(See BOX WARNINGS)
Severe Infusion Reactions (See BOX WARNINGS, ADVERSE REACTIONS and Hypersensitivity Reactions): RITUXAN has caused severe infusion reactions. In some cases, these reactions were fatal. These severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reactions may include hypotension, angioedema, hypoxia or bronchospasm, and may require interruption of RITUXAN administration. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. In the reported cases, the following factors were more frequently associated with fatal outcomes: female gender, pulmonary infiltrates, and chronic lymphocytic leukemia or mantle cell lymphoma.
Management of severe infusion reactions: The RITUXAN infusion should be interrupted for severe reactions and supportive care measures instituted as medically indicated (e.g., intravenous fluids, vasopressors, oxygen, bronchodilators, diphenhydramine, and acetaminophen). In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Patients requiring close monitoring during first and all subsequent infusions include those with pre-existing cardiac and pulmonary conditions, those with prior clinically significant cardiopulmonary adverse events and those with high numbers of circulating malignant cells (>/= 25,000/mm3) with or without evidence of high tumor burden.
Tumor Lysis Syndrome [TLS] (See BOX WARNINGS and ADVERSE REACTIONS): Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatasemia, have been reported within 12 to 24 hours after the first RITUXAN infusion. Rare instances of fatal outcome have been reported in the setting of TLS following treatment with RITUXAN. The risks of TLS appear to be greater in patients with high numbers of circulating malignant cells (>/= 25,000/mm3) or high tumor burden. Prophylaxis for TLS should be considered for patients at high risk. Correction of electrolyte abnormalities, monitoring of renal function and fluid balance, and administration of supportive care, including dialysis, should be initiated as indicated. Following complete resolution of the complications of TLS, RITUXAN has been tolerated when re-administered in conjunction with prophylactic therapy for TLS in a limited number of cases.
Hepatitis B Reactivation with Related Fulminant Hepatitis: Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with RITUXAN. The majority of patients received RITUXAN in combination with chemotherapy. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of RITUXAN and approximately one month after the last dose.
Persons at high risk of HBV infection should be screened before initiation of RITUXAN. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and for up to several months following RITUXAN therapy.
In patients who develop viral hepatitis, RITUXAN and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy initiated. There are insufficient data regarding the safety of resuming RITUXAN therapy in patients who develop hepatitis subsequent to HBV reactivation.
RITUXAN has been associated with hypersensitivity reactions (non-IgE-mediated reactions) which may respond to adjustments in the infusion rate and in medical management. Hypotension, bronchospasm, and angioedema have occurred in association with RITUXAN infusion (see Severe Infusion Reactions). RITUXAN infusion should be interrupted for severe hypersensitivity reactions and can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Treatment of these symptoms with diphenhydramine and acetaminophen is recommended; additional treatment with bronchodilators or IV saline may be indicated. In most cases, patients who have experienced non-life-threatening hypersensitivity reactions have been able to complete the full course of therapy. (See DOSAGE and ADMINISTRATION.) Medications for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and corticosteroids, should be available for immediate
use in the event of a reaction during administration.
Cardiovascular: Infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias. Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of RITUXAN. Patients with pre-existing cardiac conditions including arrhythmias and angina have had recurrences of these events during RITUXAN therapy and should be monitored throughout the infusion and immediate post-infusion period.
Renal: RITUXAN administration has been associated with severe renal toxicity including acute renal failure requiring dialysis and in some cases, has led to a fatal outcome. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden who experience tumor lysis syndrome (see Tumor Lysis Syndrome) and in patients administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN is not an approved treatment regimen. If this combination is used in clinical trials extreme caution should be exercised; patients should be monitored closely for signs of renal failure. Discontinuation of RITUXAN should be considered for those with rising serum creatinine or oliguria.
Severe Mucocutaneous Reactions (See BOX WARNINGS and ADVERSE REACTIONS): Mucocutaneous reactions, some with fatal outcome, have been reported in patients treated with RITUXAN. These reports include paraneoplastic pemphigus (an uncommon disorder which is a manifestation of the patient's underlying malignancy),16 Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of the reaction in the reported cases has varied from 1 to 13 weeks following RITUXAN exposure. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Skin biopsy may help to distinguish among different mucocutaneous reactions and guide subsequent treatment. The safety of readministration of RITUXAN to patients with any of these mucocutaneous reactions has not been determined.
Laboratory Monitoring: Because RITUXAN targets all CD20-positive B lymphocytes, malignant and nonmalignant, complete blood counts (CBC) and platelet counts should be obtained at regular intervals during RITUXAN therapy and more frequently in patients who develop cytopenias (see ADVERSE REACTIONS). The duration of cytopenias caused by RITUXAN can extend well beyond the treatment period.
Drug/Laboratory Interactions: There have been no formal drug interaction studies performed with RITUXAN. However, renal toxicity was seen with this drug in combination with cisplatin in clinical trials. (See WARNINGS, Renal.)
HACA Formation: Human antichimeric antibody (HACA) was detected in 4 of 356 patients and 3 had an objective clinical response. The data reflect the percentage of patients whose test results were considered positive for antibodies to RITUXAN using an enzyme-linked immunosorbant assay (limit of detection = 7 ng/mL). The observed incidence of antibody positivity in an assay is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RITUXAN with the incidence of antibodies to other products may be misleading.
Immunization: The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied. The ability to generate a primary or anamnestic humoral response to vaccination is currently being studied.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN, or to determine its effects on fertility in males or females. Individuals of childbearing potential should use effective contraceptive methods during treatment and for up to 12 months following RITUXAN therapy.
Pregnancy Category C: Animal reproduction studies have not been conducted with RITUXAN. It is not known whether RITUXAN can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. Human IgG is known to pass the placental barrier, and thus may potentially cause fetal B-cell depletion; therefore, RITUXAN should be given to a pregnant woman only if clearly needed.
Nursing Mothers: It is not known whether RITUXAN is excreted in human milk. Because human IgG is excreted in human milk and the potential for absorption and immunosuppression in the infant is unknown, women should be advised to discontinue nursing until circulating drug levels are no longer detectable. (See CLINICAL PHARMACOLOGY.)
Pediatric Use: The safety and effectiveness of RITUXAN in pediatric patients have not been established.
Geriatric Use: Among the 331 patients enrolled in clinical studies of single agent RITUXAN, 24% were 65 to 75 years old and 5% were 75 years old and older. The overall response rates were higher in older (age >/= 65 years) vs. younger (age < 65 years) patients (52% vs. 44%, respectively). However, the median duration of response, based on Kaplan-Meier estimates, was shorter in older vs. younger patients: 10.1 months (range, 1.9 to 36.5+) vs. 11.4 months (range, 2.1 to 42.1+), respectively. This shorter duration of response was not statistically significant. Adverse reactions, including incidence, severity and type of adverse reaction were similar between older and younger patients.