Drug Interaction Report

MONITOR: Coadministration of an azole antifungal agent and hepatitis C virus (HCV) NS3/4A protease inhibitor (boceprevir, telaprevir) may result in increased plasma concentrations of both drugs. The mechanism may involve both competitive and noncompetitive inhibition of CYP450 3A4, since these drugs are all substrates as well as inhibitors of the isoenzyme. When a single 400 mg oral dose of boceprevir was given in combination with ketoconazole (400 mg twice daily for 6 days), boceprevir mean peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 40% and 130%, respectively. Likewise, coadministration of a single 750 mg dose of telaprevir and a single 400 mg dose of ketoconazole in 17 study subjects resulted in an average 24% and 62% increase in the Cmax and AUC of telaprevir, respectively. The pharmacokinetics of ketoconazole were not reported in these studies. In separate studies involving 81 and 28 subjects, administration of a single 400 mg dose of ketoconazole during treatment with telaprevir (1250 mg every 8 hours for 4 doses) increased the ketoconazole Cmax by an average of 23% and AUC by an average of 46%, while administration of a single 200 mg dose of ketoconazole during treatment with telaprevir increased the ketoconazole Cmax by an average of 75% and AUC by an average of 125%. Clinically, high plasma levels of an azole antifungal agent may increase the risk of QT interval prolongation and torsade de pointes arrhythmia.

MANAGEMENT: Caution is advised if azole antifungal agents are used in combination with HCV NS3/4A protease inhibitors. Dosage adjustments may be required. According to the product information for boceprevir and telaprevir, high dosages of ketoconazole and itraconazole (>200 mg/day) should be avoided.

ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of boceprevir. When given at 800 mg three times daily with food, boceprevir exposure increased by up to 65% relative to administration in the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat versus low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, boceprevir may be taken without regard to either meal type or timing of the meal.

MANAGEMENT: To ensure maximal oral absorption, boceprevir should be administered with a meal or light snack.