Summary Safety Review - Vascular Endothelial Growth Factor Receptor Inhibitors - Thrombotic Microangiopathy

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: 2015-01-14

issue

A safety review was initiated to evaluate the possible risk of blood clots in small vessels, called thrombotic microangiopathy (TMA) associated with the use of vascular endothelial growth factor (VEGF) receptor inhibitors. This review was prompted by information submitted by one of the manufacturers of this class of drugs. VEGF inhibitors developed from living sources, known as biologic drugs, were not included in this review. A safety summary review of biologic drugs was published in September 2014.

Background

Approved use of VEGF receptor inhibitors in Canada

VEGF receptor inhibitors are used for treating various types of cancer. The type of cancer treated varies with each specific VEGF receptor inhibitor used. VEGF receptor inhibitors work by slowing down the growth and spread of cancer cells by cutting off the blood supply that keeps cancer cells growing. The VEGF receptor inhibitors included in this review are: SUTENT (sunitinib); NEXAVAR (sorafenib); VOTRIENT (pazopanib); CAPRELSA (vandetanib); INLYTA (axitinib); and STIVARGA (regorafenib).

Thrombotic microangiopathy

Thrombotic microangiopathy, or blood clots in small vessels, refers to a group of disorders that involve the occurrence of blood clots in small blood vessels which can damage organs. Signs and symptoms of these disorders may include increased bruising, bleeding, fewer numbers of platelets and red blood cells, high blood pressure, and extreme weakness. Other organs and body systems that can be affected include the kidneys and the nervous system.

Information on the risk of TMA is included in the prescribing information of certain VEGF inhibitors, specifically SUTENT and VOTRIENT.

Objective

To assess the available evidence concerning VEGF receptor inhibitors and the risk of TMA and whether the risk of TMA is associated with all VEGF receptor inhibitors. This review considered Canadian adverse reaction reports, scientific literature, and international data, as well as what is known about the use of these products both in Canada and internationally.

Key findings

Canadian reports of thrombotic microangiopathy associated with the use of VEGF receptor inhibitors

At the time of this review, Health Canada had not received any reports of TMA suspected of being associated with any of the VEGF receptor inhibitors considered.

Scientific reports and international data

Eleven cases of TMA involving SUTENT were published in the scientific literature. In some of these cases, TMA resolved or improved when treatment with SUTENT was stopped. At the time of the review, no cases of TMA were published for the other VEGF receptor inhibitors (NEXAVAR, CAPRELSA, INLYTA, STIVARGA and VOTRIENT).

The exact reason behind a possible association between TMA and VEFG receptor inhibitors is not known.

Conclusions and actions

  • TMA is a rare but serious adverse reaction. Several cases of TMA involving SUTENT have been published in the literature. Although the risk of TMA is recognized for certain VEGF receptor inhibitors (SUTENT and VOTRIENT), based on the information reviewed, there is not sufficient information, at this time, for updating the prescribing information for all VEGF receptor inhibitors.

    Health Canada will continue to monitor adverse reaction information involving VEGF receptor inhibitors to identify and assess potential harms. Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.

References

  1. Moreira IS, Fernandes PA, Ramos MJ. Vascular endothelial growth factor (VEGF) inhibition-a critical review. Anticancer Agents Med Chem 2007;7(2):223-45.
  2. Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res 2011;17(18):5858-66.
  3. Levey SA, Bajwa RS, Picken MM, et al. Thrombotic microangiopathy associated with sunitinib, a VEGF inhibitor, in a patient with factor V Leiden mutation. NDT Plus 2008;1(3):154-6.
  4. Kapiteijn E, Brand A, Kroep J, et al. Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 2007;18(10):1745-7.
  5. Bollée G, Patey N, Cazajous G, et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant 2009;24(2):682-5.
  6. Frangié C, Lefaucheur C, Medioni J, et al. Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol 2007;8(2):177-8.
  7. Talebi TN, Stefanovic A, Merchan J, et al. Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome. Am J Ther 2012;19(4):143-5.
  8. Choi MK, Hong JY, Jang JH, et al. TTP-HUS associated with sunitinib. Cancer Res Treat 2008;40(4):211-3.
  9. Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27(9):1432-9.
  10. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358(11):1129-36.

Footnotes

  1. This list of references is not intended to be exhaustive. References have been selected as suggestions for further reading and reflect the most current information at the time of the safety review.

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