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Simvastatin

Pronunciation

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

Introduction

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

Uses for Simvastatin

Prevention of Cardiovascular Events

Adjunct to nondrug therapies (e.g., dietary management) in patients with CHD or CHD risk equivalents (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease) to reduce the risk of total mortality by reducing CHD death, to reduce the risk of nonfatal MI and stroke, and to reduce the need for coronary and non-coronary revascularization procedures.1

Slowing progression or inducing regression of atherosclerosis in coronary arteries by reducing intimal-medial wall thickness.1 48 51 53

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 (as Vytorin) for additive antilipemic effects.88 89

Slideshow: Grapefruit and Medicines: A Possible Deadly Mix?

Grapefruit and grapefruit juice can react adversely with over 85 prescription medications.

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 (as Vytorin) for additive antilipemic effects.88 89

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

Reduction of total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia),13 55 58 59 74 cardiac76 or renal transplantation,77 or nephrotic syndrome.63 64

Simvastatin Dosage and Administration

General

  • Patients should be placed on a standard lipid-lowering diet before initiation of simvastatin therapy and should remain on this diet during treatment with the drug;1 in patients with CHD or CHD risk equivalents, initiate simvastatin simultaneously with dietary management.1

Monitoring during Antilipemic Therapy

  • Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.

Administration

Oral Administration

Administer orally in the evening without regard to meals.1 2 3 4

Simvastatin/ezetimibe fixed-combination preparation: Administer orally in the evening without regard to meals.88

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

Prevention of Cardiovascular Events or Management of 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 LDL-cholesterol target goal cannot be achieved 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.102 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 Determine serum lipoprotein concentrations ≥2 weeks after initiation of therapy and adjust dosage as needed.102 Usual maintenance dosage is simvastatin 10–40 mg and ezetimibe 10 mg once daily.102 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.102 Restrict use of simvastatin 80 mg/ezetimibe 10 mg dosage.102 (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.102

Prescribing Limits

Pediatric Patients

Dyslipidemias
Oral

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

Adults

Prevention of Cardiovascular Events or Management of Dyslipidemias
Oral

Restrict use of 80-mg daily dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects.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.102 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.102

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

Simvastatin/Ezetimibe Fixed Combination

Mild hepatic impairment: No dosage adjustment needed.103

Moderate or severe hepatic impairment: Use not recommended.102

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.)

Cautions for Simvastatin

Contraindications

  • Concomitant use with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, clarithromycin, erythromycin, telithromycin, nefazodone), gemfibrozil, cyclosporine, or danazol.1 (See Specific Drugs and Foods under Interactions.)

  • Active liver disease, including unexplained, persistent elevations of serum aminotransferases.1

  • Pregnancy or lactation.1 Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards.1

  • Known hypersensitivity to simvastatin or any ingredient in the formulation.1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm.1 Congenital anomalies following intrauterine exposure to statins reported rarely.1

Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards.1 If the patient becomes pregnant while taking the drug, immediately discontinue therapy and apprise the patient of the potential hazard to the fetus.1

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

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

Risk of myopathy increased in patients receiving higher dosages of statins; patients with multisystem disease (e.g., renal or hepatic impairment), concurrent serious infections, or uncontrolled hypothyroidism; geriatric patients (≥65 years of age); women; patients with small body frame and frailty; and patients undergoing surgery (i.e., during perioperative periods).1

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.1 88 90 91 92 93 103 (See Contraindications under Cautions and also see Interactions.)

Risk of myopathy, including rhabdomyolysis, is greater with 80-mg daily dosage compared with lower daily dosages or compared with other statins with similar or greater LDL-cholesterol lowering efficacy.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

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

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 damage201 ).1 Although manufacturers previously recommended more frequent monitoring,104 FDA concluded that serious statin-related liver injury is rare and unpredictable, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.200

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

Also see Hepatic Impairment under Cautions.

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported.1 200 Possible increased risk of developing diabetes.200 May need to monitor glucose concentrations following initiation of statin therapy.201

FDA states that cardiovascular benefits of statins outweigh these small increased risks.200

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).1 200 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

Fixed combination of simvastatin and ezetimibe reported in one trial (Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] study) to be possibly associated with increased risk of cancer. Preliminary results of this study in approximately 1900 patients revealed a higher incidence of cancer and fatal cancer in patients receiving the fixed-combination preparation (11.1 and 4.1%, respectively) compared with those receiving placebo (7.5 and 2.5%, respectively). However, interim data from 2 ongoing randomized trials evaluating >20,000 patients with chronic kidney disease or acute coronary syndrome showed no increased risk of cancer following use of the fixed-combination preparation. FDA will review final study report of the SEAS trial to assess additional safety data and provide insight into the risk of cancer.

Use of Fixed Combinations

When used in fixed combination with ezetimibe, consider the cautions, precautions, and contraindications associated with ezetimibe.88

Specific Populations

Pregnancy

Category X.1 (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)

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

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.102 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.102

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

Simvastatin/ezetimibe fixed combination: No overall differences in safety or efficacy relative to younger patients; however, increased sensitivity cannot be ruled out.88 103 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

Simvastatin/ezetimibe fixed combination: Use not recommended in patients with moderate or severe hepatic impairment.102 (See Hepatic Impairment under Dosage and Administration.)

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 (See Renal Impairment under Dosage and Administration.)

In patients with moderate to severe renal impairment receiving simvastatin 20 mg/ezetimibe 10 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.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

Interactions for Simvastatin

Metabolized by CYP3A4; does not inhibit CYP3A4.1

When used in fixed combination with ezetimibe, consider interactions associated with ezetimibe.103 No formal drug interaction studies to date with fixed-combination preparation other than that with extended-release niacin.103 (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic (increased plasma simvastatin concentrations) and pharmacodynamic (increased risk of myopathy or rhabdomyolysis) interaction.1 Concomitant use contraindicated.1 (See Contraindications under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

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

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

Antifungals, azoles

Itraconazole, ketoconazole, or posaconazole: Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in substantially increased simvastatin peak plasma concentration and/or AUC and increased risk of myopathy and/or rhabdomyolysis1

Voriconazole: Possible inhibition of simvastatin metabolism, resulting in increased risk of myopathy and/or rhabdomyolysis1

Itraconazole, ketoconazole, or posaconazole: Concomitant use contraindicated; if therapy with antifungal is unavoidable, interrupt simvastatin therapy during antifungal treatment1

Voriconazole: If concomitant use is unavoidable, consider adjusting simvastatin dosage1

Antileukotrienes (e.g., zileuton)

Possible inhibition of CYP3A4

Concomitant use generally should be avoided or undertaken with caution

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

Increased simvastatin peak plasma concentration and AUC;1 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

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

Colchicine

Myopathy, including rhabdomyolysis, reported1

Use concomitantly with caution1

Cyclosporine

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

Concomitant use contraindicated1

Danazol

Increased risk of myopathy and/or rhabdomyolysis1

Concomitant use contraindicated1

Digoxin

Possible increased plasma digoxin concentrations1

Appropriately monitor patients receiving digoxin when simvastatin is initiated1

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

Increased risk of myopathy and/or rhabdomyolysis1

Fenofibrate: Pharmacokinetic interaction unlikely1

Gemfibrozil: Increased peak plasma concentration and AUC of simvastatin acid1

Gemfibrozil: Concomitant use contraindicated1

Other fibric acid derivatives (e.g., fenofibrate): Use concomitantly with caution; weigh benefits against risks of concomitant use1

Fluvoxamine

Possible inhibition of CYP3A4

Concomitant use generally should be avoided or undertaken with caution

Glyburide

Possible increased bioavailability of glyburide

Grapefruit juice

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

Concomitant use should be discouraged, or simvastatin dosage reduced accordingly;14 avoid large quantities (>1 quart daily) of grapefruit juice1

HCV protease inhibitors (boceprevir, telaprevir)

Boceprevir or telaprevir: Inhibition of simvastatin metabolism via CYP3A4, resulting in increased simvastatin plasma concentrations and increased risk of myopathy and/or rhabdomyolysis1

Boceprevir or telaprevir: Concomitant use contraindicated1

HIV protease inhibitors

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

Concomitant use contraindicated1

Macrolides (clarithromycin, erythromycin)

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

Clarithromycin or erythromycin: Concomitant use contraindicated; if therapy with anti-infective is unavoidable, interrupt simvastatin therapy during anti-infective treatment1

Metronidazole

Possible inhibition of CYP3A4

Concomitant use generally should be avoided or undertaken with caution

Nefazodone

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

Concomitant use contraindicated1

Niacin (antilipemic dosages [≥1 g daily])

Increased risk of myopathy and/or rhabdomyolysis; myopathy, including rhabdomyolysis, reported1

Extended-release niacin (2-g single dose): Increased simvastatin peak plasma concentration and AUC1

Extended-release niacin (Niaspan) with fixed-combination simvastatin/ezetimibe: Increased peak plasma concentrations and AUC of niacin and nicotinuric acid; increased peak plasma concentrations of simvastatin acid; increased AUC of total ezetimibe, simvastatin, and simvastatin acid102

Increased risk of myopathy observed in Chinese versus non-Chinese patients receiving simvastatin 40 mg daily with antilipemic dosages of niacin1 95 101

Use concomitantly with caution; weigh benefits against risks of concomitant therapy1

Extended-release niacin: No dosage adjustments required if used with simvastatin monotherapy1

Patients of Chinese descent: Caution when used concomitantly with simvastatin dosages >20 mg daily; avoid concomitant use with simvastatin 80 mg daily1 101

Propranolol

Pharmacokinetic interaction unlikely1

No dosage adjustments required1

Ranolazine

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

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

Telithromycin

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

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

Troleandomycin

Possible inhibition of CYP3A4

Concomitant use generally should be avoided or undertaken with caution

Warfarin

Possible increased PT;1 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

Simvastatin Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; undergoes extensive first-pass metabolism in the liver.1 Absolute bioavailability is <5%.1 88 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.88

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

0.5–3 hours.

Special Populations

Patients with moderate to severe renal insufficiency may have decreased clearance of simvastatin and its metabolites. (See Renal Impairment under Dosage and Administration.)

Stability

Storage

Oral

Tablets

Simvastatin: 5–30°C.1

Simvastatin/ezetimibe fixed combination: Well-closed containers at 20–25°C.88

Actions

  • Prodrug requiring hydrolysis in vivo for activity.1

  • Inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol synthesis.1 Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, and triglycerides.1

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

Advice to Patients

  • Importance of adhering to nondrug therapies and measures (i.e., therapeutic lifestyle changes, including dietary management, weight control, physical activity, and management of potentially contributory disease [e.g., diabetes mellitus]).1

  • Importance of obtaining fasting lipoprotein profile periodically.1

  • Risk of myopathy and/or rhabdomyolysis; risk increased with higher dosages (i.e., 80 mg daily) or when used concomitantly with certain other drugs or large quantities of grapefruit juice.1 90 91 92 93 Importance of patients promptly reporting unexplained muscle pain, tenderness, or weakness;1 90 brown urine; flu-like symptoms; and malaise.

  • Risk of adverse hepatic effects.1 Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1

  • Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).1 200

  • Risk of increased glucose concentrations and development of type 2 diabetes.1 200 May need to monitor glucose concentrations following initiation of statin therapy.201

  • Importance of advising women and adolescent girls to avoid pregnancy (i.e., using effective and appropriate contraceptive methods) during therapy and informing pregnant women of risk to fetus.1

  • Importance of avoiding breast-feeding during therapy.1 If the patient has a lipid disorder and is breast-feeding, importance of contacting a clinician to discuss other antilipemic treatment options.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

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

Simvastatin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg*

Simvastatin Tablets

Zocor

Merck

10 mg*

Simvastatin Tablets

Zocor

Merck

20 mg*

Simvastatin Tablets

Zocor

Merck

40 mg*

Simvastatin Tablets

Zocor

Merck

80 mg*

Simvastatin Tablets

Zocor

Merck

Simvastatin Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg with Ezetimibe 10 mg

Vytorin

Merck

20 mg with Ezetimibe 10 mg

Vytorin

Merck

40 mg with Ezetimibe 10 mg

Vytorin

Merck

80 mg with Ezetimibe 10 mg

Vytorin

Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Simcor 1000-20MG 24-hr Tablets (ABBOTT): 90/$460.00 or 270/$1,318.02

Simcor 1000-40MG 24-hr Tablets (ABBOTT): 30/$160.00 or 90/$437.99

Simcor 500-20MG 24-hr Tablets (ABBOTT): 90/$258.00 or 270/$744.00

Simvastatin 10MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 30/$19.99 or 90/$49.97

Simvastatin 20MG Tablets (DR.REDDY'S LABORATORIES): 30/$27.99 or 90/$73.97

Simvastatin 40MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 30/$27.99 or 90/$75.97

Simvastatin 5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$17.99 or 90/$42.98

Simvastatin 80MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 30/$35.99 or 90/$95.97

Vytorin 10-10MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$148.48 or 90/$422.56

Vytorin 10-20MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$146.00 or 90/$415.99

Vytorin 10-40MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$146.00 or 90/$419.99

Vytorin 10-80MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$144.99 or 90/$411.99

Zocor 10MG Tablets (MERCK SHARP &amp; DOHME): 30/$100.99 or 90/$288.97

Zocor 20MG Tablets (MERCK SHARP &amp; DOHME): 30/$173.99 or 90/$498.97

Zocor 40MG Tablets (MERCK SHARP &amp; DOHME): 90/$465.99 or 180/$924.64

Zocor 5MG Tablets (MERCK SHARP &amp; DOHME): 30/$77.30 or 90/$206.49

Zocor 80MG Tablets (MERCK SHARP &amp; DOHME): 30/$178.99 or 90/$533.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† 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. West Point, PA; 2012 Jun.

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