Drug Interactions between cobicistat / darunavir / emtricitabine / tenofovir alafenamide and Neo-Diaral

MONITOR CLOSELY: Coadministration with drugs that enhance the gastrointestinal absorption or inhibit the metabolism of loperamide (e.g., potent CYP450 3A4 or 2C8 inhibitors) may increase the plasma concentrations and adverse effects of loperamide. When a single 16 mg dose of loperamide was administered to 12 healthy volunteers with a single 600 mg dose of ritonavir, a potent CYP450 3A4 inhibitor, median loperamide systemic exposure (AUC) increased by 223% compared to administration with placebo. Likewise, administration of a single 4 mg dose of loperamide to 12 healthy volunteers on day 3 of treatment with the potent CYP450 2C8 inhibitor gemfibrozil (600 mg twice day for 5 days) increased loperamide peak plasma concentration (Cmax) and AUC by 1.6- and 2.2-fold, respectively, and prolonged its elimination half-life from 11.9 to 16.7 hours. The same study also found that gemfibrozil had substantial additive effects with itraconazole, a strong CYP450 3A4 and P-glycoprotein inhibitor, on the pharmacokinetics of loperamide. Whereas itraconazole (100 mg twice daily for 5 days) alone increased the Cmax and AUC of loperamide by 2.9- and 3.8-fold, respectively, gemfibrozil combined with itraconazole increased loperamide Cmax and AUC by 4.2- and 12.6-fold, respectively. The elimination half-life of loperamide was 18.7 hours during coadministration of itraconazole, compared to 36.9 hours during coadministration of gemfibrozil plus itraconazole. High levels of loperamide, including through abuse or misuse, has been associated with serious and potentially fatal cardiac adverse events such as syncope, cardiac arrest, and arrhythmia related to prolongation of the QT interval. According to the FDA, the agency received reports of 48 cases of serious heart problems associated with use of loperamide from when it was first approved in 1976 through 2015. Thirty-one of these cases resulted in hospitalizations, and 10 patients died. The serious heart problems occurred mostly in patients who were using loperamide dosages that were much higher than recommended in an attempt to achieve euphoria, prevent opioid withdrawal, or treat diarrhea. In the most severe cases, individuals self-treated with dosages ranging from 70 to 1600 mg/day, or 4 to 100 times the recommended dosage. In other cases, patients were taking the recommended dosage, but with concomitant interacting drugs that caused an increase in loperamide levels. There have been additional cases of serious heart problems associated with loperamide use reported in the medical literature.

MANAGEMENT: Caution is recommended if loperamide is used with drugs that enhance its gastrointestinal absorption or inhibit its metabolism. Particular caution is advised when drugs that inhibit CYP450 3A4 (e.g., azole antifungal agents, clarithromycin, cobicistat, conivaptan, delavirdine, erythromycin, idelalisib, nefazodone, protease inhibitors, telithromycin) and CYP450 2C8 (e.g., gemfibrozil, clopidogrel) are used together with loperamide, or when one or more of these drugs are combined with inhibitors of P-glycoprotein transport (e.g., amiodarone, cyclosporine, diltiazem, dronedarone, quinidine, verapamil), since they may act synergistically to increase loperamide concentrations. Patients should be counseled to not exceed the recommended dosage and frequency or duration of use of loperamide, and to seek prompt 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 loperamide-induced cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported cases of loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and electrical pacing or cardioversion was necessary.

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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.

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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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