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Simvastatin

Class: HMG-CoA Reductase Inhibitors
- Statins
VA Class: CV350
Chemical Name: [1S-[1α,3α,7β,8β(2S*,4S*)8aβ-2,2-Dimethyl-,1,2,3,7,8,8a-hexahedron-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester
Molecular Formula: C25H38O5
CAS Number: 79902-63-9
Brands: Zocor

Medically reviewed by Drugs.com on Dec 13, 2021. Written by ASHP.

Introduction

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

Uses for Simvastatin

Reduction in Risk of Cardiovascular Events

Adjunct to diet and other lifestyle modifications in patients with CHD or CHD risk equivalents (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease) to reduce the risk of total mortality by reducing CHD death, to reduce the risk of nonfatal MI and stroke, and to reduce the need for revascularization procedures.

Extensive evidence demonstrates that statins can substantially reduce LDL-cholesterol concentrations and associated risk of atherosclerotic cardiovascular disease (ASCVD); may be used for secondary prevention or primary prevention in high-risk patients.

AHA/ACC cholesterol management guideline states that lifestyle modification is the foundation of ASCVD risk reduction. Patients with established ASCVD or high risk of ASCVD should also be treated with a statin.

Because relative ASCVD risk reduction is correlated with degree of LDL-cholesterol lowering, use maximum tolerated intensity of a statin to achieve greatest benefit. High-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by ≥50%) is recommended; if high-intensity statin therapy not possible (e.g., because of a contraindication or intolerable adverse effect), may consider moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30–49%). AHA/ACC considers simvastatin 20–40 mg daily to be a moderate-intensity statin. Although simvastatin 80 mg daily was evaluated in randomized controlled studies, this dosage is not recommended by FDA because of increased risk of myopathy.

When considering whether to initiate statin therapy for primary prevention, AHA/ACC recommends an individualized approach and shared decision making between patient and clinician. According to the guidelines, statin therapy may be considered in certain high-risk groups such as adults 20–75 years of age with LDL-cholesterol ≥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%.

Has been shown to slow the progression and/or induce regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness.

The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be considered in certain high-risk patients who require further reduction in LDL-cholesterol concentrations, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events.

In the IMPROVE-IT study, addition of ezetimibe to simvastatin therapy in post-ACS patients further reduced LDL cholesterol and improved cardiovascular outcomes.

Randomized controlled studies do not support the addition of niacin to statin-based therapy, and such combination may increase the risk of adverse effects.

In the SHARP study, fixed-combination preparation of simvastatin and ezetimibe was found to reduce risk of major vascular and atherosclerotic events in patients with chronic kidney disease, a population known to be at increased risk of cardiovascular disease.

Dyslipidemias

Adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hyperlipidemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIa or IIb).

May use in combination or fixed combination with ezetimibe for additive antilipemic effects.

Also used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are on optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that provided by statin monotherapy.

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

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

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride and VLDL-cholesterol concentrations in the management of primary dysbetalipoproteinemia (Fredrickson type III).

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride concentrations in the management of hypertriglyceridemia (Fredrickson type IV).

Also has been used to reduce total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), cardiac or renal transplantation, or nephrotic syndrome.

Simvastatin Dosage and Administration

General

Patient Monitoring

    Antilipemic Therapy
  • Manufacturers recommend obtaining lipoprotein concentrations within 4 weeks following initiation of simvastatin monotherapy or 2 or more weeks after initiation or titration of therapy with the fixed-combination preparation (Vytorin), and then periodically thereafter. AHA/ACC cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy and after dosage changes (to assess response and adherence); continue monitoring every 3–12 months thereafter as clinically indicated.

  • Periodically reinforce adherence to lifestyle modifications. Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of ASCVD.

Administration

Oral Administration

Administer orally (as tablets or oral suspension) in the evening without regard to meals.

Simvastatin/ezetimibe fixed-combination preparation: Administer orally in the evening without regard to meals.

Concomitant use of certain drugs can increase plasma concentrations of simvastatin and risk of myopathy. (See Specific Drugs and Foods under Interactions.)

Pharmacogenetic Testing

Pharmacogenetic testing for SLCO1B1 (gene encoding organic anion transport protein [OATP] 1B1) may be useful for identifying patients at increased risk of simvastatin-induced myopathy. Patients with a specific variant of SLCO1B1 (rs4149056T>C) are likely to have increased systemic exposure to simvastatin and increased risk of muscle toxicity. (See Pharmacogenomics of Simvastatin-induced Myopathy under Cautions.)

The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides dosing guidelines based on results of SLCO1B1 genotyping. CPIC recommends reducing simvastatin dosage (e.g., to 20 mg daily) or using an alternative statin (e.g., rosuvastatin, pravastatin) in individuals with SLCO1B1 genotypes associated with an intermediate or high risk of myopathy. 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). Consider limitations of SLCO1B1 genotyping when interpreting and applying results.

Dosage

Pediatric Patients

Dyslipidemias
Oral

Children 10–17 years of age: Initially, 10 mg once daily.

Adjust dosage at intervals of ≥4 weeks until the desired effect on lipoprotein concentrations is observed. Recommended dosage range is 10–40 mg daily.

Adults

Reduction in Risk of Cardiovascular Events
Oral

Use maximally tolerated statin intensity to achieve optimal ASCVD risk reduction benefit. High-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by ≥50%) is preferred; if high-intensity statin therapy not possible (e.g., because of a contraindication or intolerable adverse effect), may consider moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30–49%).

The AHA/ACC guideline panel considers simvastatin 20–40 mg daily to be a moderate-intensity statin. Although simvastatin 80 mg daily was evaluated in randomized controlled studies, this dosage is not recommended by FDA because of increased risk of myopathy.

Dyslipidemias
Oral

Initially, 10 or 20 mg once daily.

Patients with CHD or CHD risk equivalents: Initially, 40 mg once daily.

Adjust dosage at intervals of ≥4 weeks until desired effect on lipoprotein concentrations is observed. Usual dosage range is 5–40 mg daily.

If response is inadequate with 40 mg daily, do not increase dosage; instead, switch to alternative antilipemic agent(s) that provide greater LDL-cholesterol reduction. Restrict use of 80-mg daily dosage. (See Prescribing Limits under Dosage and Administration.)

Simvastatin/ezetimibe fixed combination (Vytorin): Initially, simvastatin 10 mg/ezetimibe 10 mg or simvastatin 20 mg/ezetimibe 10 mg once daily in the evening. In patients requiring LDL-cholesterol reductions >55%, may initiate therapy with simvastatin 40 mg/ezetimibe 10 mg once daily in the absence of moderate to severe renal impairment (GFR <60 mL/minute per 1.73 m2). Usual maintenance dosage is simvastatin 10–40 mg and ezetimibe 10 mg once daily. If LDL-cholesterol target goal cannot be achieved with simvastatin 40 mg/ezetimibe 10 mg once daily, do not increase dosage; instead, switch to alternative antilipemic agent(s) that provide greater LDL-cholesterol reduction. Restrict use of simvastatin 80 mg/ezetimibe 10 mg dosage. (See Prescribing Limits under Dosage and Administration.)

Homozygous Familial Hypercholesterolemia
Oral

40 mg once daily in the evening.

Simvastatin/ezetimibe fixed combination (Vytorin): Simvastatin 40 mg/ezetimibe 10 mg once daily in the evening.

Prescribing Limits

Pediatric Patients

Dyslipidemias
Oral

Children 10–17 years of age: Maximum 40 mg once daily.

Adults

Reduction in Risk of Cardiovascular Events or Management of Dyslipidemias
Oral

Restrict use of 80-mg daily dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects. (See Musculoskeletal Effects under Cautions.) In patients currently tolerating the 80-mg daily dosage 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), switch to an alternative statin or statin-based regimen with less drug interaction potential.

Simvastatin/ezetimibe fixed combination (Vytorin): Restrict use of simvastatin 80 mg/ezetimibe 10 mg dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects. In patients currently tolerating the simvastatin 80 mg/ezetimibe 10 mg daily dosage 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), switch to an alternative statin or statin-based regimen with less drug interaction potential.

Special Populations

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.

Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Renal Impairment

Simvastatin

Mild to moderate renal impairment: No dosage adjustment needed.

Severe renal impairment: Initially, 5 mg once daily. Use with caution; monitor closely.

Simvastatin/Ezetimibe Fixed Combination

Mild renal impairment (estimated GFR ≥60 mL/minute per 1.73 m2): No dosage adjustment needed.

Chronic kidney disease and estimated GFR <60 mL/minute per 1.73 m2: Simvastatin 20 mg/ezetimibe 10 mg once daily; use higher dosages with caution and close monitoring. (See Renal Impairment under Cautions.)

Cautions for Simvastatin

Contraindications

  • Concomitant use with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, clarithromycin, erythromycin, telithromycin, nefazodone, cobicistat-containing preparations), gemfibrozil, cyclosporine, or danazol.

  • Active liver disease, including unexplained, persistent elevations of serum aminotransferases.

  • Lactation.

  • Known hypersensitivity to simvastatin or any ingredient in the formulation.

Warnings/Precautions

Musculoskeletal Effects

Myopathy (manifested as muscle pain, tenderness, or weakness and serum CK [CPK] concentration increases >10 times the ULN) reported.

Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [>10 times the ULN] in serum CK concentrations and increases in Scr [usually accompanied by brown urine and urinary myoglobinuria]) with or without acute renal failure secondary to myoglobinuria also reported; rare fatalities have occurred.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins. Characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.

Incidence of myopathy, including rhabdomyolysis, reportedly highest during first year and then notably decreased during subsequent years of treatment.

Risk of myopathy is increased in patients receiving higher dosages of statins; risk also may be increased in geriatric patients (≥65 years of age), women, and patients with renal impairment or uncontrolled hypothyroidism.

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.

Risk of myopathy, including rhabdomyolysis, is greater with 80-mg daily dosage compared with lower daily dosages or compared with other statins with similar or greater LDL-cholesterol lowering efficacy. Restrict use of 80-mg daily dosage. (See Prescribing Limits under Dosage and Administration.)

May consider periodic monitoring of CK concentrations when initiating therapy or increasing dosage; however, there is no assurance that such monitoring will prevent myopathy. AHA/ACC recommends measuring CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.

Discontinue if serum CK concentrations increase markedly or if myopathy is diagnosed or suspected.

Temporarily withhold therapy in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).

Pharmacogenomics of Simvastatin-induced Myopathy

Genetic polymorphism of SLCO1B1, the gene encoding OATP1B1, can affect pharmacokinetics of simvastatin and risk of myopathy. Many variants in SLCO1B1 have been identified, but the c.521T>C variant (rs4149056) is most clinically relevant. Relationship between rs4149056 and simvastatin-induced muscle toxicity clearly established.

Genetic testing for SLCO1B1 may be considered to identify patients at increased risk of developing simvastatin-induced myopathy.

Hepatic Effects

Associated with increases in serum aminotransferase (AST, ALT) concentrations.

Pancreatitis, hepatitis, jaundice, increased serum alkaline phosphatase concentrations, increased serum γ-glutamyl transpeptidase concentrations, and fatal and nonfatal hepatic failure reported.

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage). Serious statin-related liver injury is rare and unpredictable, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. AHA/ACC cholesterol management guideline states that it is reasonable to obtain liver function tests in patients with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera); however, routine monitoring not recommended.

ALT may emanate from muscle; therefore, concurrent increases in ALT and CK concentrations may indicate myopathy. (See Musculoskeletal Effects under Cautions.)

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt simvastatin therapy. If an alternate etiology is not found, do not restart simvastatin.

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported. Possible increased risk of developing diabetes.

AHA/ACC cholesterol management guideline states that in patients with increased risk of diabetes mellitus or new-onset diabetes mellitus, statin therapy and lifestyle modifications should be continued to reduce risk of ASCVD.

Endogenous Steroid Production

No substantial effects on adrenal reserve or basal plasma cortisol concentration observed with simvastatin.

Small reductions from baseline in basal plasma testosterone concentrations observed in men; however, unlikely to be clinically important since no substantial effects on plasma gonadotropin concentrations, plasma testosterone response to human chorionic gonadotropin, spermatogenesis, or incidence of male adverse sexual effects observed.

Effects on pituitary-gonadal axis in premenopausal women unknown.

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy). Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline. Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.

If manifestations consistent with cognitive impairment occur, National Lipid Association (NLA) statin safety assessment task force recommends evaluating and managing patients appropriately.

Role as Adjunct Therapy

Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality.

Risk of Cancer

Findings from the SEAS study suggested a possible increased risk of cancer with use of the fixed combination of simvastatin and ezetimibe. The results of 2 subsequent randomized trials (SHARP and IMPROVE-IT) found no such association. Based on currently available evidence, FDA has concluded that the fixed-combination preparation of ezetimibe and simvastatin (Vytorin) is not likely to increase the risk of cancer.

Use of Fixed Combinations

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

Specific Populations

Pregnancy

All statins were previously contraindicated in pregnant women because fetal risk was thought to outweigh any possible benefit. However, the totality of evidence to date indicates limited potential for statins to cause malformations and other adverse embryofetal effects; FDA has therefore requested removal of the contraindication. Most pregnant patients should still discontinue statins because of the possibility of fetal harm; however, some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) may benefit from continued therapy. Consider patient's individual risks and benefits.

Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician; clinician should advise patient on the appropriate course of action.

Increased risk of miscarriage reported in pregnant women exposed to statins; however, not clear whether drug-related or due to other confounding factors.

Lactation

Not known whether simvastatin is distributed into milk; however, a small amount of another statin is distributed into milk. Use is contraindicated in nursing women; women who require simvastatin therapy should not breast-feed their infants. Discontinue nursing or the drug. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.

Pediatric Use

Safety and efficacy of simvastatin not established in children <10 years of age or in premenarchal girls. Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.

Safety and efficacy of simvastatin in fixed combination with ezetimibe not established in children <10 years of age or in premenarchal girls. In patients 10–17 years of age, combination of simvastatin and ezetimibe associated with higher discontinuance rate and higher incidence of elevated aminotransferase or CK concentrations compared with simvastatin monotherapy.

Geriatric Use

Simvastatin: No overall differences in safety or efficacy relative to younger adults. However, increased sensitivity cannot be ruled out; higher dosages (i.e., 80 mg daily) associated with increased risk of myopathy, including rhabdomyolysis, in patients ≥65 years of age. Use with caution, since age ≥65 years is a predisposing factor for myopathy.

Patients >75 years of age may have higher risk of adverse effects and lower adherence to statin therapy; consider expected benefits versus adverse effects prior to initiating statin therapy in this population.

Simvastatin/ezetimibe fixed combination: No overall differences in safety or efficacy relative to younger patients; however, increased sensitivity cannot be ruled out. Use with caution, since age ≥65 years is a predisposing factor for myopathy.

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.

Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Renal Impairment

Because many patients who have developed rhabdomyolysis during simvastatin therapy have had complicated medical histories, including renal impairment secondary to chronic diabetes mellitus, closely monitor such patients.

Use with caution in patients with severe renal impairment; dosage adjustments necessary in such patients.

In patients with moderate to severe renal impairment receiving simvastatin 20 mg/ezetimibe 10 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo. Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Upper respiratory tract infections, headache, abdominal pain, constipation, nausea.

Interactions for Simvastatin

Metabolized by CYP3A4; does not inhibit CYP3A4.

Substrate of organic anion transport protein (OATP) 1B1.

When used in fixed combination with ezetimibe, consider interactions associated with ezetimibe.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, cobicistat-containing drugs): May increase plasma simvastatin concentrations and increase risk of myopathy or rhabdomyolysis. Concomitant use contraindicated.

CYP3A4 substrates: Simvastatin not expected to affect plasma concentrations of CYP3A4 substrates.

Drugs Affecting OATP

OATP1B1 inhibitors: May increase plasma simvastatin acid concentrations and increase risk of myopathy.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Increased simvastatin peak plasma concentration and AUC; increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 20 mg daily

Antifungals, azoles (i.e., itraconazole, ketoconazole, posaconazole, voriconazole)

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in substantially increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated; if short-term therapy with antifungal is unavoidable, interrupt simvastatin therapy during antifungal treatment

Calcium-channel blocking agents (amlodipine, diltiazem, verapamil)

Increased simvastatin peak plasma concentration and AUC; increased risk of myopathy and/or rhabdomyolysis when used with higher dosages of simvastatin

Weigh benefits against risks of concomitant use

Amlodipine: If used concomitantly, do not exceed simvastatin dosage of 20 mg daily

Diltiazem, verapamil: If used concomitantly, do not exceed simvastatin dosage of 10 mg daily

Cobicistat-containing preparations

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated; if short-term therapy with a cobicistat-containing preparation is unavoidable, interrupt simvastatin therapy during treatment

Colchicine

Myopathy, including rhabdomyolysis, reported

Use concomitantly with caution

Conivaptan

Rhabdomyolysis reported

Avoid concomitant use

Danazol

Increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated

Daptomycin

Cases of rhabdomyolysis reported with concomitant use

Temporarily suspend simvastatin therapy

Digoxin

Slight increase in plasma digoxin concentrations observed

Appropriately monitor patients when simvastatin is initiated

Dronedarone

Increased simvastatin peak plasma concentration and AUC, and risk of myopathy and/or rhabdomyolysis

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 10 mg daily

Fenofibrate

Increased risk of myopathy and/or rhabdomyolysis

Slight changes in peak plasma concentrations and AUC of simvastatin and simvastatin acid observed

Use concomitantly with caution and weigh benefits against risks of concomitant use; no dosage adjustment required

Gemfibrozil

Increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated

Grapefruit juice

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Manufacturer and some clinicians recommend avoiding concomitant use

HIV protease inhibitors

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated; if short-term therapy with HIV protease inhibitor is unavoidable, interrupt simvastatin therapy during treatment

Immunosuppressive agents (i.e., cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine: Increased simvastatin AUC and increased risk of myopathy and/or rhabdomyolysis

Everolimus, sirolimus, tacrolimus: Data more limited, but interaction potential expected to be similar to cyclosporine because of similar metabolism

Cyclosporine: Concomitant use contraindicated

Everolimus, sirolimus, tacrolimus: Some experts recommend avoiding concomitant use

Lomitapide

Increased peak plasma concentration and AUC of simvastatin and simvastatin acid

Weigh benefits against risks of concomitant therapy

When initiating lomitapide, reduce simvastatin dosage by 50%

In patients with homozygous familial hypercholesterolemia, do not exceed simvastatin dosage of 20 mg daily (or 40 mg daily in such patients who have received the 80-mg daily dosage for ≥12 months without evidence of adverse muscular effects)

Macrolides (clarithromycin, erythromycin)

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated; if short-term therapy with anti-infective is unavoidable, interrupt simvastatin therapy during anti-infective treatment

Mipomersen

No clinically relevant pharmacokinetic interactions observed

No dosage adjustment of simvastatin or mipomersen required

Nefazodone

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated; if short-term therapy with nefazodone is unavoidable, interrupt simvastatin therapy during treatment

Niacin (dosage ≥1 g daily)

Cases of myopathy and rhabdomyolysis reported with concomitant use of niacin dosages ≥1 g daily; risk is greater in Chinese patients

Increased risk of severe adverse effects (disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, bleeding) with concomitant use of niacin (1.5–2 g daily) and simvastatin (40–80 mg daily, with or without ezetimibe)

Concomitant use of simvastatin and niacin dosages ≥1 g daily not recommended in Chinese patients

Propranolol

Pharmacokinetic interaction unlikely

No dosage adjustments required

Ranolazine

Increased simvastatin peak plasma concentration and AUC; increased risk of myopathy and/or rhabdomyolysis

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 20 mg daily

Telithromycin

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis

Concomitant use contraindicated; if short-term therapy with telithromycin is unavoidable, interrupt simvastatin therapy during anti-infective treatment

Ticagrelor

Possible increased simvastatin plasma concentrations

Some experts recommend limiting simvastatin dosage to 40 mg daily

Warfarin

Possible increased PT; bleeding observed with other statins

Closely monitor PT until stabilized if simvastatin is initiated or dosage is adjusted in patients receiving warfarin; thereafter, monitor PT at intervals usually recommended for patients receiving warfarin

Simvastatin Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; undergoes extensive first-pass metabolism in the liver. Absolute bioavailability is <5%. Peak plasma concentrations are attained at 4 hours.

Onset

Maximal to near-maximal therapeutic response occurs within 4–6 weeks.

Simvastatin/ezetimibe fixed-combination preparation (Vytorin) is bioequivalent to corresponding dosages of the individual components.

Special Populations

Patients with severe renal insufficiency may have higher systemic exposure. (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Distributed mainly to the liver. Crosses the blood-brain barrier.

Not known whether distributed into milk.

Plasma Protein Binding

About 95% bound to plasma proteins.

Elimination

Metabolism

Metabolized by CYP3A4 to active metabolites.

Elimination Route

Excreted in urine (13%) and feces (60%).

Half-life

Most statins generally have short half-lives (between 0.5–3 hours).

Stability

Storage

Oral

Oral Suspension

20–25°C. Do not freeze or refrigerate. Protect from heat.

Use within 30 days of opening.

Tablets

Simvastatin: 5–30°C.

Simvastatin/ezetimibe fixed combination: Well-closed containers at 20–25°C.

Actions

  • Prodrug requiring hydrolysis in vivo for activity.

  • Inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol synthesis. Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, and triglycerides.

  • Statins may slow progression and/or induce regression of atherosclerosis in coronary and/or carotid arteries, modulate BP in hypercholesterolemic patients with hypertension, and possess anti-inflammatory activity.

Advice to Patients

  • Importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.

  • Importance of obtaining fasting lipoprotein profile periodically.

  • Risk of myopathy and/or rhabdomyolysis; risk increased with higher dosages (i.e., 80 mg daily) or when used concomitantly with certain other drugs or grapefruit juice. Importance of patients promptly reporting unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if such manifestations persist after discontinuance of therapy.

  • Risk of adverse hepatic effects. Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).

  • Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).

  • Risk of increased glucose concentrations and development of type 2 diabetes.

  • Importance of advising women to contact their clinician if they become pregnant during therapy.

  • Importance of avoiding breast-feeding during therapy. If the patient has a lipid disorder and is breast-feeding, importance of contacting a clinician to discuss other antilipemic treatment options.

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

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.

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

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

Zocor

Merck

10 mg*

Simvastatin Tablets

Zocor

Merck

20 mg*

Simvastatin Tablets

Zocor

Merck

40 mg*

Simvastatin Tablets

Zocor

Merck

80 mg*

Simvastatin Tablets

Zocor

Merck

* 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

Merck

20 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

40 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

80 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

AHFS DI Essentials™. © Copyright 2022, Selected Revisions December 13, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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