Summary Safety Review - Imuran (azathioprine) - Serious Brain Infection (Progressive Multifocal Leukoencephalopathy)

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: 2014-09-30

issue

A safety review was conducted to evaluate the available information regarding the potential risk of developing a serious brain infection called progressive multifocal leukoencephalopathy or PML with azathioprine. This review was conducted because several cases of PML had been reported worldwide in patients who had received azathioprine.

Background

Approved use of azathioprine in Canada

Azathioprine has been on the market in Canada since 1966 under the name Imuran. Since then, generics of Imuran have also been made available on the Canadian market. Azathioprine is an immunosuppressant. It lowers the body's defenses by reducing the strength of the immune system. The drug is indicated for people with kidney transplants and with rheumatoid arthritis (RA). The prescribing information (Canadian Product Monograph or CPM) includes information concerning the possibility of infection but does not specifically mention PML.

Progressive multifocal leukoencephalopathy

PML is a rare, serious infection of the brain caused by the John Cunningham (JC) virus. PML develops most commonly in people whose body defense mechanisms are very low; the virus does not cause PML in healthy individuals. Some people with Acquired Immunodeficiency Syndrome (AIDS), certain cancers, tuberculosis or organ transplantation may be at higher risk of having PML. It may also develop when people are taking certain drugs such as other immunosuppressants. PML, if severe, may cause death.

People with PML may have paralysis on one side of the body, unsteady gait, abnormal behaviour, seizures, and coma.  Diagnosis of PML is based on radiological testing such as magnetic resonance imaging (MRI) and laboratory tests that detect the virus in the brain and spinal fluid.  However, the best test for PML is a brain biopsy. There is no specific drug to treat PML. The main goal of treatment is to support the body's defense mechanisms.

Objective

To assess the risk of a person developing PML while taking azathioprine. The evidence considered included Canadian adverse reaction reports, scientific and medical literature, international safety data, and what is known about the use of this product both in Canada and internationally.

Key findings

Use of azathioprine in Canada1

Prescription data over approximately a 5 year period suggest that the use of azathioprine in Canada is on the rise in the community, whereas its use in hospitals is on the decline.

Canadian reports of PML associated with azathioprine

At the time of this review, no Canadian cases had been reported suggesting PML in association with azathioprine.

Scientific reports and International data2

At the time of this review, 56 cases of PML associated with azathioprine had been identified worldwide. Of these cases, 24 had sufficient information to be further reviewed by Health Canada. Azathioprine was found to be a possible cause for the development of PML in all 24 cases. However, it is difficult to determine to what extent azathioprine contributes to PML because azathioprine is usually given in combination with other drugs that can cause PML. In addition, the disease being treated with azathioprine can also cause PML.

There was no evidence to suggest that the dose of azathioprine taken had an effect on the development of PML. However, people may get better when the dose of azathioprine is decreased or the drug is stopped.

Conclusions and actions

  • There is evidence that suggests a link between azathioprine and PML, a rare and serious brain infection. It is difficult to determine to what extent azathioprine contributes to PML. However, healthcare professionals and patients should be aware of the possibility for PML to develop with azathioprine.

    Health Canada is working with manufacturers to update the CPM for Imuran and generics and the risk of PML.

    Health Canada will keep Canadians informed and take action, as appropriate, if any other new safety information is identified.

References

  1. Imuran® (azathioprine) Canadian Product Monograph, January 31, 2013.
  2. Chihara D, Takeoka T, Shirase T, et al. Progressive multifocal leukoencephalopathy in myelodysplastic syndrome involving pure red cell aplasia. Intern Med 2010; 49:2347-52.
  3. Schmedt N, Andersohn F, Garbe E. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2012; 21(11):1216-20.
  4. Keene DL, Légaré C, Taylor E, et al. Monoclonal antibodies and progressive multifocal leukoencephalopathy. Can J Neurol Sci 2011; 38(4):565-571.
  5. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006; 60(2):162-73.
  6. Palazzo E, Yahia SA. Progressive multifocal leukoencephalopathy in autoimmune diseases. Joint Bone Spine 2012; 79(4):351-5.
  7. Carson KR, Focosi D, Major EO, et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncology 2009;10(8):816-24.
  8. Piccinni C, Sacripanti C, Poluzzi E, et al. Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents. Eur J Clin Pharmacol 2010; 66(2):199-206.
  9. Mentzer D, Prestel J, Adams O, et al. Case definition for progressive multifocal leukoencephalopathy following treatment with monoclonal antibodies. J Neurol Neurosurg Psychiatry 2012; 83(9):927-933.
  10. Calabrese L. A rational approach to PML for the clinician. Cleve Clin J Med 2011; 78(Suppl 2):S38-41.
  11. Brew BJ, Davies NW, Cinque P, et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010; 6(12):667-79.

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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