Summary Safety Review - Xarelto (rivaroxaban) - Assessing the potential risk of liver injury

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: 2019-10-23

Product

Xarelto (rivaroxaban)

Potential Safety Issue

Liver injury

Key Messages

  • Health Canada reviewed the potential risk of liver injury with Xarelto, as a follow-up to a review of Xarelto and the risk of liver injury completed in 2015.
  • Health Canada's review of the available information did not establish a definitive link between the use of Xarelto and the risk of liver injury.
  • Health Canada will continue to monitor the safety of Xarelto.

Overview

Health Canada reviewed the potential risk of liver injury with Xarelto (rivaroxaban) in 2015. The 2015 safety review was completed after 2 international publications in scientific literature 1, 2 described liver injury in 16 patients using Xarelto. The 2015 review did not find a definitive link between the use of Xarelto and liver injury because the information in some of the Canadian and international reports was incomplete. The reports published in the scientific literature showed that patients had underlying liver diseases before using Xarelto, or were taking other medications that may have contributed to the liver injury. Following completion of the review, Health Canada published an article in the August 2015 issue of the Health Product InfoWatch to summarize the Department's understanding of the risk of liver injury associated with Xarelto use.

In 2019, Health Canada reviewed all new available evidence regarding the potential risk of liver injury with Xarelto.

Use in Canada

  • Xarelto (rivaroxaban ) is a prescription drug authorized for sale in Canada to:
    • prevent blood clots after major hip or knee surgery;
    • prevent blood clots in the brain (stroke) and in other blood vessels if patients have an irregular heart rhythm (atrial fibrillation); and
    • treat or prevent blood clots in the veins of legs or lungs.
  • Xarelto (rivaroxaban) has been marketed in Canada since 2008. It is available as a tablet for oral administration and is dispensed in 2.5 mg, 10 mg, 15 mg, and 20 mg strengths.
  • The average number of prescriptions filled in Canada for Xarelto is estimated at 1.8 million prescriptions per year.

Safety Review Findings

  • From October 1, 2014, to November 14, 2018, Health Canada received 57 unique Canadian reportsa of potential liver injury related to Xarelto use. Of these, 17 reports were assessed further because they met the criteria set for this review. The review of these 17 cases could not conclude whether Xarelto played a direct role in the development of liver injury because there was not enough information to establish a definitive link.
  • A search in the World Health Organization's Adverse Drug Reaction Databaseb found 183 cases of liver-related adverse events reported in patients treated with Xarelto from October 1, 2014, to December 3, 2018, (including 2 reports from Canada). There was not enough information available in the reports to establish a definitive link between Xarelto use and liver injury.
  • Due to the limited information in the Canadian and international reports, Health Canada also looked at the scientific and medical literature published since the 2015 review. This portion of the review identified 9 additional cases of liver injury in patients treated with Xarelto from the literature. Although these cases provided further evidence of a potential risk of liver injury, other contributing factors could not be ruled out, including the presence of other medical conditions and the use of other drugs known to be associated with the development of liver injury. Other published population studies were often limited to hospitalization data, which lacked detailed medical records or history.

Conclusions and actions

  • Health Canada's 2019 review of the available information did not establish a definitive link between the use of Xarelto and the risk of liver injury.
  • Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of this product.
  • Health Canada will continue to monitor safety information involving Xarelto (rivaroxaban), 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 when any new health risks are 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 this drug both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

References

  1. Liakoni E, Ratz Bravo AE, Terracciano L, Heim M, & Krahenbuhl S. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban. JAMA Intern Med. 2014; 174:1683-1686.
  2. Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014; 61:293-300.

Footnotes

  1. Canadian reports can be accessed through the Canada Vigilance Online Database.
  2. VigiBase is the World Health Organization global database of individual case safety reports. This information comes from a variety of sources, and the likelihood that the suspected adverse reaction is drug-related is not the same in all cases. This information does not represent the opinion of the World Health Organization.

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