Bexxar

tositumomab

Dosage Form: injection
Bexxar®

(Tositumomab and Iodine I 131 Tositumomab)

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.

Bexxar 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 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 4.4%−6.6% (w/v) povidone, 1−2 mg/mL maltose (dosimetric dose) or 9−15 mg/mL maltose (therapeutic dose), 8.5−9.5 mg/mL sodium chloride, and 0.9−1.3 mg/mL ascorbic acid. The pH 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

• A carton containing two single-use 225 mg vials and one single-use 35 mg vial of Tositumomab supplied by McKesson BioServices and

• 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

• A carton containing two single-use 225 mg vials and one single-use 35 mg vial of Tositumomab, supplied by McKesson BioServices 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 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.

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)

Bexxar - 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 antibody 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.

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. The median total body effective half-life, as measured by total body gamma camera counts, in 980 patients with NHL was 67 hours (range: 28-115 hours).

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.

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.

Table 3: Estimated Radiation-Absorbed Organ Doses

		Bexxar	Bexxar
		mGy/MBq	mGy/MBq
		Median	Range
From Organ ROIs
	Thyroid	2.71	1.4 - 6.2
	Kidneys	1.96	1.5 - 2.5
	ULI Wall	1.34	0.8 - 1.7
	LLI Wall	1.30	0.8 - 1.6
	Heart Wall	1.25	0.5 - 1.8
	Spleen	1.14	0.7 - 5.4
	Testes	0.83	0.3 - 1.3
	Liver	0.82	0.6 - 1.3
	Lungs	0.79	0.5 - 1.1
	Red Marrow	0.65	0.5 - 1.1
	Stomach Wall	0.40	0.2 - 0.8
From Whole Body ROIs
	Urine Bladder Wall	0.64	0.6 - 0.9
	Bone Surfaces	0.41	0.4 - 0.6
	Pancreas	0.31	0.2 - 0.4
	Gall Bladder Wall	0.29	0.2 - 0.3
	Adrenals	0.28	0.2 - 0.3
	Ovaries	0.25	0.2 - 0.3
	Small Intestine	0.23	0.2 - 0.3
	Thymus	0.22	0.1 - 0.3
	Uterus	0.20	0.2 - 0.2
	Muscle	0.18	0.1 - 0.2
	Breasts	0.16	0.1 - 0.2
	Skin	0.13	0.1 - 0.2
	Brain	0.13	0.1 - 0.2
	Total Body	0.24	0.2 - 0.3

Clinical Studies

The efficacy of the Bexxar therapeutic regimen was evaluated in 2 studies conducted in patients with low-grade, transformed low-grade, or follicular large-cell lymphoma. 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 had received prior treatment without an objective response or had progression of disease following treatment. Patients were required to have a granulocyte count >1500 cells/mm3, a platelet count ≥100,000/mm3, 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.

Study 1 was a multicenter, single-arm study of 40 patients whose disease had not responded to or had progressed after at least four doses of Rituximab therapy. The median age was 57 (range: 35−78); the median time from diagnosis to protocol entry was 50 months (range: 12−170); and the median number of prior chemotherapy regimens was 4 (range: 1−11). The efficacy outcome data from this study, as determined by an independent panel that reviewed patient records and radiologic studies, are summarized in Table 4.

Among the forty patients in the study, 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. In this subset of patients the overall objective response was 63% (95% confidence interval 45%, 79%) with a median duration of 25 months (range of 4 - 38+ months). The complete response in this subset of patients was 29% (95% CI of 15%, 46%) with a median duration of response not yet reached (range of 4 - 38+ months).

Study 2 was a multicenter, single arm, open-label study of 60 chemotherapy refractory patients. The median age was 60 (range 38-82), the median time from diagnosis to protocol entry was 53 months (range: 9-334), and the median number of prior chemotherapy regimens was 4 (range 2-13). Fifty-three patients had not responded to prior therapy and 7 patients had responded with a duration of response of<6 months. The efficacy outcome data from this study, as determined by an independent panel that reviewed patient records and radiologic studies are also summarized in Table 4. Investigators continued to follow eight patients with complete response after the last independent review panel assessment. The updated duration of ongoing response as per investigators was reported to range from 42 to 85 months.

Table 4: Efficacy Outcomes in Bexxar Clinical Studies

	Study 1 (n = 40)	Study 2 (n = 60)
Overall Response
Rate 95% CI a	68% (51%, 81%)	47% (34%, 60%)
Response Duration (mos)
Median 95% CI a Range	16 (10, NRb) 1+ to 38+	12 (7, 47) 2 to 47
Complete Response c
Rate 95% CI a	33% (19%, 49%)	20% (11%, 32%)
Complete response c duration (mos)
Median 95% CI a Range	NR b (15, NR) 4 to 38+	47 (47, NR) 9 to 47

a CI = Confidence Interval

b NR = Not reached, Median duration of follow up: Study 1 = 26 months; Study 2 = 30 months

c Complete response rate = Pathologic and clinical complete responses

The results of these studies were supported by demonstration of durable objective responses in three single-arm studies. In these studies, 130 patients with Rituximab-naïve follicular non-Hodgkin’s lymphoma with or without transformation were evaluated for efficacy. All patients had relapsed following, or were refractory to, chemotherapy. The overall response rates ranged from 49% to 64% and the median durations of response ranged from 13 to 16 months. Due to small sample sizes in the supportive studies, as in studies 1 and 2, the 95% confidence intervals for the median durations of response are wide.

Indications and Usage for Bexxar

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. (See ADVERSE REACTIONS, Immunogenicity.)

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.

Contraindications

The Bexxar therapeutic regimen is contraindicated in patients with known hypersensitivity to murine proteins or any 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).

Warnings

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 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, Hypersensitivity Reactions and Immunogenicity)

Serious hypersensitivity reactions, including some with fatal outcome, 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 10% (24/230) of patients enrolled in the clinical studies and 3% (20/765) of patients included in expanded access programs, with median follow-up of 39 and 27 months, respectively. Among the 44 reported cases, the median time to development of MDS/leukemia was 31 months following treatment; however, the cumulative rate continues to increase.

Additional non-hematological malignancies were also reported in 54 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 colorectal cancer (7), head and neck cancer (6), breast cancer (5), lung cancer (4), bladder cancer (4), melanoma (3), and gastric cancer (2). 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 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 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 MDS, secondary leukemia, and solid tumors have also been observed in patients receiving the Bexxar therapeutic regimen.

Due to lack of controlled clinical studies, and high background incidence in the heavily pretreated patient population, the relative risk of development of myelodysplastic syndrome/acute leukemia and solid tumors due to the Bexxar therapeutic regimen cannot be determined.

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 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.

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 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 39 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 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 the 230 (45%) patients experienced one or more adverse events possibly related to infection. The majority were viral (e.g., rhinitis, pharyngitis, flu symptoms, or herpes) or other minor infections. Twenty of 230 (9%) patients experienced infections that were considered serious because the patient was hospitalized to manage the infection. Documented infections included pneumonia, bacteremia, septicemia, bronchitis, and skin infections.

Hypersensitivity Reactions

Fourteen patients (6%) experienced one or more of the following adverse events: allergic reaction, face edema, injection site hypersensitivity, a