Summary Safety Review - Stivarga (regorafenib) - Assessing the Potential Risk of Thrombotic Microangiopathy

Stivarga (regorafenib)

Thrombotic microangiopathy (TMA), a rare, but serious and life-threatening, condition involving the formation of clots in small blood vessels

• Health Canada's review found a possible link between Stivarga and the risk of TMA.

• Health Canada will work with the manufacturer to update the product safety information in the Canadian product monograph (CPM) for Stivarga to include the risk of TMA. Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

In 2015, Health Canada reviewed the risk of TMA with the use of vascular endothelial growth factor (VEGF) receptor inhibitors, the drug class to which Stivarga belongs. At that time, although the risk of TMA was recognized for certain VEGF receptor inhibitors (Sutent [sunitinib] and Votrient [pazopanib]), there was insufficient evidence to support a labelling update across the entire drug class. Health Canada committed to continued monitoring of VEGF receptor inhibitors to identify and assess potential harms.

In 2022, Health Canada reviewed the risk of TMA with the use of Nexavar (sorafenib), another VEGF receptor inhibitor. The review determined that there may be a link between the use of Nexavar and the risk of TMA, and Health Canada is working with the manufacturer to update the product labelling for Nexavar. No other VEGF receptor inhibitors were assessed as part of the 2022 review.

In 2024, Health Canada reviewed the potential risk of TMA with the use of Stivarga. This was not a review of the entire VEGF receptor inhibitors drug class. The safety review was triggered by a labelling update by the European Medicines Agency for Stivarga, and an international case report published in the medical literature.

Thrombotic microangiopathy is a rare, but serious and life-threatening, condition involving the formation of clots in the small blood vessels. These clots can cause damage to organs and body systems by blocking proper blood flow. Thrombotic microangiopathy is a medical emergency and requires rapid intervention. A number of factors, including congenital conditions (those present at birth), infection, cancer and drugs, can cause TMA.

• Stivarga is a prescription drug authorized in Canada for the treatment of:

  • metastatic cancer (cancer that has spread) of the colon and rectum (colorectal) in patients who have already received other treatments,

  • metastatic and/or unresectable (not treatable with surgery) gastric cancer (gastrointestinal stromal tumors) in patients who have had disease progression on or intolerance to other treatments, and

  • patients with liver cancer (hepatocellular carcinoma) as a second line treatment.

• Stivarga has been marketed in Canada since 2013. It is currently available as 40 mg tablets.

• Between September 2018 and August 2024, an estimated 6,000 prescriptions for Stivarga (new and renewals) were dispensed in Canada.

• Health Canada reviewed the available information provided by the manufacturer, as well as from searches of the Canada Vigilance database^a and the scientific literature¹.

• At the time of the review, Health Canada had not received any Canadian reports of TMA in patients taking Stivarga.

• Health Canada reviewed 7 international cases of TMA in patients taking Stivarga. Six of the 7 cases, including 1 published in the scientific literature, were found to be possibly linked to the use of Stivarga, while the remaining case was unlikely to be linked. Two deaths were reported among the 7 cases. It was determined that 1 death was unlikely to be linked to the use of Stivarga, while the second death could not be assessed.

• The evidence from the scientific literature regarding the association between regorafenib and TMA was limited to the trigger case report. While Health Canada reviewed the findings from 2 other publications, they did not provide additional information about the risk of TMA with Stivarga.

• Health Canada's review of the available information found a possible link between Stivarga and the risk of TMA.

• Health Canada will work with the manufacturer to update the CPM for Stivarga to include the risk of TMA.

• 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 related to the use of Stivarga, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving Stivarga, 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.

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 Stivarga both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Yin Q, Zhang Y, Song X, et al. Regorafenib-induced renal-limited thrombotic microangiopathy: a case report and review of the literature. BMC Nephrol. 2022;23(1):112

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