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Simvastatin (Monograph)

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

Medically reviewed by Drugs.com on Dec 4, 2023. 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 patients with CHD or CHD risk equivalents (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease) to reduce the risk of total mortality by reducing CHD death, to reduce the risk of nonfatal MI and stroke, and to reduce the need for revascularization procedures.1 132

Extensive evidence demonstrates that statins can substantially reduce LDL-cholesterol concentrations and associated risk of atherosclerotic cardiovascular disease (ASCVD); may be used for secondary prevention or primary prevention in high-risk patients.336 337 338 350 400

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

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.400

In the IMPROVE-IT study, addition of ezetimibe to simvastatin therapy in post-ACS patients further reduced LDL cholesterol and improved cardiovascular outcomes.309

Randomized controlled studies do not support the addition of niacin to statin-based therapy, and such combination may increase the risk of adverse effects.354 371 400

In the SHARP study, fixed-combination preparation of simvastatin and ezetimibe was found to reduce risk of major vascular and atherosclerotic events in patients with chronic kidney disease, a population known to be at increased risk of cardiovascular disease.103 308

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).1 3 4 18

May use in combination or fixed combination with ezetimibe for additive antilipemic effects.89 103

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.105 353

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.1

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.1 May use in combination or fixed combination with ezetimibe for additive antilipemic effects.89 103

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).1

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum triglyceride concentrations in the management of hypertriglyceridemia (Fredrickson type IV).1

Also has been used to reduce total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus† [off-label] (diabetic dyslipidemia),13 55 58 59 74 cardiac† [off-label]76 or renal† [off-label] transplantation,77 or nephrotic syndrome† [off-label].63 64

Simvastatin Dosage and Administration

General

Patient Monitoring

Administration

Oral Administration

Administer orally (as tablets or oral suspension) in the evening without regard to meals.1 2 3 4 132

Simvastatin/ezetimibe fixed-combination preparation: Administer orally in the evening without regard to meals.103

Concomitant use of certain drugs can increase plasma concentrations of simvastatin and risk of myopathy.1 103 379 (See Specific Drugs and Foods under Interactions.)

Pharmacogenetic Testing

Pharmacogenetic testing for SLCO1B1 (gene encoding organic anion transport protein [OATP] 1B1) may be useful for identifying patients at increased risk of simvastatin-induced myopathy.372 Patients with a specific variant of SLCO1B1 (rs4149056T>C) are likely to have increased systemic exposure to simvastatin and increased risk of muscle toxicity.372 (See Pharmacogenomics of Simvastatin-induced Myopathy under Cautions.)

The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides dosing guidelines based on results of SLCO1B1 genotyping.372 CPIC recommends reducing simvastatin dosage (e.g., to 20 mg daily) or using an alternative statin (e.g., rosuvastatin, pravastatin) in individuals with SLCO1B1 genotypes associated with an intermediate or high risk of myopathy.372 These individuals include those with 2 reduced-function alleles at rs4149056 (CC genotype) and those with 1 reduced-function allele plus 1 normal-function allele at rs4149056 (TC genotype).372 Consider limitations of SLCO1B1 genotyping when interpreting and applying results.372

Dosage

Pediatric Patients

Dyslipidemias
Oral

Children 10–17 years of age: Initially, 10 mg once daily.1

Adjust dosage at intervals of ≥4 weeks until the desired effect on lipoprotein concentrations is observed.1 Recommended dosage range is 10–40 mg daily.1

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

Dyslipidemias
Oral

Initially, 10 or 20 mg once daily.1

Patients with CHD or CHD risk equivalents: Initially, 40 mg once daily.1

Adjust dosage at intervals of ≥4 weeks until desired effect on lipoprotein concentrations is observed.1 Usual dosage range is 5–40 mg daily.1

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.1 Restrict use of 80-mg daily dosage.1 (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.103 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).103 Usual maintenance dosage 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 (See Prescribing Limits under Dosage and Administration.)

Homozygous Familial Hypercholesterolemia
Oral

40 mg once daily in the evening.1

Simvastatin/ezetimibe fixed combination (Vytorin): Simvastatin 40 mg/ezetimibe 10 mg once daily in the evening.103

Prescribing Limits

Pediatric Patients

Dyslipidemias
Oral

Children 10–17 years of age: Maximum 40 mg once daily.1

Adults

Reduction in Risk of Cardiovascular Events or Management of Dyslipidemias
Oral

Restrict use of 80-mg daily dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects.1 (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.1

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.103 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.103

Special Populations

Hepatic Impairment

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

Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.1

Renal Impairment

Simvastatin

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

Severe renal impairment: Initially, 5 mg once daily.1 Use with caution; monitor closely.1

Simvastatin/Ezetimibe Fixed Combination

Mild renal impairment (estimated GFR ≥60 mL/minute per 1.73 m2): No dosage adjustment needed.103

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.103 (See Renal Impairment under Cautions.)

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

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])257 with or without acute renal failure secondary to myoglobinuria also reported; rare fatalities have occurred.1

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins.1 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.1

Incidence of myopathy, including rhabdomyolysis, reportedly highest during first year and then notably decreased during subsequent years of treatment.1

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

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.1 90 91 92 93 103

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

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).1

Pharmacogenomics of Simvastatin-induced Myopathy

Genetic polymorphism of SLCO1B1, the gene encoding OATP1B1, can affect pharmacokinetics of simvastatin and risk of myopathy.97 99 372 373 374 381 Many variants in SLCO1B1 have been identified, but the c.521T>C variant (rs4149056) is most clinically relevant.372 374 Relationship between rs4149056 and simvastatin-induced muscle toxicity clearly established.372 373

Genetic testing for SLCO1B1 may be considered to identify patients at increased risk of developing simvastatin-induced myopathy.372

Hepatic Effects

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

Pancreatitis,1 hepatitis,1 jaundice,1 increased serum alkaline phosphatase concentrations,1 increased serum γ-glutamyl transpeptidase concentrations,1 and fatal and nonfatal hepatic failure1 reported.1

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage).1 400 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.350 400

ALT may emanate from muscle; therefore, concurrent increases in ALT and CK concentrations may indicate myopathy.1 (See Musculoskeletal Effects under Cautions.)

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

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported.1 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

Endogenous Steroid Production

No substantial effects on adrenal reserve or basal plasma cortisol concentration observed with simvastatin.1

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.1

Effects on pituitary-gonadal axis in premenopausal women unknown.1

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.1

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy).1 Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline.200 Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.200

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.200

If manifestations consistent with cognitive impairment occur, National Lipid Association (NLA) statin safety assessment task force recommends evaluating and managing patients appropriately.202

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.1

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.304 306 The results of 2 subsequent randomized trials (SHARP and IMPROVE-IT) found no such association.305 307 308 309 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.307

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 homozygous familial hypercholesterolemia or established cardiovascular disease) may benefit from continued therapy.400 405 Consider patient's individual risks and benefits.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 milk;1 however, a small amount of another statin is distributed into milk.1 Use is contraindicated in nursing women; women who require simvastatin therapy should not breast-feed their infants.1 Discontinue nursing or the drug.1 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.400 405

Pediatric Use

Safety and efficacy of simvastatin not established in children <10 years of age or in premenarchal girls.1 Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.1

Safety and efficacy of simvastatin in fixed combination with ezetimibe not established in children <10 years of age or in premenarchal girls.103 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.103

Geriatric Use

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

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

Simvastatin/ezetimibe fixed combination: No overall differences in safety or efficacy relative to younger patients; however, increased sensitivity cannot be ruled out.103 Use with caution, since age ≥65 years is a predisposing factor for myopathy.1

Hepatic Impairment

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

Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.1

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.1

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

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 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Upper respiratory tract infections, headache, abdominal pain, constipation, nausea.1

Drug Interactions

Metabolized by CYP3A4; does not inhibit CYP3A4.1

Substrate of organic anion transport protein (OATP) 1B1.1 381

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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

Drugs Affecting OATP

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

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Increased simvastatin peak plasma concentration and AUC;1 339 increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin1 90 91 92 93 339

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

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

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

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

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

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

Weigh benefits against risks of concomitant use1

Amlodipine: If used concomitantly, do not exceed simvastatin dosage of 20 mg daily1 339

Diltiazem, verapamil: If used concomitantly, do not exceed simvastatin dosage of 10 mg daily1 339

Cobicistat-containing preparations

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

Concomitant use contraindicated; if short-term therapy with a cobicistat-containing preparation is unavoidable, interrupt simvastatin therapy during treatment1

Colchicine

Myopathy, including rhabdomyolysis, reported1

Use concomitantly with caution1

Conivaptan

Rhabdomyolysis reported339

Avoid concomitant use339

Danazol

Increased risk of myopathy and/or rhabdomyolysis1

Concomitant use contraindicated1

Daptomycin

Cases of rhabdomyolysis reported with concomitant use1

Temporarily suspend simvastatin therapy1

Digoxin

Slight increase in plasma digoxin concentrations observed1

Appropriately monitor patients when simvastatin is initiated1

Dronedarone

Increased simvastatin peak plasma concentration and AUC, and risk of myopathy and/or rhabdomyolysis1 339

Weigh benefits against risks of concomitant use; if used concomitantly, do not exceed simvastatin dosage of 10 mg daily1 339

Fenofibrate

Increased risk of myopathy and/or rhabdomyolysis1

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

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

Gemfibrozil

Increased risk of myopathy and/or rhabdomyolysis1

Concomitant use contraindicated1

Grapefruit juice

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

Manufacturer and some clinicians recommend avoiding concomitant use1 379

HIV protease inhibitors

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

Concomitant use contraindicated; if short-term therapy with HIV protease inhibitor is unavoidable, interrupt simvastatin therapy during treatment1

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

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

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

Cyclosporine: Concomitant use contraindicated1

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

Lomitapide

Increased peak plasma concentration and AUC of simvastatin and simvastatin acid1

Weigh benefits against risks of concomitant therapy1

When initiating lomitapide, reduce simvastatin dosage by 50%1

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)1

Macrolides (clarithromycin, erythromycin)

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

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

Mipomersen

No clinically relevant pharmacokinetic interactions observed375

No dosage adjustment of simvastatin or mipomersen required375

Nefazodone

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

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

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

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)369 371

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

Propranolol

Pharmacokinetic interaction unlikely1

No dosage adjustments required1

Ranolazine

Increased simvastatin peak plasma concentration and AUC; increased risk of myopathy and/or rhabdomyolysis1 339

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

Telithromycin

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

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

Ticagrelor

Possible increased simvastatin plasma concentrations339

Some experts recommend limiting simvastatin dosage to 40 mg daily339

Warfarin

Possible increased PT;1 339 bleeding observed with other statins1

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 warfarin1 339
Simvastatin drug interactions (more detail)

Simvastatin Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; undergoes extensive first-pass metabolism in the liver.1 Absolute bioavailability is <5%.1 103 Peak plasma concentrations are attained at 4 hours.1

Onset

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

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

Special Populations

Patients with severe renal insufficiency may have higher systemic exposure.1 (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Distributed mainly to the liver.1 Crosses the blood-brain barrier.1

Not known whether distributed into milk.1

Plasma Protein Binding

About 95% bound to plasma proteins.1

Elimination

Metabolism

Metabolized by CYP3A4 to active metabolites.1

Elimination Route

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

Half-life

Most statins generally have short half-lives (between 0.5–3 hours).129 130 131

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

Preparations

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

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

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

Simvastatin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

4 mg per mL

Flolipid

Salerno

8 mg per mL

Flolipid

Salerno

Tablets, film-coated

5 mg*

Simvastatin Tablets

Zocor

Merck

10 mg*

Simvastatin Tablets

Zocor

Merck

20 mg*

Simvastatin Tablets

Zocor

Merck

40 mg*

Simvastatin Tablets

Zocor

Merck

80 mg*

Simvastatin Tablets

Zocor

Merck

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

Simvastatin Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

20 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

40 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

80 mg with Ezetimibe 10 mg*

Ezetimibe and Simvastatin Tablets

Vytorin

Merck

AHFS DI Essentials™. © Copyright 2024, Selected Revisions December 13, 2021. 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. Merck & Co., Inc. Zocor (simvastatin) tablets prescribing information. Whitehouse Station, NJ; 2020 Apr.

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

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

4. Todd PA, Goa KL. Simvastatin: review of its pharmacological properties and therapeutic potential in hypercholesterolemia. Drugs. 1990; 40:583-607. http://www.ncbi.nlm.nih.gov/pubmed/2083515?dopt=AbstractPlus

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

6. Brown MS, Goldstein JL. The hyperlipoproteinemias and other disorders of lipid metabolism. In: Harrison’s principles of internal medicine. 11th ed. New York: McGraw-Hill Book Co; 1987:1650-61.

7. Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Ann Rev Biochem. 1977; 46:897-930. http://www.ncbi.nlm.nih.gov/pubmed/197883?dopt=AbstractPlus

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

9. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988; 148:36-69. http://www.ncbi.nlm.nih.gov/pubmed/3422148?dopt=AbstractPlus

10. National Institutes of Health Office of Medical Applications of Research. Consensus conference: lowering blood cholesterol to prevent heart disease. JAMA. 1985; 25:2080-6.

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. http://www.ncbi.nlm.nih.gov/pubmed/7968073?dopt=AbstractPlus

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

13. Campana C, Iacona I, Regazzi MB et al. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacother. 1995; 29:235-9. http://www.ncbi.nlm.nih.gov/pubmed/7606066?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9834039?dopt=AbstractPlus

15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993; 269:3015-23. http://www.ncbi.nlm.nih.gov/pubmed/8501844?dopt=AbstractPlus

16. England DDF, Viles A, Labib S. Liver side effects associated with simvastatin therapy. Med J Aust. 1991; 155:61. http://www.ncbi.nlm.nih.gov/pubmed/2067448?dopt=AbstractPlus

17. Manson JM, Freyssinges C, Ducrocq MB et al. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reproductive Toxicology. 1996; 10:439-46. http://www.ncbi.nlm.nih.gov/pubmed/8946557?dopt=AbstractPlus

18. Merck. Zocor formulary information. West Point, PA; 1999 Sep.

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. http://www.ncbi.nlm.nih.gov/pubmed/9708659?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8005129?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9024733?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9208356?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8458112?dopt=AbstractPlus

25. Expert Panel on Detection, Evaluation, and Treatment of high Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of high Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285:2486-97. http://www.ncbi.nlm.nih.gov/pubmed/11368702?dopt=AbstractPlus

26. The Expert Panel. Second Report of the Expert Panel on Detection, Evaluation , and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994; 89:1329-1445.

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. http://www.ncbi.nlm.nih.gov/pubmed/1468089?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8517385?dopt=AbstractPlus

30. The European Study Group. Efficacy and tolerability of simvastatin and pravastatin in patients with primary hypercholesterolemia. Am J Cardiol. 1992; 70:1281-6. http://www.ncbi.nlm.nih.gov/pubmed/1442579?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9205017?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9514454?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/1951069?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7575771?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/1801793?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9105566?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/2679084?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8117177?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8847874?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/3254824?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/2405804?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9526816?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9416884?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9468077?dopt=AbstractPlus

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

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. http://www.ncbi.nlm.nih.gov/pubmed/7864934?dopt=AbstractPlus

52. Merck, West Point, PA: Personal communication.

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. http://www.ncbi.nlm.nih.gov/pubmed/8635262?dopt=AbstractPlus

54. Jenkins GH, Grieve LA, Yacoub MH et al. Effect of simvastatin on ejection fraction in cardiac transplant patients. Am J Cardiol. 1996; 78:1453-6. http://www.ncbi.nlm.nih.gov/pubmed/8970428?dopt=AbstractPlus

55. Jaeger BR, Meiser B, Nagel D et al. Aggressive lowering of fibrinogen and cholesterol in the prevention of graft vessel disease after heart transplantation. Circulation. 1997; 96(suppl II):II154-II158.

56. American Heart Association Committee to Design a Dietary Treatment of Hyperlipoproteinemia. Recommendations for treatment of hyperlipidemia in adults: a joint statement of the Nutrition Committee and the Council on Arteriosclerosis. Circulation. 1984; 69:1065-90A. http://www.ncbi.nlm.nih.gov/pubmed/6713610?dopt=AbstractPlus

57. Reviewers’ comments (personal observations) on Lovastatin 24:06.

58. Wenke K, Meiser B, Thiery J et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation. Circulation. 1997; 96:1398-402. http://www.ncbi.nlm.nih.gov/pubmed/9315523?dopt=AbstractPlus

59. Pyorala K, Olsson AG, Pedersen T et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes care. 1997; 20:614-20. http://www.ncbi.nlm.nih.gov/pubmed/9096989?dopt=AbstractPlus

60. Christenson JT. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG. E J Cardio-thoracic Surg. 1999; 15:394-400.

61. Woolfson RG, Lachmann H. Improvement in renal cholesterol emboli syndrome after simvastatin. Lancet. 1998; 351:1331-2. http://www.ncbi.nlm.nih.gov/pubmed/9643803?dopt=AbstractPlus

62. Rumpf KW, Schult S, Mueller GA. Simvastatin treatment in cholesterol emboli syndrome. Lancet. 1998; 352: 321-2. http://www.ncbi.nlm.nih.gov/pubmed/9690435?dopt=AbstractPlus

63. Sanjad SA, Al-Abbad A, Al-Shorafa S. Management of hyperlipidemia in children with refractory nephrotic syndrome: the effect of statin therapy. J Pediatr. 1997; 130:470-4. http://www.ncbi.nlm.nih.gov/pubmed/9063427?dopt=AbstractPlus

64. Olbricht CJ, Wanner C, Thiery J et al. Simvastatin in nephrotic syndrome. Kidney International. 1999; 56(Suppl 71):S113-S116.

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. http://www.ncbi.nlm.nih.gov/pubmed/10335764?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9228438?dopt=AbstractPlus

67. McKenney JM. Dyslipidemias. In: Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver: Applied Therapeutics, Inc; 1995; 9-1-9-23.

68. Anon. Choice of lipid-regulating drugs. Med Lett Drugs Ther. 2001; 43:43-8. http://www.ncbi.nlm.nih.gov/pubmed/11378632?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9430375?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10385780?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10684396?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10597756?dopt=AbstractPlus

75. Merck & Co. Zocor (simvastatin) tablets prescribing information. West Point, PA; 1999 Nov.

76. Keogh A, Macdonald P, Kaan A et al. Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation. Clin Heart Lung Transplant. 2000; 19:529-37.

77. Lepre F, Rigby R, Hawley C et al. A double-blind placebo controlled trial of simvastatin for the treatment of dyslipidaemia in renal allograft recipients. Clin Transplantation. 1999; 13:520-5.

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. http://www.ncbi.nlm.nih.gov/pubmed/10656170?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/2368763?dopt=AbstractPlus

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

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. http://www.ncbi.nlm.nih.gov/pubmed/1472833?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10692755?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10913488?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10680028?dopt=AbstractPlus

85. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm

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. http://www.ncbi.nlm.nih.gov/pubmed/12114036?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15337732?dopt=AbstractPlus

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

90. Food and Drug Administration. Information for healthcare professionals: Simvastatin (marketed as Zocor and generics), ezetimibe/simvastatin (marketed as Vytorin), niacin extended-release/simvastatin (marketed as Simcor), used with amiodarone (Cordarone, Pacerone). 2008 Aug 8. From FDA website. Accessed 2008 Aug 12. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124362.htm

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. http://www.ncbi.nlm.nih.gov/pubmed/16537817?dopt=AbstractPlus

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

94. Food and Drug Administration. Follow-up to the January 25, 2008 early communication about an ongoing data review for ezetimibe/simvastatin (marketed as Vytorin), ezetimibe (marketed as Zetia), and simvastatin (marketed as Zocor). Rockville, MD; 2009 Jan 8. Available from FDA website. Accessed 2009 Sep 10. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079524.htm

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. http://www.ncbi.nlm.nih.gov/pubmed/19920157?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/18650507?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/20571015?dopt=AbstractPlus

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

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. http://www.ncbi.nlm.nih.gov/pubmed/18376000?dopt=AbstractPlus

103. Merck & Co., Inc. Vytorin (ezetimibe and simvastatin) tablets prescribing information. Whitehouse Station, NJ; 2016 Oct.

104. Merck & Co., Inc. Zocor (simvastatin) tablets prescribing information. Whitehouse Station, NJ; 2002 May.

105. Abbvie. Trilipix (fenofibric acid) capsules prescribing information. North Chicago, IL; 2013 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. http://www.ncbi.nlm.nih.gov/pubmed/9264419?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7594023?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7863988?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7743614?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/2215615?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7734010?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9626835?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10601131?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10774784?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10411845?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10665838?dopt=AbstractPlus

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

132. Salerno Pharmaceuticals. Flolipid (simvastatin) oral suspension prescribing information. Brooksville, FL; 2017 Oct.

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

202. McKenney JM, Davidson MH, Jacobson TA et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006; 97(suppl):89-94C.

257. Pasternak RC, Smith SC Jr, Bairey-Merz CN et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute. Circulation. 2002;106:1024-8.

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. http://www.ncbi.nlm.nih.gov/pubmed/18765433?dopt=AbstractPlus

305. Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008; 359:1357-66. http://www.ncbi.nlm.nih.gov/pubmed/18765432?dopt=AbstractPlus

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. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm162899.htm

307. Food and Drug Administration. Follow-Up to the August 2008 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; 2009 Dec 21. Available from FDA website. Accessed 2008 Oct 9. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm194964.htm

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3145073&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/21663949?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/26039521?dopt=AbstractPlus

310. Boudreau DM, Yu O, Johnson J. Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf. 2010; 9:603-21. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2910322&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/20377474?dopt=AbstractPlus

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3437972&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/22607822?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/16214597?dopt=AbstractPlus

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2988224&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/21067804?dopt=AbstractPlus

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.

350. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Epub ahead of print] .

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; :. http://www.ncbi.nlm.nih.gov/pubmed/24474185?dopt=AbstractPlus

352. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol. 2013 Nov; S0735-1097(13)06029-4.

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2879499&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/20228404?dopt=AbstractPlus

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.

356. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011 May 24;123(20):2292-333.

357. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011 Dec;128 Suppl 5:S213-56.

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. http://www.ncbi.nlm.nih.gov/pubmed/25014686?dopt=AbstractPlus

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4156937&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/25014706?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/24918167?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/18650507?dopt=AbstractPlus

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

375. Genzyme Corporation. Kynamro (mipomersen sodium) injection solution for subcutaneous injection prescribing information. Cambridge, MA; 2013 Jan.

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

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. http://www.ncbi.nlm.nih.gov/pubmed/11061578?dopt=AbstractPlus

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1884539&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/15206993?dopt=AbstractPlus

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

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. http://www.ncbi.nlm.nih.gov/pubmed/19884908?dopt=AbstractPlus

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

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC7403606&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/30586774?dopt=AbstractPlus

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

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