INDICATION
The BEXXAR^® therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin’s lymphoma, 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 alone or to chemotherapy and Rituximab. The effects of the BEXXAR therapeutic regimen on survival are not known.

The BEXXAR therapeutic regimen is not indicated for the initial treatment of patients with CD20-positive non-Hodgkin’s lymphoma. The BEXXAR therapeutic regimen is intended as a single course of treatment. The safety of multiple courses of the BEXXAR therapeutic regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated.

COMPLETE BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION FOR BEXXAR

CONTRAINDICATIONS
The BEXXAR^® therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is contraindicated in patients with known hypersensitivity to murine proteins or any other component of BEXXAR.
BEXXAR is contraindicated for use in women who are pregnant.

ADDITIONAL IMPORTANT SAFETY INFORMATION
Data regarding adverse events were primarily obtained in 230 patients with non-Hodgkin’s lymphoma enrolled in 5 clinical trials. Data from 765 patients enrolled in an expanded access program were used to supplement the characterization of delayed adverse events.

Prolonged and Severe Cytopenias: The majority of patients, 71% of 230, who received the BEXXAR therapeutic regimen, experienced severe or life-threatening (Grade 3/4) cytopenias. The most common were Grade 3/4 thrombocytopenia (53%) and Grade 3/4 neutropenia (63%). Time to nadir was 4-7 weeks, lasting approximately 30 days. Due to the variable nature of the onset of the cytopenias, complete blood counts should be obtained weekly for 10-12 weeks. More frequent monitoring is indicated in patients with evidence of moderate or more severe cytopenias. Blood counts should be monitored weekly until severe cytopenias have resolved. Sequelae included infections (45%), hemorrhage (12%), and requirement for hematological supportive care (27%).

Hypersensitivity Reactions, Including Anaphylaxis: Serious hypersensitivity reactions, including some with fatal outcome, were reported during and following administration of BEXXAR.  Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA) as they may be at increased risk for anaphylaxis and serious hypersensitivity reactions during administration of BEXXAR. In clinical studies, 6% (14) of 230 patients experienced one or more hypersensitivity reactions.

Secondary Leukemia, Myelodysplastic Syndrome (MDS), and Secondary Malignancies: At a median follow-up of 29 months, 44 cases of myelodysplastic syndrome and/or secondary leukemia were reported in 995 patients enrolled in clinical studies and an expanded access program. Additional malignancies (65 cases) were also reported in 54 of the patients. Approximately half of these were nonmelanomatous skin cancers (26). The remainder, which occurred in 2 or more patients, included colorectal cancer, head and neck cancer, breast cancer, lung cancer, bladder cancer, melanoma, and gastric cancer, in order of decreasing incidence. The relative risk of developing secondary malignancies in patients receiving BEXXAR over the background rate in this population cannot be determined due to the absence of controlled studies.

Hypothyroidism: Administration of BEXXAR may result in hypothyroidism. Thyroid-blocking medications should be initiated at least 24 hours before receiving the dosimetric dose and continued until 14 days after the therapeutic dose. All patients must receive thyroid-blocking agents; any patient who is unable to tolerate thyroid-blocking agents should not receive BEXXAR. Patients should be evaluated for signs and symptoms of hypothyroidism and screened for biochemical evidence of hypothyroidism annually. Of the 230 patients in the clinical studies, 203 did not have elevated thyroid-stimulating hormones (TSH) upon study entry. Of these, 137 patients had at least 1 posttreatment TSH value available and were not taking thyroid hormonal treatment upon study entry. With a median follow-up period of 46 months, the incidence of hypothyroidism based on elevated TSH or initiation of thyroid replacement therapy in these patients was 18%, with a median time to development of hypothyroidism of 16 months. The cumulative incidences of hypothyroidism at 2 and 5 years in these 137 patients were 11% and 19%, respectively. New events have been observed up to 90 months posttreatment.

Patients With Impaired Renal Function: Iodine I 131 Tositumomab and Iodine-131 are excreted primarily by the kidneys. Impaired renal function may decrease the rate of excretion of the radiolabeled iodine and increase patient exposure to the radioactive component of the BEXXAR therapeutic regimen. There are no data regarding the safety of administration of BEXXAR in patients with impaired renal function.

Immunization: The safety of immunization with live viral vaccines following administration of BEXXAR has not been studied. The ability of patients who have received BEXXAR to generate a primary or anamnestic humoral response to any vaccine has not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Radiation is a potential carcinogen and mutagen. There is a potential risk that BEXXAR may cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for 12 months following administration of BEXXAR.

Nursing Mothers: Radioiodine is excreted in breast milk and may reach concentrations equal to or greater than maternal plasma concentrations. Immunoglobulins are also known to be excreted in breast milk. The absorption potential and potential for adverse effects of the monoclonal antibody component (Tositumomab) in the infant are not known. Therefore, formula feedings should be substituted for breast feedings before starting treatment. Women should be advised to discontinue nursing.

Adverse Reactions: The most serious adverse reactions observed in the clinical trials were severe and prolonged cytopenias and the sequelae of cytopenias which included infections (sepsis) and hemorrhage in thrombocytopenic patients, allergic reactions (bronchospasm and angioedema), secondary leukemia and myelodysplasia. The most common adverse reactions occurring in the clinical trials included neutropenia (63%), thrombocytopenia (53%), and anemia (29%) that were both prolonged and severe (NCI CTC grade 3 or 4). Less common but severe adverse reactions included pneumonia (6%), pleural effusion (<5%) and dehydration (<5%).

Infusional Toxicities: Infusional toxicities including fever, rigors, chills, sweating, nausea, hypotension, dyspnea, and bronchospasm have been reported during and/or following the infusion of BEXXAR. In the clinical studies, fever, rigors, chills, or sweating were reported in 67 patients (29%) within 14 days following the dosimetric dose. Infusional toxicities were managed by slowing and/or temporarily interrupting the infusion. Adjustments occurred in 7% of the patients and included reduction in the rate of infusion by 50%, temporary interruption of the infusion, and in 2 patients, infusion was permanently discontinued.

Immunogenicity (HAMA): Administration of BEXXAR may result in the development of HAMA. Of the 230 patients in the clinical studies, 220 were seronegative for HAMA prior to treatment and 219 had at least 1 posttreatment HAMA value obtained. With a median observation period of 6 months, 23 patients (11%) became seropositive for HAMA posttreatment. The median time of HAMA development was 6 months. The cumulative incidences of HAMA seropositivity at 6 months, 12 months, and 18 months were 6%, 17%, and 21%, respectively. The presence of HAMA may affect the toxicity and/or efficacy of in vivo diagnostic or therapeutic agents that rely on murine antibodies and may affect the accuracy of in vitro and in vivo diagnostic tests. 

Assessment of Biodistribution: The biodistribution of Iodine I 131 Tositumomab should be assessed. If biodistribution is altered, the therapeutic dose should not be administered.

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