- Rituxan® (rituximab), in combination with methotrexate, is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis (RA) who have had an inadequate response to one or more TNF antagonist therapies
- Limitations of Use: Rituxan is not recommended for use in patients with severe, active infections
BOXED WARNINGS and Additional Important Safety Information
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. Monitor patients closely. Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions.
Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction.
Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan. Discontinue Rituxan and concomitant medications in the event of HBV reactivation.
Progressive Multifocal Leukoencephalopathy (PML): PML, including fatal PML, can occur in patients receiving Rituxan. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Warnings and Precautions
Tumor Lysis Syndrome (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.
Infections: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituxan-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after Rituxan exposure). 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.
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. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.
Immunization: The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live vaccines is not recommended. For RA patients, physicians should follow current immunization guidelines and administer non-live vaccines at least 4 weeks prior to a course of Rituxan.
Laboratory Monitoring: Obtain complete blood counts (CBC) and platelet counts at 2- to 4-month intervals during Rituxan therapy. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period.
Concomitant Use With Biologic Agents and DMARDs Other Than Methotrexate in RA, GPA, and MPA: Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in RA 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 of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituxan.
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 non-biologic 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.
Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion-related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis.
In placebo-controlled studies, adverse reactions reported in ≥5% of patients 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%) in Rituxan-treated vs placebo, respectively.
Infusion Reactions: In the Rituxan RA pooled, placebo-controlled studies, incidence of any adverse event within 24 hours of an infusion was 32% vs 23% after the first infusion, and 11% vs 13% after the second infusion in the Rituxan-treated patients and placebo group, respectively. Incidence of acute infusion reactions was 27% vs 19% after the first infusion, 9% vs 11% after the second infusion in the Rituxan-treated patients and placebo group, 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 Rituxan or placebo, respectively, after the first course.
Infections: In the pooled, placebo-controlled studies, incidence of any type of infection was 39% vs 34%, Rituxan-treated vs placebo, respectively. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis. The incidence of serious infections was 2% vs 1%, Rituxan-treated vs placebo group, respectively.
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.
Cardiac Events: In the pooled, placebo-controlled studies, incidence of serious cardiovascular reactions was 1.7% vs 1.3%, Rituxan-treated vs placebo, respectively. Three cardiovascular deaths occurred during the double-blind period of the RA studies including all Rituxan 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 consistent with MI rates in the general RA population. Rituxan should be discontinued in the event of a serious or life-threatening cardiac event.
Hypophosphatemia and Hyperuricemia: In the pooled, placebo-controlled studies, newly-occurring hypophosphatemia (<2.0 mg/dL) was 12% vs 10%, Rituxan-treated vs placebo, respectively. Hypophosphatemia was more common in patients who received corticosteroids. Newly-occurring hyperuricemia (>10 mg/dL) was observed in 1.5% vs 0.3%, Rituxan-treated vs placebo, respectively.
Immunogenicity: A total of 273/2578 (11%) patients with RA tested positive for anti-human anti-chimeric antibody (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.
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.
For additional safety information, please see the Rituxan full prescribing information, including BOXED WARNINGS.