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INDICATIONS AND USAGE
Relapsed or Refractory CD20-Positive, Non-Hodgkin’s Lymphoma
The BEXXAR therapeutic regimen (tositumomab and iodine I 131 tositumomab) is indicated for the treatment of patients with CD20-positive relapsed or refractory, low grade, follicular, or transformed non-Hodgkin’s lymphoma who have progressed during or after rituximab therapy, including patients with rituximab-refractory non-Hodgkin’s lymphoma.
Determination of the effectiveness of the BEXXAR therapeutic regimen is based on overall response rates in patients whose disease is refractory to chemotherapy and rituximab. The effects of the BEXXAR therapeutic regimen on survival are not known.
Important Limitations of Use
• The BEXXAR therapeutic regimen is only indicated for a single course of treatment.
• The safety and efficacy of additional courses of the BEXXAR therapeutic regimen have not been established.
• The BEXXAR therapeutic regimen is not indicated for first-line treatment of patients with CD20-positive non-Hodgkin’s lymphoma.
BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS ALLERGIC REACTIONS (INCLUDING ANAPHYLAXIS), PROLONGED AND SEVERE CYTOPENIAS, AND RADIATION EXPOSURE
Serious Allergic Reactions (Including Anaphylaxis): Serious, including fatal, allergic reactions have occurred during or following administration of the BEXXAR therapeutic regimen. Have medications for the treatment of allergic reactions available for immediate use. Permanently discontinue the BEXXAR therapeutic regimen for serious allergic reactions and administer appropriate medical treatment [see Warnings and Precautions (5.1)].
Prolonged and Severe Cytopenias: The BEXXAR therapeutic regimen resulted in severe and prolonged thrombocytopenia and neutropenia in more than 70% of the patients in clinical studies. The BEXXAR therapeutic regimen should not be administered to patients with greater than 25% lymphoma marrow involvement, platelet count less than 100,000 cells/mm3 or neutrophil count less than 1,500 cells/mm3 [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].
Radiation Exposure: The BEXXAR therapeutic regimen may be administered only under the supervision of physicians who are certified under or participating in the BEXXAR therapeutic regimen certification program and who are authorized under the Radioactive Materials License at their clinical site. Follow institutional radiation safety practices and applicable federal guidelines to minimize radiation exposure during handling and after administration of the BEXXAR therapeutic regimen [see Warnings and Precautions (5.3)].
ADDITIONAL IMPORTANT SAFETY INFORMATION
Serious Allergic Reactions, Including Anaphylaxis: The BEXXAR therapeutic regimen can cause severe, including fatal, allergic reactions. In clinical trials, 14 patients (6%) experienced allergic reactions. Premedicate with acetaminophen and diphenhydramine. Have medications for the treatment of allergic reactions available for immediate use during administration. Signs and symptoms of severe allergic reactions may include fever, rigors or chills, sweating, hypotension, dyspnea, bronchospasm, and nausea during or within 48 hours of infusion. Immediately interrupt BEXXAR infusions for severe reactions and provide appropriate medical and supportive care measures. Permanently, discontinue the BEXXAR therapeutic regimen in patients who develop serious allergic reactions.
Prolonged and Severe Cytopenias: Patients receiving the BEXXAR therapeutic regimen experienced severe (NCI CTC grade 3-4) and prolonged neutropenia (63%), thrombocytopenia (53%), and anemia (29%). The time to nadir was 4 to 7 weeks and the duration of cytopenias was approximately 30 days. Due to the variable nature of the onset of cytopenias, monitor patients with weekly complete blood counts for up to 12 weeks. The BEXXAR therapeutic regimen should not be administered to patients with >25% lymphoma marrow involvement, platelet count <100,000 cells/mm3, or neutrophil count <1,500 cells/mm3.
Radiation Exposure: The BEXXAR therapeutic regimen contains Iodine-131. Follow institutional radiation safety practices and applicable federal guidelines to minimize radiation exposure during handling and after administration of the BEXXAR therapeutic regimen. Advise patients of the risks of radiation exposure of household contacts, pregnant women, and small children and of the steps to be taken to reduce these risks. The BEXXAR therapeutic regimen should be administered only by physicians enrolled in the certification program for dose calculation and administration of the BEXXAR therapeutic regimen. Further information regarding the BEXXAR therapeutic regimen certification program is available by phone at 1-877-423-9927.
Secondary Malignancies: Myelodysplastic syndrome (MDS) or acute leukemia may occur with the use of the BEXXAR therapeutic regimen and were reported in 10% of patients enrolled in clinical trials and in 3% of patients enrolled in the expanded access program (median follow-up 39 and 27 months, respectively). The median time to development of MDS or leukemia was 31 months. Non-hematologic malignancies may occur with the use of the BEXXAR therapeutic regimen and were reported in 5% of patients enrolled in clinical trials or the expanded access program. In the absence of controlled studies, the relative risk of secondary malignancies in patients receiving the BEXXAR therapeutic regimen cannot be determined
Hypothyroidism: The BEXXAR therapeutic regimen can cause hypothyroidism. Initiate thyroid-blocking medications at least 24 hours before administering the dosimetric dose and continue until 14 days after the therapeutic dose. The risk of hypothyroidism is likely to be increased in patients who do not complete the recommended thyroid-protective regimen. Evaluate for clinical evidence of hypothyroidism and thyroid-stimulating hormone (TSH) level before treatment and annually thereafter. In clinical studies, 203 patients did not have elevated TSH at study entry. Of these, 137 patients had at least one post-treatment TSH value available and were not taking thyroid hormonal treatment at study entry. With a median follow up of 46 months, the incidence of hypothyroidism (elevated TSH or initiation of thyroid replacement therapy) was 18% with a median time to development of 16 months. The cumulative incidences of hypothyroidism at 2 and 5 years in these 137 patients were 11% and 19%, respectively. Onset of hypothyroidism has occurred up to 90 months post-treatment.
Embryo-fetal Toxicity: The BEXXAR therapeutic regimen can cause fetal harm when administered to a pregnant woman including severe, and possibly irreversible, neonatal hypothyroidism. Inform patients who are pregnant or become pregnant after the BEXXAR therapeutic regimen about the potential hazard to a fetus. Evaluate infants born to mothers treated with the BEXXAR therapeutic regimen during pregnancy for hypothyroidism at time of delivery and during the neonatal period. Patients should use effective contraception during treatment with the BEXXAR therapeutic regimen and for 12 months after the therapeutic dose.
Nursing Mothers: Because immunoglobulins are secreted in human milk, it is expected that tositumomab would be present in human milk. Radiolabeled iodine is excreted in breast milk and may reach concentrations equal to or greater than maternal plasma concentrations. Because of the potential for serious adverse reactions in nursing infants from the BEXXAR therapeutic regimen, advise women to discontinue nursing or to consider alternative treatment, taking into account the importance of the BEXXAR therapeutic regimen to the mother.
Excessive Radiation Exposure in Patients With Impaired Renal Function: There are no data regarding the safety of administration of the BEXXAR therapeutic regimen in patients with impaired renal function. Since the BEXXAR therapeutic regimen is primarily cleared through the kidneys, the rate of excretion of radiolabeled iodine is expected to be decreased in patients with impaired renal function or obstructive uropathy, which may result in increased patient exposure to I-131 tositumomab.
Immunization: The safety of immunization with live viral vaccines following administration of the BEXXAR therapeutic regimen and the ability to generate a primary or anamnestic humoral response to any vaccine have not been studied. Do not administer live viral vaccines to patients recently treated with BEXXAR.
Immunogenicity Human Anti-mouse Antibody (HAMA): There is a potential for immunogenicity with therapeutic proteins such as tositumomab. In clinical trials (N = 219), 11% of patients who received BEXXAR developed HAMA seropositivity. Ten percent (10%) of the patients in the expanded access program (N = 569) developed HAMA seropositivity. The post-treatment incidences of HAMA seropositivity at 6, 12, and 18 months were 6%, 17%, and 21%, respectively.
Assessment of Biodistribution: The biodistribution of Iodine I 131 Tositumomab should be assessed. If biodistribution is altered, the therapeutic dose should not be administered.
Adverse Reactions: The most common adverse reactions (>25%) during therapy with BEXXAR were neutropenia (63%), thrombocytopenia (53%), anemia (29%), infections (including pneumonia, bacteremia, septicemia, bronchitis, and skin infections) (45%), infusion reactions (29%), asthenia (46%), fever (37%), and nausea (36%). The most common Grade 3 and 4 adverse (NCI CTC grade 3-4) with BEXXAR were neutropenia (7%), thrombocytopenia (7%), anemia (5%), infections (including pneumonia, bacteremia, septicemia, bronchitis, and skin infections) (9%), serious allergic reactions (including bronchospasms and angioedema) (14 patients [6%]), infusion reactions (67 patients [29%]), and secondary leukemia/myelodysplastic syndrome (24/230 patients [10%]).
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