Drug Interaction Report

ADJUST DOSE: Coadministration with simeprevir may significantly increase the plasma concentrations of rosuvastatin. The proposed mechanism is simeprevir inhibition of the hepatic uptake of rosuvastatin via organic anion transporting polypeptide 1B1 (OATP1B1). In 16 healthy study subjects, administration of a single 10 mg dose of rosuvastatin in combination with simeprevir 150 mg once daily for 7 days increased mean rosuvastatin peak plasma concentration (Cmax) by approximately 3.2-fold and systemic exposure (AUC) by 2.8-fold compared to rosuvastatin administered alone. High levels of 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.

MANAGEMENT: Rosuvastatin therapy should be initiated at a dosage of 5 mg once daily, and not exceed a dosage of 10 mg daily, when prescribed with simeprevir. Alternatively, fluvastatin may be substituted, as it has been shown to have no significant interaction with simeprevir. 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.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of simeprevir, although the type of food does not seem to matter. In healthy study subjects, administration of simeprevir after a high-fat, high-caloric (928 kcal) breakfast increased systemic exposure (AUC) by 61% and delayed absorption by 1 hour, while administration after a normal caloric (533 kcal) breakfast increased AUC by 69% and delayed absorption by 1.5 hours.

MANAGEMENT: To ensure maximal oral absorption, simeprevir should be administered with food.