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Updated Safety Information - October 2009

Boxed Warnings

Fatal Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion.

Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) patients with Rituxan.

Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions, can occur in patients receiving Rituxan.

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients treated with Rituxan.

WARNINGS

Severe 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. Interrupt the infusion for severe reactions. Methylprednisolone 100-mg intravenous or its equivalent is recommended 30 minutes prior to each infusion.

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML have received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had a history of prior, or concurrent, immunosuppressive therapy and were diagnosed with PML within 12 months of the patient's last infusion of Rituxan.

Hepatitis B Reactivation with Related Fulminant Hepatitis: Persons at high risk of HBV infection should be screened before initiation of Rituxan.

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.

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.

Immunization: The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live vaccines is not recommended in patients receiving Rituxan. Follow current immunization guidelines and administer non-live vaccines at least 4 weeks prior to a course of Rituxan.

Concomitant Use With Biologic Agents and DMARDs Other Than Methotrexate in RA: Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly.

Use in Patients With RA Who Had No Prior Inadequate Response to TNF Antagonists: While the efficacy of Rituxan was supported in 4 controlled trials in patients with RA with prior inadequate responses to nonbiologic DMARDs, and in a controlled trial in MTX-naive patients, a favorable risk-benefit relationship has not been established in these populations. The use of Rituxan in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended

Adverse Events

The most common adverse events with greater incidence in the group receiving Rituxan (n=540) vs the placebo group (n=398) were hypertension (8% vs 5%), nausea (8% vs 5%), upper respiratory tract infection (7% vs 6%), arthralgia (6% vs 4%), pyrexia (5% vs 2%), and pruritus (5% vs 1%). These data are based on 938 patients treated in phase 2 and 3 studies of Rituxan (2 x 1000 mg) or placebo administered in combination with methotrexate.

Infusion Reactions: In RA studies, 32% of Rituxan patients experienced an adverse event during or within 24 hours following their first infusion, compared to 23% for placebo. This decreased to 11% and 13%, respectively following the second infusion. Acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of Rituxan patients following their first infusion, compared to 19% for placebo. These acute infusion reactions decreased to 9% and 11%, respectively. Serious acute infusion reactions were experienced by <1% of patients in either treatment group.

Infections: In RA clinical studies, 39% of patients in the Rituxan group experienced an infection of any type compared to 34% for placebo. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis.

The incidence of serious infections was 2% in the Rituxan patients and 1% in the placebo group. In the experience with Rituxan in 2578 RA patients, the rate of serious infection was 4.31 per 100 patient-years. The most common serious infections (≥0.5%) were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections. Fatal serious infections included pneumonia, sepsis, and colitis. Rates of serious infection remain stable in patients receiving subsequent courses.

In 185 Rituxan treated RA patients with active disease, subsequent treatment with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the rate of serious infection. 13 serious infections were observed in 186.1 patient-years (6.99 per 100 patient-years) prior to exposure and 10 were observed in 182.3 patient-years (5.49 per 100 patient-years) after exposure.

Cardiac Events: The incidence of serious cardiovascular events in the double-blind part of the clinical trials was 1.7% and 1.3% in Rituxan and placebo treatment groups, respectively. 3 cardiovascular deaths occurred during the double-blind period of the RA studies including all rituximab regimens (3/769=0.4%) as compared to none in the placebo treatment group (0/389). In the experience with Rituxan in 2578 RA patients the rate of myocardial infarction (MI) was 0.56 per 100 patient years (28 events in 26 patients), which is consistent with MI rates in the general RA population.

Immunogenicity: A total of 273/2578 (11%) patients with RA tested positive for HACA at any time after receiving Rituxan. HACA positivity was not associated with increased infusion reactions or other adverse reactions. Upon further treatment, the proportions of patients with infusion reactions were similar between HACA-positive and HACA-negative patients, and most reactions were mild to moderate. Four HACA-positive patients had serious infusion reactions, and the temporal relationship between HACA positivity and infusion reaction was variable. The clinical relevance of HACA formation in Rituxan treated patients is unclear.

General Counseling Information

Patients should be provided the Rituxan Medication Guide and provided an opportunity to read it prior to each treatment session. It is important that the patient's overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient's reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to 6 months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy.

Please see full prescribing information, including Boxed Warnings for additional safety information.