Drug Interactions between emtricitabine / lopinavir / ritonavir / tenofovir and Up and Up Anti-Diarrheal Solution

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: The use of higher than recommended dosages of loperamide (e.g., through abuse or misuse) has been associated with serious and potentially fatal cardiac adverse events, including syncope, cardiac arrest, and arrhythmia related to prolongation of the QT interval. Under such circumstances, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias such as torsade de pointes and sudden death. 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. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if loperamide is used in combination with other drugs that can prolong the QT interval. 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 with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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