FDA Drug Safety Communication: New risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab)

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary

Safety Announcement

[01-20-2012] The U.S. Food and Drug Administration (FDA) is informing the public that testing positive for anti-JC virus (JCV) antibodies has been identified as a risk factor for progressive multifocal leukoencephalopathy (PML). PML is a rare but serious brain infection associated with use of Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) or Crohn's disease.

Facts about Tysabri (natalizumab)

In a class of medications called immunomodulators. It works by stopping certain cells of the immune system from causing damage to the body.
Has been approved by the FDA for the treatment of relapsing forms of multiple sclerosis since November 2004 and for the treatment of moderately to severely active Crohn's disease since January 2008.

The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more of the other known risk factors for PML. Patients with all three known risk factors have an estimated risk of PML of 11/1,000 users. The risk factors are:

The presence of anti-JCV antibodies.
Longer duration of Tysabri treatment, especially beyond 2 years.
Prior treatment with an immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil).

The drug label for Tysabri¹ has been revised to reflect this updated information including a table estimating the rate of PML stratified by the three known risk factors (see Table 1 below).

A patient's anti-JCV antibody status may be determined using an anti-JCV antibody detection test that has been analytically and clinically validated, and has been ordered by a healthcare professional. The Stratify JCV Antibody ELISA test² was cleared by FDA on January 20, 2012. Testing positive for anti-JCV antibodies means that a person has been exposed to JCV in the past.

PML is a rare disorder in which the coating (myelin) of some brain nerve fibers gets damaged. Although JCV is a common virus that is generally harmless and does not cause symptoms in people whose immune systems function normally, it can cause PML in people with weakened immune systems. Causes of a weakened immune system may include human immunodeficiency virus (HIV) infection, leukemia or lymphoma, or taking a medication such as Tysabri.

The FDA issued two previous Drug Safety Communications (DSCs) on the risk of PML with the use of Tysabri on February 5, 2010³ and on April 22, 2011⁴.

Additional Information for Patients

As a result of this new information, your healthcare professional may recommend a blood test to see if you have ever been exposed to JCV, the virus that causes PML. This test measures antibodies to the virus, which are often referred to as "anti-JCV antibodies."
The risk of developing PML increases if you have tested positive for anti-JCV antibodies and have one or two of the other known risk factors.
The risk of PML is greatest if you have all three known risk factors.
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 a newly identified third risk factor for PML (see Data Summary).
For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered to be anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody test.
Consideration should be given to testing patients prior to treatment or during treatment if antibody status is unknown.
Patients who test negative for anti-JCV antibodies are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Consideration should be given to periodic re-testing of patients previously determined to be anti-JCV antibody negative.
When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay.
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.

Data Summary

201 cases of PML have been reported among approximately 96,582 patients treated with Tysabri worldwide through January 4, 2012.

New data have identified the presence of anti-JCV antibodies as a risk factor for developing PML in Tysabri-treated patients. The Stratify JCV Antibody ELISA test, which can detect these antibodies, was cleared by FDA on January 20, 2012⁵.

The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000. (See Table 1).

The PML incidence information in Table 1 below is being added to the Tysabri label:

Table 1: Estimated PML Incidence Stratified by Risk Factor

Notes: Based on postmarketing PML data and Tysabri use data as of September 1, 2011.
^†Data beyond 4 years of treatment are limited.
* Risk in anti-JCV antibody positive patients was estimated based on the assumptions that 18% of Tysabri-treated MS patients have a history of prior immunosuppressant treatment and that 55% of Tysabri-treated MS patients are anti-JCV antibody positive.
^* The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with a false negative rate of 3%.

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

References

U.S. National Library of Medicine. National Institutes of Health. Health Topics-Progressive multifocal leukoencephalopathy. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000674.htm⁶ Accessed January 11, 2012.