Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors

Abstract

SUMMARY Purpose To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high-risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration. Methods We conducted a comparative case series of rhabdomyolysis reports associated with SV and PV. Domestic spontaneous reports were obtained from the FDA’s Adverse Event Reporting System (AERS). Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). Adverse event reporting rates (AER) and ratios (AERR) of rhabdomyolysis associated with SV and PV—with and without stratification by CYP3A4 inhibitor concomitancy were determined. Results Stratification by CYP3A4 inhibitor concomitancy did not change the rhabdomyolysis AER for PV with or without a CYP3A4 inhibitor (2.4 cases and 3.1 cases per 10 million Rx, respectively). However, stratification of SV reports with or without a concomitant CYP3A4 inhibitor resulted in a rhabdomyolysis AER (38.4 and 6.0 cases per 10 million Rx, respectively). The corresponding AERR with or without a CYP3A4 inhibitor were 0.77 for PV and 6.43 for SV. Conclusions Spontaneous adverse event reports provide evidence of increased risk for rhabdomyolysis based on interaction between SV and selected CYP3A4 inhibitors.

Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers

“…Although not studied in a clinical trial setting, case studies have reported significant interactions between fluconazole and the statins [22][23][24][25]. It is well established that increased plasma statin concentrations can be associated with rhabdomyolysis [22,26,27].…”

Update on Toxic Myopathies

“…A review of the risk of rhabdomyolysis with simvastatin and pravastatin over the period 1991 to 2001 carried out by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research confirmed an association between co-administration of CYP3A4 inhibitors and simvastatin but not pravastatin [17]. The most frequent co-medications in simvastatin-associated cases were clarithromycin, mibefradil, verapamil, nefazodone, cyclosporine, diltiazem, and itraconazole.…”

“…Of the others, based upon a meta-analysis of 18 prospective randomized controlled trials (comprising 71,108 individuals), the highest rate of adverse effects, including greater than 10-fold CK elevations and rhabdomyolysis, was found to be associated with atorvastatin and the lowest risk with fluvastatin, whereas the risks for simvastatin, lovastatin, and pravastatin were intermediate and comparable [15]. Differences in pharmacodynamics and pharmacokinetics may account for these differences and it is noteworthy in this regard that atorvastatin has a much longer plasma elimination half-life (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) …”

Gene Polymorphism and Coronary Heart Disease

“…Essentially all statins are, in fact, substrates of membrane transporters, whereby SLCO1B1 polymorphisms can decrease the liver uptake, as well as the therapeutic potential of these agents, and may be linked to their muscular side-effects. Elevated levels of simvastatin metabolites (but not pravastatin) have been observed among carriers of SLCO1B1*5 allele, pointing to a genetic susceptibility to both myopathy and statin-induced myalgias in the absence of elevated serum creatinine kinase 167 . The risk of myalgia among SLCO1B1 carriers appears to be unique for artovastatin.…”