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 Product(s)

Cotrimoxazole is a broad-spectrum antibiotic combining sulfamethoxazole and trimethoprim. It acts synergistically by inhibiting sequential steps in bacterial folate synthesis, resulting in a bactericidal effect against a wide range of aerobic Gram-positive and Gram-negative bacteria.^1-4

In Malaysia, a total of 12 cotrimoxazole-containing products are registered with the Drug Control Authority (DCA), comprising 11 oral (tablet or suspension) and one (1) intravenous formulation.⁵ Cotrimoxazole is indicated for the treatment and prophylaxis of bacterial infections caused by susceptible organisms, including those affecting the respiratory, urinary, or gastrointestinal systems, and skin or soft tissues.^6-16

 

Overview of Safety Concern

Circulatory shock is a life-threatening condition characterised by acute circulatory failure that leads to decreased oxygen delivery, increased oxygen demand, and/or impaired oxygen utilisation, resulting in cellular and tissue hypoxia, cell death, organ dysfunction, and ultimately multiorgan failure. Common signs and symptoms include hypotension, tachycardia, cold or clammy cyanotic skin, decreased urine output, confusion and disorientation. However, hypotension may not always be present in the early stages due to compensatory mechanisms.^17-19

Recently, concerns have been raised regarding the occurrence of circulatory shock in patients receiving cotrimoxazole, prompting regulatory review by international authorities.

 

Source of Safety Concern²⁰

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) regarding the risk of circulatory shock associated with the use of cotrimoxazole. This information was based on the EMA’s review of evidence from published literature and the EudraVigilance database, as well as a cumulative safety review submitted by the Marketing Authorisation Holder (MAH).

The review identified several cases of circulatory shock associated with cotrimoxazole use, often accompanied by fever and unresponsive to standard treatment for hypersensitivity, occurring mainly in immunocompromised patients. Consequently, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended updating the product information (PI) for cotrimoxazole-containing products to include this risk.

 

Background of the Safety Issue²¹

As part of the evidence reviewed by the EMA, a published case review identified 18 cases of cotrimoxazole-induced circulatory shock, most of which (15) occurred in human immunodeficiency virus (HIV)-positive patients. All patients developed fever and hypotension within minutes to hours after cotrimoxazole administration.

The exact mechanism of cotrimoxazole-induced circulatory shock remains unclear. Current evidence suggests that it is not a classic immunoglobulin E (IgE)-mediated anaphylactic reaction, as tumour necrosis factor-alpha (TNF-α) and IgE levels typically remain normal after rechallenge. Instead, a transient rise in interleukin-6 (IL-6) indicates a cytokine-mediated inflammatory response, which may explain the poor response to standard treatments for hypersensitivity. Patients with HIV may be at higher risk, as sulfamethoxazole metabolites appear to be significantly more toxic to HIV-infected cells compared to non-infected cells.

 

Local Adverse Drug Reaction Reports²²

To date, the NPRA has received 3,849 reports involving 6,955 adverse events suspected to be related to cotrimoxazole-containing products. No cases of circulatory shock associated with cotrimoxazole have been reported locally.

 

Advice for Health Care Professionals

• Be vigilant of the risk of circulatory shock, particularly in immunocompromised patients (e.g., those with HIV) receiving cotrimoxazole.
• Inform patients about early symptoms of shock, which may include fever, very low blood pressure or an increased heart rate.
• Advise patients to discontinue cotrimoxazole immediately and seek medical attention promptly if they develop symptoms suggestive of circulatory shock.
• Be aware that circulatory shock associated with cotrimoxazole may not respond to standard treatments for hypersensitivity reactions (e.g., antihistamines, corticosteroids, or adrenaline), as the mechanism is not IgE-mediated.
• Report all suspected adverse events related to cotrimoxazole use to the NPRA.

 

References

1. Church JA, Fitzgerald F, Walker AS, Gibb DM, Prendergast AJ. The expanding role of co-trimoxazole in developing countries. Lancet Infect Dis. 2015;15(3):327–39.
2. Waghchaure P, Thange T, Vishal G. Basic Chemistry, Mode of Action and Clinical Uses of Co-Trimoxazole. Int J Pharm Sci. 2023;12:135–149.
3. Batra P, Deo V, Mathur P, Gupta AK. Cotrimoxazole, a wonder drug in the era of multiresistance: Case report and review of literature. J Lab Physicians. 2017;9(3):210–213. Available from: https://doi.org/10.4103/0974-2727.208261
4. Manski D. Cotrimoxazole: Adverse Effects, Contraindications and Dosage [Internet]. Urology-Textbook.com. 2025 [cited 2025 Oct 14]. Available from: https://www.urology-textbook.com/co-trimoxazole.html
5. National Pharmaceutical Regulatory Agency. QUEST3+ Product Search [Internet]. 2025 [cited 2025 June 17].
6. National Pharmaceutical Regulatory Agency (NPRA). B.S. Tablet (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2023 Jul 5 [cited 2025 June 18]. Available from: http://www.npra.gov.my
7. National Pharmaceutical Regulatory Agency (NPRA). B.S. Suspension (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2016 Mar 14 [cited 2025 Jun 18]. Available from: http://www.npra.gov.my
8. National Pharmaceutical Regulatory Agency (NPRA). Suprim Suspension (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2023 Jun [cited 2025 Jun 18] Available from: http://www.npra.gov.my
9. National Pharmaceutical Regulatory Agency (NPRA). Pharmaniaga Co-Trimoxazole Tablet (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2024 Apr 29 [cited 2025 June 18]. Available from: http://www.npra.gov.my
10. National Pharmaceutical Regulatory Agency (NPRA). Cotrim Ds 960mg Tablet (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2022 Apr 15 [cited 2025 Jun 18]. Available from: http://www.npra.gov.my
11. National Pharmaceutical Regulatory Agency (NPRA). Cotrim 480mg Tablet (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2022 Apr 15 [cited 2025 Jun 18] Available from: http://www.npra.gov.my
12. National Pharmaceutical Regulatory Agency (NPRA). Dynaprim Suspension (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2023 Jul [cited 2025 Jun 18]. Available from: http://www.npra.gov.my
13. National Pharmaceutical Regulatory Agency (NPRA). Comazole Suspension (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2022 Jun 17 [cited 2025 Jun 18] Available from: http://www.npra.gov.my
14. National Pharmaceutical Regulatory Agency (NPRA). Comazole N Tablet (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2022 Jun 17 [cited 2025 June 18]. Available from: http://www.npra.gov.my
15. National Pharmaceutical Regulatory Agency (NPRA). DBL™ Sulfamethoxazole and Trimethoprim Concentrate Injection (sulfamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2023 May 11 [cited 2025 Jun 18]. Available from: http://www.npra.gov.my
16. National Pharmaceutical Regulatory Agency (NPRA). Dynaprim Tablet (sulphamethoxazole trimethoprim) [Package Insert]. QUEST3+ Product Search. 2022 Aug [cited 2025 Jun 18] Available from: http://www.npra.gov.my
17. Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Intensive Care Med. 2014;40(12):1795–815.
18. Haseer Koya H, Paul M. Shock. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.
19. Libretexts.org. Circulatory Shock [Internet]. 2025 Apr 4 [cited 2025 Jul 27].
20. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 5–8 May 2025 PRAC meeting. 2025 June 2 [cited 2025 June 13].
21. Liu P, Ranches GP, Gold JA. Trimethoprim-sulfamethoxazole induced circulatory shock in a human immunodeficiency virus uninfected patient: A case report and review. BMC Pharmacol Toxicol. 2018;19(1):76. Available from: https://doi.org/10.1186/s40360-018-0269-3
22. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2025 [cited 2025 June 18]. Available from https://www.npra.gov.my (access restricted)

 

Written by: Nafiza Mohd. Ismail

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