Effect of loperamide on heart rhythm: Randomized, double-blind, controlled study in healthy adults

Background: Excessively high doses of loperamide (of up to 792mg/day) have recently been associated with reports of cardiac events.However, no data currently demonstrate a direct effect of high doses of loperamide on the occurrence of cardiovascular abnormalities. Objectives:To assess the effects of loperamide on QT/corrected QT (QTc) intervals, electrocardiogram (ECG) morphology, and overall safety and tolerability at therapeutic and supratherapeutic exposures in healthy adults.Methods: This randomized, double-blind, four-way-crossover study enrolled 65 healthy adults to receive loperamide 8mg (therapeutic dose), loperamide 48mg (supratherapeutic dose), moxifloxacin 400mg (positive control), and placebo.Least square (LS) mean difference in change from baseline in Fridericia-corrected QT (ΔQTcF) intervals between loperamide (8mg and 48mg) and placebo with the two-sided 90% confidence interval (CI) was calculated for each timepoint.A non-inferiority criterion of mean difference in ΔQTcF of 10ms evaluated whether loperamide was non-inferior to placebo.Treatment safety was assessed throughout the study. Results:The majority of participants were female (66.2%) and White (95.4%).The mean (standard deviation) age was 36.4 (9.77) years.The highest upper limit of the two-sided 90% CI for LS mean difference in ΔQTcF between loperamide and placebo was 3.39ms for the therapeutic dose and 9.28ms for the supratherapeutic dose of loperamide, which were below the 10ms threshold, thereby demonstrating non-inferiority of loperamide to placebo.There were no significant morphological ECG changes after loperamide administration.There were no deaths, serious adverse events, or severe treatment-emergent adverse events. Conclusion:Single-dose loperamide at therapeutic (8mg) and supratherapeutic (48mg) doses do not show evidence of QTc prolongation of clinical concern in healthy participants.No new safety findings were identified.