Loperamide and P‐glycoprotein inhibition: assessment of the clinical relevance

Objectives Loperamide is a peripherally acting μ opioid receptor agonist and an avid substrate for P‐glycoprotein. This may give rise to drug–drug interactions and increased risk for central adverse effects. The objective of this study was to re‐evaluate the predictability of non‐clinical data using loperamide as a probe P‐glycoprotein substrate. We searched the literature for papers containing data on drug–drug interactions of loperamide‐containing products in humans. We also reviewed the internal worldwide safety database of Johnson & Johnson for spontaneous case reports suggestive of a central opioid effect after coadministration of loperamide with a P‐glycoprotein inhibitor or substrate. Key findings Only one of the ten studies in our review supported the finding that inhibition of P‐glycoprotein is associated with clinically relevant signs or symptoms of central nervous system (CNS) depression/opioid toxicity of loperamide. None of the 25 spontaneous case reports of interest were suggestive of signs or symptoms of CNS depression/opioid toxicity due to coadministration of loperamide and a P‐glycoprotein inhibitor or substrate. Summary Based on a review of the literature and a cumulative review of the sponta‐neous case reports, there is insufficient evidence that an interaction between loperamide and a P‐glycoprotein inhibitor or substrate is associated with clinical symptoms of CNS depression/opioid toxicity when loperamide is taken at the recommended dose.