Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir and flibanserin

CONTRAINDICATED: Coadministration with moderate and potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of flibanserin, which is primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 2C19. High plasma levels of flibanserin may increase the risk of severe hypotension, syncope, and central nervous system depression. In 15 healthy female subjects, administration of a single 100 mg dose of flibanserin following pretreatment with fluconazole (400 mg once, then 200 mg once daily for 5 days), a moderate CYP450 3A4 and potent CYP450 2C19 inhibitor, increased flibanserin peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.2- and 7-fold, respectively, compared to administration of flibanserin alone. Hypotension or syncope requiring therapeutic intervention (placement in supine position with legs elevated) occurred in 3 (20%) subjects given flibanserin and fluconazole, compared to no subject given flibanserin alone or fluconazole alone. One of the 3 subjects became unresponsive with a blood pressure of 64/41 mmHg and was taken to the hospital emergency department, where she required intravenous saline. In another study, flibanserin Cmax increased by 1.8-fold and AUC increased by 4.5-fold when a single 50 mg dose was administered to 24 healthy female subjects following pretreatment with ketoconazole (400 mg once daily for 5 days), a potent CYP450 3A4 inhibitor. Syncope occurred in 1 (4%) of 24 subjects receiving flibanserin and ketoconazole, 1 (4%) of 24 subjects receiving flibanserin alone, and no subject receiving ketoconazole alone. Likewise, when a single 50 mg dose of flibanserin was given to 12 healthy male and female subjects following pretreatment with itraconazole (400 mg once, then 200 mg once daily for 4 days), flibanserin Cmax and AUC increased by 1.7- and 2.6-fold, respectively. It should be noted that the 200 mg itraconazole dose does not maximally inhibit CYP450 3A4.

MANAGEMENT: Concomitant use of flibanserin with moderate or potent CYP450 3A4 inhibitors is considered contraindicated. When initiating flibanserin following treatment with a moderate or potent CYP450 3A4 inhibitor, the manufacturer recommends waiting until 2 weeks after the last dose of CYP450 3A4 inhibitor. Conversely, if a moderate or potent CYP450 3A4 inhibitor is required during flibanserin therapy, flibanserin should be discontinued at least 2 days before starting the CYP450 3A4 inhibitor. Close monitoring for signs of hypotension and syncope is advised if the CYP450 3A4 inhibitor is needed sooner.

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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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