ST LOUIS (MD Consult) - On February 5, 2010, the US Food and Drug Administration (FDA) issued an alert about updated information concerning the risk of progressive multifocal leukoencephalopathy (PML) occurring in patients who receive the immunosuppressant drug Tysabri (natalizumab). The product label will now state that the risk of PML increases with the number of Tysabri infusions given. This new safety information was added after the FDA received reports of 31 confirmed cases of PML (as of January 21, 2010) in patients who had received Tysabri infusions.
In February 2005, the marketing of Tysabri was suspended by the manufacturer after 3 patients in clinical trials (2 patients in multiple sclerosis [MS] trials and 1 patient in a Crohn's disease [CD] trial) experienced PML. In June 2006, the FDA approved an application for the remarketing of Tysabri as monotherapy for the treatment of patients with relapsing forms of MS.
Approximately 66,000 persons worldwide have received at least 1 dose of Tysabri since marketing resumption (through December 31, 2009), and no reported cases of PML occurred in patients treated for <12 months. In patients treated with 24 to 36 infusions of Tysabri, the overall worldwide rate and the rate in the United States of PML development is similar to the rate seen during clinical trials (1 case per 1,000 patients treated). Outside of the United States, the rate is approximately 2 cases per 1,000 patients. The reasons for this difference are unknown. Limited clinical experience exists beyond 36 Tysabri infusions either in clinical trials or in the postmarketing setting.
Tysabri is generally recommended for patients with MS who have demonstrated an inadequate response to, or are unable to tolerate, an alternate MS therapy. Tysabri is also approved for inducing and maintaining a clinical response and remission in patients with moderately to severely active CD who have shown an inadequate response to, or are unable to tolerate, conventional CD therapies.
Progressive multifocal leukoencephalopathy 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 experience PML. The virus appears to remain inactive unless certain circumstances, such as an immunosuppressive state, foster viral reactivation. Once reactivated, the virus may infect the brain and cause PML.
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 speech. Rarely, headaches and seizures occur. Symptoms of PML may be similar to those associated with multiple sclerosis.
Tysabri should be withheld at the first sign or symptom suggestive of PML. A diagnosis of PML is made on the basis of results from magnetic resonance imaging of the brain, and is confirmed by the discovery of JC virus in cerebrospinal fluid.
An additional update to the Warnings and Precautions section of Tysabri's drug label has been added to inform healthcare professionals about the occurrence of Immune Reconstitution Inflammatory Syndrome in patients in whom PML developed and who subsequently discontinued Tysabri. Immune Reconstitution Inflammatory Syndrome is a rare condition characterized by a severe inflammatory response that can occur during or after immune system recovery, causing an unexpected decline in a patient's condition.
At this time, despite all of these concerns, the FDA believes that the clinical benefits of Tysabri continue to outweigh the potential risks.
