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 judgement. 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 16 June 2022.

Overview

Olmesartan is an angiotensin II receptor antagonist indicated for the treatment of essential hypertension.¹ In Malaysia, there are currently 12 products containing olmesartan registered with the Drug Control Authority (DCA).² Of these, 7 products are single-ingredient products, and five (5) products are in combination with either hydrochlorothiazide or amlodipine.

Autoimmune hepatitis is a rare, chronic inflammatory liver injury with autoimmune features characterised by circulating autoantibodies, liver enzyme elevations (e.g., serum aminotransferase and alkaline phosphatase), hypergammaglobulinaemia, interface hepatitis on liver histology, and a positive response to corticosteroid therapy.^3-4 The clinical features generally present with the insidious onset of fatigue, weakness, nausea, poor appetite, right upper quadrant discomfort and jaundice or pruritus. Extrahepatic manifestations of autoimmunity such as arthralgia and skin rash may also occur.^3-5 If left untreated or in severe instances, the injury can lead to cirrhosis, liver failure, and death.^4-5

Background of Safety Issue

Based on the evidence from the literature and EudraVigilance, the European Medicines Agency (EMA) concluded that there is a plausible causal association between olmesartan and autoimmune hepatitis.⁶ Hence, an update to the product information for all olmesartan-containing products was compelled by the EMA in January 2022. Similar regulatory actions have been taken by regulatory authorities in reference countries, including France, United Kingdom, Switzerland and Australia.^7-10

The pathogenesis of drug-induced autoimmune hepatitis is still obscure.⁴ However, it is postulated that hepatocytes, which have the ability to metabolise drugs, can form drug-protein adducts that may be immunogenic and subsequently trigger CD4+ and CD8+ cytotoxic lymphocytes and natural killer cell proliferative responses. In addition, drugs may interact with T cell receptors to induce an immune response without forming drug-protein adducts. There may also be a human leukocyte antigens (HLA)-associated genetic predisposition to autoimmune hepatitis from medications.

According to the literature and post-marketing reports, there have been occurrences of autoimmune hepatitis associated with olmesartan use, which reported a latency of few months to years and were reversible after drug withdrawal.^6,11-12

Adverse Drug Reaction Reports¹³

The NPRA has received a total of 53 reports with 7 adverse events suspected to be related to olmesartan-containing products. The most frequently reported adverse events were dizziness (7 reports), headache (7), abdominal distension (3), and gastro-oesophageal reflux disease (2). Although no local cases of autoimmune hepatitis following the use of olmesartan have been reported to the NPRA to date, there was 1 report of acute hepatitis received.

Advice for Healthcare Professionals

• Be aware that there have been post-marketing reports of autoimmune hepatitis associated with olmesartan use.
• Advise patients to seek medical attention immediately if they develop signs and symptoms such as yellowing of the whites of the eyes, dark urine, or skin itchiness, even if they have been taking olmesartan for a long period of time.
• Recognise the signs and symptoms of autoimmune hepatitis the soonest possible as untreated autoimmune hepatitis has a high mortality rate.
• Consider the possible role of omelsartan in patients with clinical symptoms, unexplained liver enzyme elevations, and laboratory findings suggestive of autoimmune hepatitis.
• Consider stopping omelsartan and carefully monitor for possible relapse to rule out idiopathic autoimmune hepatitis
• Report all adverse events suspected to be related to the use of olmesartan to the NPRA.

Regulatory Action

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (42) Jld.1] had been issued for all registration holders of products containing olmesartan (including combination products) to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). OLMETEC (olmesartan) package insert [Internet]. 2023 Apr 4 [cited 2024 Jan 12]. Available from: http://www.npra.gov.my (access restricted).
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ system [Internet]. 2024 [cited 2024 Apr 17]. Available from: https://www.npra.gov.my/index.php/en/consumers/information/products-search.html
3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: autoimmune hepatitis. Journal of Hepatology. 2015;63(4):971-1004. Available from: https://doi.org/10.1016/j.jhep.2015.06.030
4. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Autoimmune hepatitis [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2019 [cited 2024 Jan 12]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548188/
5. Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011 Dec;60(12):1611-29. Available from: https://doi.org/10.1136/gut.2010.235259
6. European Medicines Agency (EMA). PRAC recommendations on signals - adopted at the 29 November-2 December 2021 PRAC meeting [Internet]. 2022 January [cited 2024 Jan 12]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-29-november-2-december-2021-prac-meeting_en.pdf  
7. Agence nationale de sécurité du médicament et des produits de santé (ANSM). Public Drug Database. OLMETEC (olmesartan) [Package Insert]. 2022 Apr 7 [cited 2024 Jan 12]. Available from: https://base-donnees-publique.medicaments.gouv.fr/affichageDoc.php?specid=67258011&typedoc=R
8. Medicines and Healthcare products Regulatory Agency (MHRA). Products: OLMETEC (olmesartan) [Package Insert]. 2022 Mar 31 [cited 2024 Jan 12]. Available from: https://mhraproducts4853.blob.core.windows.net/docs/6a57fff90e2ed6ae4c6b54f4fbd3e2440c3aa714
9. Swiss Agency for Therapeutic Products. SAI- Individual search. OLMETEC (olmesartan) [Package Insert]. 2022 Mar [cited 2024 Jan 12]. Available from: https://swissmedicinfo.ch/showText.aspx?textType=FI&lang=EN&authNr=55907&supportMultipleResults=1
10. Therapeutic Goods Administration (TGA). Australian Register of Therapeutic Goods (ARTG). OLMETEC (olmesartan) [Package Insert]. 2022 Aug 15 [cited 2024 Jan 12]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2010-PI-06038-3&d=20240415172310101
11. de la Torre-Aláez M, Iñarrairaegui M. Drug liver injury induced by olmesartan mediated by autoimmune-like mechanism: a case report. Eur J Case Rep Intern Med. 2020;7(1):001407. Available from: https://dx.doi.org/10.12890%2F2020_001407
12. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2022 [cited 2022 May 30]. Available from: https://www.vigilyze.who-umc.org (access restricted).
13. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2024 Jan 12]. Available from: https://www.npra.gov.my (access restricted).

Written by: Wo Wee Kee, Ng Chiew Seng
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali