Drug interactions between Diltia XT and simvastatin

diltiazem ↔ simvastatin

Applies to:Diltia XT (diltiazem) and simvastatin

ADJUST DOSE: Coadministration with diltiazem may significantly increase the plasma concentrations of simvastatin and its active metabolite, simvastatin acid, and potentiate the risk of statin-induced myopathy. The proposed mechanism is diltiazem inhibition of simvastatin metabolism via intestinal and hepatic CYP450 3A4. In ten healthy volunteers, administration of a single 20 mg dose of simvastatin following two weeks of treatment with diltiazem SR 120 mg twice a day resulted in an approximately 4-fold increase in the mean peak plasma concentration (Cmax) of simvastatin and a 3.7-fold increase in that of simvastatin acid compared to administration of simvastatin alone. Diltiazem also increased mean simvastatin systemic exposure (AUC) by nearly 5-fold and elimination half-life by 2.4-fold. Similarly, another pharmacokinetic study found that administration of a single 80 mg dose of simvastatin following ten days of treatment with diltiazem 120 mg twice a day increased the Cmax and AUC of simvastatin by an average of 2.9- and 3.1-fold, respectively, while Cmax and AUC of simvastatin acid each increased by 2.7-fold. In a retrospective study of a cohort of hypertensive patients started consecutively on simvastatin over a two-year period, median cholesterol reduction after approximately 8 weeks of simvastatin treatment was 33.3% in patients who took diltiazem concurrently at a mean dosage of 226 mg/day (n=19), compared to 24.7% in patients who did not take diltiazem (n=116). The authors suggest that coadministration of simvastatin with diltiazem was roughly equivalent in therapeutic potency to doubling the dosage of simvastatin. Another study consisting of 30 Chinese patients found that patients receiving simvastatin 20 mg/day had an additional 1.66% reduction in LDL cholesterol levels during coadministration with diltiazem 60 mg three times a day for 4 weeks compared to administration of simvastatin alone. The additional change in LDL cholesterol showed a nonsignificant positive correlation with the trough serum diltiazem concentration. In addition to enhanced pharmacologic effects, high levels of statin or HMG-CoA reductase inhibitory activity in plasma is also 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. An analysis of the data from available clinical trials found that patients on diltiazem treated concomitantly with simvastatin 80 mg/day have a slightly increased risk (approximately 1% incidence) of myopathy. The risk in patients taking simvastatin 40 mg/day was not increased by concomitant diltiazem.

MANAGEMENT: Simvastatin dosage should not exceed 10 mg daily when used in combination with diltiazem. The benefits of this combination should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving diltiazem, since they are not metabolized by CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.