ZETIA (ezetimibe)

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Important Information About ZETIA
SIMVASTATIN – Stalenhoef 1993(5) A Titration Step Delivered LIMITED LDL-C Reduction
Examine Additional Statin Titration Studies
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bullet gif The effect of ZETIA on cardiovascular morbidity and mortality has not been determined.
bullet gif ZETIA, administered alone or in combination with an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated TOTAL-C, LDL-C, and Apo B in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia when diet alone is not enough.
bullet gif Contraindications: hypersensitivity to any component of this medication.
bullet gif Statin contraindications apply when used with a statin: active liver disease; unexplained persistent elevations in hepatic transaminase levels. Statins are contraindicated in pregnant and nursing women. Refer to the statin label for details.
SELECTED CAUTIONARY INFORMATION
bullet gif When using ZETIA with a statin, also follow the label recommendations for that specific statin.
bullet gif When ZETIA was coadministered with a statin, consecutive elevations in hepatic transaminase levels (≥3 × ULN) were slightly higher (1.3%) than those of statins alone (0.4%). Liver function tests should be performed when ZETIA is added to statin therapy and according to statin recommendations. Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of ZETIA and/or the statin.
bullet gif Patients should be advised to promptly report muscle pain, tenderness, or weakness. Risk for skeletal muscle toxicity increases with higher statin doses, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. Discontinue drug if myopathy is diagnosed or suspected.

Before prescribing ZETIA, please read the Prescribing Information.

Important Information About VYTORIN
bullet gif VYTORIN contains 2 active ingredients: ezetimibe and simvastatin. No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
bullet gif 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) hyperlipidemia or mixed hyperlipidemia when diet alone is not enough.
bullet gif Contraindications: hypersensitivity to any component of this medication; active liver disease; unexplained persistent elevations in hepatic transaminase levels; and women who are pregnant, nursing, or may become pregnant.
SELECTED CAUTIONARY INFORMATION
bullet gif 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.
bullet gif 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. Predisposing factors for myopathy include advanced age (≥65 years), uncontrolled hypothyroidism, and renal impairment. As with other statins, the risk of myopathy/rhabdomyolysis is dose related. VYTORIN should be discontinued immediately if myopathy is diagnosed or suspected. Please read WARNINGS in the Prescribing Information for additional information.
bullet gif 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.
bullet gif The concomitant use of VYTORIN and fibrates (especially gemfibrozil) should be avoided. Although not recommended, the dose of VYTORIN should not exceed 10/10 mg if used with gemfibrozil.
bullet gif The benefit of further alterations in lipid levels by the combined use of VYTORIN with niacin (≥1 g/day) should be carefully weighed against the potential risks of myopathy. Chinese patients should not receive VYTORIN 10/80 mg daily with niacin (≥1 g/day). The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving cyclosporine or danazol, 10/20 mg daily in patients receiving amiodarone or verapamil, and 10/40 mg daily in patients receiving diltiazem, due to the increased risk of myopathy. The combined use of VYTORIN at doses higher than 10/20 mg daily with amiodarone or verapamil or at doses higher than 10/40 mg daily with diltiazem should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
bullet gif Liver: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, VYTORIN is not recommended in these patients.
bullet gif 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.
bullet gif 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.
bullet gif In clinical trials, the most commonly reported side effects, regardless of cause, included headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).
SELECTED DOSAGE AND ADMINISTRATION INFORMATION
bullet gif 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).
bullet gif 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.
bullet gif No dosage adjustment is necessary in patients with mild or moderate renal impairment. 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.
Before prescribing VYTORIN, please read the Prescribing Information.
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Study Design5: An 18-week, double-blind, randomized, parallel-group study in patients (N=48) with primary hypercholesterolemia (LDL-C >179 mg/dL and triglycerides <409 mg/dL). Patients were randomized to either simvastatin 10 mg or pravastatin 10 mg. Therapies were titrated to the next highest dose every 6 weeks (up to 40 mg), unless LDL-C was <131 mg/dL at the end of Week 12. The objective was to compare the efficacy of increasing doses of simvastatin and pravastatin. Mean baseline LDL-C was 316 mg/dL and 313 mg/dL for the simvastatin and pravastatin groups, respectively.
 

Mean LDL-C reductions from baseline were 32% vs 23% for simvastatin 10 mg vs pravastatin 10 mg (P<0.001 vs baseline for both). Mean LDL-C reductions from baseline were 40% vs 26% for simvastatin 20 mg vs pravastatin 20 mg (P<0.01). Mean LDL-C reduction from baseline was 43% for simvastatin 40 mg vs 33% for pravastatin 40 mg (P<0.01).
 

Additional LDL-C reduction provided by titration of simvastatin 10 mg to 20 mg was 8% (P<0.01) and from simvastatin 20 mg to 40 mg was 3%, corresponding to mean additional LDL-C reductions of 23 mg/dL and 10 mg/dL, respectively. Additional LDL-C reduction provided by titration of pravastatin 10 mg to 20 mg was 3% and from pravastatin 20 mg to 40 mg was 7% (P<0.05), corresponding to additional mean LDL-C reductions of 13 mg/dL and 21 mg/dL, respectively. Simvastatin 80 mg was not available at the time of the study. The additional percent reductions in LDL-C and the corresponding mean additional LDL-C reductions with successive doses were obtained by subtraction from data presented.
 

Reference:
5. Stalenhoef AFH, Lansberg PJ, Kroon AA, et al. Treatment of primary hypercholesterolaemia. Short-term efficacy and safety of increasing doses of simvastatin and pravastatin: a double-blind comparative study. J Intern Med. 1993;234:77–82.

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21050228(1)-06/10-ZET