Overview

Anastrozole, exemestane, and letrozole are categorised as third-generation aromatase inhibitors approved for the treatment of hormone receptor-positive breast cancer in postmenopausal women.^1-4 These medications work by reducing the concentration of serum oestrogen through the inhibition of aromatase.^2-4 In Malaysia, there are currently five (5) products containing anastrozole, two (2) products containing exemestane, and seven (7) products containing letrozole registered with the Drug Control Authority (DCA).⁵

Tendon disorders encompass a spectrum of conditions affecting the tendons, including tendon inflammation (tendonitis), tendon tears (tendon rupture), and tendon sheath inflammation (tenosynovitis).¹ Tendons play an important role in connecting muscles to bones, and disruptions in their structure or function can lead to significant restrictions in physical abilities. In severe cases, surgical intervention may be necessary.^1,6

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) recently learned through its global safety signal monitoring activity that Health Canada has requested all product registration holders for products containing third-generation aromatase inhibitors to update package inserts with the specific risk of tendon disorders (tendonitis, tendon rupture, and tenosynovitis).¹ This regulatory action was prompted by the safety measures taken by the European Medicines Agency (EMA) in response to the potential association between letrozole-containing products and the risks of tendonitis and tendon rupture.^1,7 Health Canada has expanded its review of tendon disorder risks to include all third-generation aromatase inhibitors available in Canada.¹

Health Canada's comprehensive review of available information, including randomised controlled trials (RCTs) and case reports from published literature, drug manufacturers, and Canada Vigilance database, concluded that there is a likely association between the use of third-generation aromatase inhibitors and the risks of tendonitis and tenosynovitis, which are uncommon in occurrence.¹ Although tendon rupture is rare in occurrence, a link to the use of third-generation aromatase inhibitors could not be ruled out.

Tendonitis and tendon rupture were observed to affect both the upper and lower limbs, including shoulders, Achilles tendons, elbows, hands, and wrists.^1,6-8 The reported onset of tendinopathy symptoms ranged from 2 weeks to 19 months after treatment initiation.^6,8 The proposed pathophysiological mechanism may be explained by the presence of oestrogen receptors within the intermediate layer of the pulleys and retinacula, which may contribute to the observed tendon alterations.⁸

Adverse Drug Reaction Reports⁹

To date, the NPRA has received 113 reports with 253 adverse events suspected to be related to products containing anastrozole, exemestane, and letrozole. No events related to tendon disorders have been reported locally. However, there have been reports of related events such as musculoskeletal pain, with one (1) report each associated with the use of anastrozole and letrozole.

Advice for Health Care Professionals

• Be aware of the potential associations between the use of third-generation aromatase inhibitors and the risks of tendonitis and tenosynovitis (uncommon occurrences), as well as tendon rupture (rare occurrence).
• Closely monitor patients receiving third-generation aromatase inhibitors with risk factors for tendon disorders:
  • Educate patients about the signs and symptoms, which include:
    • pain, swelling, and tenderness near a joint (tendon inflammation), or
    • feeling of a snap or pop at the time of injury with severe pain and swelling (tendon tear).
  • Advise patients to rest the painful area and seek immediate medical attention if they experience such signs and symptoms.
• Consider appropriate management based on the severity of the tendon disorder:
  • Treatment options may include rest, physical therapy, immobilisation of the affected area, or pharmacological treatment.
  • Consider discontinuing the use of the third-generation aromatase inhibitor if deemed necessary.
  • In severe cases, consider referring the patient to an orthopaedic surgeon for further evaluation and management.
• Report all suspected adverse events associated with the use of aromatase inhibitor products to the NPRA.

References:

1. Health Canada. Summary safety review – third generation aromatase inhibitors (anastrazole-, exemestane-, letrozole-containing products) [Internet]. 2023 Jan 17 [cited 2023 Apr 20]. Available from: https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00289
2. National Pharmaceutical Regulatory Agency. ARIMIDEX^® (Anastrozole) [Package Insert]. QUEST3+ Product Search. 2022 Mar [cited 2023 Apr 14]. Available from: https://quest3plus.bpfk.gov.my/front-end/attachment/668/pharma/210527/V_66241_20220428_155000_D3.pdf 
3. National Pharmaceutical Regulatory Agency. AROMASIN^® (Exemestane) [Package Insert]. QUEST3+ Product Search. 2021 Aug 17 [cited 2023 Apr 14]. Available from: https://quest3plus.bpfk.gov.my/front-end/attachment/286/pharma/211213/V_58032_20210914_170048_D3.pdf 
4. National Pharmaceutical Regulatory Agency. FEMARA^® (Letrozole) [Package Insert]. QUEST3+ Product Search. 2022 Apr 22 [cited 2023 Apr 14]. Available from: https://quest3plus.bpfk.gov.my/front-end/attachment/17050/pharma/210509/V_66227_20220428_132058_D3.pdf 
5. National Pharmaceutical Regulatory Agency. QUEST3⁺ Product Search [Internet]. 2023 [cited 2023 Apr 14]. Available from: https://www.npra.gov.my
6. Mitsimponas N, Klouva E, Tryfonopoulos D, Grivas A, Demiri S, Koumakis G, Gouveris P. Aromatase inhibitor-associated tendinopathy and muscle tendon rupture: report of three cases of this exceedingly rare adverse event. Case Rep Oncol. 2018 Aug 17;11(2):557-561. Available from: https://doi.org/10.1159%2F000491874
7. European Medicines Agency (EMA). Letrozole: CMDh scientific conclusions and grounds for variation, amendments to product information and implementation timetable - PSUSA/00001842/201810. 2019 Jul 30 [cited 2023 Apr 14]. Available from: https://www.ema.europa.eu/en/documents/psusa/letrozole-cmdh-scientific-conclusions-grounds-variation-amendments-product-information/00001842/201810_en.pdf
8. Kirchgesner T, Larbi A, Omoumi P, Malghem J, Zamali N, Manelfe J, Lecouvet F, Vande Berg B, Djebbar S, Dallaudière B. Drug-induced tendinopathy: from physiology to clinical applications. Joint Bone Spine. 2014 Dec;81(6):485-92. Available from: doi: 10.1016/j.jbspin.2014.03.022.
9. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2023 [cited 2023 Apr 14]. Available from: https://www.npra.gov.my

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: Nafiza Mohd. Ismail
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali