Apr 11, 2011
Updated January 20, 2012
According to a safety announcement released by the U.S. Food and Drug Administration, as of January 4, 2012 there have been 201 confirmed cases of progressive multifocal leukoencephalopathy (PML, a viral infection of the brain that usually leads to death or severe disability) among people who have used Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals) after it became available for prescription in July 2006.
In January 2012, the prescribing information was updated to include new information about the incidence and risk factors of PML among people with MS taking Tysabri. Read more in the safety announcement from the FDA. Originally the risk of PML was estimated to be 1 case of PML per 1000 people taking the therapy. The updated prescribing information indicates that people who test positive for anti-JC virus antibodies is a risk factor for PML. Other risk factors identified include prior use of immune-suppressing therapies (such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil) and longer duration of Tysabri treatment, especially beyond two years. Those with all three risk factors have an estimated risk of PML of 11/1000 users.
The FDA’s announcement stresses that 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. It also notes that doctors should consider testing patients prior to treatment or during treatment if antibody status is unknown, and that periodic re-testing should also be considered.
About the Cases of PML:
Cases are occurring in both men and women who had been given infusions of Tysabri every four weeks. About nineteen percent of those who have developed PML have died. The degree of disability in the survivors is a wide spectrum: at the milder end, some have recovered enough to return to work, and at the other extreme, some are confined to bed, requiring extensive assistance with activities of daily living, and others were in between this range.
When PML was suspected, Tysabri infusions were halted. There is no specific therapy to treat PML, but the best hope is to reconstitute a person’s immune responses. In most of the cases, once PML was confirmed, Tysabri was removed from their systems with the blood-cleansing treatments of either plasma exchange or immunoadsorption.
During the aftermath of PML, as the immune system begins to recover, a condition called IRIS (immune reconstitution inflammatory syndrome) usually occurs within days or weeks after the removal of Tysabri from the system. According to the prescription label information, appropriate treatment of the associated inflammation should be undertaken.
Signs of PML:
Typical symptoms associated with PML progress quickly over days to weeks, and can include:
• personality or behavioral changes
• changes in thinking, memory, and orientation leading to confusion
• onset of seizures, clumsiness or progressive weakness on one side of the body
• disturbances of vision
If individuals taking Tysabri experience new, unusual symptoms, they should contact their prescribing physician immediately. Tysabri infusions should be halted; updates to the labeling information indicate that even if initial evaluations are negative but clinical symptoms remain, Tysabri dosing should continue to be withheld and the evaluations repeated.
A definitive diagnosis of PML is made by evaluating clinical and MRI findings plus the identification of JC virus (the virus that causes PML) DNA in the cerebrospinal fluid (a clear liquid that bathes the brain and spinal cord and that is obtained through lumbar puncture or “spinal tap”). It is imperative to analyze samples as quickly as possible, with as much sensitivity and specificity as possible. Biogen Idec recommends sending samples to Focus Diagnostics of California. Physicians who need more information on this or any other aspect of the protocol to follow when they have a patient on Tysabri who experiences unusual symptoms should contact Biogen Idec at 1-800-456-2255. The company also has launched a Website (http://medinfo.biogenidec.com/) to provide U.S.-based health care professionals updated information on its MS products including monthly Tysabri updates. (Practice license information is required for accessing the site.)
Additional Details:
• Based on the cases so far, the company stresses that the presence of gadolinium-enhancing lesions on MRI does not exclude the possibility of PML. Likewise, the absence of JC virus DNA in the spinal fluid does not exclude PML.
• Clinical studies investigating the value of antibody testing continue. Read more about antibody studies
The FDA provides post-marketing safety warnings on Tysabri at this link.
Tysabri is a registered trademark of Biogen Idec and Elan