At the end of July 2008, two cases of progressive multifocal leukoencephalopathy ( PML ) were reported in patients with multiple sclerosis receiving Natalizumab ( Tysabri ) in the European post-marketing setting.
PML is a subacute evolving CNS disease caused by reactivation of JC virus predominantly in immunocompromised patients. Progressive multifocal leukoencephalopathy usually leads to severe disability or death.
There have been a total of four cases of PML in multiple sclerosis patients receiving Tysabri. Two cases had been observed in patients receiving Tysabri in combination with Beta-interferon in pre-authorisation clinical trials. Combination therapy is contraindicated in the Summary of Product Characteristics (SmPC). One of these two cases was fatal.
The two cases, reported at the end of July 2008, have been observed post-marketing; Tysabri was given as monotherapy for approximately 17 and 14 months. In both cases the diagnosis was confirmed on the basis of a combination of clinical signs, symptoms, MRI scan and detection of JC viral DNA in the cerebrospinal fluid ( CSF ). Both patients have had plasma exchange to remove Tysabri from circulation and both are being actively followed up.
As of June 2008, approximately 31,800 patients with multiple sclerosis worldwide are being treated with Tysabri. Considering all patients treated with Tysabri, both in clinical trials and in the post-marketing setting, approximately 13,900 patients have received at least one year of therapy with Natalizumab and approximately 6,600 patients have been on therapy for 18 months or longer.
The absolute risk of PML in patients treated with Tysabri cannot be precisely estimated.
Tysabri must be permanently discontinued, if a patient develops progressive multifocal leukoencephalopathy.
Before initiation of treatment with Tysabri, a recent MRI should be available. During treatment, patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If new neurological symptoms occur, further dosing is to be suspended until PML has been excluded.
The physicians should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are typical of multiple sclerosis or possibly suggestive of PML. If they are suggestive of PML, or if any doubt exists, treatment with Tysabri should be discontinued and further evaluation, that may include MRI scan, lumbar puncture to test for JC Viral DNA in CSF and repeat neurological assessments, should be conducted. Once the clinician has excluded PML, dosing of Tysabri can resume.
Tysabri is contraindicated in patients with increased risk for opportunistic infections, including immunocompromised patients ( including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies, e.g. Mitoxantrone or Cyclophosphamide ).
Source: Medicines and Healthcare product Regulatory Agency MHRA, 2008