed into human milk.1,132 Because of the potential for serious adverse reactions from simvastatin in nursing infants, breastfeeding is not recommended during treatment.1,132 Many patients can stop statin therapy temporarily until breastfeeding is complete; patients who require ongoing statin treatment should not breastfeed and should use alternatives such as infant formula.400,402,405

Females and Males of Reproductive Potential

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.1,132 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).1,132 No microscopic changes in the testes were observed in either study.1,132 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/m2 basis), seminiferous tubule degeneration was observed.1,132 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).1,132 The clinical importance of these effects has not been established.1,132

The 2018 AHA/ACC cholesterol management guideline recommends that women (including adolescents) of childbearing age who are sexually active should be counseled to use a reliable form of contraception.132,400

Pediatric Use

Safety and effectiveness of simvastatin in pediatric patients with heterozygous familial hypercholesterolemia (HeFH), as an adjunct to diet to reduce LDL-cholesterol, have been established in a randomized, double-blind, placebo-controlled study in boys and postmenarchal girls 10-17 years of age.1,132 The adverse effect profile of simvastatin was similar to that of placebo; dosages exceeding 40 mg daily have not been evaluated in this population.1,132 There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls.1,132 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.1,132 The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.1,132 Safety and efficacy of simvastatin have not been evaluated in prepubertal girls, or in children younger than 10 years of age or with types of hyperlipidemia other than HeFH.1,132

Safety and effectiveness of simvastatin in combination with ezetimibe in pediatric patients with HeFH have been established in a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age.103 There was no significant effect on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls.103 Safety and efficacy of simvastatin in fixed combination with ezetimibe have not been evaluated in children younger than 10 years of age or in pediatric patients with other types of hyperlipidemia.103

Geriatric Use

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.1,132 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.1,132 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).1,132 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.1,132 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.1,132

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.1,132 Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be used with caution in geriatric patients.1,132 Cautious dosage selection of simvastatin is recommended in geriatric patients, whether used alone or in combination with ezetimibe.1,103

Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400

Hepatic Impairment

Simvastatin alone or in combination with ezetimibe should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1,103,132 Simvastatin alone or in combination with ezetimibe is contraindicated in patients with active liver disease, acute liver failure, decompensated cirrhosis, or unexplained, persistent increases in serum aminotransferase concentrations.1,103,132

Renal Impairment

Simvastatin does not undergo significant renal excretion; however, renal impairment is a risk factor for myopathy and rhabdomyolysis and patients should be monitored for adverse musculoskeletal effects.1,103,132

Simvastatin should be administered with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/minute), initiating therapy with the drug under close monitoring at a dosage of 5 mg daily.1,132

In patients with moderate to severe renal impairment (dialysis and nondialysis patients) receiving simvastatin 20 mg/ezetimibe 10 mg in fixed combination, the incidence of certain adverse effects (serious adverse effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.103 When used in combination with ezetimibe, doses exceeding 20 mg of simvastatin with 10 mg of ezetimibe should be used with caution in patients with moderate to severe renal impairment; closely monitor patients.103

Pharmacogenomic Considerations

Patients with solute carrier organic anion transporter (SLCO) 1B1 decreased or possible decreased function phenotypes or poor function phenotypes will have increased simvastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms.97,99,372,373,374,381,500,500 Dosage should be limited to <20 mg/day in patients with decreased or possible decreased function phenotypes and an alternative statin is recommended in those with poor function phenotypes.500

Patients with a specific genetic variant of SLCO1B1 (rs4149056T>C) are likely to have increased systemic exposure to simvastatin and increased risk of muscle toxicity.372 These individuals include those with 2 reduced-function alleles at rs4149056 (CC genotype) and those with 1 reduced-function allele plus 1 normal-function allele at rs4149056 (TC genotype).372 The limitations of SLCO1B1 genotyping should be considered when interpreting and applying the results of these tests.372

Genetic variation in the solute carrier organic anion transporter (SLCO) family member (SLCO1B1), ABCG2 (also known as breast cancer resistance protein [BCRP]), and CYP2C9 genes alter systemic exposure to statins (i.e., lovastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin), which can increase the risk for statin-associated musculoskeletal symptoms.500 SLCO1B1 encodes a transporter (SLCO1B1; alternative names include organic ion transporter protein [OATP] 1B1 or OATP-C) that facilitates the hepatic uptake of all statins.500 ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin and CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins (e.g., fluvastatin).500

Patients with SLCO1B1 decreased or possible decreased function phenotypes will have increased simvastatin exposure compared to those with normal function which may increase the risk of statin-associated musculoskeletal symptoms.500 In such patients, based on pharmacokinetic data, limit simvastatin dosage to <20 mg per day; the risk of musculoskeletal symptoms is high with daily dosages of 20 mg or higher.500 Patients with SLCO1B1 poor function phenotypes will have increased simvastatin exposure compared to those with normal and decreased function which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 In such patients, an alternative statin is recommended due to the highly increased risk of musculoskeletal symptoms.500

In patients with phenotypes that result in increased statin exposure, the potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions) must also be considered.500 Experts state that given the balance of statin-associated musculoskeletal symptoms risk versus known cardiovascular disease benefit, for patients who are candidates for new statin therapy, pharmacogenetic test results may provide additional useful information.500

Pharmacogenetic test results may be used as the basis for changing to another statin type or dose for patients currently prescribed statin therapy, depending on how long the patient has been tolerating the statin.500 Experts state statin therapy should neither be discontinued nor avoided based on SLCO1B1, ABCG2, or CYP2C9 genotype results for patients with an indication for statin therapy, especially if the statin therapy is based on the shared decision making between patient and provider.500

There are no data available regarding SLCO1B1 genotype effects on statin response or myopathy in pediatric patients.500 The impact of the SLCO1B1 variant rs4149056 SNV, the most common and well-studied variant, may affect simvastatin disposition more in children compared with adults.500

Common Adverse Effects !!navigator!!

Simvastatin: Adverse effects reported in ≥5% of patients include upper respiratory tract infection, headache, abdominal pain, constipation, and nausea.1,132

Simvastatin/ezetimibe: Adverse effects reported in ≥2% of patients, and greater than placebo, in clinical trials include headache, increased alanine aminotransferase, myalgia, upper respiratory tract infection, and diarrhea.103

Drug Interactions ⬆ ⬇

[Section Outline]

When simvastatin is used in fixed combination with ezetimibe, drug interactions associated with ezetimibe should be considered.103

Simvastatin is metabolized by cytochrome P-450 isoenzyme (CYP) 3A4, but has no CYP3A4 inhibitory activity.1,132 Simvastatin is a substrate of P-glycoprotein (P-gp) and organic anion transporter protein (OATP) 1B1.1,132,339,381,501,502

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes !!navigator!!

Simvastatin is metabolized by CYP3A4.1,132 Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cobicistat-containing drugs) can increase plasma simvastatin concentrations and increase the risk of myopathy.1,132 Concomitant use of simvastatin and strong CYP3A4 inhibitors is therefore contraindicated.1,132 If short-term therapy with a strong CYP3A4 inhibitor is unavoidable, simvastatin therapy must be suspended during the course of treatment.1,132

Simvastatin does not inhibit CYP3A4 and is not expected to alter plasma concentrations of drugs metabolized by CYP3A4.1,132

Drugs Affecting or Affected by Transport Systems !!navigator!!

Simvastatin acid is a substrate of the organic anion transport protein (OATP) 1B1.1,132,372 Drugs that inhibit OATP1B1 (e.g., cyclosporine) may increase plasma concentrations of simvastatin acid and increase the risk of myopathy.1,132,339

Simvastatin is also a substrate of P-gp; concomitant administration of simvastatin with drugs that inhibit P-gp may increase drug exposure and increase the risk of statin-induced toxicity (e.g., myopathy).339,501,502

Other Lipid-lowering Drugs !!navigator!!

The risk of simvastatin-induced myopathy is increased by other lipid-lowering drugs (e.g., gemfibrozil, other fibrates) that are not strong CYP3A4 inhibitors, but which can also cause myopathy when used alone.1,132,339 Combined use of gemfibrozil and simvastatin is contraindicated.1,132 Caution should be used if simvastatin is administered with other fibrates or niacin (dosage ≥1 g/day).1,132 Experts state it is safer to use fenofibrate than gemfibrozil because of a lower risk of severe myopathy.400 The benefit of further alterations in lipid levels by the combined use of simvastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.1,132

Amiodarone !!navigator!!

Concomitant use of simvastatin and amiodarone can increase plasma concentrations of simvastatin and increase the risk of myopathy and/or rhabdomyolysis, particularly when higher dosages of simvastatin are used.1,91,92,93,132,339

Concomitant administration of simvastatin 40 mg on day 3 of amiodarone 400 mg once a day for 3 days resulted in an increase in simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (75 and 76% and 72 and 79%, respectively).1,132

The benefits versus risks of such concomitant therapy should be considered.1,132 If used concomitantly with amiodarone, simvastatin dosage should not exceed 20 mg daily.1,132

Antifungals, Azoles !!navigator!!

Azole antifungal drugs (e.g., itraconazole, ketoconazole, posaconazole, voriconazole) are strong CYP3A4 inhibitors that can increase the risk of myopathy by reducing the elimination of simvastatin.1,132

Concomitant administration of simvastatin 80 mg with itraconazole 200 mg once daily for 4 days resulted in substantially increased (13.1-fold) simvastatin acid and simvastatin peak plasma concentration mean ratios.1,132 Concomitant administration of simvastatin 40 mg with posaconazole 100 mg (oral suspension) once daily for 13 days resulted in substantially increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (7.3- and 10.3-fold and 9.2- and 9.4-fold), respectively.132 Concomitant administration of simvastatin 40 mg with posaconazole 200 mg (oral suspension) once daily for 13 days also resulted in substantially increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (8.5- and 10.6-fold and 9.5- and 11.4-fold), respectively.1,132 Similar results are expected with coadministration of simvastatin and ketoconazole.1,132

Concomitant use of simvastatin and itraconazole, ketoconazole, posaconazole, or voriconazole is contraindicated.1,132 If therapy with an azole antifungal is unavoidable, interrupt simvastatin therapy during antifungal treatment.1,132

Calcium-channel Blocking Agents !!navigator!!

Concomitant use of simvastatin and certain calcium-channel blocking agents (amlodipine, diltiazem, verapamil) can increase plasma concentrations of simvastatin and increase the risk of myopathy and/or rhabdomyolysis, particularly when higher dosages of simvastatin are used.1,132

Concomitant administration of simvastatin 80 mg on day 10 of verapamil SR 240 mg once daily for days 1-7 and 240 mg two times day on days 8-10 resulted in increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (2.3- and 2.5-fold and 2.4- and 2.1-fold, respectively).1,132 Concomitant administration of simvastatin 80 mg on day 10 of diltiazem 120 mg two times a day for 10 days resulted in increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (2.69- and 3.1-fold and 2.69- and 2.88-fold, respectively).1,132

Concomitant administration of simvastatin 20 mg on day 14 of diltiazem 120 mg two times a day for 14 days also resulted in increased simvastatin AUC and peak plasma concentration mean ratios (4.6- and 3.6-fold, respectively).1,132 Concomitant administration of simvastatin 80 mg on day 10 of amlodipine 10 mg once a day for 10 days resulted in increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (58 and 77% and 56 and 47%, respectively).1,132

The benefits versus risks of such concomitant therapy should be considered.1,132 If used concomitantly with amlodipine, simvastatin dosage should not exceed 20 mg daily.1,132,339 If used concomitantly with diltiazem or verapamil, simvastatin dosage should not exceed 10 mg daily.1,132,339

Cobicistat-containing Preparations !!navigator!!

Cobicistat is a strong CYP3A4 inhibitor that increases simvastatin exposure and peak plasma concentrations increasing the risk of myopathy and rhabdomyolysis.1,132 Concomitant use of simvastatin and cobicistat-containing preparations is contraindicated.1,132

Colchicine !!navigator!!

Myopathy, including rhabdomyolysis, has been reported when simvastatin was used concomitantly with colchicine.1,132 Therefore, the drugs should be used concomitantly with caution.1,132

Conivaptan !!navigator!!

Rhabdomyolysis has been reported when simvastatin was used concomitantly with conivaptan.339 Concomitant use of these drugs should be avoided.339

Danazol !!navigator!!

Concomitant use of simvastatin and danazol may increase the risk of myopathy and/or rhabdomyolysis, and is therefore contraindicated.1,132

Daptomycin !!navigator!!

Cases of rhabdomyolysis have been reported with concomitant use of simvastatin and daptomycin.1 The manufacturer of simvastatin recommends temporary suspension of simvastatin therapy in patients receiving daptomycin.1

Digoxin !!navigator!!

A slight increase in plasma digoxin concentrations has been observed when the drug was used concomitantly with simvastatin.1,132 Patients receiving digoxin should be appropriately monitored when simvastatin is initiated.1,132

Dronedarone !!navigator!!

Concomitant use of simvastatin and dronedarone can increase plasma concentrations of simvastatin and increase the risk of myopathy and/or rhabdomyolysis, particularly when higher dosages of simvastatin are used.1,132,339

Concomitant administration of simvastatin 40 mg once a day for 14 days with dronedarone 400 mg two times a day for 14 days resulted in increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (96% and 3.9-fold and 2.14- and 3.75-fold, respectively).1,132

The benefits versus risks of such concomitant therapy should be considered.1,132 If used concomitantly with dronedarone, simvastatin dosage should not exceed 10 mg daily.1,132

Efavirenz !!navigator!!

Concomitant administration of simvastatin and efavirenz, a CYP3A4 inducer, results in decreased simvastatin and simvastatin active metabolite AUC (60-80% and 60% respectively).503 Experts recommend that dosage of simvastatin be adjusted based on clinical response, not to exceed the maximum recommended dose.503

Etravirine !!navigator!!

Decreased simvastatin concentrations are possible when administered with etravirine, a CYP3A4 inducer.503 Experts recommend that dosage of simvastatin be adjusted based on clinical response, not to exceed the maximum recommended dose.503

Fenofibrate !!navigator!!

Concomitant use of fenofibrate and simvastatin resulted in slight changes in peak plasma concentrations and AUC of simvastatin and simvastatin acid.1 Although dosage adjustments are not required, caution is advised when these drugs are coadministered because of the potential for increased risk of myopathy.1

Concomitant administration of simvastatin 80 mg once daily with fenofibrate 160 mg once daily resulted in a slight decrease in simvastatin acid and simvastatin AUC and peak plasma concentrations.1,132

The benefits versus risks of such concomitant therapy should be considered.1,132 If concomitant use is necessary, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.1

Gemfibrozil !!navigator!!

Concomitant use of simvastatin and gemfibrozil may increase the risk of myopathy and/or rhabdomyolysis, and is therefore contraindicated.1,132

Concomitant administration of simvastatin 40 mg with gemfibrozil 600 mg twice daily for 3 days resulted in increased simvastatin acid AUC and peak plasma concentration mean ratios (2.85- and 2.18-fold, respectively).1,132

Grapefruit Juice !!navigator!!

Administration of simvastatin with grapefruit juice has resulted in substantial increases in plasma concentrations of the antilipemic agent, potentially increasing the risk of myopathy and/or rhabdomyolysis; therefore, the manufacturer and some clinicians recommend that concomitant administration of simvastatin with grapefruit juice should be avoided.1,132,378,379

Concomitant administration of simvastatin 60 mg on day 3 of grapefruit juice (double-strength) 200 mL three times a day for 3 days resulted in a substantial increase in simvastatin and simvastatin acid AUC mean ratios (16- and 7-fold, respectively).1,132 Concomitant administration of simvastatin 20 mg in the evening on day 3 of grapefruit juice (single-strength) 237 mL once daily in the morning resulted in a minimal increase in simvastatin and simvastatin acid AUC mean ratios (90 and 30%, respectively).1,132

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; large quantities (>1 quart per day) should be avoided.200,376,378

HIV Protease Inhibitors !!navigator!!

Concomitant use of simvastatin and HIV protease inhibitors can increase the risk of myopathy and/or rhabdomyolysis by reducing simvastatin elimination.1,132

Concomitant administration of simvastatin 20 mg once daily for 28 days administered with nelfinavir 1250 mg twice daily for 14 days resulted in substantially increased simvastatin AUC and peak plasma concentration mean ratios (6- and 6.2-fold, respectively).1,132 Similar results are expected with other HIV protease inhibitors.1,132

Concomitant use of simvastatin and HIV protease inhibitors is contraindicated.1,132

Immunosuppressive Agents !!navigator!!

Cyclosporine, a strong inhibitor of CYP3A4 and OATP1B1, can increase systemic exposure of simvastatin and increase the risk of myopathy and/or rhabdomyolysis.1,132 Concomitant use of simvastatin and cyclosporine is contraindicated.1,132

Although data are more limited with everolimus, sirolimus, and tacrolimus, the interaction potential of these immunosuppressive agents is expected to be similar to cyclosporine because of similar metabolism.339 Some experts recommend avoiding concomitant use of simvastatin and these other immunosuppressive agents.339

Lenacapavir !!navigator!!

Increased simvastatin concentrations are expected when administered with lenacapavir, a CYP3A4 inhibitor.503 Experts recommend selecting the lowest effective simvastatin dosage while monitoring for adverse events.503

Lomitapide !!navigator!!

Concomitant use of simvastatin and lomitapide can increase simvastatin exposure by twofold and increase the risk of myopathy and rhabdomyolysis. The benefits versus risks of concomitant therapy should be considered.1,132

Concomitant administration of a single simvastatin 40 mg dose with lomitapide 60 mg once a day for 7 days resulted in increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (1.7-2-fold and 1.6-2-fold, respectively).1,132 Concomitant administration of a single simvastatin 20 mg dose with lomitapide 10 mg once a day for 7 days also resulted in increased simvastatin acid and simvastatin AUC and peak plasma concentration mean ratios (40-60% and 40-70%, respectively).1,132

The benefits versus risks of such concomitant therapy should be considered.132 When lomitapide is being initiated in a patient with homozygous familial hypercholesterolemia, simvastatin dosage should be reduced by 50%.1,132 Simvastatin dosage should not exceed 20 mg daily (or 40 mg daily in patients who have received the 80-mg daily dosage for at least 12 months without evidence of adverse muscular effects).1,132

Macrolide Antibiotics !!navigator!!

Macrolide antibiotics (i.e., clarithromycin, erythromycin) are strong CYP3A4 inhibitors that can increase the risk of myopathy by reducing the elimination of simvastatin.1,132

Concomitant use of simvastatin and erythromycin or clarithromycin is contraindicated.1,132 If therapy with a macrolide antibiotic is unavoidable, interrupt simvastatin therapy during macrolide treatment.1,132

Nefazodone !!navigator!!

Concomitant use of simvastatin and nefazodone increases simvastatin exposure and increases the risk of myopathy and/or rhabdomyolysis.1,132 Concomitant use of simvastatin and nefazodone is contraindicated.1,132

Nevirapine !!navigator!!

Decreased simvastatin is possible when administered with nevirapine, a CYP3A4 inducer.503 Experts recommend that dosage of simvastatin be adjusted based on clinical response, not to exceed the maximum recommended dose.503

Niacin !!navigator!!

Concomitant administration of a single simvastatin 20 mg dose with a single niacin extended-release 2 g dose resulted in increased simvastatin and simvastatin acid AUC and peak plasma concentration mean ratios (40-60% and 8-84%, respectively).1,132

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of simvastatin and niacin dosages ≥1 g daily; the risk is greater in Chinese patients.1,132 Concomitant use of simvastatin and niacin dosages ≥1 g daily is not recommended in Chinese patients.1

If the benefits of combined use of such drugs outweighs the increased risk of myopathy and rhabdomyolysis, caution should be used when treating Chinese patients with simvastatin in dosages exceeding 20 mg/day coadministered with lipid-modifying doses (≥1 g/day) of niacin-containing products.1,132 Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.132

It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses (≥1 g/day) of niacin-containing products observed in Chinese patients applies to other Asian patients.132

Propranolol !!navigator!!

Concomitant use of simvastatin and propranolol did not result in a substantial pharmacokinetic interaction.1,132

Ranolazine !!navigator!!

Concomitant use of simvastatin and ranolazine can increase plasma concentrations of simvastatin and increase the risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin.1,132,339

Concomitant administration of simvastatin 80 mg on day 1 and days 6-9 of ranolazine SR 1000 mg twice a day for 7 days resulted in increased simvastatin and simvastatin acid AUC and peak plasma concentration mean ratios (1.86-2.26-fold and 1.75-2.28-fold, respectively).1,132

The benefits versus risks of concomitant use should be considered.1,1 If used concomitantly with ranolazine, simvastatin dosage should not exceed 20 mg daily.1

Ticagrelor !!navigator!!

Increased simvastatin plasma concentrations are possible when the drug is used concomitantly with ticagrelor.339 Some experts recommend limiting simvastatin dosage to 40 mg daily during concomitant use.339

Warfarin !!navigator!!

Clinical studies have shown that simvastatin may potentiate the effect of warfarin (as evidenced by increased prothrombin time [PT] and International Normalized Ratio [INR]); bleeding and/or increased PT/INR has been observed with concomitant use of other statins.1,132,339 PT/INR should be monitored when simvastatin is initiated or dosage is adjusted in patients receiving warfarin; thereafter, PT/INR can be monitored at usually recommended intervals.1,132,339

Other Information ⬆ ⬇

Description

Simvastatin is a specific inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis).1,132,501 Simvastatin is pharmacologically related to other statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin).2,3,4,5,501 Simvastatin is a derivative of lovastatin and differs from this agent by the presence of an additional methyl group on the butyryl ester side chain.69 This structural modification enhances the in vitro HMG-CoA reductase-inhibitory activity of simvastatin acid by a factor of 2 compared with that of lovastatin;3 however, it also increases simvastatin's lipophilicity, resulting in a greater potential for the drug to cross the blood-brain barrier.69 Simvastatin is a prodrug and has little, if any, antilipemic activity until hydrolyzed in vivo to mevinolinic acid (the corresponding ring-opened, β-hydroxyacid form), which is a potent inhibitor of HMG-CoA reductase.1,69,132

Simvastatin reduces elevated low-density lipoprotein (LDL)-cholesterol concentrations.1,132 The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of very low-density lipoprotein (VLDL) concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-cholesterol.1,132,501 Triglyceride and apolipoprotein B may decrease and high-density lipoprotein (HDL)-cholesterol concentration may increase during treatment with simvastatin.1,132,501 Other favorable effects of statins (pleiotropic effects) include an antiproliferative influence on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.501

Simvastatin is lipophilic and undergoes extensive first-pass metabolism in the liver; peak plasma concentrations (including metabolites) are attained in 4 hours, and absolute bioavailability of the drug is low (<5%).1,132,501 The plasma profile of total (HMG-CoA reductase) inhibitor concentration was not affected when simvastatin was administered with a low fat meal.1,132 Simvastatin AUC decreased by 18% and simvastatin β-hydroxyacid AUC increased by 44% following administration of the oral suspension preparation with a high fat meal compared to fasting conditions.132 The preparation of simvastatin in fixed-combination with ezetimibe (Vytorin® and generic equivalents) is bioequivalent to corresponding dosages of the individual components.103

Maximal to near-maximal therapeutic response is generally achieved within 4-6 weeks.1,132 Both simvastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.1,132 Animal studies demonstrate that simvastatin crosses the blood-brain barrier.132

The major active metabolites of simvastatin present in human plasma are simvastatin acid, 6'-hydroxy , 6'-hydroxymethyl, and 6'-xomethylene derivatives.1,132 Peak plasma concentrations of both active and total inhibitors are attained within 1.3 to 2.4 hours postdose.1,132 Simvastatin is a substrate of cytochrome P-450 (CYP) 3A4, P-glycoprotein (P-gp), and organic anion transporter protein (OATP) 1B1.1,132,339,501,502 Concomitant administration of simvastatin with drugs inhibiting CYP3A4, P-gp, and/or OATP1B1 decrease simvastatin metabolism, raise HMG-CoA reductase inhibitory activity plasma levels, and increase the risk of myopathy.1,132,502 In humans, simvastatin is excreted in the urine (13%) and in the feces (60%).1,132 The half-life is 2 to 3 hours.501

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Simvastatin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

4 mg per mL

Flolipid®

Salerno

8 mg per mL

Flolipid®

Salerno

Tablets, film-coated

5 mg*

Simvastatin Tablets

10 mg*

Simvastatin Tablets

Zocor®

Organon

20 mg*

Simvastatin Tablets

Zocor®

Organon

40 mg*

Simvastatin Tablets

Zocor®

Organon

80 mg*

Simvastatin Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Simvastatin Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin®

Organon

20 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin®

Organon

40 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin®

Organon

80 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin®

Organon

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

Only references cited for selected revisions after 1984 are available electronically.

1. Organon. Zocor® (simvastatin) tablets prescribing information. Jersey City, NJ; 2023 Aug.

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4. Todd PA, Goa KL. Simvastatin: review of its pharmacological properties and therapeutic potential in hypercholesterolemia. Drugs . 1990; 40:583-607. [PubMed 2083515]

5. Rosen T, Heathcock CH. The synthesis of mevinic acids. Tetrahedron . 1986; 42:4909-51.

7. Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Ann Rev Biochem . 1977; 46:897-930. [PubMed 197883]

8. Brown MS, Goldstein JL. Lipoprotein receptors in the liver: control signals for plasma cholesterol traffic. Clin Invest . 1983; 72:743-7.

11. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients withcoronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet . 1994; 344:1383-9. [PubMed 7968073]

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14. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther . 1998; 64:477-83. [PubMed 9834039]

16. England DDF, Viles A, Labib S. Liver side effects associated with simvastatin therapy. Med J Aust . 1991; 155:61. [PubMed 2067448]

17. Manson JM, Freyssinges C, Ducrocq MB et al. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reproductive Toxicology . 1996; 10:439-46. [PubMed 8946557]

19. Stein EA, Davidson MH, Dobs AS et al. Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. Am J Cardiol . 1998; 82:311-6. [PubMed 9708659]

20. Keech A, Collins R, MacMahon S et al. Three-year follow-up of the oxford cholesterol study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J . 1994; 15:255-69. [PubMed 8005129]

21. Davidson MH, Stein EA, Dujovne CA et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol . 1997; 79:38-42. [PubMed 9024733]

22. Chan P, Huang TY, Tomlinson B et al. Short-term safety and efficacy of low-dose simvastatin in elderly patients with hypertensive hypercholesterolemia and fasting hyperinsulinemia. J Clin Pharmacol . 1997; 37:496-501. [PubMed 9208356]

23. Ito T, Matsumoto M, Hougaku H et al. Effects of low-dose simvastatin therapy on serum lipid levels in patients with moderate hypercholesterolemia: a 12-month study. Clin Ther . 19:487-97. (IDIS 387685)

24. Simons LA. Simvastatin in severe primary hypercholesterolemia: efficacy, safety, and tolerability in 595 patients over 18 weeks. Clin Cardiol . 1993; 16:317-22. [PubMed 8458112]

27. Ose L, Scott R, and the Simvastatin-Fluvastatin Study Group. Double-blind comparison of the efficacy and tolerability of simvastatin and fluvastatin in patients with primary hypercholesterolemia. Clin Drug Invest . 1995; 10:127-38.

28. Farmer JA, Washington LC, Jones PH et al. Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. Clin Ther . 1992; 14:708-17. [PubMed 1468089]

29. The Simvastatin Pravastatin Study Group. Comparison of the efficacy, safety and tolerability of simvastatin and pravastatin for hypercholesterolemia. Am J Cardiol . 1993; 71:1408-14. [PubMed 8517385]

30. The European Study Group. Efficacy and tolerability of simvastatin and pravastatin in patients with primary hypercholesterolemia. Am J Cardiol . 1992; 70:1281-6. [PubMed 1442579]

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