Summary Safety Review - Xeljanz/Xeljanz XR (tofacinitib), Olumiant (baricitinib) and Rinvoq (upadacitinib) - Janus Kinase (JAK) Inhibitors - Assessing the Potential Risks of Serious Heart-related Problems, Blood Clots, Cancer and Death

Review decision

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.


Issued: 2022-09-16

Product

Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib) and Rinvoq (upadacitinib) - Janus Kinase (JAK) Inhibitors

Potential Safety Issue

Serious heart-related problems (heart attack, stroke or cardiovascular death), blood clots (thrombosis), cancer (malignancies) and death (all-cause mortality)

Key Messages

  • Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib) and Rinvoq (upadacitinib) are prescription drugs belonging to the JAK inhibitors drug class. They are authorized for sale in Canada for the treatment of chronic inflammatory diseases when other medicines do not work.
  • Health Canada reviewed the potential risks of serious heart-related problems, blood clots, cancer and death with the use of Olumiant and Rinvoq. The Department also reviewed the risk of blood clots with the use of Xeljanz/Xeljanz XR as part of an update to its 2019 review of this product.
  • Health Canada's review of the available information found that the risks of serious heart-related problems, blood clots, cancer and death cannot be excluded for Olumiant and Rinvoq, and that there continues to be an increased risk of blood clots associated with the use of Xeljanz/Xeljanz XR.
  • As a precautionary measure, Health Canada is working with the manufacturers to update and align these risks in the Canadian product monographs (CPMs) for JAK inhibitors indicated for chronic inflammatory diseases.
  • Health Canada will communicate these updates to healthcare professionals and the public through a Health Product Risk Communication and Public Advisory.
  • Health Canada is also working with the manufacturers to update and align the CPMs of other JAK inhibitors, for which the findings are relevant.

Overview

Xeljanz/Xeljanz XR, Olumiant and Rinvoq belong to a class of drugs called JAK inhibitors that interfere with inflammation, immune response and growth factors in order to treat several diseases. These products have similar mechanisms of action and are authorized for the treatment of chronic inflammatory diseases.

Health Canada completed a safety review in 2019 that found a link between the use of Xeljanz/Xeljanz XR and the risk of blood clots, especially among patients at increased risk of thrombosis. The Department then completed a safety review in 2021 that found a link between the use of Xeljanz/Xeljanz XR and the risks of serious heart-related problems and cancer, especially among patients with rheumatoid arthritis who are older, current or past smokers, and those who have cardiovascular or cancer risk factors. Based on these findings, the CPM for Xeljanz/Xeljanz XR was updated with strengthened warnings about these risks in May 2022.

In 2022, Health Canada completed a review of the potential risks of serious heart-related problems, blood clots, cancer and death with the use of 2 JAK inhibitors indicated for inflammatory conditions (Olumiant and Rinvoq) to determine the need for labelling changes across the JAK inhibitors drug class. As part of this review, the Department also updated its 2019 review on the risk of blood clots with the use of Xeljanz/Xeljanz XR.

Use in Canada

  • Xeljanz/Xeljanz XR, Olumiant and Rinvoq are prescription drugs authorized for sale in Canada for the treatment of chronic inflammatory diseases, when other medicines do not work.
    • Xeljanz has been marketed in Canada since 2014 and is used for the treatment of rheumatoid arthritis, psoriatic arthritis (inflammation of the joints with red, scaly patches on the skin), and ulcerative colitis (inflammation of the large intestine causing sores and bleeding); Xeljanz XR has been marketed as an extended release formulation in Canada since 2018 and is used for the treatment of rheumatoid arthritis.
    • Olumiant has been marketed in Canada since 2018 and is used for the treatment of rheumatoid arthritis; and
    • Rinvoq has been marketed in Canada since 2020 and is used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis (eczema), and ankylosing spondylitis (inflammatory disease that affects the spine).
  • The yearly number of prescriptions dispensed by Canadian retail pharmacies for Xeljanz/Xeljanz XR, Olumiant and Rinvoq have increased in recent years:
    • For Xeljanz/Xeljanz XR, they have increased from approximately 11,000 prescriptions in 2016 to approximately 79,000 prescriptions in 2020.
    • For Olumiant, they have increased from approximately 10 prescriptions in 2018 to approximately 2,000 prescriptions in 2020.
    • For Rinvoq, they have increased from approximately 3,500 prescriptions in 2020 to approximately 8,000 prescriptions in 2021.

Safety Review Findings

  • Health Canada reviewed the available information from searches of the Canada Vigilance databasea, international databases, scientific literature, as well as clinical and observational studies related to the risks of serious heart-related problems, blood clots, cancer and death with Xeljanz/Xeljanz XR, Olumiant and Rinvoq.
  • The final findings1 from the clinical research study linked Xeljanz/Xeljanz XR to higher risks of serious heart-related problems, cancer and death, and confirmed the initial findings of an increased risk of blood clots from 2019. These risks have already been reflected in the CPM of Xeljanz/Xeljanz XR.
  • Health Canada also looked at the interim findings from a 2021 observational study with Olumiant, which showed increased rates of serious heart-related problems and blood clots with its use.
  • Given the similar mechanisms of action and indications for Xeljanz/Xeljanz XR, Olumiant and Rinvoq, Health Canada considers that they may have similar risks.
  • Overall, the findings are supportive of the need for precautionary measures with the use of JAK inhibitors for inflammatory conditions.

Conclusions and actions

  • Health Canada's current review found that a drug class effect for the risks of serious heart-related problems, blood clots, cancer and death with JAK inhibitors used for the treatment of chronic inflammatory diseases cannot be excluded at this time.
  • As a precautionary measure, Health Canada is working with the manufacturers to update and align these risks in the CPMs for JAK inhibitors indicated for chronic inflammatory diseases.
  • Health Canada will communicate these updates to healthcare professionals and the public through a Health Product Risk Communication and Public Advisory.
  • These findings are relevant to JAK inhibitors other than those in Health Canada's review, including Cibinqo (abrocitinib), Jakavi (ruxolitinib) and Inrebic (fedratinib). These products were either not yet marketed or not indicated for chronic inflammatory diseases at the time of the review. Health Canada is working with the manufacturers to update and align the CPMs for these products as well.
  • Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of JAK inhibitors and other health products to the Canada Vigilance Program.
  • Health Canada will continue to monitor safety information involving Xeljanz/Xeljanz XR, Olumiant and Rinvoq, 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.

Additional information

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 Xeljanz/Xeljanz XR, Olumiant, and Rinvoq both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

References

  1. Ytterberg, S. R., Bhatt, D. L., Mikuls, T. R., Koch, G. G., Fleischmann, R., Rivas, J. L., Germino, R., Menon, S., Sun, Y., Wang, C., Shapiro, A. B., Kanik, K. S., Connell, C. A., & ORAL Surveillance Investigators (2022). Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. The New England journal of medicine, 386(4), 316–326.

Footnotes

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

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