Drug Interactions between fosamprenavir and rifabutin

ADJUST DOSE: Coadministration with amprenavir or its prodrug, fosamprenavir, may significantly increase the plasma concentrations of rifabutin and its pharmacologically active 25-O-desacetyl metabolite. The mechanism is amprenavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of rifabutin and 25-O-desacetylrifabutin. In six healthy volunteers, amprenavir (1200 mg twice a day for 10 days) increased the mean steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of rifabutin (300 mg once a day for 10 days) by 119%, 193% and 271%, respectively, compared to administration of rifabutin alone. Mean steady-state Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 7.39-, 13.35-, and 32.9-fold, respectively. In another study, the combination was poorly tolerated, resulting in withdrawal of 5 of 11 subjects from the study. Adverse events consisted primarily of influenza-like symptoms and leucopenia. Rifabutin given at regular dosages in combination with other protease inhibitors has been associated with uveitis secondary to rifabutin toxicity.

MANAGEMENT: To minimize the risk of rifabutin toxicity including leucopenia, uveitis, arthralgias and skin discoloration, product labeling recommends that rifabutin dosage be reduced by at least 50% of the normally recommended dosage in patients treated with amprenavir or by 75% (maximum of 150 mg every other day or three times a week) when treated with fosamprenavir in combination with ritonavir. A complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia.