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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-hexahydro-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. Last updated on June 16, 2020.

Introduction

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

Uses for Simvastatin

Prevention of Cardiovascular Events

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

Adjunct to nondrug therapies (i.e., 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 coronary and non-coronary revascularization procedures. Unless contraindicated, statins are considered first-line therapy in patients 21–75 years of age with clinical ASCVD (i.e., acute coronary syndromes [ACS]; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin).

Slows the progression and/or induces regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness.

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

Addition of niacin to statin-based therapy (i.e., simvastatin with or without ezetimibe) in patients with established cardiovascular disease not shown to provide incremental ASCVD risk reduction benefit beyond that provided by statin monotherapy.

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.

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

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). However, fibric acid derivatives provide greater benefit in patients with elevated triglyceride concentrations compared with statins.

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

  • Patients should be placed on a standard lipid-lowering diet before initiation of simvastatin therapy and should remain on this diet during treatment with the drug; in patients with CHD or CHD risk equivalents, initiate simvastatin simultaneously with dietary management.

Monitoring during 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. ACC/AHA cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy (to assess response and adherence) and monitoring every 3–12 months thereafter as clinically indicated.

  • Periodically reinforce adherence to lifestyle modifications.

Administration

Oral Administration

Administer orally in the evening without regard to meals.

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

Manufacturer and some clinicians recommend that patients avoid grapefruit juice. (See Specific Drugs and Foods under Interactions.) Because extent of the interaction may be influenced by quantity and timing of grapefruit juice consumption, other clinicians suggest that small amounts (e.g., 240 mL) may be acceptable.

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

Prevention of Cardiovascular Events

Select appropriate statin intensity to achieve optimal ASCVD risk reduction. Giving maximally tolerated statin intensity is preferred over giving lower statin dosages in combination with nonstatin drugs, a strategy not yet shown to reduce ASCVD risk.

Although 10 mg once daily is an FDA-labeled dosage, it was not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.

Primary Prevention† in Patients with LDL-cholesterol Concentrations ≥190 mg/dL (≥21 years of age)
Oral

ACC/AHA cholesterol management guideline recommends initiating high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated.

Primary Prevention† in Patients with Type 1 or 2 Diabetes Mellitus (40–75 years of age)
Oral

ACC/AHA cholesterol management guideline recommends moderate-intensity statin therapy (e.g., simvastatin 20–40 mg once daily).

If estimated 10-year ASCVD risk ≥7.5%, consider high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated.

In patients <40 or >75 years of age, consider potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

Primary Prevention† in Patients with LDL-cholesterol Concentrations 70–189 mg/dL and Elevated ASCVD Risk (40–75 years of age)
Oral

Estimated 10-year ASCVD risk ≥7.5%: ACC/AHA cholesterol management guideline recommends moderate- (e.g., simvastatin 20–40 mg once daily) to high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin).

Estimated 10-year ASCVD risk of 5 to <7.5%: ACC/AHA cholesterol management guideline states may consider moderate-intensity statin therapy.

Consider potential benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.

Secondary Prevention in Patients with Clinical ASCVD (i.e., ACS; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) (21–75 years of age)
Oral

ACC/AHA cholesterol management guideline recommends high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated.

In patients at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, consider moderate-intensity statin therapy (e.g., simvastatin 20–40 mg once daily) if tolerated.

Patients >75 years of age: Individualize therapy based on potential benefits, adverse effects, drug interactions, and patient preferences; may consider moderate-intensity statin therapy if tolerated.

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.

Dosage Modification
Oral

ACC/AHA cholesterol management guideline states may consider decreasing statin dosage when LDL-cholesterol concentrations are <40 mg/dL on 2 consecutive measurements; however, no data to suggest that LDL-cholesterol concentrations <40 mg/dL increase risk of adverse effects.

Prescribing Limits

Pediatric Patients

Dyslipidemias
Oral

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

Adults

Prevention 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. (See Specific Drugs and Foods under Interactions.)

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

  • Pregnancy or lactation. Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards.

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

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm. Congenital anomalies following intrauterine exposure to statins reported rarely.

Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking the drug, immediately discontinue therapy and apprise the patient of the potential hazard to the fetus.

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. (See Contraindications under Cautions and also see Interactions.)

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.

ACC/AHA cholesterol management guideline does not recommend routine monitoring of CK concentrations in adults; however, may obtain CK concentrations before initiating therapy in adults at increased risk of developing adverse musculoskeletal effects (e.g., patients with personal or family history of statin intolerance or muscle disease, patients receiving concomitant therapy with myotoxic drugs). During statin therapy, may measure CK concentrations in adults with muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).

National Heart, Lung, and Blood Institute (NHLBI) expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents recommends obtaining CK concentrations in pediatric patients before initiating statin therapy and routinely monitoring for muscle toxicity during therapy.

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).

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 ). Although manufacturers previously recommended more frequent monitoring, FDA concluded that serious statin-related liver injury is rare and unpredictable, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. ACC/AHA cholesterol management guideline recommends obtaining liver function tests in adults with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera). However, NHLBI expert panel on cardiovascular health and risk reduction in children and adolescents strongly recommends routine monitoring of hepatic function in children and adolescents receiving statins.

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.

Also see Hepatic Impairment under Cautions.

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported. Possible increased risk of developing diabetes. May need to monitor glucose concentrations following initiation of statin therapy.

FDA states that cardiovascular benefits of statins outweigh these small increased risks.

ACC/AHA cholesterol management guideline recommends evaluating patients for new-onset diabetes mellitus according to current diabetes screening guidelines.

If diabetes mellitus develops during statin therapy, encourage patients to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of 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.

If patients present with confusion or memory impairment, ACC/AHA cholesterol management guideline recommends evaluating patient for statin as well as nonstatin causes (e.g., other drugs, systemic or neuropsychiatric causes).

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

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

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.

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. In patients >75 years of age, consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.

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. (See Renal Impairment under Dosage and Administration.)

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. No formal drug interaction studies to date with fixed-combination preparation other than that with extended-release niacin. (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic (increased plasma simvastatin concentrations) and pharmacodynamic (increased risk of myopathy or rhabdomyolysis) interaction. Concomitant use contraindicated. (See Contraindications under Cautions.)

Drugs Transported by OATP

OATP1B1 inhibitors: Potential pharmacokinetic (increased plasma simvastatin acid concentrations) and pharmacodynamic (increased risk of myopathy) interaction.

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

Itraconazole, ketoconazole, posaconazole, or voriconazole: Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in substantially increased simvastatin peak plasma concentration and/or AUC and increased risk of myopathy and/or rhabdomyolysis

Itraconazole, ketoconazole, posaconazole, or voriconazole: 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 or 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

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

Digoxin

Possible increased plasma digoxin concentrations

Appropriately monitor patients receiving digoxin when simvastatin is initiated

Dronedarone

Increased simvastatin peak plasma concentration and AUC

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

Fibric acid derivatives (e.g., fenofibrate, gemfibrozil)

Increased risk of myopathy and/or rhabdomyolysis

Fenofibrate: Pharmacokinetic interaction unlikely

Gemfibrozil: Increased peak plasma concentration and AUC of simvastatin acid

Gemfibrozil: Concomitant use contraindicated

Other fibric acid derivatives (e.g., fenofibrate): Use concomitantly with caution; weigh benefits against risks of concomitant use

Grapefruit juice

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

Concomitant use contraindicated

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%

Do not exceed simvastatin dosage of 20 mg daily (or 40 mg daily in patients who have received the 80-mg daily dosage for ≥12 months without evidence of adverse muscular effects)

Macrolides (clarithromycin, erythromycin)

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

Clarithromycin or erythromycin: 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

Niacin (antilipemic dosages [≥1 g daily])

Extended-release niacin (2-g single dose): Increased simvastatin peak plasma concentration and AUC

Extended-release niacin (Niaspan) with fixed-combination simvastatin/ezetimibe: Increased peak plasma concentrations and AUC of niacin and nicotinuric acid; increased peak plasma concentrations of simvastatin acid; increased AUC of total ezetimibe, simvastatin, and simvastatin acid

Increased risk of myopathy and/or rhabdomyolysis; myopathy, including rhabdomyolysis, reported

Increased risk of myopathy observed in Chinese versus non-Chinese patients receiving simvastatin 40 mg daily with antilipemic dosages of niacin

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)

Use concomitantly with caution; weigh benefits against risks of concomitant therapy

Extended-release niacin: No dosage adjustments required if used with simvastatin monotherapy

Patients of Chinese descent: Caution when used concomitantly with simvastatin dosages >20 mg daily; avoid concomitant use with simvastatin 80 mg daily

Omega-3-acid ethyl esters

No effect on rate or extent of exposure to simvastatin or β-hydroxysimvastatin at steady state

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 substantially increased simvastatin peak plasma concentration and AUC 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

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. May need to monitor glucose concentrations following initiation of statin therapy.

  • Importance of advising women and adolescent girls to avoid pregnancy (i.e., using effective and appropriate contraceptive methods) during therapy and informing pregnant women of risk to fetus.

  • 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

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

Simvastatin Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg with Ezetimibe 10 mg

Vytorin

Merck

20 mg with Ezetimibe 10 mg

Vytorin

Merck

40 mg with Ezetimibe 10 mg

Vytorin

Merck

80 mg with Ezetimibe 10 mg

Vytorin

Merck

AHFS DI Essentials™. © Copyright 2021, Selected Revisions June 26, 2017. 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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