Summary Safety Review - Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) - Assessing the potential risk of abnormal structural changes of the artery walls including rupture (Artery Dissections and Artery Aneurysms)

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: 2018-12-03

Product

Vascular endothelial growth factor receptor tyrosine kinase inhibitorsa

Potential Safety Issue

Artery Dissections and Artery Aneurysms

Key Messages

  • Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are prescription drugs authorized for sale in Canada for the treatment of various types of cancer, including kidney, liver and soft tissue cancers.
  • Health Canada reviewed the potential risk of 2 types of abnormal structural changes of the artery walls (artery dissections and artery aneurysms) with the use of VEGFR TKIs. This review was triggered by the publication of a Canadian case of artery dissection with the use of the VEGFR TKI drug Sutent1.
  • Health Canada's review of the available information found that there may be a link between the use of VEGFR TKIs and the risk of artery dissections and aneurysms (including rupture), in individuals with or without high blood pressure (hypertension).
  • Health Canada is working with the manufacturers to update the product safety information for all VEGFR TKIsa to inform the Canadian public and healthcare professionals about this risk.

Overview

Health Canada began to review the group of VEGFR TKI drugs for the potential risk of artery dissections and aneurysms after receiving a Canadian case of artery dissection with the use of the VEGFR TKI drug Sutent.

An artery dissection is a tear of the inside lining of an artery. An artery aneurysm is a balloon-like bulge in the wall of a blood vessel that carries oxygen to various tissues in the body (artery). A rupture of the aneurysm can cause bleeding and may lead to death.

These disorders of the arterial wall occur more frequently in the largest artery of the body (the aorta), but can also develop in any other artery. High blood pressure (hypertension) and the build-up of plaques inside arteries (atherosclerosis) are major risk factors for artery dissections and/or aneurysms (D/A). Hypertension is a well-known side effect of VEGFR TKIs.

Use in Canada

  • There are currently 8 VEGFR TKIs marketed in Canada: Sutent (sunitinib), Nexavar (sorafenib), Inlyta (axitinib), Votrient (pazopanib), Iclusig (ponatinib), Stivarga (regorafenib), Caprelsa (vandetanib) and Lenvima (lenvatinib)a. These products are available as tablets or capsules. They are prescribed for the treatment of various types of advanced/metastatic cancers, including kidney (renal cell carcinoma), liver (hepatocellular carcinoma), thyroid, and soft tissue cancers (sarcomas), as well as certain types of blood cancers (leukemia and lymphoma).
  • Sutent (sunitinib) and Nexavar (sorafenib) were the first 2 VEGFR TKIs marketed in Canada, in 2006.
  • In 2017, there were more than 1.2 million tablets/capsules of VEGFR TKIs dispensed in Canadab. The 3 most commonly prescribed VEGFR TKIs were Votrient (about 428,000 tablets), Sutent (about 284,000 capsules) and Nexavar (about 212,000 tablets).

Safety Review Findings

  • At the time of the review, Health Canada had received 1 Canadian reportc of artery dissection and 1 Canadian report of artery aneurysm suspected to be linked to Sutent use. Health Canada also looked at 208 international reports of artery D/A suspected to be linked to the use of VEGFR TKIs.
  • Of the 210 reports (2 Canadian and 208 international), 80 reports (43 artery dissections and 37 artery aneurysms) were further reviewed as they contained the necessary information for a thorough assessment.
  • Of the 43 reports of artery dissections, 20 showed a possible link between VEGFR TKIs use and artery dissections. In 2 of these reports, dissection occurred without hypertension. For the remaining 23 reports, the dissection was more likely due to another medical condition (3 reports), or the link could not be assessed due to insufficient information (20 reports).
  • Of the 37 reports of artery aneurysms, only 3 had a documented absence of aneurysm prior to VEGFR TKI use and were further assessed. Of these 3 reports, 1 report showed a possible link between VEGFR TKI use and the artery aneurysm; in the other 2 reports, the aneurysm was either due to another condition, or the link could not be assessed due to insufficient information. The review of the remaining 34 reports revealed a worsening of the condition, with a rupture of the aneurysm in the majority of cases (23/34) during VEGFR TKI use.
  • Of the 46 reports that were further assessed to find if VEGFR TKIs use was the cause of the artery D/A (43 artery dissections and 3 artery aneurysms), 10 deaths were reported (9 artery dissections and 1 artery aneurysm). Of these, 3 deaths were found to have a possible link with VEGFR TKI use; 1 was more likely due to another condition, and in 6 reports the link could not be assessed due to insufficient information.
  • In Canada, the United States and the European Union, the product safety information for all VEGFR TKIs (except Lenvima) does not contain any information specific to artery dissections and/or aneurysms.

Conclusions and actions

  • Health Canada's review concluded that there may be a link between the use of VEGFR TKIs and artery dissections/artery aneurysms.
  • Health Canada is working with the manufacturers to update the product safety information of all VEGFR TKIs to inform about this risk. A communication about this risk will be published in the Health Product InfoWatch, once the product safety information is updated.
  • Health Canada will continue to monitor safety information involving VEGFR TKIs to identify and assess potential risks, as it does for all health products on the Canadian market. Health Canada will take appropriate and timely action if and 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 these drugs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

References

  1. Hatem, R. Potential Sunitinib-Induced Coronary Artery and Aortic Dissections. Canadian Journal of Cardiology. 2017; 33(6):830.

Footnotes

  1. Authorized VEGFR TKIs in Canada: Sutent (sunitinib), Nexavar (sorafenib), Inlyta (axitinib), Votrient (pazopanib), Iclusig (ponatinib), Stivarga (regorafenib), Caprelsa (vandetanib) and Lenvima (lenvatinib). Cabozantinib was not assessed, as it was not authorized for sale at the time of the review of the risks of artery dissections/artery aneurysms with VEGFR TKIs.
  2. For this report, the Marketed Health Products Directorate of Health Canada used the IQVIA Canadian Drug Store and Hospital (CDH) Purchases Audit, which measures the dollar value and unit volume of pharmaceutical products purchased by Canadian retail pharmacy outlets and hospitals. Data for CDH are collected from a representative sample of 2997 drug stores and 801 hospitals and long-term care facilities (May 2018). The sample data are then projected to the universe of drug stores and hospitals, to reflect all purchases across Canada.
  3. Canadian reports can be accessed through the Canada Vigilance Online Database.

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