The NPRA has updated information about this safety issue. See the NPRA Safety Alerts published on 6 May 2024.

Overview

Olmesartan is an angiotensin II receptor antagonist indicated for the treatment of essential hypertension.¹

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.^2-3 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.^2-4 If left untreated or in severe instances, the injury can lead to cirrhosis, liver failure, and death.^3-4

In Malaysia, there are currently 12 products containing olmesartan registered with the Drug Control Authority (DCA). Of these, seven (7) products are single-ingredient products, and five (5) products are in combination with either hydrochlorothiazide or amlodipine.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. Hence, an update to the product information for all olmesartan-containing products was compelled by the EMA in January 2022.⁶

The pathogenesis of drug-induced autoimmune hepatitis is still obscure. 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.³

The time to onset of drug-induced autoimmune hepatitis is often more than six (6) months, but can sometimes be up to several years after initiating the drugs.³ 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.^6-8

Adverse Drug Reaction Reports⁹

The NPRA has received a total of 51 reports with 71 adverse events suspected to be related to olmesartan-containing products. The most frequently reported adverse events were dizziness (7 reports), headache (5), abdominal distension (2), and gastro-oesophageal reflux disease (2). However, no local cases of autoimmune hepatitis following the use of olmesartan have been reported to the NPRA to date.

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that there have been post-marketing reports of autoimmune hepatitis associated with olmesartan use.
• Recognise the signs and symptoms of autoimmune hepatitis the soonest possible.
• 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.
• Consider the possible role of omelsartan in patients with clinical symptoms, unexplained liver enzyme elevations, and laboratory findings suggestive of autoimmune hepatitis.
• Report all adverse events suspected to be related to the use of olmesartan to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). OLMETEC (olmesartan) package insert [Internet]. 2017 Dec [cited 2022 May 30]. Available from: http://www.npra.gov.my (access restricted).
2. 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
3. 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 2022 May 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548188/
4. 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
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ system [Internet]. 2022 [cited 2022 May 30]. Available from: https://www.npra.gov.my/index.php/en/consumers/information/products-search.html
6. European Medicines Agency (EMA). PRAC recommendations on signals - adopted at the 29 November-2 December 2021 PRAC meeting [Internet]. 2022 January [cited 2022 May 30]. 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. 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
8. 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).
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2022 May 30]. Available from: https://www.npra.gov.my (access restricted).

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.

Written by: Ng Chiew Seng
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli