Drug Interactions between nefazodone and Pepto Diarrhea Control

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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