Drug Interactions between alfentanil and amoxicillin / clarithromycin / lansoprazole

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.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.