Drug Interactions between cobicistat / darunavir / emtricitabine / tenofovir alafenamide and flecainide

MONITOR CLOSELY: Coadministration with cobicistat may significantly increase the plasma concentrations of certain antiarrhythmic agents such as amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine. The mechanism involves inhibition of CYP450 2D6 (flecainide, propafenone) and/or 3A4 (amiodarone, bepridil, disopyramide, quinidine) metabolism, as cobicistat is a potent inhibitor of both isoenzymes. The interaction has not been specifically studied, but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities if levels are significantly increased. The use of these antiarrhythmic agents has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death.

MANAGEMENT: Caution is advised if cobicistat must be used concomitantly with antiarrhythmic agents that are primarily metabolized by CYP450 2D6 and/or 3A4. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever cobicistat is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR: Coadministration of tenofovir with other drugs that are also eliminated by active tubular secretion may result in increased plasma concentrations of tenofovir and/or the coadministered drug(s) due to competition for renal excretion. Drugs that are thought to undergo active tubular secretion include acyclovir, amiloride, cidofovir, cimetidine, flecainide, ganciclovir, metformin, midodrine, procainamide, quinidine, ranitidine, triamterene, valacyclovir, and valganciclovir.

MANAGEMENT: Patients receiving tenofovir in combination with other drugs that undergo active tubular secretion should be monitored for excessive pharmacologic effects of all drugs, and the dosages adjusted as necessary. Because tenofovir is associated with dose-related nephrotoxicity, especially proximal renal tubulopathy, renal function tests including serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein should be performed prior to and during therapy. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

MONITOR: Coadministration with darunavir may increase the plasma concentrations of disopyramide, flecainide and mexiletine. The proposed mechanism is darunavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. The interaction has not been studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities.

MANAGEMENT: Caution is advised if darunavir, including boosted darunavir, must be used with disopyramide, flecainide or mexiletine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever darunavir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR: Coadministration of tenofovir and darunavir-ritonavir or darunavir-cobicistat may result in increased plasma concentrations of tenofovir and darunavir. Increased tenofovir plasma concentration 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 is unknown; however, increased tenofovir concentrations may be related to inhibition of P-glycoprotein by darunavir, cobicistat, or ritonavir in the renal tubules. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. In 12 study subjects, administration of darunavir-ritonavir (300 mg-100 mg twice daily) with tenofovir (300 mg once daily) increased the systemic exposure (AUC) and trough plasma concentration (Cmin) of darunavir by 21% and 24%, respectively, compared to administration without tenofovir. Tenofovir AUC and Cmin also increased by 22% and 37%, respectively, in the presence of darunavir-ritonavir. 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: Caution and close monitoring of renal function is recommended if darunavir-ritonavir or darunavir-cobicistat is to be used in combination with tenofovir, particularly in patients with risk factors for renal impairment. No dose adjustments appear necessary during coadministration of darunavir-ritonavir with tenofovir. However, 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.

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.