o diagnostic tests and may affect the toxicity profile and efficacy of therapeutic agents that rely on murine antibody technology. Patients who are HAMA positive may be at increased risk for serious allergic reactions and other side effects if they undergo in vivo diagnostic testing or treatment with murine monoclonal antibodies.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of the BEXXAR therapeutic regimen or to determine its effects on fertility in males or females. However, radiation is a potential carcinogen and mutagen. Administration of the BEXXAR therapeutic regimen results in delivery of a significant radiation dose to the testes. The radiation dose to the ovaries has not been established. There have been no studies to eva luate whether administration of the BEXXAR therapeutic regimen causes hypogonadism, premature menopause, azoospermia and/or mutagenic alterations to germ cells. There is a potential risk that the BEXXAR therapeutic regimen 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 the BEXXAR therapeutic regimen.
Pregnancy Category X
(See CONTRAINDICATIONS; WARNINGS.)
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.
Pediatric Use
The safety and effectiveness of the BEXXAR therapeutic regimen in children have not been established.
Geriatric Use
Clinical studies of the BEXXAR therapeutic regimen did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In clinical studies, 230 patients received the BEXXAR therapeutic regimen at the recommended dose. Of these, 27% (61 patients) were age 65 or older and 4% (10 patients) were age 75 or older. Across all studies, the overall response rate was lower in patients age 65 and over (41% vs. 61%) and the duration of responses was shorter (10 months vs. 16 months); however, these findings are primarily derived from 2 of the 5 studies. While the incidence of severe hematologic toxicity was lower, the duration of severe hematologic toxicity was longer in those age 65 or older as compared to patients less than 65 years of age. Due to the limited experience greater sensitivity of some older individuals cannot be ruled out.
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 (see BOXED WARNINGS and WARNINGS).
The most common adverse reactions occurring in the clinical trials included neutropenia, thromobocytopenia, and anemia that are both prolonged and severe. Less common but severe adverse reactions included pneumonia, pleural effusion
