Drug Interaction Report

MONITOR: Coadministration with simeprevir may increase the plasma concentrations of certain antiarrhythmic agents that are metabolized by CYP450 1A2 or 3A4 such as amiodarone, disopyramide, flecainide, mexiletine, propafenone, and quinidine. In vivo, simeprevir mildly inhibits CYP450 1A2 and intestinal CYP450 3A4, but does not affect hepatic CYP450 3A4 activity. Serious and/or life-threatening reactions including cardiac arrhythmias like torsade de pointes may occur if antiarrhythmic drug levels are significantly increased.

MANAGEMENT: Caution is advised if simeprevir is prescribed in combination with antiarrhythmic agents that are metabolized by CYP450 1A2 or 3A4. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever simeprevir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

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.