Rituxan® (Rituximab) for Rheumatoid Arthritis (RA)

Full Prescribing Information, including Boxed Warnings

Rituxan is the only B-cell-targeted therapeutic antibody approved for the treatment of rheumatoid arthritis (RA) in the United States and is indicated, in combination with methotrexate (MTX), to reduce the signs and symptoms and to slow the progression of structural damage in adult patients with moderately-to-severely active RA who have had an inadequate response to tumor necrosis factor (TNF) antagonist therapy.

Mechanism of Action Rituxan represents an entirely new approach to treating RA. It is the first RA treatment that targets immune cells called B-cells, which originate from stem cells in the bone marrow. B-cells may play multiple roles in the initiation and development of RA including:

• Presentation of antigens (substances capable of triggering an immune response), which may contribute significantly to T-cell responses.
• Production of antibodies that trigger an immune attack against a person's own cells or tissues (autoantibodies) and perpetuate the disease process.
• Production of chemical signal molecules (cytokines) known to promote inflammation and joint damage.

Rituxan binds to a specific protein (the CD20 marker on the surface of the cell) that is found on the surface of some B-cells. From there, Rituxan works with the immune system to selectively deplete CD20-positive B cells. Through this unique mechanism of action, Rituxan may affect three pathways by which B-cells are believed to contribute to the initiation and development of RA.

Rituxan does not target stem cells (B-cell progenitors) in the bone marrow, which lack the CD20 marker on the surface of the cells. Thus, B-cells can regenerate and gradually return to normal levels after treatment with Rituxan. Rituxan also does not target plasma cells.

Clinical Trial Results In clinical trials for RA, Rituxan demonstrated significant improvement in RA signs and symptoms, with an extended duration of effect through six months from a single treatment course in adult RA patients who had an inadequate response to one or more TNF antagonist therapies.

The FDA approval of Rituxan for RA was based on data from three randomized, double-blind, placebo-controlled studies. Following is a summary of the results of the pivotal Phase III REFLEX study, which included patients with active RA who had an inadequate response or were intolerant to prior treatment with one or more tumor necrosis factor (TNF) antagonist therapies.

ACR Responses: A significantly greater proportion of patients who received a single treatment course of two infusions of Rituxan (1000 mg on days one and 15) with a stable dose of MTX displayed clinically and statistically significant improvements in RA signs and symptoms, including pain and disability, after 24 weeks. In patients receiving Rituxan:

• 51 percent achieved ACR 20, the primary endpoint of the study, versus 18 percent of placebo patients (p<0.0001)
• 27 percent achieved ACR 50, versus 5 percent of placebo patients (p<0.0001)
• 12 percent achieved ACR 70, versus 1 percent of placebo patients (p<0.0001)

ACR responses indicate a 20, 50 and 70 percent improvement in the number of swollen and tender joints, respectively, as well as a 20, 50 and 70 percent improvement compared with baseline in three of five disease-activity measures: patient global assessment, physician global assessment, assessment of pain, Health Assessment Questionnaire and the value for one acute phase reactant (erythrocyte sedimentation rate or C-reactive protein, markers of inflammation).

Dosing In patients with RA, Rituxan is given as two-1000 mg IV infusions separated by two weeks. Glucocorticoids administered as methylprednisolone 100 mg IV or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. The safety and efficacy of retreatment have not been established in controlled trials.

Rituxan is given in combination with methotrexate.

Approved Indications

• Rituxan was approved in November 1997 by the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin's lymphoma.
• In April 2001, the FDA updated the prescribing information for Rituxan adding new information, including: retreatment of patients with Rituxan who have relapsed following initial Rituxan therapy; new administration (eight weekly doses compared to original four per course of treatment); and treatment of patients with bulky disease (lesions >10 cm).
• In February 2006, Rituxan received FDA approval for the first-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin's lymphoma, in combination with CHOP or other anthracycline-based chemotherapy regimens.

Safety Profile The safety profile of Rituxan has been established in more than 730,000 patient exposures over a period of eight years.

In general, the adverse events observed in patients with RA were similar in type to those seen in patients with non-Hodgkin's lymphoma (NHL). The most common adverse events observed in patients treated with Rituxan for RA in clinical trials were infusion reactions and infections. No significant change in average immunoglobulin levels was observed in Rituxan-treated patients in clinical trials. There was no increase in hematologic malignancies, demyelinating events, or risk of opportunistic infections (including tuberculosis) in Rituxan-treated patients over 24 weeks of treatment. Although 5 percent of Rituxan-treated patients developed human anti-chimeric antibodies (HACA), this was not associated with loss of clinical response or additional safety observations.

The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to: flu-like illness, fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema, hypotension, and hypoxia. These symptoms vary in severity and generally are reversible with medical intervention.

Severe infusion reactions have been reported in patients treated with Rituxan, some with fatal outcomes in patients with NHL. These severe reactions typically occur during the first infusion. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. Patients who develop clinically significant infusion reactions should have their Rituxan infusion discontinued and receive medical treatment. Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of tumor lysis syndrome following treatment with Rituxan. Severe mucocutaneous skin reactions, some with fatal outcome, have been reported in association with Rituxan treatment. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving Rituxan in combination with chemotherapy for DLBCL. Other serious or potentially life-threatening adverse reactions that have been reported following Rituxan therapy include Hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, and cardiac arrhythmias.

Additional Rituxan Information Rituxan, discovered by Biogen Idec, is co-marketed by Genentech, Inc. and Biogen Idec in the United States and Roche markets MabThera® in the rest of the world, except Japan, where Rituxan is co-marketed with Zenyaku Kogyo Co. Ltd. Rituxan has become the most widely studied and prescribed monoclonal antibody in the world.

Rituxan is also being studied in other autoimmune diseases with significant unmet medical needs, including systemic lupus erythematosus, lupus nephritis, multiple sclerosis and ANCA-associated vasculitis.

For a copy of the Rituxan full prescribing information, including Boxed Warning, please call (800) 821-8590 or visit http://www.rituxan.com.