Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir disoproxil and methadone

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-glycoprotein (P-gp) efflux transporter may increase the plasma concentrations of methadone, which is metabolized primarily by CYP450 3A4, 2B6, 2C19, and to a lesser extent by CYP450 2C9 and 2D6 and which is also a substrate of the P-gp efflux transporter. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression should be considered, particularly when an inhibitor is added after a stable dose of methadone is achieved. In addition, high dosages (particularly above 200 mg/day) and serum levels of methadone have been associated with QT interval prolongation and torsade de pointes arrhythmia.

MANAGEMENT: Caution and close clinical monitoring for adverse effects associated with methadone are advised if concurrent use with a CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-glycoprotein (P-gp) inhibitor. ECG monitoring should be considered for patients on methadone with heart or liver disease; conduction abnormalities; electrolyte disturbances (i.e., hypokalemia, hypomagnesemia); concomitant use of drugs that may cause QT prolongation or electrolyte loss; or concomitant use of CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-gp inhibitors. Respiratory depression, sedation and pharmacologic response to methadone should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of the CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-gp inhibitors in patients who are stabilized on their methadone regimen. Patients should be advised to report excessive drowsiness, nausea, or asthenia to their physician, and to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. If taking drugs that also cause CNS-depressant or orthostatic effects, patients should be made aware of the possibility of additive effects with methadone and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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.

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.