Advice for healthcare professionals:
serious cardiovascular events (such as QT prolongation, torsades de pointes, and cardiac arrest), including fatalities, have been reported in association with large overdoses of loperamide
healthcare professionals are reminded that if symptoms of overdose occur, naloxone can be given as an antidote
since the duration of action of loperamide is longer than that of naloxone (1–3 hours), repeated treatment with naloxone might be indicated; patients should be monitored closely for at least 48 hours to detect possible CNS depression
as for all medicines, pharmacists should remind patients not to take more than the recommended dose on the label
report all suspected adverse reactions, including those associated with abuse or misuse, to the Yellow Card Scheme
Review of cardiovascular adverse reactions associated with loperamide
Loperamide has been on the market since the 1970s and is considered very safe when used in accordance with instructions on the label and in the patient information leaflet.
A European review of worldwide spontaneous reports identified 19 cases suggestive of cardiac rhythm disorders associated with loperamide abuse and misuse. In all cases, there was evidence of intentional high doses being taken for unapproved indications.
In 13 of the 19 reports, QT prolongation or torsades de pointes were recorded with daily dosages ranging from 40–80 mg up to 800 mg (the recommended maximum daily dose is 16 mg).
Of the other 6 reports, one described syncope and irregular heart beat (daily dose 400–600 mg), one described cardiac arrest with a rhythm of pulseless electrical activity (daily dose 400–800 mg), one described ventricular dysrhythmia (daily dose 400 mg), and one described asystole and death (chronic massive overdose). Two reports did not provide specific information on cardiac rhythm disorders or dose, with one describing syncope and death and one loss of consciousness.
As a result of the European review, all manufacturers of loperamide products have been asked to update their product information to include warnings of cardiac events associated with high doses. The patient leaflet will also be updated to warn patients never to take more than the recommended amount.
We have received 16 UK Yellow Card reports of cardiac-related adverse events associated with loperamide; however, most of these cases date back to the 1970s and 1980s and provide few details. We are aware that adverse events associated with misuse of drugs are under-reported.
Two of 16 reports list doses higher than the licensed daily limit. Dose was not recorded in 10 of the 16 cases. Of 4 cases reporting doses within the licensed range, only one report was not associated with anaphylaxis or underlying cardiac disease.
Of the 16 cardiac-related adverse events described by Yellow Cards, 5 were fatal. One death was suspected to be due to a large overdose of loperamide, whereas 4 deaths were associated with underlying cardiac disease or anaphylaxis.
Mechanism of adverse reaction
Non-clinical data offer a biologically plausible mechanism for the reaction (QT prolongation and arrhythmias caused by potassium channel (hERG) inhibition at high doses). At extremely high concentrations, loperamide also has the potential to slow cardiac conduction via inhibition of sodium channels, and produce conduction arrhythmias.
Loperamide is a synthetic opioid that inhibits gut motility by binding to opiate receptors in the gut wall and may also reduce gastrointestinal secretions, resulting in improvement in diarrhoea symptoms. Loperamide also increases the tone of the anal sphincter.
Loperamide is indicated for the symptomatic treatment of acute diarrhoea. In the UK, loperamide (brand name Imodium) is available on general sale (maximum daily dose 12 mg) and from pharmacists (maximum daily dose 16 mg).
PRAC recommendations on signals. 1.1. Loperamide – Serious cardiac events with high doses of loperamide from abuse and misuse. Accessed August 2017.
Article citation: Drug Safety Update volume 11 issue 2, September 2017: 2.