Important Safety Information
Updated Safety Information
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. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions.
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 caused 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, or anaphylactoid events. Interrupt the infusion for severe reactions.
Management of severe infusion reactions: Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor patients with pre-existing cardiac or pulmonary conditions, patients who experienced prior cardiopulmonary adverse reactions.
Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or autoimmune diseases for which Rituxan has not been approved. 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 their last infusion of Rituxan.
Consider the diagnosis of PML in any patient presenting with new onset neurologic manifestations Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Hepatitis B Reactivation with Related Fulminant Hepatitis: Hepatitis B virus (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.
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 arrhythmias and angina.
Immunization: The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live vaccines are not recommended Physicians should review the vaccination status of patients with RA being considered for RITUXAN treatment and follow the Centers for Disease Control and Prevention (CDC) guidelines for adult vaccination against infectious disease prior to therapy.
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 RITUXAN. 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 Tumor Necrosis Factor (TNF) antagonists: While efficacy of RITUXAN was supported in two well-controlled trials in patients with RA with prior inadequate responses to non-biologic DMARDs, a favorable risk benefit relationship has not been established in this population. The use of RITUXAN in patients with RA who have no prior inadequate response to one or more TNF antagonists is not recommended.
Retreatment of patients with RA: Safety and efficacy of retreatment have not been established in controlled trials. A limited number of patients have received two to five courses (two infusions per course) of treatment in an uncontrolled setting. In clinical trials in patients with RA, most of the patients who received additional courses did so 24 weeks after the previous course and none were retreated sooner than 16 weeks.
Adverse Reactions
The most common adverse reactions of Rituxan (incidence > 2% and at least 1% greater than placebo) observed in patients with rheumatoid arthritis are hypertension, nausea, upper respiratory tract infection, arthralgia, pruritus, and pyrexia. The most serious adverse reactions on RITUXAN are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation.
Infusion Reactions: In RA placebo-controlled studies, 32% of RITUXAN patients experienced an adverse reaction during or within 24 hours following their first infusion, compared to 23% of placebo-treated patients. This decreased to11% 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 of placebo-treated patients. These incidence of these acute infusion reactions decreased to 9% and 11%, respectively. Serious acute infusion reactions were experienced by <1% of patients in either treatment group.
Acute infusion reactions required dose modification (stopping, slowing or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course.
The administration of intravenous glucocorticoids prior to Rituxan infusions reduced the incidence and severity of such reactions, however, there was no clear benefit from the administration of oral glucocorticoids for the prevention of acute infusion reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to Rituxan infusions.
Infections: : In RA clinical studies, 39% of patients in the RITUXAN group experienced an infection of any type compared to 34% of patients in the placebo group. 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-treated patients and 1% in the placebo group.
One fatal infection (bronchopneumonia) occurred with rituximab monotherapy during the 24-weeks placebo-controlled period in one of the Phase 2 RA studies.
In 107 Rituxan-treated RA patients with active disease, subsequent treatment with a TNF inhibitor was associated with a higher rate of serious infections. Six serious infections were observed in 100.8 patient years (0.06 per patient year) prior to exposure and 9 were observed in 97.8 patient years (0.09 per patient year) after exposure.
Cardiac Adverse Reactions: The incidence of serious cardiovascular events in the double-blind part of the RA clinical trials was 1.7% and 1.3% in RITUXAN and placebo treatment groups, respectively. Three 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).
Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and RITUXAN should be discontinued in the event of a serious or life-threatening cardiac event.
Hypophosphatemia and hyperuricemia: In the 24 week double-blind RA clinical trial program, newly-occurring hypophosphatemia (<2.0 mg/dl) was observed in 12% (67/540) of patients on Rituxan versus 10% (39/398) of patients on placebo. Hypophosphatemia was more common in patients who received corticosteroids. Newly occurring hyperuricemia (>10 mg/dl) was observed in 1.5% (8/540) of patients on Rituxan versus 0.3% (1/398) of patients on placebo.
At any time after treatment with up to seven courses of Rituxan, at least one episode of newly-occurring hypophosphatemia was observed in 23% (245/1048) of patients and newly-occurring hyperuricemia was observed in 3% (32/1048) of patients.
Immunogenicity: A total of 118/1053 patients (11%) with RA tested positive for HACA at any time after treatment with Rituxan. Limited data are available on the safety or efficacy of Rituxan retreatment in patients who develop HACA. Of the 8 patients who experienced serious acute infusion reactions, 2 were subsequently found to be HACA positive. Approximately 12% (14/118) of patients who were HACA-positive had a subsequent infusion reaction of any severity. The clinical relevance of HACA formation in rituximab treated patients is unclear.
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