Drug interactions between Multaq and simvastatin

simvastatin ↔ dronedarone

Applies to:simvastatin and Multaq (dronedarone)

ADJUST DOSE: Coadministration with dronedarone may significantly increase the plasma concentrations of simvastatin and its active metabolite, simvastatin acid. The mechanism probably involves enhanced absorption as well as reduced clearance of simvastatin and simvastatin acid due to inhibition of both intestinal P-glycoprotein (P-gp) drug efflux transporter and hepatic/intestinal CYP450 3A4 isoenzyme by dronedarone. When simvastatin is given with dronedarone 400 mg twice daily, simvastatin and simvastatin acid exposure increased by 4-fold and 2-fold, respectively. 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 clinical trials, concomitant use of simvastatin with other moderate CYP450 3A4/P-gp inhibitors such as amiodarone, diltiazem, and verapamil has been associated with an increased risk of myopathy, especially at high dosages of simvastatin (e.g., 80 mg/day).

MANAGEMENT: A lower dosage of simvastatin and lovastatin should be considered when prescribed in combination with dronedarone, a moderate CYP450 3A4 and P-gp inhibitor. The manufacturers generally recommend that simvastatin dosage not exceed 10 mg daily and lovastatin dosage not exceed 40 mg daily when used in combination with other moderate CYP450 3A4/P-gp inhibitors. In addition, the benefits of the combination should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. Fluvastatin, pitavastatin, and rosuvastatin are probably safer alternatives in patients receiving dronedarone, since they are not substrates of CYP450 3A4 or P-gp. 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.