Drug Interactions between atazanavir / cobicistat and efavirenz

ADJUST DOSE: Coadministration with efavirenz may significantly decrease the plasma concentrations of atazanavir. Plasma concentrations of cobicistat, a pharmacokinetic enhancer given concomitantly with atazanavir, may also be reduced. Reduced atazanavir plasma levels may lead to diminished virologic response and possible resistance to atazanavir. The mechanism is efavirenz induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of atazanavir and cobicistat. In 27 subjects, efavirenz (600 mg once a day for 14 days) decreased the mean steady-state peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) of atazanavir (400 mg once a day) by 59%, 74%, and 93%, respectively, compared to administration of atazanavir alone. When ritonavir 100 mg was added to the regimen and given simultaneously with atazanavir 300 mg once a day in 13 study subjects, daily administration of efavirenz 600 mg two hours later resulted in atazanavir systemic exposure that was similar to that produced by 400 mg of atazanavir alone. Atazanavir boosted with cobicistat appears more sensitive to the effects of CYP450 3A4 induction by efavirenz than atazanavir boosted with ritonavir; however, pharmacokinetic data are not available.

MANAGEMENT: Concomitant use of efavirenz with unboosted atazanavir, atazanavir-ritonavir, or atazanavir-cobicistat is not generally recommended in either treatment-naive or treatment-experienced patients. Some authorities consider the administration of atazanavir-cobicistat with efavirenz to be contraindicated. However if considered necessary in treatment-naive patients, a prescription of atazanavir 400 mg-ritonavir 100 mg or atazanavir 400 mg-cobicistat 150 mg once daily with food, and efavirenz 600 mg administered once daily on an empty stomach at bedtime, may be considered. Other authorities have also recommended atazanavir 400 mg-ritonavir 200 mg and efavirenz 600 mg, all as a single daily dose with food and close clinical monitoring.

Switch to consumer interaction data

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.

Switch to consumer interaction data