Full Prescribing Information, including Boxed WARNINGS and Medication Guide
Dear Healthcare Provider Letter (PML December 2006)
Dear Healthcare Provider Letter (PML September 2008)
Dear Healthcare Provider Letter (PML October 2009)

Rituxan is indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular CD20-positive, B-cell NHL as a single agent
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as a single-agent maintenance therapy
• Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
• Previously untreated and previously treated CD20-positive CLL in combination with fludaribine and cyclophosphamide (FC)

People with serious infections should not receive Rituxan.

WARNINGS
Rituxan can cause serious side effects that can lead to death, including:

• Infusion Reactions: Serious infusion reactions can happen during the infusion or within 24 hours of receiving Rituxan. Patients must tell their doctor or get medical help right away if they get any of these symptoms: hives (itchy red welts) or rash, itching, swelling of the lips, tongue, throat, or face, sudden cough, shortness of breath, difficulty breathing or wheezing, weakness, dizziness or feel faint, palpitations (feel like your heart is racing or fluttering) chest pain.
• Progressive Multifocal Leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus. People with a weakened immune system can get PML. PML can result in death or severe disability. Patients must tell their doctor right away if they have any of the following symptoms: confusion or problems thinking, loss of balance, change in the way they walk or talk, decreased strength or weakness on one side of their body, blurred vision or loss of vision.
• Tumor Lysis Syndrome (TLS): TLS is caused by the fast breakdown of cancer cells and can occur after treatment with Rituxan. TLS can cause a person to have kidney failure and the need for dialysis treatment. TLS may also cause abnormal heart rhythm.
• Severe Skin and Mouth Reactions: Patients may get painful sores on the skin or in the mouth, ulcers, blisters, or peeling skin while receiving or after receiving Rituxan.

Status Approved by the U.S. Food and Drug Administration (FDA) in November 1997, Rituxan was the first therapeutic antibody approved for treating cancer in the United States.

A supplemental Biological License Application (sBLA) was approved for Rituxan in April 2001, adding several new uses including:

• retreatment of patients with Rituxan who have relapsed following initial Rituxan therapy
• use of eight weekly doses (compared to original four) per course of treatment
• treatment of patients with bulky disease (lesions > 10 cm).

In September 2006, the FDA approved two additional uses for Rituxan for patients with CD-20 positive, B-Cell NHL.

In February 2010, the FDA approved Rituxan in combination with fludarabine and cyclophosphamide (FC) for people with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL).

Rituxan's safety and efficacy have been documented in more than 200 Phase II and Phase III clinical studies over the past 10 years. For additional detailed information please see the Rituxan Fact Sheet.

Important Safety Information Rituxan can cause serious side effects that can lead to death, including: infusion reactions, tumor lysis syndrome (TLS; kidney failure due to fast breakdown of cancer cells), severe skin and mouth reactions, and progressive multifocal leukoencephalopathy (PML; a rare, serious brain infection).

• Infusion Reactions: Serious infusion reactions can happen during the infusion or within 24 hours of receiving Rituxan. The doctor should give the patient medicines before their infusion of Rituxan to decrease the chance of having a severe infusion reaction. If a serious reaction occurs, the infusion may be stopped and the patient should receive medical care. Patients must tell their doctor or get medical help right away if they get any of these symptoms: hives or rash, itching, swelling of the lips, tongue, throat, or face, sudden cough, shortness of breath, difficulty breathing or wheezing, weakness, dizziness or feel faint, palpitations, or chest pain.
• Tumor Lysis Sydrome (TLS): TLS is caused by the fast breakdown of cancer cells and can occur after treatment with Rituxan. TLS can cause a person to have kidney failure and the need for dialysis treatment. TLS may also cause abnormal heart rhythm. The doctor may give the patient medicines to help prevent TLS and do blood tests to check the patient for TLS.
• Severe Skin and Mouth Reactions: Severe skin and mouth reactions can occur in patients who receive Rituxan.
• Progressive Multifocal Leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus. People with a weakened immune system can get PML. Patients must tell their doctor right away if they have any of the following symptoms: confusion or problems thinking, loss of balance, change in the way they walk or talk, decreased strength or weakness on one side of their body, blurred vision or loss of vision.
• Rituxan has also been associated with serious and life-threatening side effects, including: the return of active hepatitis B virus infection with sudden and serious liver problems including liver failure, and death, other serious infections that can lead to death, heart problems, kidney problems, and stomach and serious bowel problems including blockage and tears in the bowel that can sometimes lead to death.
• The most common side effects of Rituxan in patients with non-Hodgkin's lymphoma (NHL) include: infusion reactions, fever, chills, low white blood cells, infections, body aches, and tiredness. The most common serious side effect in NHL patients was low white blood cells.
• The most common side effects of Rituxan in patients with chronic lymphocytic leukemia (CLL) were infusion reactions and low white blood cells.
• Most CLL patients treated with Rituxan plus FC chemotherapy had at least one serious side effect. In clinical trials, CLL patients 70 years or older who received Rituxan with FC chemotherapy were more likely to experience severe side effects compared with younger patients who received the same treatment.
• Patients should tell their doctor about any side effects that bothers them or that does not go away. These are not all of the possible side effects with Rituxan.

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

Proposed Mechanism of Action Rituxan works by binding to a particular protein (the CD20 antigen) on the surface of normal and malignant B-cells. From there, it recruits the body's natural defenses to attack and kill the marked B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels.

Non-Hodgkin's Lymphoma Non-Hodgkin's lymphoma (NHL) is a cancer that develops in the lymphatic system. A vital part of the immune system, the lymphatic system is a network of thin vessels that branch into tissues throughout the body and help fight disease and infection.

Along the network, small organs called lymph nodes are clustered in the abdomen, chest, groin, and neck. A colorless and watery fluid called lymph circulates through the system carrying infection-fighting cells called lymphocytes. When these cells divide and multiply uncontrollably, malignant tumors can form. Since lymph is carried throughout the body, NHL may form anywhere and can spread easily to other parts of the lymphatic system, including the tonsils, stomach, skin, intestines and bone marrow.

• More than 66,000 Americans are expected to be diagnosed with NHL in 2008
• Approximately 360,000 Americans are diagnosed and living with NHL