Rituxan® (Rituximab) for Rheumatoid Arthritis (RA)

Full Prescribing Information, including Boxed WARNINGS
Medication Guide (79K/PDF)

Rituxan® (Rituximab) in combination with methotrexate is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

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).

Rituxan can cause serious side effects, including:

• Progressive Multifocal Leukoencephalopathy (PML), which is a rare brain infection. PML usually causes death or severe disability. PML usually happens in patients with weakened immune systems. PML can occur during treatment with Rituxan or after treatment has finished. There is no known treatment, prevention, or cure for PML.
• Infusion reactions: Patients may get hives, swelling, dizziness, blurred vision, drowsiness, headache, cough, wheezing, or have trouble breathing while receiving or after receiving Rituxan.
• Tumor Lysis Syndrome (TLS): TLS is caused by the fast breakdown of certain types of cancer cells. TLS can cause kidney failure and the need for dialysis treatment.
• Severe skin reactions: Patients may get painful sores on the skin or in the mouth, ulcers, blisters, or peeling skin while receiving or after receiving Rituxan.

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.

Important Safety Information, including Boxed WARNINGS Rituxan can cause serious side effects including:

• Progressive Multifocal Leukoencephalopathy (PML)
  
  • PML is a rare brain infection.
  • PML usually causes death or severe disability.
  • Patients should call their doctor right away if they notice any new or worsening medical problems, such as a new or sudden change in thinking, walking, strength, vision, or other problems that have lasted over several days.
  • PML usually happens in patients with weakened immune systems.
  • PML can occur during treatment with Rituxan or after treatment has finished. There is no known treatment, prevention, or cure for PML.
• Infusion reactions. Patients should tell their doctor or get medical treatment right away if they get hives, swelling, dizziness, blurred vision, drowsiness, headache, cough, wheezing, or have trouble breathing while receiving or after receiving Rituxan.
• Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of certain types of cancer cells. Patients receiving Rituxan for non-Hodgkin's lymphoma (NHL) may get TLS.
• Severe skin reactions. Patients should tell their doctor or get medical treatment right away if they get any of these symptoms: painful sores on the skin or in the mouth, ulcers, blisters, or peeling skin while receiving or after receiving Rituxan.

Rituxan can cause other serious and life-threatening side effects, including:

• Hepatitis B virus reactivation. Patients should tell their doctor if they had hepatitis B virus or are a carrier of hepatitis B virus. Receiving Rituxan could cause the hepatitis B virus to become an active infection again. This may cause serious liver problems and death. People with active liver disease due to hepatitis B should stop receiving Rituxan.
• Heart problems. Patients should tell their doctor about any heart problems they have including chest pain (angina) and irregular heart beats. Rituxan can cause chest pain and irregular heart beats which may require treatment.
• Infections. Rituxan can increase the chances for getting infections. Patients should call their doctor right away if they have a cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Rituxan. These symptoms may be signs of a serious infection.

Common side effects during Rituxan infusions include fever, headache, chills and shakes, nausea, itching, hives, cough, sneezing, throat irritation or tightness.

Other side effects with Rituxan include aching joints, upper respiratory tract infection, decreased blood cell counts, and lung problems.

These are not all of the possible side effects with Rituxan. Patients should tell their doctor about any side effect that bother them or that do not go away.

Patients should read the Rituxan Full Prescribing Information including Boxed WARNINGS, and the Medication Guide.

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.

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.