Summary Safety Review - AVASTIN (bevacizumab) and LUCENTIS (ranibizumab) - 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: 2014-09-29
issue
A safety review was initiated to evaluate the currently available information regarding the possible risk of thrombotic microangiopathy (TMA), a blood clotting disorder affecting small blood vessels, associated with the use of AVASTIN (bevacizumab) and LUCENTIS (ranibizumab). AVASTIN and LUCENTIS are biologic drugs (products developed from living sources) called vascular endothelial growth factor (VEGF) inhibitors. These drugs help to stop the abnormal growth of blood vessels that surround tumours and in the eye. This review was a continuation of Health Canada's review activities of the large class of VEGF inhibitors. At the time, TMA was a known safety issue for AVASTIN, but not LUCENTIS.
Background
Approved use of AVASTIN and LUCENTIS in Canada
AVASTIN is used in combination with chemotherapy to treat colon, rectal, or lung cancers. It is also conditionally approved to be used to treat a particular type of brain cancer called glioblastoma. AVASTIN is given through a needle placed in a vein (intravenously).
LUCENTIS is used to treat damage to the light-sensitive back part of the eye, known as the retina, in various diseases of the eye, such as wet age-related macular degeneration. LUCENTIS is given as an injection into the eye (intravitreally).
Thrombotic microangiopathy
Thrombotic microangiopathy refers to a group of disorders that involve the occurrence of blood clots in small blood vessels and can end in organ damage. 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. TMA in the kidneys can result in excess proteins in the urine (proteinuria), which is an early sign of kidney damage. The risk of TMA in the kidneys, including proteinuria, is described in the Canadian product monograph (CPM) for AVASTIN. The association of TMA with VEGF inhibitors, including AVASTIN, has previously been communicated by Health Canada in 2008 and 2014.
Objective
To assess the latest evidence for AVASTIN regarding the risk of TMA to determine if current risk minimization measures continue to be appropriate. Safety data for LUCENTIS was also assessed to determine if TMA is a new risk that needs to be minimized for this product. This review considered information from Canadian and international adverse reaction reports, scientific and medical literature, as well as what is known about the use of these products both in Canada and internationally.
Key findings
Use of AVASTIN and LUCENTIS in Canada1, 2
Health Canada estimates the number of prescriptions dispensed by pharmacies for AVASTIN between 2009 and 2013 to be 24,504.
The number of prescriptions dispensed by pharmacies for LUCENTIS between 2009 and 2013 is estimated to be 338,889.
Canadian reports of thrombotic microangiopathy associated with the use of AVASTIN and LUCENTIS
At the time of this review, Health Canada had received 7 reports of TMA suspected of being associated with AVASTIN. These reports involved patients being treated with AVASTIN for various types of cancer. Health Canada also received 27 reports of proteinuria suspected of being associated with AVASTIN. Proteinuria is an important sign of kidney damage which may have occurred as a result of TMA. Overall, reports of TMA or proteinuria in Canada suspected of being associated with AVASTIN are estimated to be rare.
There were no reports of TMA and one report of proteinuria suspected of being associated with LUCENTIS. Overall, reports of TMA or proteinuria in Canada suspected of being associated with LUCENTIS are estimated to be very rare.
Scientific reports
Cases of TMA and proteinuria occurring after exposure to AVASTIN have been published in the literature. In some cases, kidney function and proteinuria improved when the drug was discontinued, suggesting the adverse reaction was at least partially reversible.
There is limited information on TMA in connection with LUCENTIS in the literature. One report was retrieved in which the drug was discontinued after the occurrence of TMA, and the patient was treated and fully recovered.
The literature suggests that the risk of TMA is applicable to the entire class of VEGF inhibitors (i.e., biologic and pharmaceutical drugs). The kidney is affected in most cases of TMA; however, cases of TMA affecting all parts of the body have also been observed. The scientific literature does not clearly explain how VEGF inhibitors can cause TMA.
International data3
There are international cases of TMA associated with AVASTIN and LUCENTIS. A review of the product information for AVASTIN and LUCENTIS in the United States, Australia, and Europe was done. It confirmed that product information in Canada regarding TMA and proteinuria is consistent with international product information.
Conclusions and actions
The current CPM for AVASTIN already contains warnings about the risk of TMA in the kidney and associated proteinuria, which is based on evidence from clinical studies and real-world use.
Given the evidence available at the time of this review, TMA is not considered to be a risk for LUCENTIS.
Health Canada decided to continue its ongoing monitoring of adverse reaction information involving AVASTIN and LUCENTIS, as it does for all health products, 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
- 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.
- Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358(11):1129-36.
- Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9(6):669-76.
- 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.
- Hayman SR, Leung N, Grande JP, et al. VEGF inhibition, hypertension, and renal toxicity. Curr Oncol Rep 2012;14(4):285-94.
- Kremer Hovinga JA, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010;115(8):1500-11.
- Moake JL. Thrombotic microangiopathies. NEngl JMed 2002;347(8):589-600.
- Neufield G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13(1):9-22.
- Pellé G, Shweke N, Duong Van Huyen JP, et al. Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. Am J Kidney Dis 2011;57(5):756-9.
- Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012;158(3):323-35.
- Stokes MB, Erazo MC, D'Agati VD. Glomerular disease related to anti-VEGF therapy. Kidney Int 2008;74(11):1487-91.
Footnotes
- IMS utilization data provided by: IMS Health Canada Inc. An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.
- It should be noted that the number of prescriptions or units dispensed does not reflect the number of patients receiving the product.
- World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogeneous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.
- 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.