Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide and Doans PM

MONITOR: Coadministration with cobicistat may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 or 2D6 isoenzymes and/or P-glycoprotein (P-gp) efflux transporter.

MANAGEMENT: Caution is advised if cobicistat is used concomitantly with medications that undergo metabolism primarily by CYP450 3A4 and/or 2D6 or are substrates of P-glycoprotein, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever cobicistat is added to or withdrawn from therapy.

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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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ADJUST DOSING INTERVAL: The concomitant use of antacids or oral products containing polyvalent cations (e.g., Mg, Al, Ca, Fe, Zn) may significantly decrease the plasma concentrations of elvitegravir. According to the elvitegravir manufacturer, the mechanism of the interaction may be related to local complexation in the gastrointestinal tract and not to changes in gastric pH. When 20 mL of an antacid containing magnesium and aluminum was given 2 hours before a 50 mg dose of elvitegravir with ritonavir (100 mg pharmacokinetic booster dose) to 11 study subjects, mean elvitegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were reduced by 18%, 15%, and 10%, respectively. When the antacid was given 2 hours after elvitegravir to 10 study subjects, the mean elvitegravir Cmax, AUC, and Cmin decreased by approximately 20% each. When the antacid was given simultaneously with elvitegravir to 13 study subjects, the mean elvitegravir Cmax, AUC, and Cmin decreased by approximately 47%, 45%, and 41%, respectively. In contrast, when the antacid was given 4 hours before or 4 hours after elvitegravir, no significant differences were observed in elvitegravir pharmacokinetics compared to the administration of elvitegravir alone. The interaction has not been studied with other polyvalent cation-containing products, but they are expected to decrease elvitegravir plasma concentrations as well.

MANAGEMENT: Antacid and oral products containing polyvalent cations should be administered at least 2 hours before or 2 hours after the elvitegravir dose. Some experts recommend an interval of at least 4 hours. Alternatively, H2-receptor antagonists or proton pump inhibitors may be considered instead of antacids, with no dosage adjustment needed.

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