Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or UGT1A1 may increase the plasma concentrations of irinotecan and its active metabolite, SN-38. CYP450 3A4 and UGT1A1 are the isoenzymes responsible for the metabolic conversion of irinotecan to its inactive metabolite, APC. Inhibition of APC formation results in more irinotecan metabolism to SN-38, an active and toxic metabolite. High plasma levels of irinotecan and SN-38 may increase the risk of potentially fatal toxicities such as severe diarrhea, neutropenia, sepsis, and thromboembolism. In cancer patients receiving irinotecan, coadministration of ketoconazole, a potent CYP450 3A4 and UGT1A1 inhibitor, resulted in a 100% increase in the relative exposure to SN-38 and an 87% reduction in the exposure to APC. In HIV patients with Kaposi's sarcoma, coadministration of irinotecan with lopinavir-ritonavir decreased the clearance of irinotecan by 47%, increased the AUC of SN-38 by 204%, and decreased the AUC of APC by 81%.

MANAGEMENT: Caution is advised when irinotecan is prescribed with CYP450 3A4 or UGT1A1 inhibitors. Patients should be monitored for toxicities such as diarrhea, myelosuppression, thromboembolism, and interstitial lung disease, and the irinotecan dosage adjusted accordingly or treatment discontinued as necessary.

ADJUST DOSING INTERVAL: Food may reduce the oral absorption and bioavailability of zafirlukast. In two separate studies, one using a high-fat and the other a high-protein meal, administration of zafirlukast with food reduced the mean bioavailability by approximately 40%.

MANAGEMENT: To ensure maximal oral absorption, zafirlukast should be administered at least 1 hour before or 2 hours after meals.