Drug Interactions between Aldactazide and Kao-Paverin

MONITOR CLOSELY: Coadministration with drugs that inhibit the P-glycoprotein (P-gp) efflux transporter may increase the concentrations of loperamide in plasma and central nervous system (CNS). Inhibition of P-gp in the intestine increases the systemic absorption of loperamide, while inhibition in the blood brain barrier facilitates loperamide entry into the CNS. Opioid and other adverse effects may be enhanced. For example, when 16 mg of loperamide was administered to 8 healthy subjects with 600 mg of quinidine, a potent P-gp inhibitor, mean loperamide systemic exposure (AUC) increased by 2.5 fold and respiratory response to carbon dioxide decreased. High plasma 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 potent P-gp inhibitors. Particular caution is advised when drugs that inhibit other pathways of loperamide elimination (CYP450 2C8; CYP450 3A4) are also used, since they may act synergistically with P-gp inhibitors 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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