Detailed Safety Information

WARNINGS ¹

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 healthcare 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.

IMPORTANT SAFETY INFORMATION¹

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.

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 thrombocytopenia (53%) and 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: Hypersensitivity reactions, including some with fatal outcome, were reported during and following administration of the BEXXAR therapeutic regimen in 6% (14) of 230 patients. In the postmarketing setting, severe hypersensitivity reactions, including fatal anaphylaxis, have been reported. Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA) as they may be at increased risk for serious allergic reactions.

Immunogenicity: Administration of BEXXAR may result in the development of HAMA. Of the 230 patients in the clinical studies, 220 patients 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, a total of 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.

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. Of the 230 patients in the clinical studies, 203 patients 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. Of the 765 patients in the expanded access programs, 670 patients did not have elevated TSH upon study entry. Of these, 455 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 33 months, the incidence of hypothyroidism based on elevated TSH or initiation of thyroid replacement therapy in these 455 patients was 13%, with a median time to development of hypothyroidism of 15 months. The cumulative incidences of hypothyroidism at 2 and 5 years in these patients were 9% and 17%, respectively. Thyroid-blocking medication should be prescribed as described in the prescribing information; if patients do not tolerate the medication they should not be given BEXXAR. Patients should be evaluated for signs and symptoms of hypothyroidism and screened for biochemical evidence of hypothyroidism annually.

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. 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.

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

Complete Prescribing Information for
BEXXAR (Tositumomab and Iodine I 131 Tositumomab)

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Nonhematologic adverse events in patients treated with the BEXXAR therapeutic regimen¹

INCIDENCE OF ADVERSE EXPERIENCES IN >5% OF THE PATIENTS
TREATED WITH THE BEXXAR THERAPEUTIC REGIMEN (N=230)*

Body System Preferred Term	All Grades	Grade 3/4

Total	96%	48%

Body as a Whole Asthenia Fever Infection^† Pain Chills Headache Abdominal pain Back pain Chest pain Neck pain	81% 46% 37% 21% 19% 18% 16% 15% 8% 7% 6%	12% 2% 2% <1% 1% 1% 0% 3% 1% 0% 1%

Cardiovascular System Hypotension Vasodilatation	26% 7% 5%	3% 1% 0%

Digestive System Nausea Vomiting Anorexia Diarrhea Constipation Dyspepsia	56% 36% 15% 14% 12% 6% 6%	9% 3% 1% 0% 0% 1% <1%

Endocrine System Hypothyroidism	7% 7%	0% 0%

Metabolic and Nutritional Disorders Peripheral edema Weight loss	21% 9% 6%	3% 0% <1%

Musculoskeletal System Myalgia Arthralgia	23% 13% 10%	3% <1% 1%

Nervous System Dizziness Somnolence	26% 5% 5%	3% 0% 0%

Respiratory System Cough increased Pharyngitis Dyspnea Rhinitis Pneumonia	44% 21% 12% 11% 10% 6%	8% 1% 0% 3% 0% 0%

Skin and Appendages Rash Pruritus Sweating	44% 17% 10% 8%	5% <1% 0% <1%

* Excludes laboratory-derived hematologic adverse events.
^†The COSTART term for infection includes a subset of infections (e.g., upper respiratory infection).
Other terms are mapped to preferred terms (e.g., pneumonia and sepsis).

Infusion-related reactions and rate adjustments (N=230)¹

Fever, rigors or chills, sweating, hypotension, dyspnea, bronchospasm, and nausea have been reported during or within 48 hours of infusion
29% (67) of patients reported fever, rigors or chills, or sweating within 14 days following the dosimetric dose
Infusion rate adjustment occurred in 7% (16) of patients and included reductions in the rate of infusion by 50%, temporary interruption of the infusion, and in 2 patients, infusion was permanently discontinued
- Dosimetric infusion rate adjusted in 3% of patients (n=7)
- Therapeutic infusion rate adjusted in 1% of patients (n=2)
- Both dosimetric and therapeutic infusion rates adjusted in 3% of
patients (n=7)

Hematologic toxicities observed following the BEXXAR therapeutic regimen¹

HEMATOLOGIC TOXICITY* (N=230)¹

	Endpoint	Values

	Platelets Median nadir (cells/mm³) Per patient incidence* platelets <50,000/mm³ Median^� duration of platelets <50,000/mm³ (days) Grade 3/4 without recovery to Grade 2, N (%) Per patient incidence^� platelets <25,000/mm³	43,000 53% (n=123) 32 16 (7%) 21% (n=47)
	ANC Median nadir (cells/mm³) Per patient incidence* ANC<1,000 cells/mm³ Median^� duration of ANC<1,000 cells/mm³ (days) Grade 3/4 without recovery to Grade 2, N (%) Per patient incidence^� ANC<500 cells/mm³	690 63% (n=145) 31 15 (7%) 25% (n=57)
	Hemoglobin Median nadir (gm/dL) Per patient incidence* hemoglobin <8 gm/dL Median^� duration of hemoglobin <8.0 gm/dL (days) Grade 3/4 without recovery to Grade 2, N (%) Per patient incidence^� hemoglobin <6.5 gm/dL	10 29% (n=66) 23 12 (5%) 5% (n=11)

* Grade 3/4 toxicity was assumed if patient was missing 2 or more weeks of hematology data
   between Week 5 and Week 9.
^† Duration of Grade 3/4 of 1,000+ days (censored) was assumed for those patients with
   undocumented Grade 3/4 and no hematologic data on or after Week 9.
^� Grade 4 toxicity was assumed if patient had documented Grade 3 toxicity and was missing
   2 or more weeks of hematology data between Week 5 and Week 9.

45% (104 of 230) of the patients who received BEXXAR experienced 1 or more adverse events possibly related to infection. The majority were viral (e.g., rhinitis, pharyngitis, flu symptoms, or herpes) or other minor infections
- 9% (20 of 230) of 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
12% (28 of 230) of patients experienced hemorrhagic events
- Most were mild to moderate

Use of supportive care¹

SUPPORTIVE CARE USED FOR HEMATOLOGIC TOXICITY*

Type of Supportive Care

G-CSF
Epoetin alfa
Platelet transfusions
Packed red blood cells

Percentage of All Patients Receiving BEXXAR
12%
7%
15%
16%

*Physician determined.

� 63 of the 230 patients (27%) received at their physicians’ discretion at least 1
type of supportive care for hematologic toxicity after receiving the therapeutic
dose of BEXXAR

Hypersensitivity reactions¹

Serious hypersensitivity reactions, including some with fatal outcome, were reported during and following administration of the BEXXAR therapeutic regimen
In the postmarketing setting, severe hypersensitivity reactions, including fatal anaphylaxis, have been reported
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 develop severe hypersensitivity reactions should have infusions of the BEXXAR therapeutic regimen discontinued and receive medical attention
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
6% (14 patients) experienced 1 or more of the following adverse events: allergic reaction, face edema, injection site hypersensitivity, anaphylactic reaction, laryngismus, and serum sickness

HAMA¹

Administration of BEXXAR resulted in the development of HAMA
- 220 of the 230 patients in the clinical studies were seronegative for HAMA
   prior to treatment, and 219 patients had at least 1 posttreatment HAMA
   value. 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
- 758 of the 765 patients in the expanded access programs were
   seronegative for HAMA prior to treatment, and 569 patients had at least 1
   posttreatment HAMA value. With a median observation period of 7 months,
   57 patients (10%) became seropositive for HAMA posttreatment. The
   median time of HAMA development was 5 months. The cumulative
   incidences of HAMA seropositivity at 6 months, 12 months, and 18 months
   were 7%, 12%, and 13%, 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. Patients who are HAMA positive may be at increased risk for serious allergic reactions

Thyroid function¹

Administration of BEXXAR resulted in hypothyroidism
- Of the 230 patients in the clinical studies, 203 patients were euthyroid at
   entry; 137 had at least 1 posttreatment TSH value and were not taking
   thyroid medication upon study entry. At a median follow-up of 46 months,
   18% of these patients were hypothyroid based on elevated TSH or initiation
   of thyroid replacement therapy
- The median time to development of hypothyroidism was 16 months. The
   cumulative incidences of hypothyroidism at 2 and 5 years in these
   137 patients were 11% and 19%, respectively
- Of the 765 patients in the expanded access programs, 670 patients were
   euthyroid at entry; 455 had at least 1 posttreatment TSH value and were
   not taking thyroid medication upon study entry. At a median follow-up of 33
   months, 13% of these patients were hypothyroid based on elevated TSH
   or initiation of thyroid replacement therapy
- The median time to development of hypothyroidism was 15 months. The
   cumulative incidences of hypothyroidism at 2 and 5 years in these patients
   were 9% and 17%, respectively
Thyroid-blocking medication should be prescribed as described in the prescribing information; if patients do not tolerate the medication they should not be given BEXXAR
Patients should be evaluated for signs and symptoms of hypothyroidism and screened for biochemical evidence of hypothyroidism annually

Secondary malignancies¹

At a median follow-up of 29 months, 44 cases of myelodysplastic syndrome and/or secondary leukemia were reported among 995 patients enrolled in clinical studies and an expanded access program
Additional malignancies were also reported in 54 (65 cases) of the patients. Approximately half (26) of these were nonmelanomatous 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 BEXXAR over the background rate in this population cannot be determined due to the absence of controlled studies

Complete Prescribing Information for
BEXXAR (Tositumomab and Iodine I 131 Tositumomab)

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