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Indications
VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated TOTAL-C, LDL-C, Apo B, TG, and non–HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia or mixed hyperlipidemia when diet alone is not enough.

Contraindications
Contraindications: hypersensitivity to any component of this medication; active liver disease; unexplained persistent elevations of serum transaminases; and women who are pregnant, nursing, or may become pregnant.

SELECTED CAUTIONARY INFORMATION
Skeletal Muscle: All patients starting therapy with VYTORIN, or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy and told to promptly report any unexplained muscle pain, tenderness, or weakness. Therapy with VYTORIN should be discontinued immediately if myopathy is diagnosed or suspected.

Myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. VYTORIN contains simvastatin, which occasionally causes myopathy manifested as muscle pain, tenderness, or weakness with CK levels above 10 × ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is dose related and is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. VYTORIN should be discontinued immediately if myopathy is diagnosed or suspected. Please read WARNINGS in the Prescribing Information for additional information.

Myopathy Caused by Drug Interactions: Use of VYTORIN with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided because of the increased risk of myopathy, particularly at higher doses.

The benefit of further alterations in lipid levels by the combined use of VYTORIN with niacin should be carefully weighed against the potential risks of myopathy. The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving cyclosporine or danazol, and 10/20 mg daily in patients receiving amiodarone or verapamil, due to the increased risk of myopathy. The combined use of VYTORIN at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.

Liver: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients.

The incidence of consecutive elevations (>3 × ULN) in serum transaminases was 1.7% overall and appeared to be dose related, with an incidence of 2.6% for 10/80 mg. In long-term (48-week) extensions, which included both newly treated and previously treated patients, the incidence was 1.8% overall and 3.6% for 10/80 mg. These elevations were generally asymptomatic, not associated with cholestasis, and reversible whether treatment was maintained or discontinued.

Liver function tests should be performed at treatment initiation and thereafter when clinically indicated. Patients titrated to 10/80 mg should receive an additional test prior to titration, 3 months after titration, and periodically thereafter (eg, semiannually) during the first year. If an increase in AST or ALT of >3 × ULN persists, discontinue the drug.

In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8%), upper respiratory tract infection (3.9%), myalgia (3.5%), influenza (2.6%), and extremity pain (2.3%).

VYTORIN is available as tablets containing 10 mg of ezetimibe combined with 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40, or 10/80 mg, respectively).

The recommended usual starting dose is 10/20 mg/day. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. VYTORIN 10/10 mg may be considered for patients requiring less aggressive LDL-C reduction.

No dosage adjustment is necessary in patients with mild or moderate renal insufficiency. Caution should be exercised when VYTORIN is administered to patients with severe renal insufficiency. VYTORIN should not be initiated in such patients unless the patient has already tolerated treatment with simvastatin.