Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide and triazolam

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations and pharmacologic effects of orally administered alprazolam, midazolam and triazolam, which undergo intestinal (first-pass) and hepatic metabolism by the isoenzyme. Itraconazole and ketoconazole have been reported to increase the systemic exposure (AUC) of alprazolam by 2.7- and 4-fold, respectively, compared to placebo. Up to 3-fold increases in peak plasma concentration (Cmax) and 5- to 10-fold increases in AUC have been reported for oral midazolam during coadministration with potent CYP450 3A4 inhibitors like ritonavir, boceprevir, telaprevir, itraconazole, and ketoconazole. Similarly, up to 3-fold increases in Cmax and 14- to 22-fold increases in AUC have been observed for triazolam during coadministration with these agents. The interaction also occurs with intravenous midazolam, but to a lesser extent, with increases of 2.5- to 5-fold in AUC reported.

MANAGEMENT: Given the potential for prolonged and/or increased sedation and respiratory depression associated with excessive benzodiazepine blood levels, concomitant use of alprazolam, oral midazolam or triazolam with potent CYP450 3A4 inhibitors is considered contraindicated. Caution and close clinical monitoring are recommended when administering parenteral midazolam in combination with these agents. Appropriate medical management should be readily available in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam may be appropriate, especially if more than a single dose of midazolam is administered.

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MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

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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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