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Safety Announcement

[04-22-2011] The U.S. Food and Drug Administration (FDA) continues to evaluate the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection, associated with use of Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) and Crohn's disease. The FDA has updated the Tysabri label to give new information about the size of this risk, as well as to include new safety information about patients who have taken other drugs that suppress the immune system, who may be at a higher risk for PML.

The revised drug label includes:

•    A table summarizing rates of PML with Tysabri use according to the number of infusions (how long the drug is taken or duration of exposure).

•    Information on a newly identified PML risk factor. Patients who took an immune system suppressing medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate) prior to taking Tysabri have been shown to be at an increased risk for developing PML. The Tysabri label already warned that using immune system suppressing medications at the same time as Tysabri may increase the risk of developing PML.

The FDA anticipates that the new PML information in the label will aid healthcare professionals in assessing the risk for PML and in discussing that risk with their patients. The Tysabri label will be updated periodically as new information about the risk for PML becomes available.

Based on the available information to date, the FDA continues to believe that the benefits of taking Tysabri outweigh the potential risks. Tysabri will continue to be available to patients only through a restricted distribution program called the Tysabri Outreach Unified Commitment to Health (the TOUCH Prescribing Program).

The FDA issued a previous Drug Safety Communication (DSC) on the risk of PML with the use of Tysabri on February 5, 2010.

Additional Information for Patients

Tysabri continues to be associated with PML.

The risk of developing this disease increases with the number of Tysabri infusions received.

The risk of developing PML also increases if you have taken a medication that suppresses the immune system (called an immunosuppressant) in the past. Tell your healthcare professional if you have previously taken an immunosuppressant medication. Examples of immunosuppressants are mitoxantrone, azathioprine, methotrexate, cyclophosphamide, and mycophenolate.

Discuss any questions or concerns about Tysabri and the risk of PML with your healthcare professional.

Report any side effects you experience to your healthcare professional and the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.

Additional Information for Healthcare Professionals

Inform your patients that PML continues to occur in patients treated with Tysabri.

The Tysabri label has been updated with information about the incidence of PML as reported through January 2011 and with information about a newly identified risk factor for PML (see Data Summary).

Ask your patients if they took an immunosuppressant medication at any time before starting Tysabri. The risk of PML is increased in patients who have been treated with immunosuppressant medications prior to receiving Tysabri. The Tysabri label already warned that concurrent use of immunosuppressant drugs with Tysabri may increase the risk of developing PML over the risk observed with the use of Tysabri alone. The effects of prior treatment with immunomodulators (e.g., beta-interferons, glatiramer acetate) or of prior, short-term treatment with corticosteroids for MS flares on the risk of PML in Tysabri-treated patients have not been evaluated.

Know that patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be ordinarily treated with Tysabri.

Tell your patients to contact you if they develop any symptoms suggestive of PML. Symptoms of PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory and orientation, leading to confusion and personality changes. The progression of deficits can lead to death or severe disability over weeks or months.

Monitor your patients and withhold Tysabri immediately at the first sign or symptom of PML.

Report adverse events involving Tysabri to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.

The FDA continues to evaluate the reports of PML and is considering new ways to help patients and healthcare professionals understand the risk.

Data Summary

102 cases of PML have been reported among 82,732 patients treated with Tysabri worldwide through February 28, 2011.

New data show that the risk of developing PML is increased in patients who have been treated with immunosuppressants in the past, prior to receiving Tysabri.  The effects of prior treatment with immunomodulators (e.g., beta-interferons, glatiramer acetate) or of prior, short-term treatment with corticosteroids for MS flares on the risk of PML in Tysabri-treated patients have not been evaluated.  The Tysabri label already warned that concurrent use of immunosuppressant drugs with Tysabri may increase the risk of developing PML over the risk observed with use of Tysabri alone.

Data from the past year have confirmed that the risk of developing PML is greater in patients who have received more than 24 Tysabri infusions (corresponding to two years of continuous treatment) compared to patients who have received fewer than 24 infusions.

The Tysabri label has been updated with a table to show the risk of PML for discrete treatment intervals (durations of exposure). This PML risk table contains a date to reflect when the data were current, and will be updated periodically.

The PML incidence information that was added to the label, current as of January 2011, is presented in the table below:

Table 1. Estimated Incidence of PML in the Postmarketing Setting through January 11, 2011

†Data as of January 2011

Data beyond 4 years of treatment are limited

Previous FDA DSCs have presented PML incidence in a slightly different format, showing cumulative risks above certain thresholds of exposure.

FDA believes that presenting PML incidence for discrete intervals of treatment instead of showing cumulative risks above certain thresholds of exposure will allow prescribers to better assess risk based on duration of treatment, and will aid healthcare professionals in discussing the risk of PML with their patients.

Because the PML rates in the United States and the rest of the world have become more similar over time, the incidence rates are not separated by geographic location in the new table that has been added to the label.

References

U.S. National Library of Medicine. National Institutes of Health. Health Topics-Multiple Sclerosis. Available at http://www.nlm.nih.gov/medlineplus/multiplesclerosis.html Accessed March 16, 2011.