DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgment. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

This information is an update to the NPRA Safety Alerts published on 23 June 2022.

 

Overview

Loperamide is a synthetic opioid antidiarrhoeal agent.¹ In Malaysia, it is indicated for the treatment of symptomatic control of acute and chronic diarrhoea. It can also be used to reduce the frequency and volume of stools and to harden their consistency in patients with an ileostomy. It works by decreasing the motility of the gastrointestinal tract.

Acute pancreatitis is a transient inflammation of the pancreas associated with substantial morbidity and mortality.^2-3 Gallstones and alcohol abuse are the commonest causes of acute pancreatitis, whereas drugs have been linked to approximately 2%–4.8% of reported acute pancreatitis cases.²

There are currently nine (9) loperamide-containing products registered with the Drug Control Authority (DCA), all of which are single active ingredient oral formulations.⁴

 

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has learnt from the European Medicines Agency (EMA) regarding the risk of acute pancreatitis with the use of loperamide-containing products.⁵ The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has considered at least a possible causal relationship between loperamide and loperamide/simeticone with acute pancreatitis, based on the available evidence from the literature, spontaneous reports including nine (9) positive de-challenges and one (1) positive re-challenge, as well as a plausible mechanism of action. The PRAC concluded that the product information of products containing loperamide and loperamide/simeticone should be updated accordingly.

Sphincter of Oddi dysfunction has been described as a possible mechanism for drug-induced acute pancreatitis.⁶ This sphincter controls the flow of pancreatic and biliary secretions into the small intestine. Loperamide, which has an opioid receptor affinity, may trigger the Oddi’s sphincter to produce a reflux of secretions into the pancreas, elevating pancreatic duct pressure and eventually inducing pancreatitis. Despite this hypothesis, there may also be idiosyncratic competing causes for the development of acute pancreatitis.

According to the published literature and post-marketing reports suggestive of a plausible causal relationship, the time-to-onset of acute pancreatitis associated with loperamide use ranged around 1–5 days.⁶ Suspected pancreatitis with loperamide was more frequently reported in women. In certain cases, a history of cholecystectomy was also reported.  

Similar regulatory actions have been taken by regulatory authorities in reference countries, including the United Kingdom, France, and Sweden.^7-9

 

Adverse Drug Reaction Reports¹⁰

To date, the NPRA has received a total of 34 reports with 69 adverse events suspected to be caused by loperamide-containing products. The most frequently reported adverse events were related to the system organ class (SOC) of skin and subcutaneous tissue disorders, including pruritus (14 reports), rash (7), and urticaria (7). The NPRA has received no local reports of acute pancreatitis thus far, however symptoms such as nausea (1) and vomiting (1) have been reported.

 

Regulatory Action

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (28) Jld.1] had been issued for all registration holders of products containing loperamide to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

 

Advice for Healthcare Professionals

• Be aware of the possible risk of acute pancreatitis associated with loperamide use, especially in patients with a history of cholecystectomy.
• Advise patients taking loperamide to seek medical attention if they experience characteristic symptoms of acute pancreatitis, including upper abdominal pain, abdominal pain that radiates to back, tenderness when touching the abdomen, fever, rapid pulse, nausea, and vomiting.
• Consider the diagnosis of acute pancreatitis in patients presenting with clinical symptoms, elevated pancreatic enzymes, and/or characteristic findings in abdominal imaging following loperamide use.
• Early detection of acute pancreatitis and prompt withdrawal of the offending drug minimise complications and length of hospital stay.
• Report all suspected adverse events associated with loperamide-containing products to the NPRA.

 

References:

National Pharmaceutical Regulatory Agency (NPRA). IMODIUM CAPSULE 2MG (loperamide) [Package Insert]. 2023 Jan 16 Nov [cited 2023 Sep 1]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted)

1. Chatila AT, Bilal M, Guturu P. Evaluation and management of acute pancreatitis. World J Clin Cases. 2019; 7(9): 1006-1020. Available from: https://doi.org/10.12998%2Fwjcc.v7.i9.1006
2. Jones MR, Hall OM, Kaye AM, Kaye AD. Drug-induced acute pancreatitis: A review. Ochsner J [Internet] 2015 Spring;15(1):45-51. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365846/
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3⁺ Product Search [Internet]. 2022 [cited 2022 Apr 4] Available from: https://www.npra.gov.my 
4. European Medicines Agency (EMA). Annex I: Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s) [Internet]. 2022 Mar 14 [cited 2022 May 9]. Available from: https://www.ema.europa.eu/en/documents/psusa/loperamide-loperamide/simeticone-cmdh-scientific-conclusions-grounds-variation-amendments-product-information-timetable/00010665/202105_en.pdf
5. World Health Organization (WHO). Loperamide and acute pancreatitis in patients with a history of cholecystectomy: Signal strengthening. WHO Pharmaceuticals Newsletter [Internet]. 2018 Sep [cited 2022 May 9]. Available from: https://apps.who.int/iris/bitstream/handle/10665/339949/9789240021365-eng.pdf?sequence=1&isAllowed=y  
6. Medicines and Healthcare products Regulatory Agency (MHRA). Products: IMODIUM (loperamide) [Package Insert]. 2023 Jan 12 [cited 2023 Jan 27]. Available from: https://mhraproducts4853.blob.core.windows.net/docs/5212557b8fdaafb69be3d942fe2554457bfc3744
7. Agence nationale de sécurité du médicament et des produits de santé (ANSM). Research of pharmaceutical specialties: IMODIUM (loperamide) [Package Insert]. 2022 May 20 [cited 2023 Jan 27]. Available from: http://agence-prd.ansm.sante.fr/php/ecodex/frames.php?specid=61651634&typedoc=R&ref=R0389750.htm
8. Swedish Medical Products Agency. Search drug facts: IMODIUM (loperamide) [Package Insert]. 2022 Dec 28 [cited 2023 Jan 27]. Available from: https://docetp.mpa.se/LMF/Imodium%202%20mg%20tablet%20SmPC_09001bee807a4370.pdf
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST3+) [Internet]. 2023 [cited 2023 Jan 26]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Nafiza binti Mohd Ismail
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali