[Posted 06/08/2011] ISSUE: FDA notified healthcare professionals that it is recommending limiting the use of the highest approved dose of the cholesterol-lowering medication simvastatin (80 mg) [Zocor] because of increased risk of muscle damage. Patients taking simvastatin 80 mg daily have an increased risk of myopathy compared to patients taking lower doses of this drug or other drugs in the same class. This risk appears to be higher during the first year of treatment, is often the result of interactions with certain medicines, and is frequently associated with a genetic predisposition toward simvastatin-related myopathy. The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure which can be fatal. FDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.
BACKGROUND: The new changes to the drug labels for simvastatin-containing medicines are based on FDA’s review of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and other data described in the Agency’s March 2010 Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy).
RECOMMENDATION: Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. For more information visit the FDA website at: [Web] and [Web].
Adjunct to dietary therapy 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.
Slowing progression or inducing regression of atherosclerosis† in coronary arteries by reducing intimal-medial wall thickness.
Dyslipidemias
Adjunct to dietary therapy 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 hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia (e.g., polygenic hypercholesterolemia). May be used in combination or fixed combination with ezetimibe (as Vytorin® tablets) for additive antilipemic effects.
Adjunct to dietary therapy 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 postmenarche) ≥10 years of age who have a serum LDL-cholesterol concentration of ≥190 mg/dL or in those who have a serum LDL-cholesterol concentration of ≥160 mg/dL and either a family history of premature cardiovascular disease or ≥2 cardiovascular risk factors despite an adequate trial of dietary management.
Reduction of elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available. May be used in combination or fixed combination with ezetimibe (as Vytorin® tablets) for additive antilipemic effects.
Adjunct to dietary therapy to decrease elevated serum triglyceride and VLDL-cholesterol concentrations in the management of primary dysbetalipoproteinemia.
Adjunct to dietary therapy to decrease elevated serum triglyceride concentrations in the management of hypertriglyceridemia.
Reduction of total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus† (diabetic dyslipidemia), cardiac† or renal† transplantation, or nephrotic syndrome†.
Dosage and Administration
General
Patients should be placed on a standard lipid-lowering diet before initiation of simvastatin therapy and should remain on this diet during treatment with the drug; in patients with CHD or CHD risk equivalents, initiate simvastatin simultaneously with dietary management.
Monitoring during Antilipemic Therapy
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.
Administer simvastatin-ezetimibe fixed-combination preparation (Vytorin®) orally in the evening without regard to meals.
Dosage
Pediatric Patients
Dyslipidemias
Oral
Children ≥10 years of age: 10 mg once daily.
Adjust dosage at intervals of ≥4 weeks until the desired effect on lipoprotein concentrations is observed. Usual dosage range is 10–40 mg daily.
Adults
Dyslipidemias and Prevention of Cardiovascular Events
Oral
Initially, 20–40 mg once daily.
Patients with CHD or CHD risk equivalents: Initially, 40 mg once daily.
Adjust dosage at intervals of no less than 4 weeks until the desired effect on lipoprotein concentrations is observed. Usual dosage range is 5–80 mg daily.
Simvastatin-ezetimibe fixed combination (Vytorin®): Initially, simvastatin 20 mg and ezetimibe 10 mg once daily in the evening. In patients requiring less aggressive LDL-cholesterol lowering, consider lower dosage (simvastatin 10 mg and ezetimibe 10 mg once daily). In patients requiring LDL-cholesterol reductions >55%, give simvastatin 40 mg and ezetimibe 10 mg once daily. Determine serum lipoprotein concentrations 2 weeks after initiation of therapy and adjust dosage as needed. Usual maintenance dosage is simvastatin 10–80 mg and ezetimibe 10 mg once daily.
Homozygous Familial Hypercholesterolemia
Oral
40 mg once daily in the evening or 80 mg daily in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg.
Simvastatin-ezetimibe fixed combination (Vytorin®): Initially, simvastatin 40 or 80 mg and ezetimibe 10 mg once daily in the evening.
Prescribing Limits
Pediatric Patients
Oral
Children ≥10 years of age: Maximum 40 mg once daily.
Special Populations
Hepatic Impairment
Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease. Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.
Renal Impairment
Dosage modification is not necessary in patients with mild to moderate impairment. In patients with severe renal impairment, initially, 5 mg once daily. Use with caution; monitor closely.
Simvastatin-ezetimibe fixed combination (Vytorin®): Dosage modification is not necessary in patients with mild to moderate impairment. In patients with severe renal impairment, do not use unless patient already has tolerated treatment with simvastatin at dosage of ≥5 mg daily; in such patients, exercise caution and monitor closely.
Cautions
Contraindications
Active liver disease or unexplained, persistent elevations of serum aminotransferases.
Pregnancy or lactation. Administer to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards.
Suppression of cholesterol biosynthesis could cause fetal harm. Congenital anomalies following intrauterine exposure to statins reported rarely.
Administer to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking the drug, discontinue therapy and apprise the patient of the potential hazard to the fetus.
Hepatic Effects
Associated with increases in serum aminotransferase (AST, ALT) concentrations.
Perform liver function tests before initiation of therapy and thereafter when clinically indicated. In patients being titrated to a dosage of 80 mg daily, perform an additional liver function test prior to titration, at 3 months after titration, and periodically (e.g., semiannually) thereafter for the first year of treatment.
Patients who develop increased serum AST/ALT concentrations or manifestations of liver disease should be monitored with a second liver function evaluation to confirm the finding and should receive frequent liver function tests thereafter until the abnormalities return to normal. If increases in AST or ALT concentrations of 3 times the ULN or higher persist, discontinue therapy.
The National Lipid Association (NLA) statin safety assessment task force recommends that clinicians be alert to signs and symptoms of hepatotoxicity (e.g., jaundice, malaise, fatigue, lethargy, hepatomegaly, increased indirect bilirubin concentrations, elevated PT). If substantial hepatotoxicity is suspected, discontinue therapy, determine etiology, and refer patient to a gastroenterologist or hepatologist if indicated.
Musculoskeletal Effects
Myopathy (manifested as muscle pain, tenderness, or weakness and serum CK (CPK) concentration increases >10 times the ULN) reported occasionally.
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 has been reported; rare fatalities have occurred.
Risk of myopathy increased in patients receiving higher doses of statins; in patients with multisystem disease (e.g., renal or hepatic impairment); in patients with concurrent serious infections or hypothyroidism; in patients (particularly women) of advanced age (especially >80 years of age); in patients with small body frame and frailty; and in patients undergoing surgery (i.e., during perioperative periods). Risk also may be increased by concomitant administration of cyclosporine, danazol, niacin, fibric acid derivatives (e.g., gemfibrozil), macrolide anti-infectives (i.e., erythromycin, clarithromycin), telithromycin, certain antifungal azoles (i.e., itraconazole, ketoconazole), alcohol, HIV protease inhibitors, nefazodone, amiodarone, verapamil, and large quantities (>1 quart daily) of grapefruit juice. (See Interactions.)
Measure baseline serum CK concentrations prior to initiation of therapy, particularly in patients at high risk of developing musculoskeletal toxicity (e.g., geriatric patients, black men, patients receiving concomitant therapy with myotoxic drugs).
Obtain serum CK concentrations and compare with baseline concentrations in patients presenting with musculoskeletal symptoms suggestive of myopathy; because hypothyroidism may be a predisposing factor, TSH concentrations also should be obtained in such patients.
Discontinue if myopathy is diagnosed or suspected.
Monitor patients weekly if myalgia (muscle pain, tenderness) is present with either no CK elevation or a moderate elevation (3–10 times the ULN) until manifestations improve; discontinue if manifestations worsen.
Dosage reduction or temporary discontinuance may be prudent in patients with muscle discomfort and/or weakness in the presence of progressive elevation of CK concentrations on serial measurements.
Temporarily withhold therapy a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
General Precautions
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.
Renal Effects
NLA recommends performing renal function tests prior to initiating statin therapy; routine monitoring of Scr and proteinuria is not necessary. If Scr is elevated in the absence rhabdomyolysis, may continue therapy but dosage adjustment may be necessary per labeling recommendations. If unexpected proteinuria develops, determine etiology; may continue therapy but dosage adjustment may be necessary per labeling recommendations.
CNS Effects
CNS vascular lesions (e.g., perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels) observed in animals.
If manifestations of peripheral neuropathy occur, NLA recommends evaluating patient to rule out secondary causes (e.g., diabetes mellitus, renal impairment, alcohol abuse, vitamin B12 deficiency, cancer, hypothyroidism, acquired immunodeficiency syndrome [AIDS], Lyme disease, heavy metal intoxication). If a secondary cause is not identified, discontinue statin therapy for 3–6 months. If neurologic manifestations improve over this period, a presumptive diagnosis of statin-induced peripheral neuropathy may be made; however, consider reinitiating therapy with a different statin and dosage. If neurologic manifestations do not improve during period of discontinuance, reinitiate statin therapy, taking into consideration the risks and benefits of such therapy.
If manifestations of impaired cognition occur, NLA recommends evaluating and managing patient in similar manner as those experiencing peripheral neuropathy. First, evaluate to rule out secondary causes. If a secondary cause is not identified, discontinue statin therapy for 1–3 months. If no improvement, reinitiate statin therapy, taking into consideration the risks and benefits of such therapy.
Ocular Effects
Cataracts and optic nerve degeneration observed in animals.
Risk of Cancer
Fixed combination of simvastatin and ezetimibe (Vytorin®) 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 Combination
When used in fixed combination with ezetimibe, consider the cautions, precautions, and contraindications associated with ezetimibe.
Specific Populations
Pregnancy
Category X. (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)
Lactation
Not known whether simvastatin is distributed into milk; however, other statins are distributed into milk. Use is contraindicated; discontinue nursing or the drug.
Pediatric Use
Safety and efficacy not established in children <10 years of age or in premenarchal girls. Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.
Safety and efficacy of fixed-combination preparation (Vytorin®) not established in pediatric patients.
Geriatric Use
No substantial differences in safety or efficacy relative to younger adults. Caution in patients (particularly women) of advanced age (≥65 years of age) and in those with small body frame and frailty.
No substantial differences in safety or efficacy of fixed-combination preparation with ezetimibe in geriatric patients relative to younger patients; however, increased sensitivity cannot be ruled out.
Hepatic Impairment
Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.
Contraindicated in patients with active liver disease or unexplained, persistent increases in liver function test results.
Increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin
If used concomitantly, simvastatin dosage should not exceed 20 mg daily; if a simvastatin dosage >20 mg daily is required to achieve target LDL-cholesterol goal, consider use of another statin
Possible increased PT. Bleeding observed with other statins
Closely monitor PT until stabilized if simvastatin is initiated or dosage is adjusted in patients receiving a coumarin anticoagulant. Thereafter, monitor PT at intervals usually recommended for patients receiving coumarin anticoagulants
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis
Concomitant use generally should be avoided. If concomitant use is unavoidable, suspend simvastatin therapy during the course of treatment with antifungal. Avoid concomitant use of simvastatin with other CYP3A4 inhibitors unless benefits of combined therapy outweigh risks
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin
Weigh benefits against risks of concomitant therapy. If used concomitantly, initiate simvastatin at 5 mg daily; simvastatin dosage should not exceed 10 mg daily
Increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin
Weigh benefits against risks of concomitant therapy. If used concomitantly, initiate simvastatin at 5 mg daily; simvastatin dosage should not exceed 10 mg daily
Gemfibrozil: Increased peak plasma concentration and AUC of simvastatin acid
Use concomitantly with caution. Concomitant use with gemfibrozil generally should be avoided unless benefits of combined therapy outweigh risks; if used concomitantly, simvastatin dosage should not exceed 10 mg daily
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis
Concomitant use should be discouraged, or simvastatin dosage reduced accordingly; consumption of large quantities (>1 quart daily) of grapefruit juice should be avoided
HIV protease inhibitors
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis
Concomitant use generally should be avoided. If concomitant use is unavoidable, suspend simvastatin therapy during the course of treatment with the anti-infective. Avoid concomitant use of simvastatin with other CYP3A4 inhibitors unless benefits of combined therapy outweigh risks
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis
Concomitant use with antilipemic dosages (≥1 g daily) of niacin generally should be employed with caution; weigh benefits against risks of concomitant therapy
Inhibition of CYP3A4-dependent metabolism of simvastatin, resulting in decreased elimination of simvastatin and increased risk of myopathy and/or rhabdomyolysis
Concomitant use generally should be avoided. If concomitant use is unavoidable, suspend simvastatin therapy during the course of treatment with the anti-infective. Avoid concomitant use of simvastatin with other CYP3A4 inhibitors unless benefits of combined therapy outweigh risks
Increased plasma simvastatin concentrations. Increased risk of myopathy and/or rhabdomyolysis, particularly when used with higher dosages of simvastatin
Concomitant use generally should be avoided; if used concomitantly, simvastatin dosage should not exceed 20 mg daily
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed following oral administration; undergoes extensive first-pass metabolism in the liver. Absolute bioavailability is <5%. Peak plasma concentrations are attained at 4 hours.
Onset
Maximal to near-maximal therapeutic response occurs within 4–6 weeks.
Simvastatin-ezetimibe fixed-combination preparation (Vytorin®) is bioequivalent to corresponding dosages of the individual components.
Distribution
Extent
Distributed mainly to the liver. Crosses the blood-brain barrier.
Plasma Protein Binding
About 95% bound to plasma proteins.
Elimination
Metabolism
Metabolized by CYP3A4 to active metabolites.
Elimination Route
Excreted in urine (13%) and feces (60%).
Half-life
0.5–3 hours.
Special Populations
Patients with moderate to severe renal insufficiency may have decreased clearance of simvastatin and its metabolites.
Stability
Storage
Oral
Tablets
Simvastatin: 5–30°C.
Fixed-combination of simvastatin and ezetimibe (Vytorin®): Well-closed containers at 20–25°C.
Actions
Prodrug requiring hydrolysis in vivo for activity.
Inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol synthesis. Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, and triglycerides.
Statins may slow progression and/or induce regression of atherosclerosis in coronary and/or carotid arteries, modulate BP in hypercholesterolemic patients with hypertension, and possess anti-inflammatory activity.
Advice to Patients
Importance of informing patients about risks, especially myopathy and/or rhabdomyolysis, associated with statins alone or combined with other drugs. Importance of patients promptly reporting unexplained muscle pain, tenderness, or weakness; brown urine; flu-like symptoms; and malaise.
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]).
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Necessity for clinicians to advise women and adolescent girls to avoid pregnancy (i.e., using effective and appropriate contraceptive methods) during therapy and to advise pregnant women of risk to fetus.
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
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
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Simvastatin and Ezetimibe
Routes
Dosage Forms
Strengths
Brand Names
Manufacturer
Oral
Tablets
10 mg with Ezetimibe 10 mg
Vytorin®
Merck/Schering-Plough
20 mg with Ezetimibe 10 mg
Vytorin®
Merck/Schering-Plough
40 mg with Ezetimibe 10 mg
Vytorin®
Merck/Schering-Plough
80 mg with Ezetimibe 10 mg
Vytorin®
Merck/Schering-Plough
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 11/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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