Summary Safety Review - Opdivo (nivolumab) and Yervoy (ipilimumab) used alone, or in combination - Assessing the potential risk of Hemophagocytic Lymphohistiocytosis (HLH)

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: 2019-06-24

Product

Opdivo (nivolumab) and Yervoy (ipilimumab) used alone, or in combination.

Potential Safety Issue

Hemophagocytic Lymphohistiocytosis (HLH), a condition where large numbers of immune cells (activated macrophages) destroy other blood cells.

Key Messages

  • Opdivo (nivolumab) and Yervoy (ipilimumab) can be used alone, or in combination, to treat different types of cancers, including cancers of the skin, kidney, lung, and liver.
  • Health Canada completed a safety review of the risk of Hemophagocytic Lymphohistiocytosis (HLH - a condition where a large number of immune cells attack and destroy other blood cells) associated with the use of these products following reports of HLH published in medical literature.
  • Health Canada's review concluded that there may be a link between the use of these products and the development of HLH.
  • Health Canada will work with the manufacturer of Opdivo and Yervoy to ensure that the product safety information is appropriate.
  • If consumers have any concerns they are advised to speak with their healthcare professional.

Overview

Following reports in medical literature, Health Canada reviewed the potential risk of Hemophagocytic Lymphohistiocytosis (HLH) with Opdivo or Yervoy used alone, or in combination.

HLH is a life-threatening overreaction of the immune system where a large number of immune cells attack and destroy other blood cells. HLH is characterized by a large release of certain proteins by immune cells in the blood (referred to as a "cytokine storm" or "cytokine release syndrome"), as well as the accumulation of activated immune cells (lymphocytes and macrophages) in organs and tissues.

Use in Canada

  • Opdivo (nivolumab) and Yervoy (ipilimumab) are prescription drugs authorized for sale in Canada to treat different types of cancers. Used either alone, or in combination, they help prevent or stop the growth of a tumour (antineoplastic). Both Opdivo and Yervoy are administered directly into a vein by intravenous infusion under the supervision of a physician experienced in treating cancer.
  • Opdivo has been marketed in Canada since October 2015, and Yervoy since March 2012.

Safety Review Findings

  • The use of Opdivo and Yervoy (alone or in combination) is known to cause a range of immune-related side effects.
  • At the time of the review, Health Canada had received 1 Canadian reporta of a cancer patient who developed HLH after treatment with Opdivo, in combination with Yervoy. This report was considered serious and involved death.
  • Health Canada also looked at 21 international reports of HLH following treatment with Opdivo and Yervoy, either used alone or in combination. All reports were considered serious, and 6 of the 21 involved death.
  • Health Canada could not confirm whether the use of Opdivo or Yervoy was the cause of the reported deaths in the Canadian or the international reports.
  • Health Canada also looked at the scientific and medical literature. The articles reviewed suggest that there may be a link between the use of drugs that are in the PD-1 inhibitors class (such as Opdivo), and the development of HLH.
  • Health Canada's assessment could not rule out a link between Opdivo and Yervoy and the development of HLH.

Conclusions and actions

  • Health Canada's review of all the available information has concluded that there may be a link between the use of Opdivo and Yervoy alone, or in combination, and the risk of HLH.
  • Health Canada will work with the manufacturer to determine the appropriate changes to the product safety information.
  • Health Canada encourages consumers and healthcare professionals to report any adverse reactions related to the use of this, or other health products.
  • Health Canada will continue to monitor safety information involving Opdivo and Yervoy, 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 any new health risks are identified.

Additional information

The analysis that contributed to this risk assessment included scientific and medical literature, Canadian and international adverse reaction reports, and what is known about the use of these drugs and medical devices both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

If manufacturers of medical devices or industry associations require more information at this time, they are encouraged to contact the Therapeutic Products Directorate (hc.tpdgeneral-generaldpt.sc@canada.ca).

Footnotes

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

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