Summary Safety Review - Interferon-beta Products - 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: 2014-08-22

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, with the use of interferon-beta products. This review was prompted by a drug safety update issued in 2013 by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) regarding several reports of TMA involving interferon-beta products.

Background

Approved use of interferon-beta products in Canada

Four interferon-beta products are available in Canada: AVONEX (interferon beta-1a, first marketed in Canada in 2005); BETASERON (interferon beta-1b, first marketed in Canada in 1995); EXTAVIA (interferon beta-1b, first marketed in Canada in 2010); and REBIF (interferon beta-1a, first marketed in Canada in 1998). All four products are indicated for use in the treatment of multiple sclerosis.

In 2009, the Canadian product label for REBIF was updated to include information on the possible risk of TMA.

Thrombotic microangiopathy

Thrombotic microangiopathy refers to a group of disorders that involve the occurrence of blood clots in small blood vessels which can end in organ damage. Signs and symptoms of these disorders may include increased bruising, bleeding, reduced 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, eyes and the nervous system.

Objective

To assess the available evidence concerning the risk of developing TMA following exposure to any interferon-beta product. This review considered Canadian adverse reaction reports, scientific and medical literature, and international safety data, as well as what is known about the use of these products both in Canada and internationally, and evaluated the possible risk of TMA.

Key findings

Use of interferon-beta products in Canada1

The total number of units purchased per product from January 2009 to March 2014 was as follows: 227,100 units of AVONEX; 123,466 units of BETASERON; 75,957 units of EXTAVIA; and 2,435,321 units of REBIF.

Canadian reports of thrombotic microangiopathy associated with the use of interferon-beta products

As of February 28, 2014, Health Canada received 3 reports of TMA following exposure to REBIF. No cases of TMA were reported for AVONEX, BETASERON or EXTAVIA.

Scientific reports

A literature review identified 8 articles related to TMA involving interferon-beta products. A total of 11 cases were reported in these 8 articles. With the exception of one case, the interferon-beta product was used to treat a relapsing form of multiple sclerosis. The average time between starting the interferon-beta product and the diagnosis of TMA was approximately 4.4 years (range: 44 days to 10 years). All the cases were associated with kidney failure and the diagnosis was confirmed by kidney biopsy. In the majority of cases, the name of the interferon-beta product used was not provided. In one case, the use of BETAFERON (called BETASERON in Canada) was reported.

International data2

As of March 2014, the World Health Organization (WHO) Global Individual Case Safety Reports Database System (VigiBase) contained 48 reports of TMA suspected of being associated with interferon-beta products (AVONEX = 6, BETASERON = 3, EXTAVIA = 0, REBIF = 39). The WHO data suggested that a cluster of reports involving REBIF occurred in 2011 (10 reports) and 2013 (17 reports). These two time periods accounted for two thirds of all reported cases of TMA following exposure to REBIF and approximately half of all reported cases of TMA involving any of the 4 interferon-beta products.

Conclusions and actions

  • A small number of cases of TMA after exposure to interferon-beta products have been reported in Canada and internationally. Several cases were suspected of being associated with REBIF. The current Canadian product label for REBIF currently addresses this risk. The scientific literature does not clearly explain why interferon-beta products can cause TMA.

    Given the limited information available at the time of this review, Health Canada decided to continue its ongoing monitoring of adverse reaction information involving interferon-beta products, 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

  1. Broughton A, Cosyns JP, Jadoul M. Thrombotic microangiopathy induced by long-term interferon-ß therapy for multiple sclerosis: a case report. Clin Nephrol 2011;76(5):396-400.
  2. Nerrant E, Charif M, Ramay AS, et al. Hemolytic uremic syndrome: an unusual complication of interferon-ß treatment in a MS patient. J Neurol 2013;260(7):1915-6.
  3. Olea T, Díaz-Mancebo R, Picazo ML, et al. Thrombotic microangiopathy associated with use of interferon-beta. Int J Nephrol Renovasc Dis 2012;5:97-100.
  4. Cavoli GL, Passantino R, Tortorici C, et al. Comment on thrombotic microangiopathy induced by interferon-ß therapy. Clin Nephrol 2012;78(6):506-7.
  5. Orvain C, Augusto JF, Besson V, et al. Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis. Int Urol Nephrol 2014;46(1):239-42.
  6. Mahe J, Meurette A, Moreau A, et al.  Renal thrombotic microangiopathy caused by interferon beta-1a treatment for multiple sclerosis. Drug Des Devel Ther 2013;7:723-8.
  7. Hunt D, Kavanagh D, Drummond I, et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med 2014;370(13):1270-1.

Footnotes

  1. 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.
  2. 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.
  3. 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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