Natalizumab (Tysabri) can increases the risk of fatal brain infection progressive multifocal leukoencephalopathy (PML) with the number of doses.
US FDA notified healthcare professionals and patients that the risk of developing progressive multifocal leukoencephalopathy (PML) increases with the number of natalizumab (Tysabri) infusions received.
Natalizumab (Tysabri) is administered as a single intravenous infusion every four weeks.
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.
Information about the occurrence of Immune Reconstitution Inflammatory Syndrome (IRIS) in patients who have developed PML and subsequently discontinued Tysabri has also been added to the drug label.
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.
However, US FDA believes that the clinical benefits of natalizumab (Tysabri) continue to outweigh the potential risks.
Progressive Multifocal Leukoencephalopathy (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.
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. There is limited clinical experience beyond 36 Tysabri infusions either in clinical trials or in the postmarketing setting.
US 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 US 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, US 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 Crohn’s disease [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 Crohn’s disease [CD]. Tysabri is not approved for Crohn’s disease [CD] outside of the U.S.
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.
Tysabri is marketed by Biogen Idec.