Zocor - Warnings & Precautions

WARNINGS

Myopathy/ Rhabdomyolysis Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (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 increased by high levels of HMG-CoA reductase inhibitory activity in plasma. The risk of myopathy/ rhabdomyolysis is increased by concomitant use of simvastatin with the following:

Potent inhibitors of CYP3A4: Cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (> 1 quart daily), particularly with higher doses of simvastatin (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, CYP3A4 Interactions).

Other drugs:

Gemfibrozil particularly with higher doses of simvastatin (see below; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone; DOSAGE AND ADMINISTRATION).

Other lipid-lowering drugs (other fibrates or 1 g/ day of niacin) that can cause myopathy when given alone (see below; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone).

Amiodarone or verapamil with higher doses of simvastatin (see below; PRECAUTIONS, Drug Interactions, Other drug interactions). In an ongoing clinical trial, myopathy has been reported in 6% of

patients receiving simvastatin 80 mg and amiodarone. In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/ 635; 0.63%) than in patients taking simvastatin without a calcium channel blocker (13/ 21,224; 0.061%).

The risk of myopathy/ rhabdomyolysis is dose related. The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.02% at 20 mg, 0.07% at 40 mg and 0.3% at 80 mg.