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

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

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.

Pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, increased serum alkaline phosphatase concentrations, increased serum γ-glutamyl transpeptidase concentrations, increased bilirubin concentrations, and, rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma have been reported.

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 S_cr [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 S_cr and proteinuria is not necessary. If S_cr is elevated in the absence of 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.

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 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.

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 (especially >80 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.

Common Adverse Effects

GI disturbances (e.g., abdominal pain, constipation, diarrhea, flatulence, dyspepsia, nausea), headache, asthenia, upper respiratory tract infection, myalgia, eczema, pruritus, rash.