Overview

Co-trimoxazole is an antibacterial product with a combination of sulfamethoxazole and trimethoprim.¹ There are currently 16 products registered with the Drug Control Authority (DCA), with one (1) injection and 15 oral preparations.

Co-trimoxazole injection is indicated for pre- and post-operative infections associated with surgery, trauma or gynaecology, septicaemia and other infections due to sensitive organisms such as typhoid and paratyphoid.¹ Oral co-trimoxazole (tablet and suspension) is approved for various type of infections such as respiratory tract infections, urinary tract infections, gastrointestinal tract infections, as well as skin and soft tissue infections caused by susceptible organisms.^2,3

Background of Safety Issue

Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury usually caused by infection or trauma. ARDS causes fluid to leak into the alveoli, making breathing becomes difficult and hypoxia.⁴

The Pharmacovigilance Risk Assessment Committee (PRAC), European Medicines Agency (EMA), had requested the product registration holders of co-trimoxazole-containing medicinal products to update their package inserts with ARDS-related information.⁵

The exact mechanism of ARDS has not been confirmed. However, there is an assumption that the reactive intermediates that formed during drug metabolism, which can bind to proteins, may play an important role in these idiosyncratic reactions.⁶

Previous literature cases of adult patients reported positive outcomes following the cessation of co-trimoxazole alone (positive dechallenge) or in combination with steroid therapy. There have also been reports of symptoms reappearing following the reintroduction of co-trimoxazole (positive rechallenge).^7-8 Recent case series in the literature reported that all five cases in healthy adolescents exposed to a two- to four-week course of co-trimoxazole required invasive respiratory support, and two of the adolescents died. The onset of severe ARDS in these adolescent patients has been reported ranging between 10 and 25 days.⁶

Adverse Drug Reaction Reports⁹

As of June 2021, the NPRA had received 2,555 reports of 4,669 adverse events suspected to be related to co-trimoxazole. The most frequently reported adverse events were rash maculopapular (620), rash (557), pruritus (554) and Steven-Johnson’s syndrome (195). No report of acute respiratory distress syndrome related to co-trimoxazole received to date. However, there were reports of fever (86), dyspnoea (42) and cough (5).

Advice for Healthcare Professionals

• Be alert of the risk of very rare, severe cases of respiratory toxicity, which may sometimes progress to acute respiratory distress syndrome following the use of co-trimoxazole especially on elderly, patients with history of tobacco use, alcoholism or having chronic lung disease.
• Carefully consider this risk when a patient shows pulmonary signs and symptoms such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function. Obtain a detailed drug-exposure history for patients with acute respiratory distress syndrome of unknown origin.
• If such circumstances occur, discontinue co-trimoxazole and consider appropriate treatment for ARDS.
• Report all suspected adverse events associated with products containing co-trimoxazole to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/12(3)Jld.1] has been issued for registration holders of co-trimoxazole-containing products to update the local package inserts with this new safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). DBL Sulfamethoxazole 400mg and Trimethoprim 80mg Concentrate Injection BP local package insert [Internet]. 2020 Jul [cited 2021 Jul 21]. Available from: http://www.npra.gov.my (access restricted).
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Pharmaniaga Co-Trimoxazole Tablet local package insert [Internet]. 2017 Jul [cited 2021 Jul 21]. Available from: http://www.npra.gov.my (access restricted).
3. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). COMAZOLE (co-trimoxazole) Tablets and Suspensions local package insert [Internet]. 2017 Sep [cited 2021 Jul 21]. Available from: http://www.npra.gov.my (access restricted).
4. American Lung Association. Learn About ARDS [Internet]. 2020 Mar 24 [cited 2021 Jul 23]. Available from: https://www.lung.org/lung-health-diseases/lung-disease-lookup/ards/learn-about-ards
5. European Medicines Agency (EMA). PRAC Recommendations on Signals: Adopted at the 3-6 May 2021 PRAC Meeting [Internet]. 2021 May 31 [cited 2021 Jun 21]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-3-6-may-2021-prac-meeting_en.pdf
6. Miller JO, Taylor J, Goldman JL. Severe Acute Respiratory Failure in Healthy Adolescents Exposed to Trimethoprim-Sulfamethoxazole. Pediatrics [Internet]. 2019 Jun 1;143(6):e20183242. Available from: https://doi.org/10.1542/peds.2018-3242
7. Higgins T, Niklasson PM. Hypersensitivity pneumonitis induced by trimethoprim. BMJ. 1990 May 19;300(6735):1344. Available from: https://dx.doi.org/10.1136%2Fbmj.300.6735.1344
8. Jamous F, Ayaz SZ, Choate J. Acute fibrinous organising pneumonia: a manifestation of trimethoprim-sulfamethoxazole pulmonary toxicity. BMJ Case Rep. 2014 Oct 29;2014:bcr2014205017. Available from: http://dx.doi.org/10.1136/bcr-2014-205017
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2021 [cited 2021 Jun 23]. 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: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli