WARNINGS
Hypersensitivity Reactions, including Anaphylaxis: Serious hypersensitivity reactions, including some with fatal outcome, have been reported with the BEXXAR therapeutic regimen. Medications for the treatment of severe hypersensitivity reactions should be available for immediate use. Patients who develop severe hypersensitivity reactions should have infusions of the BEXXAR therapeutic regimen discontinued and receive medical attention (see WARNINGS).
Prolonged and Severe Cytopenias: The majority of patients who received the BEXXAR therapeutic regimen experienced severe thrombocytopenia and neutropenia. The BEXXAR therapeutic regimen should not be administered to patients with >25% lymphoma marrow involvement and/or impaired bone marrow reserve (see WARNINGS and ADVERSE REACTIONS).
Pregnancy Category X: The BEXXAR therapeutic regimen can cause fetal harm when administered to a pregnant woman.
Special requirements: The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) contains a radioactive component and should be administered only by physicians and other health care professionals qualified by training in the safe use and handling of therapeutic radionuclides. The BEXXAR therapeutic regimen should be administered only by physicians who are in the process of being or have been certified by GlaxoSmithKline in dose calculation and administration of the BEXXAR therapeutic regimen.
DESCRIPTION
The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is an anti-neoplastic radioimmunotherapeutic monoclonal antibody-based regimen composed of the monoclonal antibody, Tositumomab, and the radiolabeled monoclonal antibody, Iodine I 131 Tositumomab.
Tositumomab
Tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes. Tositumomab is produced in an antibiotic-free culture of mammalian cells and is composed of two murine gamma 2a heavy chains of 451amino acids each and two lambda light chains of 220 amino acids each. The approximate molecular weight of Tositumomab is 150 kD.
Tositumomab is supplied as a sterile, pyrogen-free, clear to opalescent, colorless to slightly yellow, preservative-free liquid concentrate. It is supplied at a nominal concentration of 14mg/mL Tositumomab in 35 mg and 225 mg single-use vials. Theformulation contains 10% (w/v) maltose, 145 mM sodium chloride, 10mM phosphate, and Water for Injection, USP. The pH is approximately 7.2.
Iodine I 131 Tositumomab
Iodine I 131 Tositumomab is a radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131. Unbound radio-iodine and other reactants have been removed by chromatographic purification steps. Iodine I 131 Tositumomab is supplied as a sterile, clear, preservative-free liquid for IV administration. The dosimetric dosage form is supplied at nominal protein and activity concentrations of 0.1 mg/mL and 0.61 mCi/mL (at date of calibration), respectively. The therapeutic dosage form is supplied at nominal protein and activity concentrations of 1.1 mg/mL and 5.6 mCi/mL (at date of calibration), respectively. The formulation for the dosimetric and the therapeutic dosage forms contains 4.4%−6.6% (w/v) povidone, 1−2 mg/mL maltose (dosimetric dose) or 9−15 mg/mL maltose (therapeutic dose), 8.5−9.5mg/mL sodium chloride, and 0.9−1.3 mg/mL ascorbic acid. ThepH is approximately 7.0.
BEXXAR Therapeutic Regimen
The BEXXAR therapeutic regimen is administered in two discrete steps: the dosimetric and therapeutic steps. Each step consists of a sequential infusion of Tositumomab followed by Iodine I 131 Tositumomab. The therapeutic step is administered 7-14 days after the dosimetric step. The BEXXAR therapeutic regimen is supplied in two distinct package configurations as follows:
BEXXAR Dosimetric Packaging
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A carton containing two single-use 225 mg vials and one single-use 35 mg vial of Tositumomab supplied by McKesson BioServices and
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A package containing a single-use vial of Iodine I 131 Tositumomab (0.61 mCi/mL at calibration), supplied by MDS Nordion.
BEXXAR Therapeutic Packaging
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A carton containing two single-use 225 mg vials and one single-use 35 mg vial of Tositumomab, supplied by McKesson BioServices and
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A package containing one or two single-use vials of Iodine I 131 Tositumomab (5.6 mCi/mL at calibration), supplied by MDS Nordion.
Physical/Radiochemical Characteristics of Iodine-131
Iodine-131 decays with beta and gamma emissions with a physical half-life of 8.04 days. The principal beta emission has a mean energy of 191.6keV and the principal gamma emission has an energy of 364.5 keV (Ref 1).
External Radiation
The specific gamma ray constant for Iodine-131 is 2.2 R/millicurie hour at 1cm. The first half-value layer is 0.24 cm lead (Pb) shielding. A range of values is shown in Table 1 for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb. To facilitate control of the radiation exposure from this radionuclide, the use of a 2.55 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1,000.
Table 1: Radiation Attenuation by Lead Shielding
|
Shield Thickness (Pb) cm
|
Attenuation Factor
|
|
0.24
|
0.5
|
|
0.89
|
10-1
|
|
1.60
|
10-2
|
|
2.55
|
10-3
|
|
3.7
|
10-4
|
The fraction of Iodine-131 radioactivity that remains in the vial after the date of calibration is calculated as follows:
Fraction of remaining radioactivity of Iodine-131 after x days = 2-(x/8.04).
Physical decay is presented in Table 2.
