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adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Serious Allergic Reactions, Including Anaphylaxis [see Boxed Warning, Warnings and Precautions (5.1) • Prolonged and Severe Cytopenias [see Warnings and Precautions (5.2)] • Secondary malignancies [see Warnings and Precautions (5.4)] • Hypothyroidism [see Warnings and Precautions (5.5)] The most common adverse reactions in patients receiving the BEXXAR therapeutic regimen (per-patient incidence greater than 25%) were neutropenia, thrombocytopenia, anemia, infections (including pneumonia, bacteremia, septicemia, bronchitis, and skin infections), infusion reactions, asthenia, fever, and nausea [see Boxed Warning, Warnings and Precautions (5.1, 5.2)] . The most common serious adverse reactions in patients receiving the BEXXAR therapeutic regimen were severe and prolonged cytopenias, infections (including pneumonia, bacteremia, septicemia, bronchitis, and skin infections), serious allergic reactions (including bronchospasm and angioedema), infusion reactions, and secondary leukemia and myelodysplastic syndrome [see Boxed Warning, Warnings and Precautions (5.1, 5.2, 5.4)] . The most common adverse reactions (≥25%) are neutropenia, thrombocytopenia, anemia, infections, infusion reactions, asthenia, fever, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 clinical practice. The reported safety data reflects exposure to the BEXXAR therapeutic regimen in 230 patients with non-Hodgkin's lymphoma enrolled in 5 clinical trials using the recommended dose and schedule. Patients were followed for a median of 39 months; 79% were followed for at least 12 months for survival and selected adverse reactions. Patients had a median of 3 prior chemotherapy regimens, a median age of 55 years, and 60% were male. Twenty-seven percent (27%) had transformation to a higher grade histology; 29% had intermediate-grade histology, and 2% had high-grade histology (IWF); 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 marrow space. Data on serious adverse reactions and human anti-mouse antibodies (HAMA) and TSH levels were obtained from an additional 765 patients enrolled in the expanded access program and used to supplement the characterization of delayed adverse reactions. Patients in the expanded access program had fewer prior chemotherapy regimens (2 versus 3) and a higher proportion had low-grade histology (77% versus 70%) compared to patients in clinical trials. Table 2. Incidence of Non-Hematologic Adverse Reactions Occurring in ≥5% of 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 81% 12% Asthenia 46% 2% Fever 37% 2% Infection a 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% a The COSTART term for infection includes a subset of infections (e.g., upper respiratory infection). Other types of infections are mapped to preferred terms (e.g., pneumonia and sepsis). Table 3. Hematologic Toxicity a (N = 230) Parameter Values Platelets Median nadir (cells/mm 3 ) 43,000 Per patient incidence a platelets <50,000/mm 3 53% (n = 123) Median b duration of platelets <50,000/mm 3 32 days Grade 3/4 without recovery to Grade 2, N (%) 16 (7%) Per patient incidence c platelets <25,000/mm 3 21% (n = 47) Absolute Neutrophil Count (ANC) Median nadir (cells/mm 3 ) 690 Per patient incidence a ANC <1,000 cells/mm 3 63% (n = 145) Median b duration of ANC <1,000 cells/mm 3 31 days Grade 3/4 without recovery to Grade 2, N (%) 15 (7%) Per patient incidence c ANC <500 cells/mm 3 25% (n = 57) Hemoglobin Median nadir (gm/dL) 10 Per patient incidence a <8 gm/dL 29% (n = 66) Median b duration of hemoglobin <8.0 gm/dL 23 days Grade 3/4 without recovery to Grade 2, N (%) 12 (5%) Per patient incidence c hemoglobin <6.5 gm/dL 5% (n = 11) a Grade 3/4 toxicity was assumed if patient was missing 2 or more weeks of hematology data between Week 5 and Week 9. b 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. c 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. Prolonged and Severe Cytopenias : The incidence and duration of severe cytopenias are shown in Table 3. Sixty-three (27%) patients received one or more hematologic supportive care measures following the therapeutic dose including G‑CSF, epoetin alfa, platelet transfusions, and packed red blood cell transfusions. Twenty-eight (12%) patients experienced hemorrhagic adverse reactions. Infections : One hundred and four patients (45%) patients experienced one or more infections. Twenty (9%) experienced serious infections including pneumonia, bacteremia, septicemia, bronchitis, and skin infections. Allergic (Hypersensitivity) Reactions : Fourteen patients (6%) experienced one or more of the following adverse reactions: allergic reaction, facial edema, injection site hypersensitivity, anaphylactic reaction, laryngismus, and serum sickness. Infusion-related Adverse Reactions : Infusion reactions including fever, rigors or chills, sweating, hypotension, dyspnea, bronchospasm, and nausea occurred during or within 48 hours of infusion. Sixty-seven patients (29%) experienced fever, rigors/chills, or sweating within 14 days following the dosimetric dose. All patients in the clinical studies received pretreatment with acetaminophen and an antihistamine. Myelodysplastic Syndrome (MDS)/Secondary Leukemia : The 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 34 months. The cumulative incidence of MDS/secondary leukemia 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 program was 3% (20/765), with a median follow-up of 27 months and a median time to development 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 secondary malignancies reported in 54 patients (5%) in clinical studies and the expanded access program. These included non‑melanoma 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). Hypothyroidism : Of the 230 patients in the clinical studies, 203 patients did not have elevated TSH at study entry. Of these, 137 patients had at least one post-treatment TSH value available and were not taking thyroid hormonal treatment at study entry. With a median follow-up period of 46 months, the incidence of hypothyroidism (elevated TSH or initiation of thyroid replacement therapy) was 18% with a median time to development of 16 months. The cumulative incidences of hypothyroidism at 2 and 5 years in these 137 patients were 11% and 19%, respectively. Onset of hypothyroidism has occurred up to 90 months post-treatment. The cumulative incidence and median time to development of hypothyroidism were similar in the expanded access program. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as tositumomab. Serum samples from 989 chemotherapy-relapsed or refractory patients included in the clinical studies or the expanded access program were tested by an enzyme-linked immunosorbent assay (ELISA) that detects antibodies to the Fc portion of IgG 1 murine immunoglobulin. One percent of the patients (11/989) had a positive serology for HAMA prior to treatment. The post-treatment incidence of HAMA seropositivity is summarized in Table 4. Table 4. Incidence of HAMA Seropositivity Among Patients With Chemotherapy-refractory or Relapsed Non-Hodgkin’s Lymphoma Receiving the BEXXAR Therapeutic Regimen Chemotherapy-refractory or relapsed patients Percent HAMA positive Kaplan-Meier estimate of HAMA positivity 6 months 12 months 18 months In clinical trials 23/219 (11%) 6% 17% 21% In expanded-access program 57/569 (10%) 7% 12% 13% 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 27 days. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to BEXXAR with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of the BEXXAR therapeutic regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Hypersensitivity reactions including fatal anaphylaxis. Nervous system disorders: Axonal neuropathy leading to quadriparesis.