Summary Safety Review - Opdivo (nivolumab) - Assessing the Potential Risks of Certain Blood Disorders, and Cytokine Release and Tumor Lysis Syndromes

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: 2021-05-19

Product

Opdivo (nivolumab)

Potential Safety Issue

  • Blood disorders: autoimmune hemolytic anemia, when the immune system destroys its own red blood cells; and aplastic anemia, when the body stops producing enough new blood cells.
  • Cytokine release syndrome, an inflammatory reaction throughout the body, characterized by fever and multiple organ damage; and tumor lysis syndrome, a rapid breakdown of cancer cells with the release of substances into the blood that cause blood chemical imbalance and organ damage.

Key Messages

  • Opdivo (nivolumab) is a prescription drug authorized for sale in Canada, for use alone or in combination with Yervoy (ipilimumab), to treat certain types of cancers of the skin, head and neck, blood cells, lungs, kidneys, liver and colon. Some of the authorized uses include conditions requiring the manufacturer to provide additional information.
  • Health Canada reviewed the following potential risks with Opdivo, used alone or in combination with Yervoy:
    • autoimmune hemolytic anemia
    • aplastic anemia
    • cytokine release syndrome
    • tumor lysis syndrome
  • These reviews were triggered by safety information received from the manufacturer and published reports in the medical literature.
  • Health Canada's review of the available information concluded that there may be a link between Opdivo, used alone or in combination with Yervoy, and the risks of autoimmune hemolytic anemia, aplastic anemia, cytokine release syndrome and tumor lysis syndrome.
  • The Canadian Product Monograph (CPM) for Opdivo has been updated to include the risks of autoimmune hemolytic anemia, aplastic anemia, cytokine release syndrome, and tumor lysis syndrome.

Overview

Health Canada reviewed the potential risks of autoimmune hemolytic anemia, aplastic anemia, cytokine release syndrome and tumor lysis syndrome with the use of Opdivo, either alone or in combination with Yervoy. These reviews were triggered by safety information provided by the manufacturer and information from the published medical literature.

Autoimmune hemolytic anemia is a condition where the body's immune system attacks and destroys its own red blood cells. Aplastic anemia is a condition where the body stops producing enough new blood cells.

Cytokines are small proteins that are important in cell function. High levels of cytokines may cause increased inflammation throughout the body. Cytokine release syndrome is a serious and potentially life-threatening inflammatory reaction where the immune system responds too aggressively to an infection or certain medications resulting in a large, rapid release of cytokines into the blood from immune cells. The symptoms of cytokine release syndrome can include fever, headache, tiredness and multiple organ damage.

Tumor lysis syndrome is a potentially life-threatening condition that can occur during cancer treatment. When cancer cells break down (die) from cancer treatment, they release their contents (salts and proteins) into the blood. When cancer cells break down quickly, these substances rise faster than the kidneys can remove them from the blood. This causes changes to the chemical balance in the blood, which can affect the functioning of several organs, most commonly the kidneys, heart and brain.

Use in Canada

  • Opdivo is a prescription drug authorized for sale in Canada, for use alone or in combination with Yervoy, to treat certain types of cancers of the skin, head and neck, blood cells, lungs, kidneys, liver and colon. Some indications are authorized with conditions requiring the manufacturer to provide additional clinical information.
  • Opdivo is administered directly into a vein under the supervision of a physician experienced in treating cancer.
  • Opdivo is available as a sterile solution for injection in 40 mg nivolumab/4mL and 100 mg nivolumab/10mL single-use vials.
  • Opdivo has been marketed in Canada since October 2015.

Safety Review Findings

  • Health Canada reviewed information received from the manufacturer, as well as information from searches of the Canada Vigilance databasea, international databases, and published literature.
  • At the request of Health Canada, the manufacturer performed safety reviews of Opdivo, used alone or in combination with Yervoy, and the risks of autoimmune hemolytic anemia, aplastic anemia, cytokine release syndrome and tumor lysis syndrome. The manufacturer concluded that there is a possible link between Opdivo and autoimmune hemolytic anemia, and agreed to include this risk in the CPM.
  • Health Canada further reviewed the risks of aplastic anemia, cytokine release syndrome and tumor lysis syndrome with Opdivo, used alone or in combination with Yervoy:
    • For aplastic anemia, Health Canada had received 3 Canadian cases, but only 1 case met the criteria for further assessment. Therefore, the safety review focused on 16 case reports (1 Canadian and 15 foreign). Of the 16 case reports, 7 (1 Canadian) reports were found to be probably linked to the use of Opdivo, 8 cases were possibly linked, and 1 case was considered unlikely to be linked with Opdivo use.
    • For cytokine release syndrome, Health Canada had received 6 Canadian cases, but only 1 case met the criteria for further assessment. Therefore, the safety review focused on 13 reports (1 Canadian and 12 foreign). A potential link between cytokine release syndrome and the use of Opdivo could not be ruled out for these 13 reports because 7 reports (1 Canadian) were found to be probably linked and 6 reports were possibly linked.
    • For tumor lysis syndrome, Health Canada had received 2 Canadian reports. The 2 reports did not meet the criteria for further assessment. Therefore, Health Canada's review focused on 12 foreign cases. A potential link between tumor lysis syndrome and the use of Opdivo could not be ruled out for these 12 cases because 2 cases were considered probably linked, and 10 cases were considered possibly linked.

Conclusions and actions

  • Health Canada's review of the available information concluded that there may be a link between Opdivo, used alone or in combination with Yervoy, and the risk of autoimmune hemolytic anemia, aplastic anemia, cytokine release syndrome and tumor lysis syndrome.
  • The Canadian Product Monograph for Opdivo has been updated to include the risks of autoimmune hemolytic anemia, aplastic anemia, cytokine release syndrome and tumor lysis syndrome.
  • Health Canada will continue to monitor safety information involving Opdivo, 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 Opdivo both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

Footnotes

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

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