Summary Safety Review - Third Generation Aromatase Inhibitors (anastrozole, exemestane, letrozole) - Assessing the Potential Risk of Tendon Disorders
A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.
Third Generation Aromatase Inhibitors (anastrozole-, exemestane-, letrozole- containing products)
Potential Safety Issue
Tendon disorders, specifically, tendon inflammation (tendonitis), inflammation of the tendon sheath (tenosynovitis) and tendon tears (tendon rupture).
Use in Canada
- Third generation aromatase inhibitors are prescription drugs authorized for sale in Canada for the treatment of breast cancer in women who have reached menopause.
- There are currently 3 aromatase inhibitors on the Canadian market: Arimidex (anastrozole), Aromasin (exemestane), and Femara (letrozole). Generic versions of all 3 aromatase inhibitors are available in Canada.
- Between June 2015 and May 2021, the average annual total prescriptions (including new and refill prescriptions) dispensed by Canadian retail pharmacies to women aged 40 or older, were 247,271 prescriptions for anastrozole, 243,238 prescriptions for letrozole, and 39,048 prescriptions for exemestane.
Safety Review Findings
- Health Canada reviewed information from published and unpublished population-based studies and case reports of individual patients. Information was obtained from searches of international databases of published literature, drug manufacturers, as well as searches of the Canada Vigilance databasea.
- Health Canada reviewed 5 randomized controlled trials (RCTs) that included a total of 28,873 patients. Reported events of tendonitis and tenosynovitis, which were uncommon in occurrence (less than 1%), were found to be likely linked to the use of third generation aromatase inhibitors. A link with tendon rupture, which was rare in occurrence (less than 0.1%), could not be ruled out.
- Health Canada also reviewed 25 case reports (2 Canadian and 23 international) of tendon rupture (10 cases) and tendonitis (15 cases). Health Canada did not review case reports of tenosynovitis as there was insufficient information in these reports to separate tenosynovitis from other labelled adverse events involving the muscles and bones. Of the 10 reported cases of tendon rupture, 4 involved the use of anastrozole, 4 letrozole and 2 exemestane (1 Canadian). Of the 15 reported cases of tendonitis, 7 involved the use of anastrozole (1 Canadian), 4 involved letrozole and 4 exemestane. Across the assessed cases, tendonitis and tendon rupture affected both upper and lower limbs.
- These 25 case reports included other medications and/or conditions that could have contributed to the reported adverse events. From these case reports, a link between the risk of tendon rupture and tendonitis with the use of a third generation aromatase inhibitor could not be ruled out.
Conclusions and actions
- Health Canada's review of the available RCTs and case reports concluded that there is likely a link between the use of third generation aromatase inhibitors and the risks of tendonitis and tenosynovitis, which were uncommon in occurrence. A link with tendon rupture, which was rare in occurrence, could not be ruled out.
- Health Canada is working with the manufacturers of third generation aromatase inhibitors to update the CPMs to include these risks. Health Canada will inform healthcare professionals about these updates through a Health product InfoWatch communication.
- Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of aromatase inhibitors and other health products to the Canada Vigilance Program.
- Health Canada will continue to monitor safety information involving aromatase inhibitors, 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 any new health risks be identified.
The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of third generation aromatase inhibitors both in Canada and internationally.
For additional information, contact the Marketed Health Products Directorate.
- Canadian reports can be accessed through the Canada Vigilance Online Database.