Summary Safety Review - Combination Sulfamethoxazole and Trimethoprim - Assessing the Potential Risk of Hemophagocytic Lymphohistiocytosis

Combination sulfamethoxazole and trimethoprim-containing products

Hemophagocytic lymphohistiocytosis (HLH), a condition where large numbers of white blood cells build up in, and damage organs and destroy other blood cells

• Combination sulfamethoxazole and trimethoprim is a prescription antibiotic drug authorized for sale in Canada to treat various bacterial infections, such as urinary tract infections, respiratory tract infections, and gastrointestinal infections.

• Health Canada reviewed the potential risk of HLH with the use of combination sulfamethoxazole and trimethoprim. The safety review was triggered by a labelling update for these products by the European Medicines Agency (EMA).

• Health Canada’s review of the available information found a possible link between the use of combination sulfamethoxazole and trimethoprim and the risk of HLH.

• Health Canada is working with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for combination sulfamethoxazole and trimethoprim-containing products to include the risk of HLH. Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

Health Canada reviewed the potential risk of HLH with the use of combination sulfamethoxazole and trimethoprim. The safety review was triggered by a labelling update for combination sulfamethoxazole and trimethoprim-containing products by the EMA.

Hemophagocytic lymphohistiocytosis is a rare but aggressive and life-threatening condition where large numbers of white blood cells build up in and damage organs and destroy other blood cells.

• Combination sulfamethoxazole and trimethoprim is a prescription antimicrobial drug authorized for sale in Canada to treat various bacterial infections, such as urinary tract infections, respiratory tract infections, and gastrointestinal infections.

• Combination sulfamethoxazole and trimethoprim has been marketed in Canada since 1973. It is currently available as oral tablets in 3 different strengths and a concentrate solution for infusion into a vein (intravenous) under different brand names and generic versions.

• Approximately 5.6 million prescriptions for combination sulfamethoxazole and trimethoprim were filled in Canadian retail pharmacies between 2017 and 2021.

• Health Canada reviewed the available information from searches of the Canada Vigilance database^a, international databases, and the scientific literature.

• At the time of the review, Health Canada had not received any Canadian reports of HLH related to the use of combination sulfamethoxazole and trimethoprim.

• Health Canada reviewed 10 international cases of HLH in patients taking combination sulfamethoxazole and trimethoprim from the Canada Vigilance database and the scientific literature. Of the 10 cases assessed, 1 was found to be probably linked to the use of combination sulfamethoxazole and trimethoprim, 8 were found to be possibly linked and 1 was unlikely to be linked. In all 8 cases found to be possibly linked, there were medical conditions (mostly common infections) that may have also played a role in the HLH. Two deaths were reported among the 10 cases assessed, of which 1 was found to be possibly linked to combination sulfamethoxazole and trimethoprim, while the other was unlikely to be linked.

• Health Canada also reviewed 2 publications in the scientific literature, which reported HLH in several patients treated with combination sulfamethoxazole and trimethoprim. Overall, evidence of a link between combination sulfamethoxazole and trimethoprim and HLH was unclear due to study limitations and contributing risk factors in patients.

• Health Canada’s review of the available information found a possible link between the use of combination sulfamethoxazole and trimethoprim and the risk of HLH.

• Health Canada is working with the manufacturers to update the CPM for combination sulfamethoxazole and trimethoprim-containing products to include the risk of HLH.

• Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch Communication.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of combination sulfamethoxazole and trimethoprim, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving combination sulfamethoxazole and trimethoprim, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific literature, Canadian and international information, and what is known about the use of combination sulfamethoxazole and trimethoprim both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Canadian reports can be accessed through the Canada Vigilance Online Database.