Drug Interactions between cobicistat / darunavir and Sustiva

MONITOR: Coadministration with efavirenz may decrease the plasma concentrations of darunavir, even in the presence of cobicistat or low-dose ritonavir as a pharmacokinetic booster. Additionally, the plasma concentration of cobicistat may be reduced. Reduced darunavir plasma levels may lead to diminished virologic response and possible resistance to darunavir. The mechanism is efavirenz induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of darunavir and cobicistat. In 12 study subjects, administration of darunavir/ritonavir (300 mg/100 mg twice a day) with efavirenz (600 mg once a day) decreased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of darunavir by 15%, 13% and 31%, respectively, compared to administration without efavirenz. In contrast, efavirenz Cmax, AUC, and Cmin increased by 15%, 21%, and 17%, respectively, in the presence of darunavir/ritonavir. The clinical significance of these changes are unknown. Data are not available for darunavir-cobicistat.

MANAGEMENT: Caution is advised if darunavir-ritonavir is coadministered with efavirenz. Antiretroviral response should be monitored closely and darunavir-ritonavir dose adjusted if necessary. Some authorities recommend a dose adjustment of darunavir 600 mg-ritonavir 100 mg twice daily. Concomitant use of darunavir-cobicistat with efavirenz is not recommended.

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GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

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