Rituxan® (Rituximab) for Non-Hodgkin's Lymphoma

Full Prescribing Information, including Boxed Warnings

Redefining Outcomes for CD20-Positive, B-Cell Lymphomas Rituxan was the first therapeutic antibody approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and was the first targeted therapy for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL).

Rituxan has been shown to extend progression-free survival (PFS) in certain patients for first-line therapy of low-grade or follicular, CD20-positive, B-cell NHL. Rituxan has been documented to improve overall response rates for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL.

Rituxan has also been shown to improve overall survival (OS) in certain patients with CD20-positive diffuse large B-cell (DLBCL) lymphoma.

Rituxan's safety and efficacy have been documented in more than 200 Phase II and Phase III clinical studies over the past 10 years.

Rituxan: A History of Firsts

• First FDA-approved therapeutic antibody to treat cancer.
• First biologic therapy for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL.
• First and only biologic therapy in combination with CVP chemotherapy that improves PFS (survival until disease progression or death) in patients with first-line follicular, CD20-positive, B-cell NHL.
• First treatment of any kind (with CHOP or anthracycline chemotherapy) to have improved OS in first-line CD20-positive, DLBCL in more than 25 years.
• First and only biologic therapy to improve PFS, with CHOP or anthracycline chemotherapy, in first-line CD20-positive, DLBCL.

Boxed Warnings Rituxan has been associated with fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with related fulminant hepatitis and other serious viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation.

Mechanism of Action Rituxan is a monoclonal antibody that targets a specific protein, known as CD20, on the surface of immune cells known as B-cells. Rituxan binds to CD20 and is believed to work with the body's own immune system to attack and kill the CD20-positive, B-cells. Scientists designed Rituxan to target CD20 because more than 85 percent of NHL cases arise from abnormal B-cells.

Stem cells (B-cell progenitors) in bone marrow lack CD20, allowing healthy B-cells to regenerate after treatment and return to normal levels. Antibody-producing B-cells (plasma cells), which help fight infection, also lack CD20.

Clinical Trial Results Clinical studies have demonstrated that Rituxan can be an effective treatment for patients with low-grade or follicular, CD20-positive, B-cell lymphoma or DLBCL at different stages of treatment. A summary of pivotal trial data that support Rituxan's indications follows.

INDICATION	CLINICAL TRIAL DATA
Follicular Lymphoma
First-line treatment of patients with low-grade or follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine, and prednisolone) chemotherapy	Data from a Phase III study (n=322) showed that patients treated with Rituxan in combination with CVP chemotherapy (R-CVP) had an improved median PFS of 2.4 years vs. 1.4 years for patients treated with CVP chemotherapy alone. R-CVP reduced the risk of disease progression, relapse or death by 56 percent compared to CVP chemotherapy alone (hazard ratio = 0.44.; p<0.0001).
Treatment of low-grade or follicular, CD20-positive, B-cell NHL in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy	Data from a Phase III study (n=322) showed that treatment with Rituxan reduced the risk of disease progression, relapse, or death by more than 50 percent over clinical observation (hazard ratio estimate in the range of 0.36 - 0.49).
Retreatment in patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL	Data from a single-arm study involving 60 patients showed that 38 percent of patients responded to a second course of single-agent Rituxan after having received an objective clinical response to a prior course of Rituxan. 10 percent experienced complete responses and 28 percent had partial responses; median duration of response was at 15 months (range, 3.0 to 25.1+ months).
Treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, NHL	Pivotal trial data showed that 48 percent of patients (n=166) responded to four weekly single-agent infusions of Rituxan. 6 percent experienced complete responses and 42 percent had partial responses; median duration of response was 11.2 months (range, 1.9 to 42.1+ months). Patients treated with Rituxan after their first relapse with chemotherapy had a higher response rate (57 percent) than those treated after second (46 percent) or third (38 percent) relapses with chemotherapy. Additional data from a multi-center, single-arm study involving 37 patients showed that 57 percent of patients responded to eight weekly infusions of Rituxan. 14 percent experienced complete responses and 43 percent had partial responses; median duration of response was 13.4 months (range, 2.5 to 36.5+ months).
Treatment in patients with relapsed or refractory, bulky disease (lesions >10 cm), low-grade or follicular, CD20-positive, B-cell NHL	Pooled data from multiple studies involving 39 patients treated with Rituxan demonstrated that 36 percent of patients responded to four weekly infusions. 3 percent experienced complete responses and 33 percent had partial responses; median duration of response was 6.9 months (range, 2.8 to 25.0+ months).
DLBCL
First-line treatment of CD20-positive, DLBCL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens	In each of three studies (combined n=1,854), Rituxan in combination with CHOP (R-CHOP) or other anthracycline-based chemotherapy induction significantly improved OS compared to chemotherapy alone. In one study with five years of follow-up, R-CHOP improved OS by 47 percent compared to CHOP alone (hazard ratio = 0.68, p<0.05, which is equivalent to a 32 percent decrease in the risk of death).

Low-Grade or Follicular, CD20-Positive, B-Cell NHL and DLBCL Dosing Rituxan is administered at 375 mg/m² for CD20-positive, B-cell NHL and DLBCL as part of FDA-approved treatment regimens.

Other Indication In February 2006 the FDA approved Rituxan for the treatment of rheumatoid arthritis (RA), in combination with methotrexate (MTX), to reduce the signs and symptoms in adult patients with moderately-to-severely active RA who have had an inadequate response to tumor necrosis factor (TNF) antagonist therapy.

Clinical Development In addition to playing a role in various cancers, B-cells are central to the progression of many immune system diseases. Genentech remains committed to fully understanding the potential of Rituxan to benefit as many patients as possible.

Numerous trials are underway worldwide studying the effectiveness and safety of Rituxan. In addition to Rituxan's FDA approved uses in NHL and rheumatoid arthritis, Rituxan is being studied in chronic lymphocytic leukemia (CLL). REACH is a randomized Phase III trial examining Rituxan as a treatment for relapsed CLL patients in combination with fludarabine plus cyclophosphamide. The primary endpoint of this study is PFS.

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.

Safety Profile BOXED WARNINGS and Additional Important Safety Information

Fatal Infusion Reactions: Deaths within 24 hours of Rituxan infusion have been reported. These fatal reactions followed an infusion reaction complex which included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Approximately 80 percent of fatal infusion reactions occurred in association with the first infusion. Patients who develop severe infusion reactions should have Rituxan infusion discontinued and receive medical treatment. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) patients with Rituxan. Severe Mucocutaneous Reactions: Severe mucocutaneous reactions, some with fatal outcome, have been reported in association with Rituxan treatment. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in patients treated with Rituxan.

Rituxan has also been associated with fatal hepatitis B reactivation with related fulminant hepatitis and other serious viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation.

Rituxan as Monotherapy in Relapsed or Refractory, Low-grade or Follicular, CD20-positive, B-cell NHL The most common adverse events were part of an infusion-related symptom complex commonly consisting of fever, chills/rigors, nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and hypertension. Pulmonary events were reported in 38 percent of patients, and 31 percent reported infectious events. Grade 3 and 4 cytopenias included lymphopenia (40 percent), neutropenia (6 percent), leukopenia (4 percent), anemia (3 percent), and thrombocytopenia (2 percent). Administration of Rituxan weekly for 8 doses resulted in higher rates of Grade 3 and 4 adverse events overall (70 percent) compared with administration weekly for 4 doses (57 percent).

Front-line Rituxan in Combination with CVP Chemotherapy in Follicular, CD20-positive, B-cell NHL Patients in the R-CVP arm had higher incidences of infusional toxicity and of neutropenia as compared to those in the CVP arm. The following adverse events were reported more frequently (≥5 percent) in patients receiving R-CVP compared to CVP alone: rash (17 percent vs 5 percent), cough (15 percent vs 6 percent), flushing (14 percent vs 3 percent), rigors (10 percent vs 2 percent), pruritus (10 percent vs 1 percent), neutropenia (8 percent vs 3 percent), and chest tightness (7 percent vs 1 percent).

Front-line CVP Chemotherapy Followed by Rituxan in Low-grade, CD20-positive, B-cell NHL The following common adverse events were reported more frequently (≥5 percent) in patients receiving Rituxan following CVP compared with those who received no further therapy: fatigue (39 percent vs 14 percent), anemia (35 percent vs 20 percent), peripheral sensory neuropathy (30 percent vs 18 percent), infections (19 percent vs 9 percent), pulmonary toxicity (18 percent vs 10 percent), hepatobiliary toxicity (17 percent vs 7 percent), rash and/or pruritus (17 percent vs 5 percent), arthralgia (12 percent vs 3 percent), and weight gain (11 percent vs 4 percent). Neutropenia was the only Grade 3 or 4 adverse event that occurred more frequently (≥2 percent) in the Rituxan arm compared with those who received no further therapy (4 percent vs 1 percent).

Front-line Rituxan in Combination with CHOP Chemotherapy in CD20-positive DLBCL The following adverse events, regardless of severity, were reported more frequently (≥5 percent) in patients age ≥60 years receiving R CHOP as compared to CHOP alone for CD20-positive DLBCL: pyrexia (56 percent vs 46 percent), lung disorder (31 percent vs 24 percent), cardiac disorder (29 percent vs 21 percent), and chills (13 percent vs 4 percent). In one of these studies (GELA LNH 98-5), more detailed assessment of cardiac toxicity revealed that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders, with 4.5 percent vs 1.0 percent incidences for R-CHOP and CHOP, respectively.

The following Grade 3 or 4 adverse events were reported more frequently among patients in the R CHOP arm compared with those in the CHOP arm: thrombocytopenia (9 percent vs 7 percent) and lung disorder (6 percent vs 3 percent). Other severe adverse events reported more commonly among patients receiving R CHOP in one or more studies were viral infection, neutropenia, and anemia.

Rituxan in Rheumatoid Arthritis Rituxan has been associated with fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions and progressive multifocal leukoencephalopathy (PML). Hepatitis B reactivation and cardiac arrhythmias have also been observed in Rituxan-treated patients. Patients should be closely observed for signs of infection if biologic agents and/or DMARDs other than methotrexate are used concomitantly.

Rituxan, discovered by Biogen Idec Inc., is co-marketed by Genentech USA, Inc. and Biogen Idec Inc. 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.

View Rituxan full prescribing information, including BOXED WARNINGS. For more information, please visit http://www.rituxan.com.