Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin

The long-term safety profile of simvastatin, established over 10 years of c linical use, is excellent. The principal adverse effect of all inhibitors o f hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infr equent, Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4), CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhib itory activity derived from simvastatin, Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopa thy, Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of m yopathy, Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed, In megatrials w ith simvastatin, the overall incidence of myopathy was 0.025%, The proporti on of patients developing myopathy who were taking a calcium channel blocke r with simvastatin (1 of 3) was similar to the:proportion of patients takin g a calcium channel blocker overall. Among marketed-use adverse event repor ts, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports w as observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. potent CYP3A4 inhibitors, especially cyclosp orine, significantly increase the risk, There is no evidence that weaker CY P3A4 inhibitors such as calcium channel blockers increase the risk, (C) 199 9 by Excerpta Medica, Inc.