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Simvastatin (Monograph)

Drug class: HMG-CoA Reductase Inhibitors

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Antilipemic agent; hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin).1 2 3 4 5

Uses for Simvastatin

Reduction in Risk of Cardiovascular Events

Adjunct to diet and other lifestyle modifications in adults with established coronary heart disease (CHD), cerebrovascular disease, peripheral vascular disease, and/or diabetes mellitus, who are at high risk of CHD; used to reduce risk of total mortality by reducing CHD death, risk of nonfatal MI and stroke, and need for revascularization procedures in such patients.1 11 66 68 86 87 132

Also has been used for primary prevention† [off-label] of atherosclerotic cardiovascular disease (ASCVD).400

Extensive evidence demonstrates that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD; may be used for secondary or primary prevention in high-risk patients.336 337 338 400 401 402

AHA/ACC cholesterol management guideline states that lifestyle modification is the foundation of ASCVD risk reduction.400 Patients with established ASCVD or high risk of ASCVD should also be treated with a statin.400

Because relative ASCVD risk reduction is correlated with degree of LDL-cholesterol lowering, use maximum tolerated intensity of a statin to achieve greatest benefit.400 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%).400 AHA/ACC 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 FDA because of increased risk of myopathy.400

When considering whether to initiate statin therapy for primary prevention, AHA/ACC recommends an individualized approach and shared decision making between patient and clinician.400 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%.400 401

Has been shown to slow the progression and/or induce regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness.1 48 51 53

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.103 308 309 400 403

Dyslipidemias

Adjunct to diet 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 (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).1 3 4 132 May be used in combination with ezetimibe for additive antilipemic effects.89 103

Adjunct to diet to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia (HeFH) in boys and girls (≥1 year postmenarchal) 10–17 years of age who, despite an adequate trial of dietary management, have LDL-cholesterol concentration ≥190 mg/dL or LDL-cholesterol concentration ≥160 mg/dL and either a family history of premature cardiovascular disease or ≥2 other cardiovascular disease risk factors.1 132 May be used in combination with ezetimibe for additive antilipemic effects.89 103

Used to reduce elevated serum total and LDL-cholesterol concentrations in adults with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1 132 May be used in combination with ezetimibe for additive antilipemic effects.89 103 504

Adjunct to diet to decrease elevated serum triglyceride and VLDL-cholesterol concentrations in adults with primary dysbetalipoproteinemia (Fredrickson type III).1 79 80 81 132

Adjunct to diet to decrease elevated serum triglyceride concentrations in adults with hypertriglyceridemia (Fredrickson type IV).1 132 383

Efficacy of simvastatin remains to be established in patients with elevated chylomicrons as their primary lipid abnormality (Fredrickson types I and V).132

Simvastatin Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Administration

Oral Administration

Administer orally (as tablets or oral suspension) in the evening.1 132

Oral Suspension

Administer on an empty stomach.132 Shake bottle well for at least 20 seconds; measure dose with accurate measuring device, not a household teaspoon.132 Utilize 8 mg/mL (40 mg/5 mL) preparation for doses ≥ 40 mg.132

Tablets

Administer without regard to meals.1 Administer a missed dose as soon as possible; do not double the next dose.1

Simvastatin/ezetimibe Fixed-combination Preparation

Administer orally in the evening without regard to meals.103 Administer a missed dose as soon as possible; do not double the next dose.103

Dosage

Pediatric Patients

Dyslipidemias
Oral

Children 10–17 years of age with heterozygous familial hypercholesterolemia (HeFH): Initially, 10 mg once daily.132

Adjust dosage at intervals of ≥4 weeks.132 Recommended dosage range is 10–40 mg daily.1 132 Maximum 40 mg once daily.1

Simvastatin/ezetimibe fixed combination (Vytorinand generic equivalents) in children 10–17 years of age with HeFH: Recommended dosage range is 10–40 mg of simvastatin and 10 mg ezetimibe daily.103

Adults

Reduction in Risk of Cardiovascular Events
Oral

Use maximally tolerated statin intensity to achieve optimal ASCVD risk reduction benefit.400 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%).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 FDA because of increased risk of myopathy.400

Manufacturers state usual dosage range is 5–40 mg daily.1 132 Some manufacturers suggest initial dosage of 10 or 20 mg once daily.1 Recommended initial dosage in patients with CHD or CHD risk equivalents is 40 mg once daily.132

If response is inadequate with 40 mg daily, do not increase dosage; instead, switch to alternative LDL-lowering treatment.1 132

Restrict use of the 80-mg daily dosage 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

Dyslipidemias
Oral

Usual dosage range is 5 to 40 mg daily.1 132

Some manufacturers suggest initial dosage of 10 or 20 mg once daily.1

Recommended initial dosage in patients with CHD or CHD risk equivalents is 40 mg once daily.1

Adjust dosage at intervals of ≥4 weeks.1

Maximum recommended dosage is 40 mg once daily.1 132

If response is inadequate with 40 mg daily, do not increase dosage; instead, switch to alternative LDL-lowering treatment.1 132 Restrict use of 80-mg daily dosage 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

Homozygous familial hypercholesterolemia (HoFH): Recommended dosage is 40 mg once daily.1

Simvastatin/ezetimibe fixed combination (Vytorinand generic equivalents): Usual dosage range is simvastatin 10–40 mg and ezetimibe 10 mg once daily.103 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.103 Restrict use of simvastatin 80 mg/ezetimibe 10 mg dosage.103

Dosage Modification for Concomitant Therapy

Amiodarone, Amlodipine, or Ranolazine

Maximum dosage: Simvastatin 20 mg or simvastatin 20 mg in fixed combination with ezetimibe 10 mg once daily.1 103 132

Lomitapide

Reduce simvastatin dosage by 50%.1 103 132

Maximum dosage: Simvastatin 20 mg or simvastatin 20 mg in fixed combination with ezetimibe 10 mg once daily.1 103 132

Restrict use of simvastatin 80 mg/ezetimibe 10 mg dosage.103

Verapamil, Diltiazem, or Dronedarone

Maximum dosage: simvastatin 10 mg or simvastatin 10 mg in fixed combination with ezetimibe 10 mg once daily.1 103 132

Special Populations

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1 103 132

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

Mild to moderate renal impairment: No dosage adjustment needed.1 132

Severe renal impairment (ClCr 15–29 mL/minute): Initially, 5 mg once daily.1 132 Use with caution; monitor closely.1 132

Simvastatin/Ezetimibe Fixed Combination

Mild renal impairment: No dosage adjustment needed.103

Moderate to severe renal impairment: Simvastatin 20 mg/ezetimibe 10 mg once daily; use higher dosages with caution and close monitoring.103

Geriatric Patients

No specific dosage recommendations at this time.1 103 132 Select dosage with caution; monitor closely.1 103 132

Pharmacogenomic Considerations in Dosing

Patients with solute carrier organic anion transporter (SLCO) 1B1 decreased or possible decreased function phenotypes: limit simvastatin dosage to <20 mg per day.500

Patients with SLCO1B1 poor function phenotypes: alternative statin recommended.500

Detailed Simvastatin dosage information

Cautions for Simvastatin

Contraindications

Warnings/Precautions

Musculoskeletal Effects

Myopathy (manifested as muscle pain, tenderness, or weakness and serum CK [CPK] concentration increases >10 times the ULN) reported.1 132

Rhabdomyolysis (defined as myopathy with a serum CK concentration >40 times the ULN) also reported; rare fatalities have occurred.1 132

Incidence of myopathy, including rhabdomyolysis, appears highest during first year and then decreases during subsequent years of treatment.1 132

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.1 132

Risk of myopathy increased in Chinese compared with non-Chinese patients taking simvastatin coadministered with lipid-modifying doses of a niacin (≥1 g/day); concomitant use not recommended.1 132

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.1 91 92 93 103 132

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.1 132 Restrict use of 80-mg daily dosage.1 132

AHA/ACC recommends measuring CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.400

Discontinue if serum CK concentrations increase markedly or if myopathy is diagnosed or suspected.1 132

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; shock or hypotension; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).1 132

Immune-mediated Necrotizing Myopathy

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins.1 132 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; treatment with immunosuppressive agents may be required.1 132

Discontinue if IMNM suspected.1 Consider risk of IMNM carefully prior to initiating therapy with another statin; monitor for signs and symptoms.132

Hepatic Effects

Associated with increases in serum aminotransferase (AST, ALT) concentrations.1 132

Rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin.1 132

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage).1 132 400 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.200 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.200 400

ALT may emanate from muscle; therefore, concurrent increases in ALT and CK concentrations may indicate myopathy.132

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt simvastatin therapy.1 132 If an alternate etiology is not found, do not restart simvastatin.132

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1 132

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 HbA1c and fasting serum glucose concentrations reported.1 132 Possible increased risk of developing diabetes.200

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.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 fetal risk was thought to outweigh any possible benefit.405 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.405 Most pregnant patients should still discontinue statins because of the possibility of fetal harm; however, some patients (e.g., those with HoFH or established cardiovascular disease) may benefit from continued therapy.400 402 405 Consider patient's individual risks and benefits.402 405

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.405

Increased risk of miscarriage reported in pregnant women exposed to statins; however, not clear whether drug-related or due to other confounding factors.400 405

Lactation

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 Breastfeeding is not recommended during simvastatin therapy.1 132 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.400 402 405

Females and Males of Reproductive Potential

AHA/ACC cholesterol management guideline states 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 efficacy of simvastatin not established in children <10 years of age or in premenarchal girls for the treatment of heterozygous familial hypercholesterolemia (HeFH).1 132 Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.1 132

Safety and efficacy of simvastatin in fixed combination with ezetimibe not established in children <10 years of age for the treatment of HeFH or in pediatric patients with other types of hyperlipidemia.103

Geriatric Use

No overall differences in safety or efficacy relative to younger adults.1 132 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.1 132 Use with caution, since age ≥65 years is a predisposing factor for myopathy.1 132

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.400

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1 103 132

Contraindicated in patients with acute liver failure, active liver disease, unexplained persistent increases in serum aminotransferase concentrations, or decompensated cirrhosis.1 103 132

Renal Impairment

History of renal impairment may be a risk factor for development of rhabdomyolysis; monitor closely for adverse musculoskeletal effects.1 103 132

Use with caution in patients with severe renal impairment; dosage adjustments necessary in such patients.1 132

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.103 Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy.103

Pharmacogenomic Considerations

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, which can increase the risk for statin-associated musculoskeletal symptoms.97 99 372 373 374 381 500

In patients with phenotypes that result in increased statin exposure, consider potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions).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.500

SLCO1B1 decreased or possible decreased function phenotype or poor function phenotype: Increased exposure.500

CYP2C9 intermediate metabolizer or poor metabolizer phenotypes: Increased exposure.500

Combined SLCO1B1 (decreased or possible decreased or poor function) and CYP2C9 intermediate or poor metabolizer phenotypes: Increased exposure.500

Patients with such phenotypes may require lower doses or an alternative.500

Common Adverse Effects

Simvastatin (≥5%): Upper respiratory tract infections, headache, abdominal pain, constipation, nausea.1 132

Simvastatin/ezetimibe (≥2%): Headache, increased alanine aminotransferase, myalgia, upper respiratory tract infection, diarrhea.103

Drug Interactions

Metabolized by CYP3A4; does not inhibit CYP3A4.1 132

Substrate of organic anion transport protein (OATP) 1B1 and P-gp.1 132 339 381 501 502

When used in fixed combination with ezetimibe, consider interactions associated with ezetimibe.103

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cobicistat-containing drugs): May increase plasma simvastatin concentrations and increase risk of myopathy or rhabdomyolysis.1 132 Concomitant use contraindicated.1 132

CYP3A4 substrates: Simvastatin not expected to affect plasma concentrations of CYP3A4 substrates.1 132

Drugs Affecting or Affected by Transport Systems

OATP1B1 inhibitors: May increase plasma simvastatin acid concentrations and increase risk of myopathy.1 132 339

P-gp inhibitors: May increase plasma simvastatin exposure and increase risk of myopathy339 501 502

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Increased simvastatin and simvastatin acid peak plasma concentration and AUC;1 132 339 increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin1 91 92 93 132 339

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 20 mg daily1 132

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

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in substantially increased simvastatin and simvastatin acid AUC, peak plasma concentrations and increased risk of myopathy and/or rhabdomyolysis1 132

Concomitant use contraindicated; if short-term therapy with antifungal is unavoidable, interrupt simvastatin therapy during antifungal treatment1 132

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

Increased simvastatin and simvastatin acid peak plasma concentration and AUC;1 132 339 increased risk of myopathy and/or rhabdomyolysis when used with higher dosages of simvastatin1 132

Weigh benefits against risks of concomitant use1 132

Amlodipine: If used concomitantly, do not exceed simvastatin dosage of 20 mg daily1 132

Diltiazem, verapamil: If used concomitantly, do not exceed simvastatin dosage of 10 mg daily1 132

Cobicistat-containing preparations

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin peak plasma concentrations and exposure, and increased risk of myopathy and rhabdomyolysis1 132

Concomitant use contraindicated1 132

Colchicine

Myopathy, including rhabdomyolysis, reported1 132

Use concomitantly with caution1 132

Conivaptan

Rhabdomyolysis reported339

Avoid concomitant use339

Danazol

Increased risk of myopathy and/or rhabdomyolysis1 132

Concomitant use contraindicated1 132

Daptomycin

Cases of rhabdomyolysis reported with concomitant use1

Temporarily suspend simvastatin therapy1

Digoxin

Slight increase in plasma digoxin concentrations observed1 132

Appropriately monitor patients when simvastatin is initiated1 132

Dronedarone

Increased simvastatin and simvastatin acid peak plasma concentration and AUC, and risk of myopathy and/or rhabdomyolysis when used with higher dosages of simvastatin1 132 339

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 10 mg daily1 132

Efavirenz

Decreased simvastatin and simvastatin active metabolite AUCs503

Experts recommend simvastatin dose adjustment based on clinical response; do not exceed maximum dosage503

Etravirine

Decreased simvastatin possible503

Experts recommend simvastatin dose adjustment based on clinical response; do not exceed maximum dose503

Fenofibrate

Increased risk of myopathy and/or rhabdomyolysis1

Slight changes in peak plasma concentrations and AUC of simvastatin and simvastatin acid observed1 132

Use concomitantly with caution and weigh benefits against risks of concomitant use; no dosage adjustment required1 132

Monitor for signs and symptoms of myopathy, particularly during initiation and upward dose titration1

Gemfibrozil

Increased risk of myopathy and/or rhabdomyolysis1 132

Increased peak plasma concentrations and AUC of simvastatin and simvastatin acid observed1 132

Concomitant use contraindicated1 132

Grapefruit juice

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations, simvastatin AUC, and increased risk of myopathy and/or rhabdomyolysis1 132 378 379

Manufacturer and some clinicians recommend avoiding concomitant use;1 132 200 379

HIV protease inhibitors

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in substantially increased simvastatin AUC and plasma concentrations and increased risk of myopathy and/or rhabdomyolysis1 132

Concomitant use contraindicated1 132

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

Cyclosporine: Increased simvastatin AUC and increased risk of myopathy and/or rhabdomyolysis1 132

Everolimus, sirolimus, tacrolimus: Data more limited, but interaction potential expected to be similar to cyclosporine because of similar metabolism339

Cyclosporine: Concomitant use contraindicated1 132

Everolimus, sirolimus, tacrolimus: Some experts recommend avoiding concomitant use339

Lenacapavir

Increased simvastatin expected503

Experts recommend selecting lowest effective simvastatin dose while monitoring for adverse events503

Lomitapide

Increased peak plasma concentration and AUC of simvastatin and simvastatin acid1 132

Weigh benefits against risks of concomitant therapy132

When initiating lomitapide, reduce simvastatin dosage by 50%1 132

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)132

Macrolides (clarithromycin, erythromycin)

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin AUC and peak plasma concentrations and increased risk of myopathy and/or rhabdomyolysis1 132

Concomitant use contraindicated; if short-term therapy with anti-infective is unavoidable, interrupt simvastatin therapy during anti-infective treatment1 132

Nefazodone

Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis1 132

Concomitant use contraindicated1 132

Nevirapine

Decreased simvastatin possible503

Experts recommend simvastatin dose adjustment based on clinical response, do not exceed maximum dose503

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 patients1 132

Concomitant use of simvastatin and niacin dosages ≥1 g daily not recommended in Chinese patients1

If benefits outweigh risks of concomitant use in Chinese patients, limit dosage to <20 mg/day132

Propranolol

Pharmacokinetic interaction unlikely1 132

Ranolazine

Increased simvastatin and simvastatin acid peak plasma concentration and AUC; increased risk of myopathy and/or rhabdomyolysis when used with higher dosages of simvastatin1 132 339

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 20 mg daily1 132 339

Ticagrelor

Possible increased simvastatin plasma concentrations339

Some experts recommend limiting simvastatin dosage to 40 mg daily339

Warfarin

Possible increased PT/INR;1 132 339 bleeding observed with other statins1 132

Closely monitor PT/INR until stabilized if simvastatin is initiated or dosage is adjusted in patients receiving warfarin; thereafter, monitor PT at intervals usually recommended for patients receiving warfarin1 132 339
Simvastatin drug interactions (more detail)

Simvastatin Pharmacokinetics

Absorption

Bioavailability

Undergoes extensive first-pass metabolism in the liver.1 132 Absolute bioavailability is <5%.1 103 132 501 Peak plasma concentrations (including metabolites) attained in 4 hours.1 132

Onset

Maximal to near-maximal therapeutic response occurs within 4–6 weeks.1 132

Simvastatin/ezetimibe fixed-combination preparation (Vytorinand generic equivalents) is bioequivalent to corresponding dosages of the individual components.103

Food

Total (HMG-CoA reductase) inhibitor concentration not affected by a low fat meal.1 132

Simvastatin oral suspension: Simvastatin AUC decreased 18% and simvastatin β-hydroxyacid AUC increased 44% when administered with a high-fat meal.132

Special Populations

Patients with severe renal insufficiency may have higher systemic exposure.132

Distribution

Extent

Crosses the blood-brain barrier in animals.1 132

Not known whether distributed into human milk.1 132

Plasma Protein Binding

About 95% bound to plasma proteins.1 132

Elimination

Metabolism

Metabolized by CYP3A4 to active metabolites.1 132

Substrate of P-gp and organic anion transporter protein (OATP) 1B1.1 132 339 501 502

Elimination Route

Excreted in urine (13%) and feces (60%).1 132

Half-life

2–3 hours.129 130 131 501

Special Populations

Dialyzability, including metabolites, unknown.132

HMG-CoA reductase inhibitory activity levels higher in geriatric patients.1 132

Stability

Storage

Oral

Oral Suspension

20–25°C.132 Do not freeze or refrigerate.132 Protect from heat.132

Use within 30 days of opening.132

Tablets

Simvastatin: 5–30°C.1

Simvastatin/ezetimibe fixed combination: Well-closed containers at 20–25°C.103

Actions

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.

* 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

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

AHFS DI Essentials™. © Copyright 2025, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

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

2. Anon. Pravastatin, simvastatin, and lovastatin for lowering serum cholesterol concentrations. Med Lett Drugs Ther. 1992; 34:57-8. https://pubmed.ncbi.nlm.nih.gov/1593973

3. Mauro VF, MacDonald JL. Simvastatin: review of its pharmacology and clinical use. DICP. 1991; 25:257-64. https://pubmed.ncbi.nlm.nih.gov/2028634

4. Todd PA, Goa KL. Simvastatin: review of its pharmacological properties and therapeutic potential in hypercholesterolemia. Drugs. 1990; 40:583-607. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/7968073

12. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Drug Dispos. 1993; 24:195-202.

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. https://pubmed.ncbi.nlm.nih.gov/9834039

16. England DDF, Viles A, Labib S. Liver side effects associated with simvastatin therapy. Med J Aust. 1991; 155:61. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/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. https://pubmed.ncbi.nlm.nih.gov/1442579

31. Dart A, Jerums G, Nicholson G et al. A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol. 1997; 80:39-44. https://pubmed.ncbi.nlm.nih.gov/9205017

32. Jones P, Kafonek S, Laurora I et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol. 1998; 81:582-7. https://pubmed.ncbi.nlm.nih.gov/9514454

33. Smith GD, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? Br Med J. 1992; 304:431-4. Editorial.

34. Boccuzzi SJ, Bocanegra TS, Walker JF et al. Long-term safety and efficacy profile of simvastatin. Am J Cardiol. 1991; 68:1127-31. https://pubmed.ncbi.nlm.nih.gov/1951069

35. Lansberg PJ, Mitchel YB, Shapiro D et al. Long-term efficacy and tolerability of simvastatin in a large cohort of elderly hypercholesterolemic patients. Atherosclerosis. 1995; 116:153-62. https://pubmed.ncbi.nlm.nih.gov/7575771

36. Leone L, Ippoliti PF, Antonicelli R. Use of simvastatin plus cholestyramine in the treatment of lysosomal acid lipase deficiency. J Pediatr. 1991; 119:1008-9. https://pubmed.ncbi.nlm.nih.gov/1801793

37. Geiss HC, Parhofer KG, Schwandt P. Atorvastatin compared with simvastatin in patients with severe LDL hypercholesterolaemia treated by regular LDL apheresis. J Int Med. 1999; 245:47-55.

38. Nestel P, Simons L, Barter P et al. A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin. Atherosclerosis. 1997; 129:231-9. https://pubmed.ncbi.nlm.nih.gov/9105566

39. Tikkanen MJ, Bocanegra TM, Walker JF et al. Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol. Am J Med. 1989; 87(suppl A):47S-53S. https://pubmed.ncbi.nlm.nih.gov/2679084

40. Farnier M, Bonnefous F, Debbas N et al. Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern Med. 1994; 154:441-9. https://pubmed.ncbi.nlm.nih.gov/8117177

41. Steinmetz A, Schwartz T, Hehnke U et al. Multicenter comparison of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipoproteinemia. J Cardiovasc Pharmacol. 1996; 27:563-70. https://pubmed.ncbi.nlm.nih.gov/8847874

42. Branchi A, Rovellini A, Sommariva D. Differential effects of simvastatin and bezafibrate on apolipoprotein-defined high-density lipoprotein subfractions in patients with hypercholesterolemia. Curr Ther Res. 1996; 57:26-33.

43. Erkelens DW, Baggen MGA, Van Doormaal JJ et al. Clinical experience with simvastatin compared with cholestyramine. Drugs. 1988; 36(suppl 3):87-92. https://pubmed.ncbi.nlm.nih.gov/3254824

44. Tikkanen MJ, Laakso M, Ilmonen M et al. Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. Diabetes Care. 1999; 21:477-81.

45. Stein E, Kreisberg R, Miller V et al. Effects of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia. Arch Intern Med. 1990; 150:341-5. https://pubmed.ncbi.nlm.nih.gov/2405804

46. Ellen RLB, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol. 1998; 81(4A):60B-65B. https://pubmed.ncbi.nlm.nih.gov/9526816

47. Miettinen TA, Pyorala K, Olsson AG et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction of angina pectoris. Findings from the Scandinavian Simvastatin Survival Study (4S). Circulation. 1997; 96:4211-8. https://pubmed.ncbi.nlm.nih.gov/9416884

48. Pedersen TR, Kjekshus J, Pyorala K et al. Effect of simvastatin on ischemic signs and symptoms on the Scandinavian Simvastatin Survival study (4S). Am J Cardiol. 1998; 81:333-5. https://pubmed.ncbi.nlm.nih.gov/9468077

49. Ducobu J, Brasseur D, Chaudron JM et al. Simvastatin use in children. Lancet. 1992; 339:1488. https://pubmed.ncbi.nlm.nih.gov/1351171

50. Giannini SD, De Goes JM, Dereviacki BE et al. Simvastatin in the treatment of elderly patients with primary hypercholesterolemia. Curr Ther Res. 1994; 55:161-71.

51. MAAS Investigators. Effect of simvastatin on coronary atheroma: the multicentre anti-atheroma study (MAAS). Lancet. 1994; 344:633-8. https://pubmed.ncbi.nlm.nih.gov/7864934

53. Kroon AA, Aengevaeren WRM, van der Werf T et al. LDL-apheresis atherosclerosis regression study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996; 93:1826-35. https://pubmed.ncbi.nlm.nih.gov/8635262

65. Crouse III JR, Frohlich J, Ose L et al. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol. 1999; 83:1476-7. https://pubmed.ncbi.nlm.nih.gov/10335764

66. Hebert PR, Gaziano JM, Chan KS et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. JAMA. 1997; 278:313-21. https://pubmed.ncbi.nlm.nih.gov/9228438

68. Anon. Choice of lipid-regulating drugs. Med Lett Drugs Ther. 2001; 43:43-8. https://pubmed.ncbi.nlm.nih.gov/11378632

69. Serajuddin ATM, Ranadive SA, Mahoney EM. Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin. J Pharmaceu Sci. 1991; 80:830-4.

70. Raal FJ, Pilcher GJ, Illingworth DR et al. Expanded-dose simvastatin is effective in homozygous familial hypercholesterolemia. Atherosclerosis. 1997; 135:249-56. https://pubmed.ncbi.nlm.nih.gov/9430375

71. Civeira F, Cenarro A, Ferrando J et al. Comparison of the hypolipidemic effect of gemfibrozil versus simvastatin in patients with type III hyperlipoproteinemia. Am Heart J. 1999; 138:156-62. https://pubmed.ncbi.nlm.nih.gov/10385780

72. Illingworth DR, Stein EA, Knopp RH et al. A randomized multicenter trial comparing the efficacy of simvastatin and fluvastatin. J Cardiovasc Pharmacol Ther. 1996; 1:23-30. https://pubmed.ncbi.nlm.nih.gov/10684396

73. Schulte KL, Beil S. Efficacy and tolerability of fluvastatin and simvastatin in hypercholesterolaemic patients. Clin Drug Invest; 1996; 12:119-26.

74. Haffner SM, Alexander CM, Cook TJ et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels. Arch Intern Med. 1999; 159:2661-7. https://pubmed.ncbi.nlm.nih.gov/10597756

78. Vigna GB, Donega P, Passaro A et al. Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic subjects with borderline hypertriglyceridemia. Nutr Metab Cardiovasc Dis. 1999; 9:234-43. https://pubmed.ncbi.nlm.nih.gov/10656170

79. Stuyt PMJ, Mol MJTM, Stalenhoef AFH et al. Simvastatin in the effective reduction of plasma lipoprotein levels in familial dysbetalipoproteinemia (type III hyperlipoproteinemia). Am J Med. 1990; 88(1N):42N-45N. https://pubmed.ncbi.nlm.nih.gov/2368763

80. Stuyt PM, Mol MJ, Stalenhoef AF. Long-term effects of simvastatin in familial dysbetalipoproteinaemia. J Intern Med. 1991; 230:151-5. https://pubmed.ncbi.nlm.nih.gov/1865167

81. Feussner G, Eichinger M, Ziegler R. The influence of simvastatin alone or in combination with gemfibrozil on plasma lipids and lipoproteins in patients with type III hyperlipoproteinemia. Clin Investig. 1992; 70:1027-35. https://pubmed.ncbi.nlm.nih.gov/1472833

82. Wierzbicki AS, Lumb PJ, Chik G et al. Comparison of therapy with simvastatin 80 mg and atorvastatin 80 mg in patients with familial hypercholesterolemia. Int J Clin Pract. 1999; 53:609-11. https://pubmed.ncbi.nlm.nih.gov/10692755

83. Kastelein JJP, Isaacsohn JL, Ose L et al. Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Cardiol. 2000; 86:221-3. https://pubmed.ncbi.nlm.nih.gov/10913488

84. Ose L, Davidson MH, Stein EA et al. Lipid-altering efficacy and safety of simvastatin 80 mg daily. Clin Cardiol. 2000; 23:39-46. https://pubmed.ncbi.nlm.nih.gov/10680028

86. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002; 360:7-22. https://pubmed.ncbi.nlm.nih.gov/12114036

87. de Lemos JA, Blazing MA, Wiviott SD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004; 292:1307-16. https://pubmed.ncbi.nlm.nih.gov/15337732

89. Merck. Zetia (ezetimibe) tablets prescribing information. Whitehouse Station, NJ; 2013 Aug.

91. Schmidt GA, Hoehns JD, Purcell JL et al. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir. J Am Board Fam Med. 2007 Jul-Aug; 20:411-6.

92. Ricaurte B, Guirguis A, Taylor HC et al. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother. 2006; 40:753-7. https://pubmed.ncbi.nlm.nih.gov/16537817

93. Roten L, Schoenenberger RA, Krähenbühl S et al. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother. 2004; 38:978-81. https://pubmed.ncbi.nlm.nih.gov/15069169

95. Food and Drug Administration. Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. Rockville, MD; 2010 Mar 19. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm

96. Backes JM, Howard PA, Ruisinger JF et al. Does simvastatin cause more myotoxicity compared with other statins?. Ann Pharmacother. 2009; 43:2012-20. https://pubmed.ncbi.nlm.nih.gov/19920157

97. SEARCH Collaborative Group, Link E, Parish S et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008; 359:789-99. https://pubmed.ncbi.nlm.nih.gov/18650507

98. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010; 303:2486-94. https://pubmed.ncbi.nlm.nih.gov/20571015

99. Mitka M. Researchers worry about myopathy risk for patients taking high-dose simvastatin. JAMA. 2009; 301:261-2. https://pubmed.ncbi.nlm.nih.gov/19155447

100. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH). From ClinicalTrials.gov registry. Accessed 2010 Sep 20. http://clinicaltrials.gov/ct2/show/NCT00124072

101. Kastelein JJ, Akdim F, Stroes ES et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008; 358:1431-43. https://pubmed.ncbi.nlm.nih.gov/18376000

103. Organon. Vytorin (ezetimibe and simvastatin) tablets prescribing information. Jersey City, NJ; 2024 Mar.

113. Herd JA, Ballantyne CM, Farmer JA et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997; 80:278-86. https://pubmed.ncbi.nlm.nih.gov/9264419

115. Pitt B, Mancini GBJ, Ellis SG et al. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol. 1995; 26:1133-9. https://pubmed.ncbi.nlm.nih.gov/7594023

116. Crouse JR III, Byington RP, Bond MG et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol. 1995; 75:455-9. https://pubmed.ncbi.nlm.nih.gov/7863988

117. Jukema JW, Bruschke AVG, van Boven AJ et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation. 1995; 91:2528-40. https://pubmed.ncbi.nlm.nih.gov/7743614

118. Salonen R, Nyyssonen K, Porkkala-Sarataho E et al. The Kuopio Atherosclerosis Prevention Study (KAPS): Effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. Am J Cardiol. 1995; 76:34-9C.

119. Blankenhorn DH, Azen SP, Kramsch DM et al. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). The MARS Research Group. Ann Intern Med. 1993; 119:969-76.

120. Waters D, Higginson L, Gladstone P et al. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) Substudy. Circulation. 1995; 92:2404-10.

121. Brown G, Albers JJ, Fisher LD et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990; 323:1289-98. https://pubmed.ncbi.nlm.nih.gov/2215615

122. Furberg CD, Adams HP, Applegate WB et al for the Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994; 90:1679-87. https://pubmed.ncbi.nlm.nih.gov/7734010

123. DeGroot E, Jukema JW, Montauban AD et al. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol. 1998; 31:1561-7. https://pubmed.ncbi.nlm.nih.gov/9626835

124. Glorioso N, Troffa C, Filigheddu F et al. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension. 1999; 34:1281-6. https://pubmed.ncbi.nlm.nih.gov/10601131

125. Borghi C, Prandin MG, Costa FV et al. Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia. J Cardiovasc Pharmacol. 2000; 35:549-55. https://pubmed.ncbi.nlm.nih.gov/10774784

126. Ridker PM, Rifai N, Pfeffer MA et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999; 100:230-5. https://pubmed.ncbi.nlm.nih.gov/10411845

127. Kluft C, de Maat MPM, Leuven JAG et al. Statins and C-reactive protein. Lancet. 1999; 353:1274-5.

129. Blum CB. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Am J Cardiol. 1994; 73:3-11D.

130. Corsini A, Besllosta S, Baetta R et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 1999; 84:413-28. https://pubmed.ncbi.nlm.nih.gov/10665838

131. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Clin Pharmacokinet. 1997; 32:403-25. https://pubmed.ncbi.nlm.nih.gov/9160173

132. Salerno Pharmaceuticals. Flolipid (simvastatin) oral suspension prescribing information. Brooksville, FL; 2020 Sept.

200. Food and Drug Administration. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. Rockville, MD; 2012 Feb 28. From FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm

304. Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-56. https://pubmed.ncbi.nlm.nih.gov/18765433

306. Food and Drug Administration. Early communication about an ongoing safety review of ezetimibe/simvastatin (marketed as Vytorin), simvastatin (marketed as Zocor) and ezetimibe (marketed as Zetia): FDA investigates a report from the SEAS trial. Rockville, MD; 2008 Aug 21. Available from FDA website. Accessed 2008 Oct 9.

308. Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011; 377:2181-92. https://pubmed.ncbi.nlm.nih.gov/21663949

309. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; 372:2387-97. https://pubmed.ncbi.nlm.nih.gov/26039521

310. Boudreau DM, Yu O, Johnson J. Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf. 2010; 9:603-21. https://pubmed.ncbi.nlm.nih.gov/20377474

336. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012; 380:581-90. https://pubmed.ncbi.nlm.nih.gov/22607822

337. Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366:1267-78. https://pubmed.ncbi.nlm.nih.gov/16214597

338. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376:1670-81. https://pubmed.ncbi.nlm.nih.gov/21067804

339. Wiggins BS, Saseen JJ, Page RL et al. Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2016; 134:e468-e495.

351. Stone NJ, Robinson JG, Lichtenstein AH et al. Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Synopsis of the 2013 ACC/AHA Cholesterol Guideline. Ann Intern Med. 2014; :. https://pubmed.ncbi.nlm.nih.gov/24474185

353. ACCORD Study Group, Ginsberg HN, Elam MB et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1563-74. https://pubmed.ncbi.nlm.nih.gov/20228404

354. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al.. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67.

369. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014; 371:203-12. https://pubmed.ncbi.nlm.nih.gov/25014686

371. Anderson TJ, Boden WE, Desvigne-Nickens P et al. Safety profile of extended-release niacin in the AIM-HIGH trial. N Engl J Med. 2014; 371:288-90. https://pubmed.ncbi.nlm.nih.gov/25014706

372. Ramsey LB, Johnson SG, Caudle KE et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014; 96:423-8. https://pubmed.ncbi.nlm.nih.gov/24918167

373. SEARCH Collaborative Group, Link E, Parish S et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008; 359:789-99. https://pubmed.ncbi.nlm.nih.gov/18650507

374. Kitzmiller JP, Mikulik EB, Dauki AM et al. Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers Med. 2016; 9:97-106. https://pubmed.ncbi.nlm.nih.gov/27757045

376. Lee JW, Morris JK, Wald NJ. Grapefruit Juice and Statins. Am J Med. 2016; 129:26-9. https://pubmed.ncbi.nlm.nih.gov/26299317

378. Lilja JJ, Kivistö KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000; 68:384-90. https://pubmed.ncbi.nlm.nih.gov/11061578

379. Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol. 2004; 58:56-60. https://pubmed.ncbi.nlm.nih.gov/15206993

380. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc. 2000; 75:933-42. https://pubmed.ncbi.nlm.nih.gov/10994829

381. Romaine SP, Bailey KM, Hall AS et al. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J. 2010; 10:1-11. https://pubmed.ncbi.nlm.nih.gov/19884908

382. Johnson JA, Cavallari LH. Pharmacogenetics and cardiovascular disease--implications for personalized medicine. Pharmacol Rev. 2013; 65:987-1009. https://pubmed.ncbi.nlm.nih.gov/23686351

383. Isaacsohn J, Hunninghake D, Schrott H, Dujovne CA, Knopp R, Weiss SR, Bays H, Crouse JR 3rd, Davidson MH, Keilson LM, McKenney J, Korenman SG, Dobs AS, Stein E, Krauss RM, Maccubbin D, Cho M, Plotkin DJ, Mitchel YB. Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia. Clin Cardiol. 2003 Jan;26(1):18-24. doi: 10.1002/clc.4960260105. PMID: 12539808; PMCID: PMC6654219.

400. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139:e1082-e1143. https://pubmed.ncbi.nlm.nih.gov/30586774

401. American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S179-S218. doi: 10.2337/dc24-S010. PMID: 38078592; PMCID: PMC10725811.

402. Virani SS, Newby LK, Arnold SV et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023 Aug 29;148(9):e9-e119. Doi: 10.1161/CIR.0000000000001168. Epub 2023 Jul 20. Erratum in: Circulation. 2023 Sep 26;148(13):e148. Erratum in: Circulation. 2023 Dec 5;148(23):e186. PMID: 37471501.

403. Writing Committee; Lloyd-Jones DM, Morris PB, Ballantyne CM et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022 Oct 4;80(14):1366-1418. doi: 10.1016/j.jacc.2022.07.006. Epub 2022 Aug 25. Erratum in: J Am Coll Cardiol. 2023 Jan 3;81(1):104. PMID: 36031461.

404. Wiegman A, Gidding SS, Watts GF, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21;36(36):2425-37. doi: 10.1093/eurheartj/ehv157. Epub 2015 May 25. PMID: 26009596; PMCID: PMC4576143.

405. US Food and Drug Administration. FDA Drug Safety Communication: FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins. Silver Spring, MD; 2021 July 20. From FDA website. Accessed 2021 Sept 9. https://www.fda.gov/safety/medical-product-safety-information/statins-drug-safety-communication-fda-requests-removal-strongest-warning-against-using-cholesterol

406. Cheeley MK, Saseen JJ, Agarwala A et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. 2022; 16:361-375.

407. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-179.

408. Bajaj A, Cuchel M. Advancements in the treatment of homozygous familial hypercholesterolemia. J Atheroscler Thromb. 2022;29(8):1125-1135.

409. Watts GF, Gidding SS, Hegele RA, etc. International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolemia. Nat Rev Cardiol. 2023; Jun 15. [online ahead of print].

500. Cooper-DeHoff RM, Niemi M, Ramsey LB, et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. doi: 10.1002/cpt.2557. Epub 2022 Mar 11. PMID: 35152405; PMCID: PMC9035072.

501. Sadowska A, Osiński P, Roztocka A, Kaczmarz-Chojnacka K, Zapora E, Sawicka D, Car H. Statins-From Fungi to Pharmacy. Int J Mol Sci. 2023 Dec 29;25(1):466. doi: 10.3390/ijms25010466. PMID: 38203637; PMCID: PMC10779115.

502. Balasubramanian R, Maideen NMP. HMG-CoA Reductase Inhibitors (Statins) and their Drug Interactions Involving CYP Enzymes, P-glycoprotein and OATP Transporters-An Overview. Curr Drug Metab. 2021;22(5):328-341. doi: 10.2174/r2029200222666210114122729. PMID: 33459228.

503. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. (February 27, 2024). Accessed 2024 Apr 18. https://clinicalinfo.hiv.gov/en/guidelines

504. Gagné C, Gaudet D, Bruckert E; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002 May 28;105(21):2469-75. doi: 10.1161/01.cir.0000018744.58460.62. PMID: 12034651.

505. van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, Veltri E, Avis HJ, Kastelein JJ. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol. 2008 Oct 21;52(17):1421-9. doi: 10.1016/j.jacc.2008.09.002. PMID: 18940534.

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