Summary Safety Review - Brukinsa (zanubrutinib), Calquence (acalabrutinib) and Imbruvica (ibrutinib) - Bruton’s Tyrosine Kinase (BTK) Inhibitors - Assessing the Potential Risk of Serious Hepatotoxicity

Brukinsa (zanubrutinib), Calquence (acalabrutinib) and Imbruvica (ibrutinib) - Bruton’s tyrosine kinase (BTK) inhibitors

Serious hepatotoxicity (liver injury), including drug-induced liver injury (DILI; a rare, but potentially life-threatening, drug reaction with elevated liver enzymes that may lead to liver failure or a need for liver transplant)

• Health Canada’s review found a possible link between the use of BTK inhibitors and the risk of serious hepatotoxicity.

• Health Canada is working with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for all BTK inhibitors to include the risk of serious hepatotoxicity. Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

Health Canada reviewed the potential risk of serious hepatotoxicity with the use of BTK inhibitors. This safety review was triggered by notifications of foreign action received from manufacturers.

Prior to Health Canada beginning its review, the manufacturer of Imbruvica initiated a labelling update to include the risk of serious hepatotoxicity in the CPM. Health Canada’s safety review, therefore, aimed to determine whether this risk is associated with all other BTK inhibitors (a class effect) and whether a labelling update is warranted across the drug class.

• Bruton’s tyrosine kinase inhibitors are a class of prescription drugs authorized for sale in Canada for the treatment of various blood cancers. In addition, Imbruvica specifically can be used for the treatment of chronic graft-versus-host-disease (a complication of bone marrow transplantation), when other treatments did not work and additional therapy is needed.

• Bruton’s tyrosine kinase inhibitors have been marketed in Canada since 2014. All BTK inhibitors are available as oral formulations.

• Approximately 65,000 prescriptions for BTK inhibitors were dispensed by Canadian retail pharmacies in 2024.

• Health Canada reviewed the available information provided by manufacturers and a foreign regulatory agency, as well as from searches of the Canada Vigilance database^a and the scientific literature.

• Health Canada reviewed 11 cases (1 Canadian and 10 international) of serious hepatotoxicity in patients using Brukinsa or Calquence, including 2 from the published literature.^{1, 2} All 11 cases were found to be possibly linked to the use of BTK inhibitors.

• Health Canada also reviewed 20 articles published in the scientific literature. Despite limitations, including the presence of confounders (other factors that may have contributed to the occurrence of hepatotoxicity) and insufficient clinical information, the evidence reviewed supported a possible link between all BTK inhibitors and the risk of serious hepatotoxicity.^{3 - 8}

• Health Canada’s review of the available information found a possible link between the use of BTK inhibitors and the risk of serious hepatotoxicity.

• Health Canada is working with the manufacturers of BTK inhibitors to update the CPM to include the risk of serious hepatotoxicity. The CPM for Jaypirca (pirtobrutinib), a BTK inhibitor that was authorized for sale in Canada after the completion of this review, will also include this risk.

• 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 with the use of BTK inhibitors, or other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving BTK 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 if and when any new health risks are 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 BTK inhibitors both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Kalsi, S., Bennett, S., Cook, D. L., & Fischer, A. (2024). Yellow urticaria secondary to acalabrutinib-induced liver injury. Oxford medical case reports, 2024(1), omad142. https://doi.org/10.1093/omcr/omad142

2. Atallah, E., Wijayasiri, P., Cianci, N., Abdullah, K., Mukherjee, A., & Aithal, G. P. (2021). Zanubrutinib-induced liver injury: a case report and literature review. BMC gastroenterology, 21(1), 244. https://doi.org/10.1186/s12876-021-01825-2

3. Kahn, A., Horsley-Silva, J. L., Lam-Himlin, D. M., Reeder, C. B., Douglas, D. D., & Carey, E. J. (2018). Ibrutinib-induced acute liver failure. Leukemia & lymphoma, 59(2), 512–514. https://doi.org/10.1080/10428194.2017.1346251

4. Nandikolla, A. G., Derman, O., Nautsch, D., Liu, Q., Massoumi, H., Venugopal, S., Braunschweig, I., & Janakiram, M. (2017). Ibrutinib-induced severe liver injury. Clinical Case Reports, 5(6). Ovid MEDLINE(R) PubMed-not-MEDLINE <2017 to 2019>.

5. Kleijwegt, F. S., Roda, A. A., Rolvink, J., Kater, A. P., Kersten, M. J., & Vos, J. M. I. (2019). Rare but Serious: Ibrutinib Induced Liver Failure. HemaSphere, 3(6), e307. https://doi.org/10.1097/HS9.0000000000000307

6. Nasser, R., Sayed Ahmad, N., Veitsman, E., & Saadi, T. (2023). Bezafibrate in severe liver toxicity due to ibrutinib. Journal of Gastrointestinal and Liver Diseases : JGLD, 32(1). Ovid MEDLINE(R) <2023>.

7. Gerardine, Supriya MD; Wan, David MD; Fortune, Brett MD; Shah, Shawn MD; Shen, Nicole MD. Ibrutinib-induced Liver Injury: 2122. American Journal of Gastroenterology 112():p S1178, October 2017.

8. Tafesh, Z. H., Coleman, M., Fulmer, C., & Nagler, J. (2019). Severe Hepatotoxicity due to Ibrutinib with a Review of Published Cases. Case reports in gastroenterology, 13(2), 357–363. https://doi.org/10.1159/000502605

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