Drug Interactions between atazanavir / cobicistat and nevirapine

CONTRAINDICATED: Coadministration with nevirapine may decrease the plasma concentrations of atazanavir, with or without cobicistat or low-dose ritonavir as a pharmacokinetic booster, while the plasma concentrations of nevirapine may be increased. The plasma concentrations of cobicistat may also be reduced. Reduced plasma concentrations of atazanavir may lead to a loss of therapeutic effect and development of resistance to atazanavir. Increased nevirapine plasma concentrations may increase the risk of nevirapine-associated toxicity, including hepatotoxicity, fatal and non-fatal skin reactions (e.g., Stevens Johnson syndrome), and hypersensitivity reactions. The proposed mechanisms are induction of the CYP450 3A4 isoenzyme by nevirapine and the inhibition of CYP450 3A4 by atazanavir and cobicistat. No clinically significant interaction has been reported between nevirapine and ritonavir. When atazanavir-ritonavir (300 mg-100 mg once daily) was given in combination with nevirapine (200 mg twice daily) in HIV-infected patients, there was a reduction in atazanavir mean systemic exposure (AUC), peak plasma concentration (Cmax) and trough plasma concentration (Cmin) of 42%, 28%, and 72%, respectively. In contrast, the mean AUC, Cmax, and Cmin of nevirapine increased by 25%, 17%, and 32%, respectively. Data are not available for atazanavir-cobicistat.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, along with the increased risk of nevirapine-associated toxicity, it is not recommended to prescribe unboosted atazanavir or atazanavir-boosted with cobicistat or low-dose ritonavir in combination with nevirapine. Some authorities consider concomitant use of nevirapine with unboosted atazanavir or atazanavir boosted with cobicistat contraindicated (US).

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.