Drug interactions between diltiazem and fentanyl

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of fentanyl, which is primarily metabolized by the isoenzyme. Increased fentanyl concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In eleven healthy volunteers, coadministration of the potent inhibitor ritonavir (200 mg orally three times a day on day 1; 300 mg three times a day on day 2; one morning dose of 300 mg on day 3) and intravenous fentanyl (5 mcg/kg two hours after the afternoon dose of ritonavir on day 2) resulted in a 174% increase in fentanyl systemic exposure (AUC) and a 67% decrease in fentanyl clearance compared to administration of fentanyl alone (with placebo). No other formulations of fentanyl such as patches or buccal tablets were studied.

MANAGEMENT: Patients receiving fentanyl in combination with CYP450 3A4 inhibitors, particularly potent and moderate ones (e.g., azole antifungal agents, protease inhibitors, ketolide and certain macrolide antibiotics, aprepitant, conivaptan, diltiazem, dalfopristin-quinupristin, delavirdine, imatinib, nefazodone, verapamil) should be carefully monitored, and dosage adjustments made accordingly if necessary. Patients and/or their caregivers should be advised to seek medical attention if potential signs and symptoms of toxicity occur such as dizziness, confusion, fainting, extreme sedation, bradycardia, slow or difficult breathing, and shortness of breath. Patients treated with transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.