Drug Interactions between alfentanil and fedratinib

MONITOR CLOSELY: Coadministration with potent and moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of alfentanil, which is primarily metabolized by the isoenzyme. In six healthy volunteers, pretreatment with erythromycin (500 mg twice a day for 7 days) increased the mean elimination half-life of alfentanil (50 mcg/kg single IV dose) from 84 to 131 minutes and decreased its clearance from 3.9 to 2.9 mL/kg/min relative to placebo. The combination was also suspected in association with isolated reports of prolonged sedation and respiratory depression. In nine healthy volunteers, pretreatment with troleandomycin (500 mg orally every 12 hours for 4 doses) resulted in a 79% decrease in the clearance of alfentanil (20 mcg/kg IV bolus dose) compared to control. Another study in twelve healthy subjects found that troleandomycin (500 mg orally 1.7 hours before alfentanil, then 250 mg every 6 hours for 3 more doses) reduced the clearance of alfentanil (15 mcg/kg single IV dose) by 88% and increased its Cmax and AUC by 31% and 83%, respectively, compared to placebo. In 30 patients undergoing coronary artery bypass grafting, the mean half-life of alfentanil (50 mcg/kg for induction and 1 mcg/kg/min for maintenance) was 50% longer and the systemic exposure (AUC) 24% to 40% greater in patients who were coadministered diltiazem (60 mg orally 2 hours before induction of anesthesia and 0.1 mg/kg/hr starting at induction and continued for 23 hours) than in patients who were not. The time for alfentanil plasma level to decrease 50% after cessation of the infusion was also 40% longer in the diltiazem group. Although the time to awakening was not significantly different, the time to extubation was delayed an average of 2.5 hours by diltiazem compared to placebo. In nine healthy volunteers administered alfentanil 20 mcg/kg in three separate phases, alfentanil clearance was 1.3 and 1.4 mL/min/kg following pretreatment (60 minutes before alfentanil) with a single 400 mg IV dose and 400 mg oral dose of fluconazole, respectively, versus 3.1 mL/min/kg following pretreatment with placebo. The mean elimination half-life of alfentanil nearly doubled after both IV and oral fluconazole compared to placebo (2.7 and 2.5 hours vs. 1.5 hours, respectively), and respiratory depression and subjective effects of alfentanil were both increased by fluconazole. In another study consisting of 19 intensive care unit patients, pretreatment with IV cimetidine (1200 mg daily for 48 hours) increased the half-life of alfentanil (125 mcg/kg single IV dose) by 75% and reduced its clearance by 64% compared to an oral aluminum/magnesium hydroxide antacid, whereas IV ranitidine (300 mg daily for 48 hours) had no significant effect.

MANAGEMENT: Lower dosages of alfentanil may be required when used in combination with potent and moderate CYP450 3A4 inhibitors (e.g., azole antifungal agents, protease inhibitors, ketolide and certain macrolide antibiotics, aprepitant, diltiazem, dalfopristin-quinupristin, delavirdine, imatinib, nefazodone, verapamil). Patients should be carefully monitored for excessive central nervous system and respiratory depression, and dosage adjustments made accordingly if necessary. Recovery time from alfentanil anesthesia may be prolonged in some cases.