Interactions between simvastatin and Isoptin sr (verapamil)
verapamil and simvastatin (Major Drug-Drug)
ADJUST DOSE: Coadministration with verapamil may significantly increase the plasma concentrations of simvastatin and lovastatin and potentiate the risk of statin-induced myopathy. In 12 healthy volunteers, verapamil (240 mg/day for 2 days) increased the mean peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of unchanged simvastatin (40 mg single dose) by 2.6-fold and 4.6-fold, respectively, compared to placebo. The proposed mechanism is verapamil inhibition of simvastatin metabolism via intestinal and hepatic CYP450 3A4. Although not studied, the interaction is also expected to occur with lovastatin due to its similar metabolic profile to simvastatin. Clinically, high levels of statin or HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. In an analysis of clinical trials involving over 25,000 patients treated with simvastatin 20 mg to 80 mg, the incidence of myopathy was higher in patients receiving concomitant verapamil than in those not receiving a calcium channel blocker (0.63% vs 0.061%). There is also a reported case of rhabdomyolysis and acute renal failure in a patient receiving multiple drugs that inhibit CYP450 3A4, including verapamil.
MANAGEMENT: Simvastatin dosage should generally not exceed 20 mg daily and lovastatin dosage not exceed 40 mg daily when used in combination with verapamil unless the clinical benefit is anticipated to outweigh the increased risk of myopathy. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving verapamil, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.
