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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.