Simvastatin

Pronunciation

(SIM va stat in)

U.S. Brand Names

Zocor®

Generic Available

Canadian Brand Names

Apo-Simvastatin®; Gen-Simvastatin; ratio-Simvastatin; Riva-Simvastatin; Zocor®

Use

Used with dietary therapy for the following:

Secondary prevention of cardiovascular events in hypercholesterolemic patients with established coronary heart disease (CHD) or at high risk for CHD: To reduce cardiovascular morbidity (myocardial infarction, coronary revascularization procedures) and mortality; to reduce the risk of stroke and transient ischemic attacks

Hyperlipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with primary hypercholesterolemia (elevations of 1 or more components are present in Fredrickson type IIa, IIb, III, and IV hyperlipidemias); treatment of homozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (HeFH): In adolescent patients (10-17 years of age, females >1 year postmenarche) with HeFH having LDL-C 190 mg/dL or LDL 160 mg/dL with positive family history of premature cardiovascular disease (CVD), or 2 or more CVD risk factors in the adolescent patient

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to simvastatin or any component of the formulation; acute liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding

Warnings/Precautions

Secondary causes of hyperlipidemia should be ruled out prior to therapy. Liver function must be monitored by laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk is dose-related and is increased with concurrent use of lipid-lowering agents which may cause rhabdomyolysis (gemfibrozil, fibric acid derivatives, or niacin at doses

1 g/day) or during concurrent use with potent CYP3A4 inhibitors (including amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, nefazodone, grapefruit juice in large quantities, verapamil, or protease inhibitors such as indinavir, nelfinavir, or ritonavir). Weigh the risk versus benefit when combining any of these drugs with simvastatin. Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Safety and efficacy have not been established in patients <10 years or in premenarcheal girls.

Adverse Reactions

1% to 10%:

Gastrointestinal: Constipation (2%), dyspepsia (1%), flatulence (2%)

Neuromuscular & skeletal: CPK elevation (>3x normal on one or more occasions - 5%)

Respiratory: Upper respiratory infection (2%)

<1%: Thrombocytopenia, dizziness, headache, vertigo, weakness, fatigue, insomnia, nausea, diarrhea, abdominal pain

Postmarketing and/or case reports: Hypotension, depression, dermatomyositis, lichen planus, photosensitivity

Additional class-related events or case reports (not necessarily reported with simvastatin therapy): Alopecia, alteration in taste, anaphylaxis, angioedema, anorexia, anxiety, arthritis, cataracts, chills, cholestatic jaundice, cirrhosis, decreased libido, depression, dermatomyositis, dryness of skin/mucous membranes, dyspnea, elevated transaminases, eosinophilia, erectile dysfunction/impotence, erythema multiforme, facial paresis, fatty liver, fever, flushing, fulminant hepatic necrosis, gynecomastia, hemolytic anemia, hepatitis, hepatoma, hyperbilirubinemia, hypersensitivity reaction, impaired extraocular muscle movement, increased alkaline phosphatase, increased CPK (>10x normal), increased ESR, increased GGT, leukopenia, malaise, memory loss, myopathy, nail changes, nodules, ophthalmoplegia, pancreatitis, paresthesia, peripheral nerve palsy, peripheral neuropathy, photosensitivity, polymyalgia rheumatica, positive ANA, pruritus, psychic disturbance, purpura, rash, renal failure (secondary to rhabdomyolysis), rhabdomyolysis, skin discoloration, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome, thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, tremor, urticaria, vasculitis, vertigo, vomiting

Overdosage/Toxicology

Very few adverse events. Treatment is symptomatic.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP2C8/9 (weak), 2D6 (weak)

Amiodarone may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 20 mg/day.

Antacids: Plasma concentrations may be decreased when given with magnesium-aluminum hydroxide containing antacids (reported with atorvastatin and pravastatin). Clinical efficacy is not altered, no dosage adjustment is necessary

Cholestyramine reduces absorption of several HMG-CoA reductase inhibitors. Separate administration times by at least 4 hours.

Cholestyramine and colestipol (bile acid sequestrants): Cholesterol-lowering effects are additive.

Clofibrate and fenofibrate may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 10 mg/day

Cyclosporine: Concurrent use may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 10 mg/day

CYP3A4 inhibitors: May increase the levels/effects of simvastatin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Gemfibrozil: Increased risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 10 mg/day.

Grapefruit juice may inhibit metabolism of simvastatin via CYP3A4; avoid high dietary intakes of grapefruit juice.

Niacin ( 1 g/day): Concurrent use may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 10 mg/day.

Verapamil may increase the risk of myopathy and rhabdomyolysis; dose of simvastatin should not exceed 20 mg/day.

Warfarin effects (hypoprothrombinemic response) may be increased; monitor INR closely when simvastatin is initiated or discontinued.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid excessive ethanol consumption (due to potential hepatic effects).

Food: Simvastatin serum concentration may be increased when taken with grapefruit juice; avoid concurrent intake of large quantities (>1 quart/day).

Herb/Nutraceutical: St John's wort may decrease simvastatin levels.

Stability

Tablets should be stored in tightly-closed containers at temperatures between 5°C to 30°C (41°F to 86°F).

Mechanism of Action

Simvastatin is a methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis

Pharmacodynamics/Kinetics

Onset of action: >3 days

Peak effect: 2 weeks

Absorption: 85%

Protein binding: ~95%

Metabolism: Hepatic via CYP3A4; extensive first-pass effect

Bioavailability: <5%

Half-life elimination: Unknown

Time to peak: 1.3-2.4 hours

Excretion: Feces (60%); urine (13%)

Dosage

Oral: Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and the patient's response; adjustments should be made at intervals of 4 weeks or more; doses may need adjusted based on concomitant medications

Children 10-17 years (females >1 year postmenarche): HeFH: 10 mg once daily in the evening; range: 10-40 mg/day (maximum: 40 mg/day)

Dosage adjustment for simvastatin with concomitant cyclosporine, fibrates, niacin, amiodarone, or verapamil: Refer to drug-specific dosing in Adults dosing section

Adults:

Homozygous familial hypercholesterolemia: 40 mg once daily in the evening or 80 mg/day (given as 20 mg, 20 mg, and 40 mg evening dose)

Prevention of cardiovascular events, hyperlipidemias: 20-40 mg once daily in the evening; range: 5-80 mg/day

Patients requiring only moderate reduction of LDL-cholesterol may be started at 10 mg once daily

Patients requiring reduction of >45% in low-density lipoprotein (LDL) cholesterol may be started at 40 mg once daily in the evening

Patients with CHD or at high risk for CHD: Dosing should be started at 40 mg once daily in the evening; simvastatin may be started simultaneously with diet

Dosage adjustment with concomitant medications:

Cyclosporine: Initial: 5 mg simvastatin, should not exceed 10 mg/day

Fibrates or niacin: Simvastatin dose should not exceed 10 mg/day

Amiodarone or verapamil: Simvastatin dose should not exceed 20 mg/day

Dosing adjustment/comments in renal impairment: Because simvastatin does not undergo significant renal excretion, modification of dose should not be necessary in patients with mild to moderate renal insufficiency.

Severe renal impairment: Clcr<10 mL/minute: Initial: 5 mg/day with close monitoring.

Administration

May be taken without regard to meals.

Monitoring Parameters

Creatine phosphokinase levels due to possibility of myopathy; serum cholesterol (total and fractionated)

Obtain liver function tests prior to initiation, dose, and thereafter when clinically indicated. Patients titrated to the 80 mg dose should be tested prior to initiation and 3 months after initiating the 80 mg dose. Thereafter, periodic monitoring (ie, semiannually) is recommended for the first year of treatment. Patients with elevated transaminase levels should have a second (confirmatory) test and frequent monitoring until values normalize. Discontinue if increase in ALT/AST is persistently >3 times ULN.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed; may be taken without regard to meals. Avoid grapefruit juice while taking this medication. Follow diet and exercise regimen as prescribed. You will have periodic blood tests while taking this medication. May cause mild GI upset (should diminish with use). Report chest pain; CNS changes (dizziness, memory loss, depression, personality changes); numbness, weakness, tingling, pain or cramping in extremities or muscles; vision changes; rash; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Consult prescriber for appropriate barrier contraceptive measures to use during and for 1 month following therapy. This drug may cause severe fetal defects. Do not donate blood during or for 1 month following therapy. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations

Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years), gender (occurs in women more frequently than men), small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery) , and drug interactions (use with caution or avoid).

Cardiovascular Considerations

HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors (

2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (ie, the percent probability of having a CHD event in next 10 years). An individual's 10-year absolute CHD risk can be calculated at www.med-decisions.com/cvtool/phys/phys.html (last accessed July 3, 2003). LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.

Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (ASCOT-LLA), patients with HTN and at least 3 other risk factors defined by the authors benefited in reducing nonfatal CV events with the use of statins; however, no significant difference in CV mortality or overall mortality was observed. These patients had a total cholesterol below 250 mg/dL before treatment.

Secondary prevention trials indicate that "statin" therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations.

HMG-CoA reductase inhibitors decrease levels of high-sensitivity C-reactive protein (hs-CRP). They also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus S, Spinler SA, 2002).

Myopathy: Currently marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery), drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause drowsiness

Mental Health: Effects on Psychiatric Treatment

Rhabdomyolysis with acute renal failure has occurred; risk is increased with concurrent use of fluvoxamine nefazodone and verapamil

Dosage Forms

Tablet: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

References

Clark CM Jr and Lee DA, "Prevention and Treatment of the Complications of Diabetes Mellitus," N Engl J Med , 1995, 332(18):1201-7.

Dagogo-Jack S and Santiago JV, "Pathophysiology of Type 2 Diabetes and Modes of Action of Therapeutic Interventions," Arch Intern Med , 1997, 157(16):1802-17.

de Denus S and Spinler SA, "Early Statin Therapy for Acute Coronary Syndromes," Ann Pharmacother , 2002, 36(11):1749-58.

"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(19):2486-97.

Fonarow GC, French WJ, Parsons LS, et al, "Use of Lipid-Lowering Medications at Discharge in Patients With Acute Myocardial Infarction: Data From the National Registry of Myocardial Infarction 3," Circulation , 2001, 103(1):38-44.

Gaster B and Hirsch IB, "The Effects of Improved Glycemic Control on Complications in Type 2 Diabetes," [Arch Intern Med , 1998, 158(2):134-40.

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: Subgroup Analyses in the Scandinavian Simvastatin Survival Study," Arch Intern Med , 1999, 159(22):2661-7.

"MRC/BHF Heart Protection Study of Cholesterol Lowering With Simvastatin in 20,536 High-Risk Individuals: A Randomised Placebo-Controlled Trial. Heart Protection Study Collaborative Group," Lancet , 2002, 360(9326):7-22.

Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al, "ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins," Stroke , 2002, 33(9):2337-41. Available at: http://www.acc.org/clinical/alerts/statins_june02.htm. Accessed June 18, 2003.

Pearson TA, Mensah GA, Alexander RW, et al, "Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association," Circulation , 2003, 107(3):499-511.

Phillips BG, Yim JM, Brown EJ Jr, et al, "Pharmacologic Profile of Survivors of Acute Myocardial Infarction at United States Academic Hospitals," Am Heart J , 1996, 131(5):872-8.

"Randomised Trial of Cholesterol Lowering in 4444 Patients With Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S)," Lancet , 1994, 344(8934):1383-9.

Sever PS, Dahlof B, Poulter NR, et al, "Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Average or Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial," Lancet , 2003, 361(9364):1149-58.

Shepherd J, Cobbe SM, Ford I, et al, "Prevention of Coronary Heart Disease With Pravastatin in Men With Hypercholesterolemia. West of Scotland Coronary Prevention Study Group," N Engl J Med , 1995, 333(20):1301-7.

International Brand Names

Adipur® (CH); Apo-Simvastatin® (CA); Arianel® (CO); Arudel® (ES); Avastin® (BD); Belmalip® (ES); BeL Simvastatin® (DE); Bestatin® (TH); Bozara® (NL); Cardin® (PL); Cholestat® (ID); Colastatina® (CO); Coledis® (AR); Colemin® (ES); Colvast® (CO); Corolin® (FI); Denan® (DE); Detrovel® (ID); Dislipina® (PT); Ethicol® (ID); Eucor® (TH); Gen-Simvastatin (CA); Glutasey® (ES); Histop® (ES); Jabastatina® (PT); Kavelor® (CR, DO, GT, PA, SV); Labistatin® (AR); Lipart® (PL); Lipcut® (FI); Lipex® (AU, HR, NZ); Lipociden® (ES); Liponorm® (IT); Lipovas® (JP); Lisac® (AR); Lochol® (TH); Lodalès® (FR); Lovacor® (BR); Medipo® (IT); Mivalen® (BR); Nimicor® (CL); Nivelipol® (AR); Normofat® (ID); Nor-Vastina® (SV); Nyzoc® (AT); Pantok® (ES, NO); Perichol® (DK); Pontizoc® (ID); ratio-Simvastatin (CA); Rechol® (ID); Redusterol® (AR); Rendapid® (ID); Revastat® (YU); Ritechol® (IE); Riva-Simvastatin (CA); Rowestin® (DO); Simbado® (ID); Simchol® (ID); Simcora® (CH); Simcor® (AT, ID); Simgal® (CZ, PL); Simirex (CZ); Simovil® (IL); Simredin® (PL); Simtan® (IE); Simtin® (SG); SimvaAPS® (DE); Simva Basics® (DE); Simvabeta® (DE); Simvacard® (CZ, DE, PL); Simvachol® (PL); Simvacol® (PT); Simvacor® (DE, IL, PL, ZA); Simvadoc® (DE); Simvadura® (DE); Simvagamma® (DE); Simva-Henning® (DE); SimvaHexal® (DE); Simvakol® (TR); Simvar® (RO); Simvasin® (CH); Simvastad® (AT); Simvastatin 1A Farma® (DK); Simvastatin 1 A Pharma® (DE); Simvastatin AAA-Pharma® (DE); Simvastatina Alter® (ES, PT); Simvastatina Bayvit® (ES); Simvastatina Bexal® (ES); Simvastatin AbZ® (DE); Simvastatina Cinfa® (ES); Simvastatina® (CL); Simvastatin ACO® (SE); Simvastatina Davur® (ES); Simvastatina Farmabion® (ES); Simvastatina Geminis® (ES); Simvastatina Kern® (ES); Simvastatin AL® (DE); Simvastatin Alpharma® (DK, SE); Simvastatin Alternova® (DK, SE); Simvastatina Mepha® (PT); Simvastatina Merck® (ES); Simvastatina MK® (CO); Simvastatina Ratiopharm® (ES); Simvastatina Rimafar® (ES); Simvastatin Arrow® (SE); Simvastatina Synthon® (ES); Simvastatina Tarbis® (ES); Simvastatina Ur® (ES); Simvastatina Uxa® (ES); Simvastatina Vir® (ES); Simvastatin-axsan® (DE); Simvastatin AZU® (DE); Simvastatin Biochemie® (DK, SE); Simvastatin-corax® (DE); Simvastatin® (DK, ID); Simvastatin Edigen® (ES); Simvastatin Gea® (DK); Simvastatin GEA® (SE); Simvastatin Genericon® (AT); Simvastatin Gen Med® (AR); Simvastatin Helvepharm® (CH); Simvastatin Heumann® (DE); Simvastatin-Isis® (DE); Simvastatin Ivax® (SE); Simvastatin KSK® (DE); Simvastatin Mabo® (ES); Simvastatin NM Pharma® (SE); Simvastatin Nycomed® (DK, SE); Simvastatin Orifarm® (DK); Simvastatin Paranova® (DK); Simvastatin Q-Pharm® (DE); Simvastatin ratiopharm® (AT); Simvastatin-ratiopharm® (DE); Simvastatin ratiopharm® (DK); Simvastatin real® (DE); Simvastatin-saar® (DE); Simvastatin Sandoz® (CH, DE); Simvastatin Stada® (DE, SE); Simvastatin-Teva® (DE, IL); Simvastatin UNP® (DK); Simvastatin von ct® (DE); Simvastatin Wolff® (DE); SimvastatinX® (DE); Simvast® (CH); Simvasterol® (PL); Simvastin-Mepha® (CH); Simvastin ratiopharm® (FI); Simva TAD® (DE); Simvatin® (AT); Simvax® (CZ); Simvor® (CZ, PL, SG, TH); Simvotin® (IN); Simzor® (IE); Sinova® (ID); Sinpor® (PT); Sinvacor® (IT, SI); Sinvascor® (BR); Sinvastatina Generis® (PT); Sinvatrox® (BR); Sivastin® (IT); Sivatin® (IE); Statex® (HR); Statin® (CO); Sumaclina® (PT); Teylor® (ES); Valemia® (ID); Vascor® (TH); Vasilip® (CZ, HR, PL, RO, SI, YU); Vasomed® (CL); Vasotenal® (AR, CL); Vaster® (ID); Vazim® (ID); Zemox® (DE); Zeplan® (RO); Zetina® (EC); Zimmex® (TH); Zocor® (AR, AU, BE, BR, CA, CH, CL, CO, CR, CZ, DE, DK, EC, ES, FI, FR, GB, GT, HK, HN, HU, ID, IE, IT, LU, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SG, SV, TH, TR, YU, ZA); Zocord® (AT, SE); Zostin® (BD); Zovast® (ID); Zovatin® (TR)

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