In agreement with the EMEA, F.Hoffmann-La Roche informed Health Care Professionals of new safety information regarding CellCept ( Mycophenolate mofetil ).

• Isolated cases of progressive multifocal leukoencephalopathy ( PML ) have been reported in patients receiving CellCept . The case reports have been associated with confounding factors in particular the nature of the underlying disease, concomitant immunosuppression and the latency between the use of CellCept and the onset of PML.
However, based on the temporal relationship observed in some cases, the contributory role of CellCept cannot be excluded.

• Physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms following treatment with CellCept and appropriate specialist referral investigation and management should be considered as clinically indicated. Consideration should be given to reducing the total immunosuppression in patients who develop PML. In transplant patients, however, reduced immunosuppression may place the graft at risk.

Progressive multifocal leukoencephalopathy is a rare, progressive, demyelinating disease of the central nervous system ( CNS ) that usually leads to death or severe disability.
PML is caused by the reactivation of the JC virus, a polyomavirus that resides in latent form in 70-90% of the adult population worldwide.
JC virus usually remains latent, typically only causing PML in immunocompromised patients.
The factors leading to activation of the latent infection are not fully understood although abnormalities in T-cells have been described as important for reactivation of JC virus and PML. Patients usually present with focal CNS abnormalities and radiographic evidence of white matter disease without mass effect.

Progressive multifocal leukoencephalopathy has been described in transplant patients involving different immunosuppressant medicines; 75% of all the PML cases reported in transplant recipients presented subacutely; hemiparesis, apathy, and confusion were the most frequent presenting features. PML should be considered in any transplant recipient who develops central neurological symptoms.

Progressive multifocal leukoencephalopathy has also been reported in other immunocompromised patients, including HIV-positive patients, cancer patients, and patients with autoimmune disease including systemic lupus erythematosus ( SLE ).
The incidence of PML in autoimmune diseases is not known, however, there are a number of cases reported in the literature. PML has been reported in patients with SLE receiving Prednisone, Azathioprine, Cyclophosphamide and other immunosuppressants.

The data related to the case reports of progressive multifocal leukoencephalopathy in CellCept treated patients has been reviewed by the CHMP ( Committee for Medicinal Products for Human Use ).

CellCept is an immunosuppressive agent indicated in combination with Ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adults receiving allogeneic renal, cardiac or hepatic transplants, and in children and adolescents ( 2-18 years ) receiving renal transplants.

Isolated cases of PML have been described in kidney, heart and lung transplant patients, and in SLE patients, receiving CellCept.

In the European Union, CellCept is not authorised for the treatment of systemic lupus erythematosus.

Transplant patients were male ( aged 33-62 years ) and were taking concomitant immunosuppressants ( e.g. Tacrolimus, Basiliximab, Prednisone and Cyclosporine ).
The patients involved in the SLE reports were females aged 40-53 years and had longstanding disease. SLE patients were taking concomitant medicines including Ciclosporin, Cyclophosphamide and steroids.

Diagnoses were confirmed by detection of JC virus in the cerebrospinal fluid and/or brain biopsy. Case outcomes varied from resolution, to improvement or death.

PML should be considered in the differential diagnosis in patients taking CellCept who develop neurological symptoms, and appropriate specialist referral for investigation and management should be considered. Consideration should be given to reducing the total immunosuppression in patients who develop PML. In transplant patients, however, reduced immunosuppression may place the graft at risk. Apart from reducing the total immunosuppression, there are no interventions that can reliably prevent progressive multifocal leukoencephalopathy, or adequately treat PML if it develops.

Source: MHRA, 2008

XagenaMedicines2008



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