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Bexxar (Tositumomab / Iodine I 131 Tositumomab) - Side Effects and Adverse Reactions

 
 



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, anaphylactic reaction, laryngismus, and serum sickness. In the post-marketing setting, severe hypersensitivity reactions, including fatal anaphylaxis have been reported.

Gastrointestinal Toxicity

Eighty-seven patients (38%) experienced one or more gastrointestinal adverse events, including nausea, emesis, abdominal pain, and diarrhea. These events were temporally related to the infusion of the antibody. Nausea, vomiting, and abdominal pain were often reported within days of infusion, whereas diarrhea was generally reported days to weeks after infusion.

Infusional Toxicity

A constellation of symptoms, including fever, rigors or chills, sweating, hypotension, dyspnea, bronchospasm, and nausea, have been reported during or within 48 hours of infusion. Sixty-seven patients (29%) reported fever, rigors/chills, or sweating within 14 days following the dosimetric dose. Although all patients in the clinical studies received pretreatment with acetaminophen and an antihistamine, the value of premedication in preventing infusion-related toxicity was not evaluated in any of the clinical studies. Infusional toxicities were managed by slowing and/or temporarily interrupting the infusion. Symptomatic management was required in more severe cases. Adjustment of the rate of infusion to control adverse reactions occurred in 16 patients (7%); seven patients required adjustments for only the dosimetric infusion, two required adjustments for only the therapeutic infusion, and seven required adjustments for both the dosimetric and the therapeutic infusions. Adjustments included reduction in the rate of infusion by 50%, temporary interruption of the infusion, and in 2 patients, infusion was permanently discontinued.

Table 5 lists clinical adverse events that occurred in ≥5% of patients. Table 6 provides a detailed description of the hematologic toxicity.

Table 5: Incidence of Clinical Adverse Experiences Regardless of Relationship to Study Drug Occurring in ≥5% of the Patients Treated with BEXXAR Therapeutic Regimena (N = 230)

Body System

Preferred Term

All Grades

Grade 3/4

Total

(96%)

(48%)

Non-Hematologic AEs

Body as a Whole

81%

12%

Asthenia

46%

2%

Fever

37%

2%

Infectionb

21%

<1%

Pain

19%

1%

Chills

18%

1%

Headache

16%

0%

Abdominal pain

15%

3%

Back pain

8%

1%

Chest pain

7%

0%

Neck pain

6%

1%

Cardiovascular System

26%

3%

Hypotension

7%

1%

Vasodilatation

5%

0%

Digestive System

56%

9%

Nausea

36%

3%

Vomiting

15%

1%

Anorexia

14%

0%

Diarrhea

12%

0%

Constipation

6%

1%

Dyspepsia

6%

<1%

Endocrine System

7%

0%

Hypothyroidism

7%

0%

Metabolic and Nutritional Disorders

21%

3%

Peripheral edema

9%

0%

Weight loss

6%

<1%

Musculoskeletal System

23%

3%

Myalgia

13%

<1%

Arthralgia

10%

1%

Nervous System

26%

3%

Dizziness

5%

0%

Somnolence

5%

0%

Respiratory System

44%

8%

Cough increased

21%

1%

Pharyngitis

12%

0%

Dyspnea

11%

3%

Rhinitis

10%

0%

Pneumonia

6%

0%

Skin and Appendages

44%

5%

Rash

17%

<1%

Pruritus

10%

0%

Sweating

8%

<1%

aExcludes laboratory derived hematologic adverse events (see Table 6).

bThe 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). For a more inclusive summary see ADVERSE REACTIONS, Infectious Events.

Table 6: Hematologic Toxicitya (N = 230)

Endpoint

Values

Platelets

Median nadir (cells/mm3)

43,000

Per patient incidencea platelets<50,000/mm3

53% (n = 123)

Medianb duration of platelets<50,000/mm3 (days)

32

Grade 3/4 without recovery to Grade 2, N (%)

16 (7%)

Per patient incidencec platelets<25,000/mm3

21% (n = 47)

ANC

Median nadir (cells/mm3)

690

Per patient incidencea ANC<1,000 cells/mm3

63% (n = 145)

Medianb duration of ANC<1,000 cells/mm3 (days)

31

Grade 3/4 without recovery to Grade 2, N (%)

15 (7%)

Per patient incidencec ANC<500 cells/mm3

25% (n = 57)

Hemoglobin

Median nadir (gm/dL)

10

Per patient incidencea <8 gm/dL

29% (n = 66)

Medianb duration of hemoglobin <8.0 gm/dL (days)

23

Grade 3/4 without recovery to Grade 2, N (%)

12 (5%)

Per patient incidencec hemoglobin <6.5 gm/dL

5% (n = 11)

aGrade 3/4 toxicity was assumed if patient was missing 2 or more weeks of hematology data between Week 5 and Week 9.

bDuration 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.

cGrade 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.

Delayed Adverse Reactions

Delayed adverse reactions, including hypothyroidism, HAMA, and myelodysplasia/leukemia, were assessed in 230 patients included in clinical studies and 765 patients included in expanded access programs. The entry characteristics of patients included from the expanded access programs were similar to the characteristics of patients enrolled in the clinical studies, except that the median number of prior chemotherapy regimens was fewer (2 vs. 3) and the proportion with low-grade histology was higher (77% vs. 70%) in patients from the expanded access programs.

Secondary Leukemia and Myelodysplastic Syndrome (MDS)

There were 44 cases of MDS/secondary leukemia reported among 995 (4.0%) patients included in clinical studies and expanded access programs, with a median follow-up of 29 months. The overall incidence of MDS/secondary leukemia among the 230 patients included in the clinical studies was 10% (24/230), with a median follow-up of 39 months and a median time to development of MDS of 34 months. The cumulative incidence of MDS/secondary leukemia in this patient population was 4.7% at 2 years and 15% at 5 years. The incidence of MDS/secondary leukemia among the 765 patients in the expanded access programs was 3% (20/765), with a median follow-up of 27 months and a median time to development of MDS of 31 months. The cumulative incidence of MDS/secondary leukemia in this patient population was 1.6% at 2 years and 6% at 5 years.

Secondary Malignancies

Of the 995 patients in clinical studies and the expanded access programs, there were 65 reports of second malignancies in 54 patients, excluding secondary leukemias. The most common included non-melanomatous skin cancers (26), colorectal cancer (7), head and neck cancer (6), breast cancer (5), lung cancer (4), bladder cancer (4), melanoma (3), and gastric cancer (2). Some of these events included recurrence of an earlier diagnosis of cancer.

Hypothyroidism

Of the 230 patients in the clinical studies, 203 patients did not have elevated TSH upon study entry. Of these, 137 patients had at least one post-treatment 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 post-treatment.

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 one post-treatment 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.

Immunogenicity

One percent (11/989) of the chemotherapy-relapsed or refractory patients included in the clinical studies or the expanded access program had a positive serology for HAMA prior to treatment and six patients had no baseline assessment for HAMA. Of the 230 patients in the clinical studies, 220 patients were seronegative for HAMA prior to treatment, and 219 had at least one post-treatment HAMA value obtained. With a median observation period of 6 months, a total of 23 patients (11%) became seropositive for HAMA post-treatment. 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.

Of the 765 patients in the expanded access programs, 758 patients were seronegative for HAMA prior to treatment, and 569 patients had at least one post-treatment HAMA value obtained. With a median observation period of 7 months, a total of 57 patients (10%) became seropositive for HAMA post-treatment. 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.

In a study of 76 previously untreated patients with low-grade non-Hodgkin’s lymphoma who received the BEXXAR therapeutic regimen, the incidence of conversion to HAMA seropositivity was 70%, with a median time to development of HAMA of 27 days.

The data reflect the percentage of patients whose test results were considered positive for HAMA in an ELISA assay that detects antibodies to the Fc portion of IgG1 murine immunoglobulin and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of HAMA in patients treated with the BEXXAR therapeutic regimen with the incidence of HAMA in patients treated with other products may be misleading.

Drug label data at the top of this Page last updated: 2008-01-30

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