FDA Updates the Information for Healthcare Professionals Sheet for Tysabri (natalizumab)
ROCKVILLE, Md., Aug. 25, 2008--FDA ALERT [8/2008]: The FDA has recently received information from the manufacturer about two new cases of progressive multifocal leukoencephalopathy (PML) in patients receiving Tysabri monotherapy for multiple sclerosis in Europe. Both patients had received Tysabri for more than one year. PML, which is usually fatal, is a known risk of Tysabri treatment, but previous cases in patients with multiple sclerosis were seen in combination with other immunomodulatory therapies. About 39,000 patients have received treatment with Tysabri worldwide, with about 12,000 patients having been treated for at least one year. No new cases have been seen in the US, where about 7,500 patients have received the drug for longer than one year and about 3,300 patients have received the drug for at least one and a half years.
In the U.S., Tysabri is available only to patients with relapsing multiple sclerosis (MS) or Crohn's disease (CD) who are enrolled in the risk minimization plan called the TOUCH Prescribing Program. Under the TOUCH Prescribing Program, every Tysabri-treated patient is closely monitored and followed for the occurrence of PML and other serious opportunistic infections.
While the two patients who developed PML were on monotherapy, the FDA still believes that Tysabri monotherapy may confer a lower risk of PML than when Tysabri is used together with other immunomodulatory medications.
The FDA is working with the manufacturer to amend the product labeling to inform prescribers and patients that cases of PML have occurred in patients taking Tysabri as monotherapy.
This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.
To report any serious adverse events associated with the use of this drug, please contact the FDA MedWatch program and complete a form online at http://www.fda.gov/medwatch/report.htm or report by faxing (1-800-FDA-0178), by mail using the postage-paid address form provided online, (5600 Fishers Lane, Rockville, MD 20852-9787), or by telephone (1-800-FDA-1088).
Recommendations and Information for Healthcare Professionals registered with the TOUCH Prescribing Program to Consider when Prescribing Tysabri
- The two new cases of PML are notable for being the first cases occurring in the absence of concomitant or recent immunomodulatory therapy (e.g., beta-interferons)
- Although PML and other opportunistic infections are known risks of Tysabri, these are the first cases of PML that have been reported following Tysabri's market re-introduction in June 2006.
- PML is a rare infection of the central nervous system caused by a virus that can affect patients who have a compromised immune system.
- Both of the recently diagnosed patients were receiving Tysabri as monotherapy (one for 14 months and one for 17 months), although one of the patients had a history of prior immunosuppressant therapy with azathioprine and beta-interferons.
- Both patients were diagnosed on the basis of physical findings, MRI findings, and the detection of JC viral DNA in the cerebrospinal fluid.
- The incidence of PML with Tysabri remains unknown, although the available data indicate that the risk of PML when Tysabri is taken as monotherapy is lower than the risk of PML when Tysabri is taken with other immunosuppressant MS treatments.
- Continued clinical vigilance and close monitoring for the signs and symptoms of PML as dictated by the TOUCH Prescribing Program is necessary.
- Tysabri should not be infused if PML is suspected.
Information for Healthcare Professionals and Patients to Consider
- Always talk to your doctor about any medications and over the counter supplements that you may be taking.
- If you and your doctor decide that the benefits of starting Tysabri outweigh possible risks, then you must be enrolled in the TOUCH Prescribing Program before receiving Tysabri. The TOUCH Prescribing Program materials will describe the signs and symptoms of PML you should watch for.
- PML is a rare infection of the brain caused by a polyomavirus, called the JC virus. The JC virus is often acquired during childhood. Most adults have been infected with the JC virus but do not develop PML. The virus appears to remain inactive until something (such as a weakened immune system) allows it to be reactivated and start to multiply. People with a weakened immune system or people taking drugs that suppress their immune system (immunosuppressants) are most likely to get the disease. This virus infects the patient's brain and nervous system when their immune system is not working optimally.
- PML can occur naturally in the course of certain diseases, and it may also occur if someone's immune system has been suppressed by medications. Tysabri is one of the medications that PML has been associated with. Symptoms of PML may be similar to MS, so the diagnosis of PML is made by brain MRI and detection of the virus in the spinal fluid.
- PML symptoms may begin gradually, but they usually worsen rapidly. Symptoms vary depending on which part of the brain is infected. In about two-thirds of patients mental function declines rapidly and progressively, causing dementia. Speaking becomes increasingly difficult. People may become partially blind. Walking may become difficult. Rarely, headaches and seizures occur.
- The two new cases of PML are notable for being the first cases in patients with multiple sclerosis treated with Tysabri who were not also taking beta-interferon therapy.
- Both patients were diagnosed on the basis of physical findings, abnormal MRI findings and the detection of JC viral DNA in the cerebrospinal fluid.
- The risk of developing PML with Tysabri remains unknown, although the available data indicate that the risk of PML when Tysabri is taken as monotherapy is lower than the risk of PML when Tysabri is taken with other treatments that affect your immune system.
- Tysabri should not be given if PML is suspected until further clinical evaluation is performed.
Background and Data Summary
Tysabri, a recombinant humanized monoclonal antibody that binds to á4-integrin, was initially approved by the FDA in November, 2004, but was withdrawn by the manufacturer in February 2005 after three patients in clinical trials (two in MS trials and one in a CD trial) developed PML. The two MS patients were receiving concomitant beta-interferon therapy, and the patient in the CD trial had received immosuppressive therapy prior to receiving Tysabri.
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, alternate multiple sclerosis therapies.
In January 2008, Tysabri was approved for inducing and maintaining a clinical response and remission in patients with moderate to severely active CD who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-á.
The European cases of PML were reported by Biogen Idec and Elan (the makers and marketers of Tysabri) as follows:
- Case 1: This postmarket case of PML occurred in a patient who had received Tysabri monotherapy for 17 months. Prior to treatment, the patient had aggressive MS with high levels of relapse and MRI activity. Signs and symptoms which led to a suspicion of PML included muscle twitching, weakness of the left upper extremity, and brain MRI changes. Tysabri dosing was suspended and the patient underwent cerebrospinal fluid (CSF) testing. The patient has been diagnosed with PML based on the detection of JC viral DNA in the CSF in the setting of these clinical symptoms and MRI findings. Follow up to the case, received by the company on July 31, 2008, reported that this patient is ambulatory and continues to be managed as an outpatient.
- Case 2: This postmarket case occurred in a patient who had received Tysabri monotherapy for 14 months. This patient with MS had a long history of treatment with disease-modifying therapies including azathioprine and beta-interferons. Initial clinical features of PML included development of hemiparesis and cognitive symptoms. Brain MRI revealed lesions that were atypical. The diagnosis of PML was confirmed when JC viral DNA was detected in the CSF in the setting of the appropriate clinical signs, symptoms, and MRI features. At the time of reporting, the patient was hospitalized and in stable condition.
Report serious adverse events to
FDA's MedWatch reporting system by completing a form on line at
http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178),
by mail using the postage-paid address form provided online
(5600 Fishers Lane, Rockville, MD 20852-9787),
or by telephone (1-800-FDA-1088).
Posted: August 2008