Important Safety Information

RITUXAN^® (Rituximab) is indicated for the treatment of patients with:

• 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 single-agent maintenance therapy
• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • •  Weekly ×4  •  Weekly ×8  •  Bulky disease  •  Retreatment
• 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 fludarabine and cyclophosphamide (FC)

RITUXAN is not recommended for use in patients with severe, active infections.

WARNINGS AND PRECAUTIONS

Infusion Reactions

• RITUXAN can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion, with time to onset of 30 to 120 minutes
• RITUXAN-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death
• Premedicate patients with an antihistamine and acetaminophen prior to dosing. Depending on the severity of the infusion reaction and the required interventions, slow the infusion rate, interrupt the infusion, or permanently discontinue RITUXAN
• Closely monitor patients with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm³)

Tumor Lysis Syndrome (TLS)

• Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12 to 24 hours after the first infusion of RITUXAN. A high number of circulating malignant cells (≥25,000/mm³) or high tumor burden confers a greater risk of TLS
• Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated

Severe Mucocutaneous Reactions

• Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with RITUXAN. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. Discontinue RITUXAN in patients who experience a severe mucocutaneous reaction

Progressive Multifocal Leukoencephalopathy (PML)

• JC virus infection resulting in PML and death can occur in RITUXAN-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received RITUXAN in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy
• Most cases of PML were diagnosed within 12 months of their last infusion of RITUXAN. Consider the diagnosis of PML in any patient presenting with new onset neurologic manifestations. Discontinue RITUXAN and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Hepatitis B Virus (HBV) Reactivation

• HBV reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients treated with RITUXAN. The median time to the diagnosis of hepatitis among patients with hematologic malignancies was approximately 4 months after the initiation of RITUXAN and approximately 1 month after the last dose
• Screen patients at high risk of HBV infection before initiation of RITUXAN. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following RITUXAN therapy. Discontinue RITUXAN and any concomitant chemotherapy in patients who develop viral hepatitis and institute appropriate treatment, including antiviral therapy

Infections

• Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and up to one year following the completion of RITUXAN-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RITUXAN for serious infections and institute appropriate anti-infective therapy

Cardiovascular

• Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Renal

• Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria

Bowel Obstruction and Perforation

• Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain

Immunization

• The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended

Laboratory Monitoring

• In patients with lymphoid malignancies, during treatment with RITUXAN monotherapy, obtain complete blood counts (CBC) and platelet counts prior to each RITUXAN course. During treatment with RITUXAN and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias. The duration of cytopenias caused by RITUXAN can extend months beyond the treatment period

Pregnancy and Nursing Mothers

• There are no adequate and well-controlled studies of RITUXAN in pregnant women. In the postmarketing experience, limited data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to RITUXAN in utero. RITUXAN was detected postnatally in the serum of infants exposed in utero. RITUXAN should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Caution should be exercised when RITUXAN is administered to a nursing woman

Geriatric Use

• Clinical trials in CLL evaluating RITUXAN in combination with fludarabine and cyclophosphamide (R-FC) showed that the incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared with younger patients for neutropenia, febrile neutropenia, anemia, thrombocytopenia, pancytopenia, and infections

Additional Important Safety Information

• The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions typically resolved with slowing or interruption of the infusion and with supportive care. The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias, including lymphopenia
• The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Infusion-related adverse reactions occurring during or within 24 hours of the start of infusion included nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The Grade 3 or 4 adverse reactions observed more frequently with R-FC compared with FC alone were neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, infusion reactions, pancytopenia, hypotension, and hepatitis B

For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.