Drug Interactions between Pepto Diarrhea Control and saquinavir

GENERALLY AVOID: Coadministration with loperamide may decrease the plasma concentrations of saquinavir. The mechanism of interaction is unknown, but may be mediated by the effects of loperamide on gastrointestinal motility and fluids. In 12 healthy volunteers, administration of a single 600 mg dose of saquinavir (three 200 mg soft gelatin capsules) with a 16 mg dose of loperamide resulted in reductions of 46% and 54% in saquinavir peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration with placebo. The renal clearance and elimination half-life of saquinavir were not affected. Conversely, loperamide AUC increased 41% with saquinavir versus placebo, presumably due to saquinavir inhibition of loperamide N-demethylation via CYP450 3A4. This change is unlikely to be of clinical significance.

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 such as saquinavir 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: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, prolonged use of loperamide should preferably be avoided in patients treated with saquinavir. However, the effect of loperamide on the pharmacokinetics of ritonavir-boosted saquinavir is unknown. Caution is recommended if coadministration is required. 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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