Important 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 and Precautions
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. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed.
Premedicate patients with an antihistamine and acetaminophen prior to dosing. For GPA and MPA patients, glucocorticoids are given in combination with Rituxan.
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, Sometimes Fatal: Persons at high risk of HBV infection should be screened before initiation of Rituxan and HBV carriers should be monitored during and several months after therapy. Discontinue Rituxan if reactivation occurs and consult a Hepatologist.
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 rituximab exposure). Pneumocystis jiroveci pneumonia (PCP) prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last Rituxan infusion.
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.
Laboratory Monitoring: Obtain CBC and platelet counts at two to four month intervals during Rituxan therapy. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period.
Concomitant Use With Immunosuppressants Other Than Corticosteroids in GPA and MPA: 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. Observe patients closely for signs of infection if immunosuppressants other than corticosteroids are used concomitantly.
Retreatment in Patients With Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA): Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with GPA and MPA. In the active-controlled, double-blind study, subsequent courses of Rituxan were allowed for patients experiencing a relapse of disease. The safety and efficacy of retreatment with Rituxan have not been established.
Adverse Events
In a clinical trial, the most common adverse events occurring in >10% of Rituxan-treated patients (n=99) and >5% more frequently than in the cyclophosphamide group (n=98) were: infections (62% vs 47%), peripheral edema (16% vs 6%), and hypertension (12% vs 5%).
Infusion Reactions: Among the 99 patients treated with Rituxan, 12% experienced at least one infusion related reaction compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the Rituxan group, the proportion of patients experiencing an infusion related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each Rituxan infusion and were on background oral corticosteroids which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.
Infections: In a clinical trial, 62% (61/99) of patients in the Rituxan group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6. The most common infections in the Rituxan group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% in the Rituxan-treated patients and 10% in the cyclophosphamide-treated patients, with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia.
Immunogenicity: A total of 23/99 (23%) Rituxan-treated patients with GPA or MPA tested positive for HACA by 18 months. 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.
To report SUSPECTED ADVERSE REACTlONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
INDICATION
Rituxan (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA).
Rituxan is not recommended for treatment of patients with severe active infections.
IMPORTANT SAFETY INFORMATION
BOXED WARNINGS
Rituxan administration can result in serious, including fatal, adverse reactions. These include:
- infusion reactions
- tumor lysis syndrome (TLS)
- severe mucocutaneous reactions
- progressive multifocal leukoencephalopathy (PML)
Warnings and Precautions
Rituxan administration can also result in additional serious, including fatal, adverse reactions including:
- hepatitis B reactivation
- other infections including bacterial, fungal, new or reactivated viral infections
- cardiovascular events
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.
Observe patients closely for signs of infection if immunosuppressants other than corticosteroids are used concomitantly.
Common adverse reactions include infections, nausea, diarrhea, headache, muscle spasms, anemia and peripheral edema.