DISCLAIMER: This publication is intended for healthcare professionals. The information provided aims to update on medication safety issues and should not substitute 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 arising from the use of or reliance on this publication.

 

Overview of Products

Angiotensin II receptor blockers (ARBs) are indicated for the treatment of hypertension, heart failure or asymptomatic left ventricular dysfunction, secondary prevention of coronary artery disease, diabetes mellitus and diabetic nephropathy, subject to certain conditions.¹ In Malaysia, there are more than 200 ARB-containing products currently registered with the Drug Control Authority (DCA) , available as both single-ingredient and combination formulations.²

 

Overview of Safety Concern

Intestinal angioedema is a condition characterised by fluid extravasation in the submucosal space of the intestinal wall, leading to symptoms such as abdominal pain, nauseaand vomiting.^3,4 These symptoms can resemble acute abdomen and may result in unnecessary surgical procedures such as laparotomies. Due to its non-specific presentation, diagnosis can be challenging.³

There have been reported cases of intestinal angioedema linked to ARB use.⁵ This condition is believed to result from ARBs blocking the angiotensin II receptor type 1 (AT1), leading to increased stimulation of angiotensin II receptor type 2 (AT2), causing bradykinin-mediated side effects.^5,6

 

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received updates from the European Medicines Agency (EMA) regarding the risk of intestinal angioedema associated with ARB use.⁷

The EMA conducted a comprehensive evaluation, triggered during routine signal detection from cases in EudraVigilance with various ARBs.¹ A total of 45 cases of intestinal angioedema were identified, involving olmesartan, olmesartan/ hydrochlorothiazide, olmesartan/ amlodipine, candesartan, irbesartan, losartan, valsartan and valsartan/sacubitril. Although not all ARBs were implicated in these cases, based on the established link between intestinal angioedema and other renin-angiotensin system inhibitors such as ACEIs, it was concluded that intestinal angioedema could be considered a class effect of ARBs.

Following the signal evaluation, which included cases from EudraVigilance and cumulative analyses provided by product registration holders, the EMA recommended updating the product information for all ARB-containing products to include information on the risk of intestinal angioedema.⁷

 

Local Adverse Drug Reaction Reports

To date, the NPRA has received a total of 3,437 adverse drug reactions reports with a total of 6,022 adverse events associated with ARB use in Malaysia.⁸ Although no confirmed cases of intestinal angioedema have been reported, related symptoms such as abdominal pain, nausea, vomiting, and diarrhoea have been reported with losartan, telmisartan, valsartan, and irbesartan.

 

Regulatory Review

Currently in Malaysia, most ACEI package inserts (PI), including those for enalapril, lisinopril, perindopril, and ramipril, specifically mention “intestinal angioedema”.⁹ However, most ARB PIs generally list  “angioedema” without specifying the intestinal form. The NPRA is currently engaging with PRHs to assess the need for PI updates to reflect this safety concern.

It is important to note that both azilsartan and eprosartan, currently under EMA review, are not registered in Malaysia.² Meanwhile, fimasartan is registered in Malaysia but is excluded from the EMA review as it is not approved in the European Union.

 

Advice for Healthcare Professionals

• Be aware that intestinal angioedema has been reported with ARBs, including olmesartan, irbesartan, valsartan, losartan, and candesartan. Caution should also be taken with other ARBs.
• Educate patients to seek medical advice if they have symptoms such as abdominal pain, nausea, vomiting, and diarrhoea.
• Consider performing radiological assessments such as abdominal CT scans or ultrasonography in patients on ARBs presenting with abdominal pain.
• If intestinal angioedema is suspected, discontinue the ARB and monitor the patient until all symptoms have completely resolved.
• Report all suspected adverse events related to ARBs-use to the NPRA.

 

References

1. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 8-11 July 2024 PRAC meeting [Internet]. 2024 Aug 23 [cited 2025 Jan 14]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-8-11-july-2024_en.pdf
2. National Pharmaceutical Regulatory Agency. QUEST3+ Product Search [Internet]. 2025 [Cited 2025 Jan 10] Available from: https://www.npra.gov.my
3. Pal NL, Fernandes Y. Intestinal Angioedema: A Mimic of an Acute Abdomen. Cureus. 2023; 15(2): e34619. Available from: https://doi.org/10.7759/cureus.34619
4. Bell DJ. Intestinal angioedema [Internet]. Radiopaedia. 2023 [cited 2025 Feb 17]. Available from: https://radiopaedia.org/articles/intestinal-angioedema
5. Rosas S, Fowler A, Stodgill E, Deyo-Svendsen M , Phillips M. A Rare Case of Losartan-Induced Visceral Angioedema. Journal of Primary Care & Community Health. 2023; 14: 1–3. Available from: https://doi.org/10.1177/21501319231213744
6. Macaulay TE, Dunn SP. Cross-Reactivity of ACE Inhibitor–Induced Angioedema with ARBs. US Pharm. [Internet]. 2007 Feb [cited 2025 Feb 17]; 32(2):HS17-HS23. Available from: https://www.uspharmacist.com/article/cross-reactivity-of-ace-inhibitorinduced-angioedema-with-arbs
7. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 28-31 October 2024 PRAC meeting [Internet]. 2024 Nov 25 [cited 2024 Dec 19]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-28-31-october-2024-prac-meeting_en.pdf
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2024 [cited 2024 Dec19]. Available from: https://www.npra.gov.my
9. National Pharmaceutical Regulatory Agency (NPRA). ARBs & ACE inhibitors [Package Insert]. QUEST3+ Product Search. 2025 [cited 2025 Jan 14]. Available from: http://www.npra.gov.my  

 

Written by: Nafiza Mohd. Ismail

Reviewed/Edited by: Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali