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Off-Label Use of Rituxan Linked to Fatal Leukoencephalopathy

Dec 19, 2006 | The US Food and Drug Administration (FDA) is warning healthcare professionals regarding the risk for progressive multifocal leukoencephalopathy (PML) in patients receiving rituximab intravenous infusion (Rituxan, made by Genentech, Inc, and Biogen Idec, Inc) for the treatment of systemic lupus erythematosus (SLE), an off-label indication.

The warning was based on 2 fatal cases of PML in patients with SLE receiving rituximab, according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program. The drug manufacturers estimate that approximately 10,000 patients with SLE have received rituximab therapy.

PML is a rare and frequently fatal demyelinating disease of the central nervous system that primarily affects patients whose immune systems are compromised by disease or medical treatments. It is caused by reactivation of the JC virus, which remains latent in up to 80% of healthy adults. There are no known effective treatments for PML.

The first death occurred during March 2006 in a woman aged 70 years with a history of lupus nephritis and hemolytic anemia. She had received prior treatment with cyclophosphamide, azathioprine, and long-term corticosteroid therapy. After receiving multiple infusions of rituximab (4 in 2004 and 2 in 2005), she developed vertigo, tongue biting, and difficulty walking. Magnetic resonance imaging (MRI) revealed multiple brain lesions, and brain autopsy showed characteristics of PML.

The second death, in July 2006, involved a woman aged 45 years with a 24-year history of SLE and prior treatment with cyclophosphamide and intravenous methylprednisolone. After receiving 3 courses of rituximab from 2002 to 2005, she developed neurologic signs and symptoms. MRI revealed multiple brain lesions, and tests of cerebrospinal fluid were positive for JC virus.

Because rituximab targets CD20-positive lymphocytes, its use is associated with an increased vulnerability to infection regardless of the indication. Postmarketing reports of serious viral illness have included 23 confirmed cases of PML in patients with lymphoid malignancies either during treatment or as long as 1 year after the last dose. The FDA notes that the majority of affected patients had also received other immunosuppressive drugs.

Healthcare professionals are advised to maintain a high index of suspicion for PML in patients receiving rituximab therapy, particularly those who develop new neurologic signs or symptoms.

Patients receiving rituximab therapy should be advised to promptly contact their healthcare professional if they develop any major changes in vision, balance/coordination, or experience disorientation/confusion.

Rituximab intravenous infusion is approved for use in combination with methotrexate to reduce signs and symptoms of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor–alpha inhibitor therapies.

It is also indicated for use with cyclophosphamide, vincristine, and prednisolone chemotherapy in the first-line treatment of follicular, CD20-positive B-cell non-Hodgkin's lymphoma (NHL), and for the treatment of low-grade NHL in patients with stable disease who achieve a partial or complete response to first-line treatment with CVP chemotherapy.

In addition, rituximab can be used for the treatment of patients with relapsed or refractory low-grade or follicular CD20-positive B-cell NHL, and for the first-line treatment of CD20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone or other anthracycline-based chemotherapy regimens.

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