New Safety Information Regarding Liver Injury and Hypersensitivity Associated with TYSABRI (natalizumab) - For Health Professionals

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Contact: Marketed Health Products Directorate (MHPD)

Health Canada Endorsed Important Safety Information on TYSABRI (natalizumab)

June 2 , 2008

Dear Health Care Professional:

Subject:

New Safety Information regarding Liver Injury and Hypersensitivity associated with TYSABRITM (natalizumab)

Biogen Idec Canada Inc., in consultation with Health Canada, would like to inform you about new safety information regarding the risk of liver injury and hypersensitivity in patients receiving TYSABRI^TM (natalizumab).

Hepatic Injury:

• In post-marketing experience, there have been rare reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurring as early as 6 days after the first dose. Some cases occurred in patients with pre-existing liver disease or in the presence of other drugs that have been associated with hepatic injury. In some patients, liver injury recurred upon rechallenge.
• TYSABRI should be discontinued in patients who develop jaundice or other evidence of clinically significant liver injury, e.g., 5-fold or greater elevation in serum hepatic enzymes, and the patient should be fully evaluated. In cases with no other identifiable cause, TYSABRI should be permanently discontinued.

Hypersensitivity:

• Results from analyses of patients receiving re-treatment with TYSABRI after a break of therapy suggest that, if initial exposure is short, there is an increased risk of hypersensitivity reactions associated with re-exposure.

Hepatic Injury:

The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients.

Patients with history of liver disease, alcohol abuse, and/or treatment with other therapies that are known to cause liver injury should be carefully evaluated prior to commencement of treatment with TYSABRI and closely monitored for possible liver damage during and after treatment. Physicians should be alert to signs and symptoms of hepatic dysfunction and, consistent with clinical judgement, should take action as described in the product monograph.

In comparative clinical trials, the incidence rates for hepatic events and an increase in liver enzymes were similar in natalizumab- and placebo-treated patients. Post-marketing surveillance reports of serious liver toxicity have been rare (<1/1000). As of November 23, 2007, the total cumulative exposure to TYSABRI in the post-marketing setting was estimated to be 24,000 patients. There were eight serious cases of hepatic events where a contributory role for TYSABRI could not be excluded, of which one was reported from Canada. Of the eight serious cases, all had at least one confounding risk factor, such as a history of liver disease or treatment with other therapies that are known to cause liver injury. Two patients showed evidence for positive dechallenge followed by positive rechallenge. Two cases were temporarily included on a liver transplant waiting list. However, to date, no case resulted in liver transplant or death.

Hypersensitivity:

Results from analyses of patients receiving re-treatment with TYSABRI after a break of therapy suggest that, if initial exposure is short, there is an increased risk of hypersensitivity reactions associated with re-exposure. If a hypersensitivity reaction occurs, administration of TYSABRI should be discontinued immediately and appropriate therapy initiated.

Antibody testing should be performed in patients who have received an initial short exposure (up to three infusions) to TYSABRI and extended periods (three months or more) without treatment.

Separate to the changes described above, Biogen Idec Canada Inc. is taking the opportunity to reaffirm other recent changes made to the product monograph.

Herpes infections:

In clinical trials, herpes infections occurred slightly more frequently in natalizumab-treated patients than in placebo-treated patients. During post-marketing experience, there have been rare reports of serious cases. Should a serious herpes infection occur, TYSABRI therapy should be withheld until the infection has been successfully treated.

The Canadian prescribing information for TYSABRI has been updated to include new information about liver injury and hypersensitivity in the Warnings and Precautions and about herpes infections in the Adverse Reactions section. The prescribing information is available upon request from the Tysabri Care Program^TM.

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious or unexpected adverse reactions in patients receiving TYSABRI^TM should be reported to the Tysabri Care Program^TM or Health Canada at the following addresses:

Tysabri Care ProgramTM Phone: 1-888-827-2827 Biogen Idec Canada Inc. 3 Robert Speck Parkway, Suite 300 Mississauga, ON L4Z 2G5 Any suspected adverse reaction can also be reported to: Canada Vigilance Program Marketed Health Products Directorate HEALTH CANADA Address Locator: 0701C Ottawa, Ontario, K1A 0K9 Tel: 613-957-0337 or Fax: 613-957-0335 To report an Adverse Reaction, consumers and health professionals may call toll free: Tel: 866-234-2345 Fax: 866-678-6789 CanadaVigilance@hc-sc.gc.ca The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties. For other inquiries related to this communication, please contact Health Canada at: Marketed Health Products Directorate (MHPD) E-mail: MHPD_DPSC@hc-sc.gc.ca Tel: 613-954-6522 Fax: 613-952-7738

Should you have any questions regarding TYSABRI^TM or require a copy of the revised TYSABRI^TM Product Monograph, please contact the Tysabri Care Program^TM at 1-888-827-2827.

Sincerely,

original signed by

Dr. Len Walt, M.D., M.B.A.
Medical Director