Vytorin - Warnings & Precautions

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Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 X ULN or greater persist, withdrawal of therapy with VYTORIN is recommended. VYTORIN should be used with caution in patients who consume substantial quantities of alcoholand/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN.

VYTORIN

CYP3A4 Interactions

Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of the simvastatin component of VYTORIN. See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions.

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

HIV protease inhibitors

Nefazodone

Cyclosporine

Large quantities of grapefruit juice (>1 quart daily)

Interactions with lipid-lowering drugs that can cause myopathy when given alone

See WARNINGS, Myopathy/Rhabdomyolysis.

The risk of myopathy is increased by gemfibrozil and to a lesser extent by other fibrates and niacin (nicotinic acid) (=1 g/day).

Other drug interactions

Amiodarone or Verapamil:

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil (see WARNINGS, Myopathy/Rhabdomyolysis).

Cholestyramine:

Concomitant cholestyramine administration decreased the mean AUC of total

ezetimibe approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be reduced by this interaction.

Cyclosporine:

Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine due to increased exposure to ezetimibe. This exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. In a pharmacokinetic study in post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), concomitant cyclosporine administration increased the mean AUC and Cmax of total ezetimibe 3.4-fold (range 2.3- to7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively. In a separate study, the total ezetimibe exposure increased 12-fold in one renal transplant patient with severe renal insufficiency receiving multiple medications, including cyclosporine. (See CLINICAL PHARMACOLOGY, Drug Interactions andWARNINGS, Myopathy/Rhabdomyolysis.)