Drug Interactions between Prezcobix and rifabutin

GENERALLY AVOID: Coadministration with cobicistat may significantly increase the plasma concentrations of rifabutin and its metabolite, 25-O-desacetylrifabutin. The proposed mechanism is cobicistat inhibition of rifabutin metabolism via CYP450 3A4. In 12 healthy volunteers, administration of rifabutin 150 mg once every other day in combination with 150 mg once daily each of cobicistat and elvitegravir had no significant effect on the pharmacokinetics of rifabutin, but increased mean 25-O-desacetyl-rifabutin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by approximately 4.8-, 6.3- and 4.9-fold, respectively, compared to administration of rifabutin alone at 300 mg once daily. Uveitis and neutropenia secondary to rifabutin toxicity may occur. On the other hand, cobicistat plasma concentrations may be significantly decreased due to CYP450 3A4 induction by rifabutin. In the same study mentioned above, the Cmin of cobicistat decreased by 66%.

MANAGEMENT: Concomitant use of cobicistat-containing fixed combination antiretroviral products with rifabutin is not recommended. However, if concomitant use is needed, to minimize the risk of rifabutin toxicity including leucopenia, uveitis, arthralgias, and skin discoloration, some authorities recommend that the rifabutin dosage be reduced to 150 mg every other day or three times a week in patients treated with cobicistat. A further dosage reduction of rifabutin to 150 mg twice weekly may be necessary for patients in whom the 150 mg three times per week dose is not tolerated. A complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Due to the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, close monitoring of antiretroviral response is also recommended. Current guidelines should be consulted for the appropriate treatment of tuberculosis in HIV-infected patients.

ADJUST DOSE: Coadministration of rifabutin and darunavir/ritonavir is expected to increase the plasma concentrations of rifabutin and its 25-O-desacetylrifabutin metabolite and may also increase the plasma concentrations of darunavir and ritonavir. The proposed mechanism involves ritonavir inhibition of rifabutin metabolism via CYP450 3A4. In 11 study subjects, administration of lower-dose rifabutin (150 mg every other day for 12 days) and darunavir/ritonavir (600 mg/100 mg twice daily for 12 days) resulted in non-significant changes in the peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) of rifabutin, as compared to the standard dose of rifabutin alone (300 mg once daily). In the same study, Cmax, AUC, and Cmin of darunavir were increased by 57%, 42% and 75% respectively. Uveitis secondary to rifabutin toxicity has been reported in some cases.

MANAGEMENT: To minimize the risk of rifabutin toxicity including leukopenia, uveitis, arthralgias and skin discoloration, darunavir labeling recommends that rifabutin dosage be reduced to 150 mg every other day in patients treated with darunavir/ritonavir or darunavir/cobicistat. A complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Local guidelines should be consulted for appropriate recommendations.