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`Rx Only
`
`BEXXAR®
`
`Tositumomab and Iodine I 131 Tositumomab
`
`WARNINGS
`
`Hypersensitivity Reactions, including Anaphylaxis: 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 Corixa Corporation 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
`
`Page 1
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`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 451 amino 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 14 mg/mL Tositumomab in 35 mg
`and 225 mg single-use vials. The formulation contains 10% (w/v) maltose,
`145 mM sodium chloride, 10 mM 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 5.0%–6.0% (w/v)
`povidone, 1–2 mg/mL maltose (dosimetric dose) or 9–15 mg/mL maltose
`(therapeutic dose), 0.85–0.95 mg/mL sodium chloride, and 0.9–1.3 mg/mL
`ascorbic acid. The pH is approximately 7.0.
`
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`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
`
`• A carton containing two single-use 225 mg vials and one single-use
`35 mg vial of Tositumomab supplied by McKesson Biosciences and
`
`• A package containing a single-use vial of Iodine I 131 Tositumomab
`(0.61mCi/mL at calibration), supplied by MDS Nordion.
`
`BEXXAR Therapeutic Packaging
`
`• A carton containing two single-use 225 mg vials and one single-use
`35 mg vial of Tositumomab, supplied by McKesson Biosciences
`and
`
`• 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
`191.6 keV 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 1 cm. 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
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`radiation exposure from this radionucide, 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
`Attenuation
`(Pb) cm
`Factor
`0.24
`0.5
`10-1
`0.89
`10-2
`1.60
`10-3
`2.55
`10-4
`3.7
`
`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.
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`Table 2
`Physical Decay Chart: Iodine-131: Half-Life 8.04 Days
`Days
`Fraction Remaining
` 0*
`1.000
`1
`0.917
`2
`0.842
`3
`0.772
`4
`0.708
`5
`0.650
`6
`0.596
`7
`0.547
`8
`0.502
`9
`0.460
`10
`0.422
`11
`0.387
`12
`0.355
`13
`0.326
`14
`0.299
`
`
`
`*(Calibration day)
`CLINICAL PHARMACOLOGY
`
`General Pharmacology
`
`Tositumomab binds specifically to the CD20 (human B-lymphocyte–
`restricted differentiation antigen, Bp 35 or B1) antigen. This antigen is a
`transmembrane phosphoprotein expressed on pre-B lymphocytes and at
`higher density on mature B lymphocytes (Ref. 2). The antigen is also
`expressed on >90% of B-cell non-Hodgkin’s lymphomas (NHL) (Ref. 3).
`The recognition epitope for Tositumomab is found within the extracellular
`domain of the CD20 antigen. CD20 does not shed from the cell surface
`and does not internalize following a ntibody binding (Ref. 4).
`
`Mechanism of Action: Possible mechanisms of action of the BEXXAR
`therapeutic regimen include induction of apoptosis (Ref. 5), complement-
`dependent cytotoxicity (CDC) (Ref. 6), and antibody-dependent cellular
`cytotoxicity (ADCC) (Ref. 5) mediated by the antibody. Additionally, cell
`death is associated with ionizing radiation from the radioisotope.
`
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`Pharmacokinetics/Pharmacodynamics
`
`The phase 1 study of Iodine I 131 Tositumomab determined that a 475 mg
`predose of unlabeled antibody decreased splenic targeting and increased
`the terminal half-life of the radiolabeled antibody. The median blood
`clearance following administration of 485 mg of Tositumomab in
`110 patients with NHL was 68.2 mg/hr (range: 30.2–260.8 mg/hr).
`Patients with high tumor burden, splenomegaly, or bone marrow
`involvement were noted to have a faster clearance, shorter terminal half-
`life, and larger volume of distribution. The total body clearance, as
`measured by total body gamma camera counts, was dependent on the
`same factors noted for blood clearance. Patient-specific dosing, based on
`total body clearance, provided a consistent radiation dose, despite
`variable pharmacokinetics, by allowing each patient’s administered activity
`to be adjusted for individual patient variables.
`
`Elimination of Iodine-131 occurs by decay (see Table 2) and excretion in
`the urine. Urine was collected for 49 dosimetric doses. After 5 days, the
`whole body clearance was 67% of the injected dose. Ninety-eight percent
`of the clearance was accounted for in the urine.
`
`Administration of the BEXXAR therapeutic regimen results in sustained
`depletion of circulating CD20 positive cells. The impact of administration
`of the BEXXAR therapeutic regimen on circulating CD20 positive cells was
`assessed in two clinical studies, one conducted in chemotherapy naïve
`patients and one in heavily pretreated patients. The assessment of
`circulating lymphocytes did not distinguish normal from malignant cells.
`Consequently, assessment of recovery of normal B cell function was not
`directly assessed. At seven weeks, the median number of circulating
`CD20 positive cells was zero (range: 0 - 490 cells/ mm3). Lymphocyte
`recovery began at approximately 12 weeks following treatment. Among
`patients who had CD20 positive cell counts recorded at baseline and at 6
`months, 8 of 58 (14%) chemotherapy naïve patients had CD20 positive
`cell counts below normal limits at six months and 6 of 19 (32%) heavily
`pretreated patients had CD20 positive cell counts below normal limits at
`six months. There was no consistent effect of the BEXXAR therapeutic
`regimen on post-treatment serum IgG, IgA, or IgM levels.
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`Radiation Dosimetry
`
`Estimations of radiation-absorbed doses for Iodine I 131 Tositumomab
`were performed using sequential whole body images and the MIRDOSE 3
`software program. Patients with apparent thyroid, stomach, or intestinal
`imaging were selected for organ dosimetry analyses. The estimated
`radiation-absorbed doses to organs and marrow from a course of the
`BEXXAR therapeutic regimen are presented in Table 3.
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`Table 3
`
`Estimated Radiation-Absorbed Organ Doses
`
`
`
`
`
`
`
`From Organ ROIs
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`
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`
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`
`
`BEXXAR BEXXAR
`
`mGy/MBq mGy/MBq
`
`Median
`
`Range
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`
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`Thyroid
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`Kidneys
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`ULI Wall
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`LLI Wall
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`Heart Wall
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`Spleen
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`Testes
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`Liver
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`Lungs
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`Red Marrow
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`Stomach Wall
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`2.71
`
`1.96
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`1.34
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`1.30
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`1.25
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`1.14
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`0.83
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`0.82
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`0.79
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`0.65
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`0.40
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`1.4 - 6.2
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`1.5 - 2.5
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`0.8 - 1.7
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`0.8 - 1.6
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`0.5 - 1.8
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`0.7 - 5.4
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`0.3 - 1.3
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`0.6 - 1.3
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`0.5 - 1.1
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`0.5 - 1.1
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`0.2 - 0.8
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`
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`From Whole Body ROIs
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`
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`Urine Bladder Wall
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`Bone Surfaces
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`Pancreas
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`Gall Bladder Wall
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`Adrenals
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`Ovaries
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`Small Intestine
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`Thymus
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`Uterus
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`Muscle
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`Breasts
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`Skin
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`Brain
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`Total Body
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`Page 8
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`0.64
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`0.41
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`0.31
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`0.29
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`0.28
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`0.25
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`0.23
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`0.22
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`0.20
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`0.18
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`0.16
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`0.13
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`0.13
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`0.24
`
`
`
`0.6 - 0.9
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`0.4 - 0.6
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`0.2 - 0.4
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`0.2 - 0.3
`
`0.2 - 0.3
`
`0.2 - 0.3
`
`0.2 - 0.3
`
`0.1 - 0.3
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`0.2 - 0.2
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`0.1 - 0.2
`
`0.1 - 0.2
`
`0.1 - 0.2
`
`0.1 - 0.2
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`0.2 - 0.3
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`

`

`
`
`CLINICAL STUDIES
`
`The efficacy of the BEXXAR therapeutic regimen was evaluated in a multi-
`center, single-arm study in patients with low grade or transformed low-
`grade or follicular large-cell lymphoma whose disease had not responded
`to or had progressed after Rituximab therapy. Determination of clinical
`benefit of the BEXXAR therapeutic regimen was based on evidence of
`durable responses without evidence of an effect on survival. All patients in
`the study were required to have received prior treatment with at least
`four doses of Rituximab without an objective response, or to have
`progressed following treatment. Patients were also required to have a
`platelet count ‡100,000/mm 3; an average of £25% of the intratrabecular
`marrow space involved by lymphoma, and no evidence of progressive
`disease arising in a field irradiated with >3500 cGy within 1 year of
`completion of irradiation.
`
`Forty patients initiated treatment with the BEXXAR therapeutic regimen.
`The median age was 57 (range: 35–78); the median time from diagnosis
`to protocol entry was 50 months (range: 11–70); and the median number
`of prior chemotherapy regimens was 4 (range: 1–11). Twenty-four
`patients had disease that did not respond to their last treatment with
`Rituximab, 11 patients had disease that responded to Rituximab for less
`than 6 months, and five patients had disease that responded to Rituximab,
`with a duration of response of 6 months or greater. Overall, 35 of the 40
`patients met the definition of “Rituximab refractory”, defined as no
`response or a response of less than 6 months duration. Table 4
`summarizes efficacy outcome data from this study, as determined by an
`independent panel that reviewed patient records and radiologic studies.
`The median duration of follow-up was 26 months for all patients and 26
`months for the Rituximab-refractory subset.
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`Table 4
`Efficacy Outcomes Patients
`
`Objective Responses to the BEXXAR
`Therapeutic Regimen in Patients
`Refractory to Rituximab
`Response Rate (%)
`Median duration
`(95% CIa)
`of response (Mos)
`(n=35)
`(Range)
`
`Objective Responses to the BEXXAR
`
`Therapeutic Regimen in All Patients
`
`Response Rate (%)
`(95% CIa)
`(n=40)
`
`Median Duration
`of Response (Mos)
`(Range)
`
`68%
`(51%, 81%)
`
`33%
`(19%, 49%)
`
`16
`(1+, 35+)
`
`NR
`(4, 35+)
`
`
`
`
`Overall
`Response
`
`
`63%
`(45%, 79%)
`
`25
`(4+, 35+)
`
`NRb
`(4, 35+)
`
`Complete
`29%
`Response c
`(15%, 46%)
`
`a C.I. = Confidence Interval
`b NR = Not reached
`c Complete response rate = Pathologic and clinical complete responses
`
`
`
`The results of this study were supported by demonstration of durable
`objective responses in four single arm studies enrolling 190 patients
`evaluable for efficacy with Rituximab-naïve, follicular non-Hodgkin’s
`lymphoma with or without transformation, who had relapsed following or
`were refractory to chemotherapy. In these studies, the overall response
`rates ranged from 47% to 64% and the median durations of response
`ranged from 12 to 18 months.
`
`INDICATIONS AND USAGE
`
`The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131
`Tositumomab) is indicated for the treatment of patients with CD20
`positive, follicular, non-Hodgkin's lymphoma, with and without
`transformation, whose disease is refractory to Rituximab and has relapsed
`following chemotherapy. 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
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`regimen, or combination of this regimen with other forms of irradiation or
`chemotherapy, has not been evaluated.
`
`
`
`CONTRAINDICATIONS
`
`The BEXXAR therapeutic regimen is contraindicated in patients with
`known hypersensitivity to murine proteins or a ny other component of the
`BEXXAR therapeutic regimen.
`
`PREGNANCY CATEGORY X
`
`Iodine I 131 Tositumomab (a component of the BEXXAR therapeutic
`regimen) is contraindicated for use in women who are pregnant. Iodine-
`131 may cause harm to the fetal thyroid gland when administered to
`pregnant women. Review of the literature has shown that transplacental
`passage of radioiodide may cause severe, and possibly irreversible,
`hypothyroidism in neonates. While there are no adequate and well-
`controlled studies of the BEXXAR therapeutic regimen in pregnant
`animals or humans, use of the BEXXAR therapeutic regimen in women of
`childbearing age should be deferred until the possibility of pregnancy has
`been ruled out. If the patient becomes pregnant while being treated with
`the BEXXAR therapeutic regimen, the patient should be apprised of the
`potential hazard to the fetus. (See BOXED WARNING, Pregnancy
`Category X).
`
`239
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`
`
`WARNINGS
`
`240
`241
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`244
`245
`246
`247
`248
`249
`
`Prolonged and Severe Cytopenias (See BOXED WARNINGS;
`ADVERSE REACTIONS, Hematologic Events):
`The most common adverse reactions associated with the BEXXAR
`therapeutic regimen were severe or life-threatening cytopenias (NCI CTC
`grade 3 or 4) with 71% of the 230 patients enrolled in clinical studies
`experiencing grade 3 or 4 cytopenias. These consisted primarily of grade
`3 or 4 thrombocytopenia (53%) and grade 3 or 4 neutropenia (63%). The
`time to nadir was 4 to 7 weeks and the duration of cytopenias was
`approximately 30 days. Thrombocytopenia, neutropenia, and anemia
`persisted for more than 90 days following administration of the BEXXAR
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`therapeutic regimen in 16 (7%), 15 (7%), and 12 (5%) patients
`respectively (this includes patients with transient recovery followed by
`recurrent cytopenia). Due to the variable nature in the onset of cytopenias,
`complete blood counts should be obtained weekly for 10-12 weeks. The
`sequelae of severe cytopenias were commonly observed in the clinical
`studies and included infections (45% of patients), hemorrhage (12%), a
`requirement for growth factors (12% G- or GM-CSF; 7% Epoetin alfa) and
`blood product support (15% platelet transfusions; 16% red blood cell
`transfusions). Prolonged cytopenias may also influence subsequent
`treatment decisions.
`
`The safety of the BEXXAR therapeutic regimen has not been established
`in patients with >25% lymphoma marrow involvement, platelet count
`<100,000 cells/mm3 or neutrophil count <1,500 cells/mm3.
`
`Hypersensitivity Reactions Including Anaphylaxis (See BOXED
`WARNINGS; ADVERSE REACTIONS, Immunogenicity):
`Hypersensitivity reactions, including a naphylaxis, were reported during
`and following administration of the BEXXAR therapeutic regimen.
`Emergency supplies including medications for the treatment of
`hypersensitivity reactions, e.g., epinephrine, antihistamines and
`corticosteroids, should be available for immediate use in the event of an
`allergic reaction during administration of the BEXXAR therapeutic
`regimen. Patients who have received murine proteins should be screened
`for human anti-mouse antibodies (HAMA). Patients who are positive for
`HAMA may be at increased risk of anaphylaxis and serious
`hypersensitivity reactions during administration of the BEXXAR
`therapeutic regimen.
`
`Secondary Malignancies: Myelodysplastic syndrome (MDS) and/or
`acute leukemia were reported in 8% (19/230) of patients enrolled in the
`clinical studies and 2% (13/765) of patients included in expanded access
`programs, with median follow-up of 35 and 20 months, respectively.
`Among the 32 reported new cases, the median time to development of
`MDS/leukemia was 27 months following treatment; however, the
`cumulative rate continues to increase. The pretreatment characteristics
`(e.g., median age, number of prior chemotherapy regimens) were similar
`Page 12
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`
`in patients developing MDS/secondary leukemias as compared with those
`who did not. Additional malignancies were also reported in 52 of the 995
`patients enrolled in clinical studies or included in the expanded access
`program. Approximately half of these were non-melanomatous skin
`cancers. The remainder which occurred in 2 or more patients included
`breast cancer, lung cancer, bladder cancer, head and neck cancer, colon
`cancer and melanoma, in order of decreasing incidence. The relative risk
`of developing secondary malignancies in patients receiving the BEXXAR
`therapeutic regimen over the background rate in this population cannot be
`determined, due to the absence of controlled studies (See ADVERSE
`REACTIONS).
`
`Pregnancy Category X: (See BOXED WARNINGS;
`CONTRAINDICATIONS).
`
`Hypothyroidism: Administration of the BEXXAR therapeutic regimen
`may result in hypothyroidism (See ADVERSE REACTIONS,
`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 (see DOSAGE and
`ADMINISTRATION). All patients must receive thyroid blocking agents;
`any patient who is unable to tolerate thyroid blocking agents should not
`receive the BEXXAR therapeutic regimen. Patients should be evaluated
`for signs and symptoms of hypothyroidism and screened for biochemical
`evidence of hypothyroidism annually.
`
`
`
`PRECAUTIONS
`
`Radionuclide Precautions: Iodine I 131 Tositumomab is radioactive.
`Care should be taken, consistent with the institutional radiation safety
`practices and applicable federal guidelines, to minimize exposure of
`medical personnel and other patients.
`
`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
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`data regarding the safety of administration of the BEXXAR therapeutic
`regimen in patients with impaired renal function.
`
`Immunization: The safety of immunization with live viral vaccines
`following administration of the BEXXAR therapeutic regimen has not been
`studied. The ability of patients who have received the BEXXAR
`therapeutic regimen to generate a primary or anamnestic humoral
`response to any vaccine has not been studied.
`
`Information for Patients: Prior to administration of the BEXXAR
`therapeutic regimen, patients should be advised that they will have a
`radioactive material in their body for several days upon their release from
`the hospital or clinic. After discharge, patients should be provided with
`both oral and written instructions for minimizing exposure of family
`members, friends and the general public. Patients should be given a copy
`of the written instructions for use as a reference for the recommended
`precautionary actions.
`
`The pregnancy status of women of childbearing potential should be
`assessed and these women should be advised of the potential risks to the
`fetus (See CONTRAINDICATIONS). Women who are breastfeeding
`should be instructed to discontinue breastfeeding and should be apprised
`of the resultant potential harmful effects to the infant if these instructions
`are not followed.
`
`Patients should be advised of the potential risk of toxic effects on the male
`and female gonads following the BEXXAR therapeutic regimen, and be
`instructed to use effective contraceptive methods during treatment and for
`12 months following the administration of the BEXXAR therapeutic
`regimen.
`
`Patients should be informed of the risks of hypothyroidism and be advised
`of the importance of compliance with thyroid blocking agents and need for
`life-long monitoring.
`
`Patients should be informed of the possibility of developing a HAMA
`immune response and that HAMA may affect the results of in vitro and
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`in vivo diagnostic tests as well as results of therapies that rely on murine
`antibody technology.
`
`Patients should be informed of the risks of cytopenias and symptoms
`associated with cytopenia, the need for frequent monitoring for up to
`12 weeks after treatment, and the potential for persistent cytopenias
`beyond 12 weeks.
`
`Patients should be informed that certain anti-neoplastic agents used in the
`treatment of malignancy, e.g., alkylating agents, topoisomerase II
`inhibitors, and ionizing radiation, have been associated with the
`development of MDS, secondary leukemia and solid tumors. Patients
`should be informed that MDS, secondary leukemia, and solid tumors have
`also been observed in patients receiving the BEXXAR therapeutic
`regimen.
`
`Laboratory Monitoring: A complete blood count (CBC) with differential
`and platelet count should be obtained prior to, and at least weekly
`following administration of the BEXXAR therapeutic regimen. Weekly
`monitoring of blood counts should continue for a minimum of 10 weeks or,
`if persistent, until severe cytopenias have completely resolved. More
`frequent monitoring is indicated in patients with evidence of moderate or
`more severe cytopenias (see BOXED WARNINGS and WARNINGS).
`Thyroid stimulating hormone (TSH) level should be monitored before
`treatment and annually thereafter. Serum creatinine levels should be
`measured immediately prior to administration of the BEXXAR therapeutic
`regimen.
`
`Drug Interactions: No formal drug interaction studies have been
`performed. Due to the frequent occurrence of severe and prolonged
`thrombocytopenia, the potential benefits of medications that interfere with
`platelet function and/or anticoagulation should be weighed against the
`potential increased risk of bleeding and hemorrhage.
`
`Drug/Laboratory Test Interactions: Administration of the BEXXAR
`therapeutic regimen may result in the development of human anti-murine
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`antibodies (HAMA). The presence of HAMA may affect the accuracy of the
`results of in vitro and in vivo 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 evaluate 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.
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`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 were 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 and dehydration.
`
`Data regarding adverse events were primarily obtained in 230 patients
`with non-Hodgkin’s lymphoma enrolled in five clinical trials using the
`recommended dose and schedule. Patients had a median follow-up of 35
`months and 79% of the patients were followed at least 12 months for
`survival and selected adverse events. Patients had a median of 3 prior
`chemotherapy regimens, a median age of 55 years, 60% male, 27% had
`transformation to a higher grade histology, 29% were intermediate grade
`and 2% high grade histology (IWF) and 68% had Ann Arbor stage IV
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`disease. Patients enrolled in these studies were not permitted to have
`prior hematopoietic stem cell transplantation or irradiation to more than
`25% of the red marrow. In the expanded access program, which included
`765 patients, data regarding clinical serious adverse events and HAMA
`and TSH levels were used to supplement the characterization of delayed
`adverse events. (See ADVERSE REACTIONS, Hypothyroidism,
`Secondary Leukemia and Myelodysplastic Syndrome,
`Immunogenicity.)
`
`Because clinical trials are conducted under widely varying conditions,
`adverse reaction rates observed in the clinical trials of a drug cannot be
`directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice. The adverse reaction information
`from clinical trials does, however, provide a basis for identifying the
`adverse events that appear to be related to drug use and for
`approximating rates.
`
`Hematologic Events: Hematologic toxicity was the most frequently
`observed adverse event in clinical trials with the BEXXAR therapeutic
`regimen (Table 6). Sixty-three (27%) of 230 patients received one or
`more hematologic supportive care measures following the therapeutic
`dose: 12% received G-CSF; 7% received Epoetin alfa; 15% received
`platelet transfusions; and 16% received packed red blood cell
`transfusions. Twenty-eight (12%) patients experienced hemorrhagic
`events; the majority were mild to moderate.
`
`Infectious Events: One hundred and four of th