By Federal Drug Administration Friday, February 5, 2010

FDA Drug Safety Communication: Risk of Progressive Multifocal Leukoencephalopathy (PML) with the use of Tysabri (natalizumab)

Safety Announcement

Additional Information for Patients

Additional Information for Healthcare Professionals

Data Summary

Safety Announcement

[02-05-2010] The U.S. Food and Drug Administration (FDA) is alerting the public that the risk of developing progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection associated with the use of Tysabri (natalizumab), increases with the number of Tysabri infusions received. This new safety information, based on reports of 31 confirmed cases of PML received by the FDA as of January 21, 2010, will now be included in the Tysabri drug label and patient Medication Guide (see Data Summary for additional information).

Tysabri was approved by the FDA in November 2004 for the treatment of relapsing forms of multiple sclerosis (MS). Tysabri is also approved by FDA for treating moderately to severely active Crohn's disease.

Since 2006, Tysabri has only been available through a risk minimization plan called Tysabri Outreach Unified Commitment to Health (the TOUCH™ Prescribing Program). The program, developed by the FDA and the manufacturer of Tysabri, Biogen-Idec, is intended to make sure that healthcare professionals and patients understand the benefits and potential risks associated with the use of Tysabri, including the risk of PML.Under the TOUCH™ program, every patient who receives Tysabri is closely monitored for the occurrence of PML and other serious opportunistic infections.  For additional information about the TOUCH™ program click here.

Based on the available information, the FDA believes that the clinical benefits of Tysabri continue to outweigh the potential risks. Revisions to the drug label and patient Medication Guide, with the continued use of the TOUCH Prescribing Program, are intended to maximize the safe use of Tysabri and the identification of new PML cases.

Additional Information for Patients

• Tysabri is a medication that has been associated with PML and the risk of developing this disease increases with the number of Tysabri infusions received.
• PML is a rare infection of the brain caused by the JC virus, which is a common virus often acquired during childhood. Most adults have been infected with JC virus, but do not develop PML. The virus appears to remain inactive until something (such as a weakened immune system) causes it to be reactivated. Once reactivated, the virus may infect the brain and cause PML.
• People with a weakened immune system or people taking drugs that suppress their immune system (immunosuppressants) are most likely to get PML. Tysabri is an immunosuppressant medication.
• The symptoms of PML may begin gradually, usually worsen rapidly, and vary depending on which part of the brain is infected. These symptoms may include difficulty with walking and other movements, decline in mental function, and problems with vision and speaking. Rarely, headaches and seizures occur. Symptoms of PML may be similar to multiple sclerosis (MS).
• If PML is suspected, Tysabri treatment should be stopped and not resumed until further clinical evaluation is performed.
• When patients have the clinical symptoms of PML, a PML diagnosis is made by an MRI of the brain and confirmation of the presence of JC virus in the cerebrospinal fluid.
• Cases of Immune Reconstitution Inflammatory Syndrome (IRIS) have been reported after stopping Tysabri because of PML. IRIS is a condition that can occur after discontinuing immunosuppressant medications. During immune system recovery, patients can experience a severe inflammatory response to an infection and their symptoms can get worse, sometimes after a period of improvement.

Additional Information for Healthcare Professionals

• An update to the Warnings and Precautions section of the drug label has been added to inform healthcare professionals that the risk of PML increases with the number of Tysabri infusions received
  • There have been no reports of PML in patients treated for less than 12 months since Tysabri's remarketing.In patients treated with 24 to 36 infusions, the overall worldwide rate and the rate in the U.S. of developing PML is similar to the rate seen during clinical trials (1 case per 1,000 patients treated). Outside of the U.S., the rate is approximately 2 cases per 1,000 patients.The reasons for this difference are unknown. There is limited clinical experience beyond 36 Tysabri infusions either in clinical trials or in the postmarketing setting.
  • PML is diagnosed on the basis of clinical symptoms, MRI findings, and the detection of JC virus in the cerebrospinal fluid.
  • Tysabri should be withheld at the first sign or symptom suggestive of PML.
  • Continued clinical vigilance and close monitoring for the signs and symptoms of PML as dictated by the TOUCH™ Prescribing Program is necessary.
• An update to the Warnings and Precautions section of the drug label has been added to inform healthcare professionals about the occurrence of Immune Reconstitution Inflammatory Syndrome (IRIS) in patients who developed PML and subsequently discontinued Tysabri.
  • IRIS is a rare condition characterized by a severe inflammatory response that can occur during or following immune system recovery, causing an unexpected decline in a patient's condition after return of immune function.
  • IRIS has been reported in patients who discontinue Tysabri as a result of developing PML, but not in patients who discontinue Tysabri for other reasons.
  • Many patients who stopped Tysabri due to PML and who received either plasma exchange or immunoadsorption (measures taken to decrease circulating Tysabri levels) developed IRIS days to several weeks after these treatments.
  • Healthcare professionals should monitor their patients for the development of IRIS and appropriate treatment of the associated inflammation after stopping Tysabri should be undertaken.

Data Summary

The FDA continues to receive reports of PML in patients receiving Tysabri in the United States and overseas.  Tysabri, an immunosuppressant medication, was first approved by the FDA in November 2004 for the treatment of relapsing forms of multiple sclerosis (MS).  In February 2005, the marketing of Tysabri was suspended by the manufacturer after three patients in clinical trials (two patients in MS trials and one in a Crohn's disease [CD] trial) developed PML. In June 2006, the FDA approved an application for the re-marketing of Tysabri as monotherapy for the treatment of patients with relapsing forms of MS.

Tysabri is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy. In January 2008, Tysabri was also approved for inducing and maintaining a clinical response and remission in patients with moderately to severely active CD who have had an inadequate response to, or are unable to tolerate, conventional CD therapies.

Since July 2006 (when marketing resumed) through January 21, 2010, there have been 31 confirmed cases of PML worldwide in patients using Tysabri. Of these 31 case reports, 10 were from patients in the U.S. As of January 21, 2010, eight patients have died. In all cases, patients were receiving Tysabri as monotherapy for the treatment of MS.  There have been no postmarketing reports of PML in patients treated with Tysabri for CD.  In the U.S., less than 2% of Tysabri use is in patients with CD. Tysabri is not approved for CD outside of the U.S. 

The risk of developing PML increases with the number of Tysabri infusions received. Tysabri is administered as a single intravenous infusion every four weeks. The overall worldwide cumulative rate of PML in patients who have received one or more Tysabri infusions is 0.5 cases of PML per 1,000 patients. Since Tysabri's re-marketing in the U.S., there have been no cases of PML in patients treated with Tysabri for less than 12 months. The overall worldwide cumulative rate of PML in patients who have received at least 24 infusions is 1.3 cases of PML per 1,000 patients. In the U.S., the cumulative rate of PML in patients who have received at least 24 infusions is 0.8 per 1,000 patients. Outside of the U.S., the cumulative rate of PML in patients who have received at least 24 infusions is 1.9 per 1,000 patients.

Approximately 66,000 people, worldwide, have received at least one dose of Tysabri since marketing resumption (through December 31, 2009). Relatively few patients have received 36 infusions or more, either in clinical trials or since marketing resumption; therefore, the magnitude of the risk of PML and other adverse events in patients who have received 36 infusions or more is not able to be well characterized.

The following table summarizes cumulative rates of PML according to geographic location and number of Tysabri infusions received since Tysabri re-marketing:

The FDA and its international counterparts remain committed to tracking and monitoring for any change in the risk of PML associated with the use of Tysabri.

This communication is intended to increase awareness about the risk of PML in patients treated with Tysabri.At this time, the FDA believes that the clinical benefits of Tysabri outweigh its risks. Tysabri will remain available to patients through the TOUCH™ Prescribing Program.  Under this program, every patient who receives Tysabri is closely monitored for the occurrence of PML and other serious opportunistic infections. 

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