Important Safety Information

WARNINGS AND PRECAUTIONS

Infusion Reactions
RITUXAN can cause severe, including fatal, infusion reactions. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Interrupt the infusion or slow the infusion rate for infusion reactions. Premedicate patients with an antihistamine and acetaminophen prior to dosing.

Tumor Lysis Syndrome (TLS)
Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia can occur within 12 to 24 hours after the first Rituxan infusion. Fatal TLS cases have occurred after administration of Rituxan. Consider prophylaxis for TLS in patients at high risk and monitor renal function.

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 for which Rituxan has not been approved. 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 and were diagnosed with PML 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 with hematologic malignancies treated with Rituxan. 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.

Other Viral Infections
The following additional serious viral infections, either new, reactivated or exacerbated, have been identified in clinical studies or post-marketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death.

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 hematologic malignancies. Consider discontinuation of Rituxan for 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, especially early in the course of Rituxan therapy.

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. The benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy.

Laboratory Monitoring
Because Rituxan binds to all CD20 positive B lymphocytes (malignant and nonmalignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias.

Additional Important Safety Information

The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions generally have resolved with slowing or interruption of the infusion and with supportive care.

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

Indication-Specific Safety

Single Agent Rituxan for Relapsed or Refractory, Low-Grade or Follicular NHL
The most common adverse reactions of Rituxan (incidence ≥ 25%) observed in patients with relapsed or refractory, low-grade or follicular NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. Respiratory system events were reported in 38% of patients, and 31% reported infectious events. Grade 3 and 4 cytopenias were reported in 48% of patients and included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%).

Rituxan in Combination with CVP for Previously Untreated, Follicular 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 reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs 5%), cough (15% vs 6%), flushing (14% vs 3%), rigors (10% vs 2%), pruritus (10% vs 1%), neutropenia (8% vs 3%), and chest tightness (7% vs 1%).

Single Agent Rituxan for Low-Grade NHL, after First-Line CVP Chemotherapy
The following common adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan following CVP compared with those who received no further therapy: fatigue (39% vs 14%), anemia (35% vs 20%), peripheral sensory neuropathy (30% vs 18%), infections (19% vs 9%), pulmonary toxicity (18% vs 10%), hepatobiliary toxicity (17% vs 7%), rash and/or pruritus (17% vs 5%), arthralgia (12% vs 3%), and weight gain (11% vs 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs 1%).

Rituxan in Combination with CHOP Chemotherapy for DLBCL
The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP).

The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).