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

Full Prescribing Information, including Boxed WARNINGS and Medication Guide

Rituxan is the first targeted cancer medicine approved by the U.S. Food and Drug Administration (FDA). Rituxan is approved for people with certain types of non-Hodgkin's lymphoma. Over the past 10 years, the safety and efficacy of Rituxan has been documented in more than 300 Phase II/III clinical studies.

Non-Hodgkin's lymphoma is the sixth most frequently diagnosed cancer in the United States. Nearly 85 percent of cases are caused by cancerous B-cells, a type of white blood cell that is part of the body's immune system. When B-cells become cancerous they may lead to blood cancers including non-Hodgkin's lymphoma.

How Rituxan Works

• Rituxan targets a specific protein called CD20 located on the surface of B-cells. Rituxan is believed to work with the body's immune system to eliminate the CD20-positive, cancerous B-cells
• Rituxan does not target cells that develop into B-cells (B-cell progenitors) or those that produce antibodies (plasma cells)

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.

Rituxan Indications 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.

Rituxan "Firsts" in Non-Hodgkin's Lymphoma

• Follicular, CD20-positive, B-cell non-Hodgkin's lymphoma: Rituxan is the first FDA-approved biologic medicine that when combined with a type of chemotherapy called CVP helps individuals with follicular, CD20-positive, B-cell non-Hodgkin's lymphoma (a slow-growing form of the disease) who have not received a prior medicine, live longer without their disease worsening (progression-free survival)
• Diffuse large B-cell lymphoma: Rituxan was the first FDA-approved medicine in 25 years to help individuals who had not received a prior treatment for their diffuse large B-cell lymphoma (an aggressive form of non-Hodgkin's lymphoma) live longer (overall survival)

Rituxan's Clinical Studies in Non-Hodgkin's Lymphoma

RITUXAN INDICATION	CLINICAL TRIAL DATA
First-Line Non-Hodgkin's Lymphoma with Chemotherapy
Rituxan plus CVP chemotherapy increases the length of time individuals with untreated follicular non-Hodgkin's lymphoma lived without their disease worsening (progression-free survival)	In a Phase III study, patients who received Rituxan plus CVP chemotherapy improved the length of time they lived without their disease worsening by 127 percent over chemotherapy alone. Individuals who received Rituxan plus CVP lived for nearly three years (2.83 years) compared to the 15 months for those who received chemotherapy alone Data also show Rituxan plus CVP chemotherapy reduced the likelihood of follicular non-Hodgkin's lymphoma getting worse, returning or causing death 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.
Ongoing Treatment Following First-Line Chemotherapy
When used by itself following CVP chemotherapy, Rituxan reduces the likelihood of low-grade non-Hodgkin's lymphoma either getting worse, returning or causing death	A Phase III study showed Rituxan, when used after CVP chemotherapy, lowered the chance that the disease either got worse, returned or resulted in death by 51 percent when compared to observation alone
Relapsed or Refractory Non-Hodgkin's Lymphoma
Early and repeated use of Rituxan may extend the time people with low-grade or follicular non-Hodgkin's lymphoma live after the disease returned (relapsed) or didn't respond to treatment (refractory)	Study results showed that retreatment with Rituxan in patients who previously received the medicine resulted in a sustained decrease in the amount of cancer cells (durable response) in their blood. The response in retreatment was on average 50 percent longer than their initial treatment In another Phase III study, patients who received previous treatment for low-grade or follicular lymphoma either experienced a decrease in the number of cancer cells in their blood (48 percent overall response rate and 42 percent partial response rate) or had no traces of cancer cells in their blood (6 percent complete response) Other Phase III study results showed patients who received Rituxan for low-grade or follicular lymphoma experienced a decrease in the cancer cells in their blood (57 percent overall response rate and 43 percent partial response rate) or had no traces of cancer cells blood (14 percent complete response rate) Other serious and life-threatening side effects with Rituxan include: hepatitis B virus reactivation, heart problems, infections, and stomach and bowel problems. Common side effects during Rituxan infusions include: fever, headache, chills and shakes, nausea, itching, hives, cough, sneezing, and throat irritation or tightness.
First-Line Diffuse Large B-Cell Lymphoma
Rituxan plus CHOP chemotherapy has been shown to improve survival in individuals with diffuse large B-cell CD20-positive lymphoma in three separate Phase III studies	In one, Rituxan plus CHOP chemotherapy increased the time patients with previously untreated diffuse large CD20-positive B-cell lymphoma lived (overall survival) from 36 percent to 53 percent, compared to those who received chemotherapy alone, after seven years In another, Rituxan plus CHOP chemotherapy increased the time patients with untreated diffuse large CD20-positive B-cell lymphoma lived (overall survival) from 46 percent to 58 percent compared with chemotherapy alone, after five years An additional study showed Rituxan plus CHOP chemotherapy increased the likelihood of individuals with previously untreated diffuse large CD20-positive B-cell lymphoma living for two years from 63 percent to 74 percent and 86 percent to 95 percent respectively, compared to chemotherapy alone

Rituxan Development Program

• Rituxan is being studied in other types of CD20-positive blood cancers and disease areas

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.