Drug Interaction Report

GENERALLY AVOID: Coadministration with nevirapine may significantly decrease the plasma concentrations of clarithromycin. The mechanism is nevirapine induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of clarithromycin. In 15 HIV-positive subjects, nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily for 2 weeks) decreased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of clarithromycin (500 mg twice a day) by 23%, 31% and 57%, respectively, compared to administration of clarithromycin alone. In contrast, the Cmax and AUC of its 14-hydroxy metabolite increased by 47% and 42%, respectively, while the Cmin remained unchanged. Although 14-hydroxy-clarithromycin is pharmacologically active, it has reduced activity against Mycobacterium avium-intracellulare complex, thus overall activity against this pathogen may be compromised.

MANAGEMENT: Clarithromycin should preferably not be used in the treatment and prophylaxis of Mycobacterium avium-intracellulare complex in patients treated with nevirapine. Alternatives such as azithromycin should be considered.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.