Bexxar Side Effects, and Drug Interactions - Tositumomab and Iodine I 131 Tositumomab

Bexxar Side Effects, and Drug Interactions - Tositumomab and Iodine I 131 Tositumomab

SIDE EFFECTS

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 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. Nineteen of 230 (8%) 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, anaphylactoid reaction, laryngismus, and serum sickness.

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 ³ 5% of patients. Table 6 provides a detailed description of the hematologic toxicity.

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 32 new cases of MDS/secondary leukemia reported among 994 (3.2%) patients included in clinical studies and expanded access programs, with a median follow-up of 21 months. The overall incidence of MDS/secondary leukemia among the 229 patients included in the clinical studies, was 8.3% (19/229), with a median follow-up of 35 months and a median time to development of MDS of 30 months. The cumulative incidence of MDS/secondary leukemia was 4.2% at 2 years and 10.7% at 4 years. Among the 765 patients included in the expanded access program, where the median duration of follow-up was shorter (20 months), the overall incidence of MDS/secondary leukemia was 1.7% (13/765) and the median time to development of MDS was 23 months. In the expanded access population, the cumulative incidence of MDS/secondary leukemia was 1.4% at 2 years and 4.8% at 4 years.

Secondary Malignancies: There were 52 reports of second malignancies, excluding secondary leukemias. The most common included non-melanomatous skin cancers, breast, lung, bladder, and head and neck cancers. Some of these events included recurrence of an earlier diagnosis of cancer.

Hypothyroidism: Twelve percent (27/230) of the patients included from the clinical studies had an elevated TSH level (8%) or no TSH level obtained (4%) prior to treatment. Of the 203 patients documented to be euthyroid at entry, 137 (67%) patients had at least one follow-up TSH value. The overall incidence of hypothyroidism, in the clinical study patients was 14% with cumulative incidences of 4.2% at 6 months and 8.1%, 12.6%, and 15.0% at 1, 2, and 4 years, respectively. New events have been observed up to 72 months post treatment. Twelve percent (117/990) of the patients included in clinical studies or the expanded access programs had an elevated TSH level (8%) or a history of hypothyroidism (4%) prior to treatment and 5 patients had no baseline information. Of the 873 who were euthyroid at entry, 583 (67%) had at least one post-treatment TSH value obtained. With a median observation period of 18 months, 54 patients (9%) became hypothyroid as determined by elevated TSH. The cumulative incidence of hypothyroidism in the combined populations was 9.1% and 17.4% at 2 and 4 years, respectively.

Immunogenicity: Two percent (4/230) of the chemotherapy-relapsed or refractory patients included in the clinical studies had a positive serology for HAMA prior to treatment and six patients had no baseline assessment for HAMA. Of the 220 patients who were seronegative prior to treatment, 219 (99.5%) had at least one post-treatment HAMA value obtained. With a median observation period for HAMA seroconversion of 6 months, 23 patients (11%) seroconverted to HAMA positivity. The median time to development of HAMA was 6 months. In a study of 77 patients who were chemotherapy-naïve, the incidence of conversion to HAMA seropositivity was 70%, with a median time to development of HAMA of 27 days.

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 patient had no baseline assessment for HAMA. Of the 978 patients who were seronegative for HAMA prior to treatment, 785 (80%) had at least one post-treatment HAMA value obtained. With a median observation period of 6 months, a total of 76 patients (10%) became seropositive for HAMA post-treatment. The median time of HAMA development was 148 days, with 45 (59%) patients seropositive for HAMA by 6 months. No patient became seropositive for HAMA more than 30 months after administration of the BEXXAR therapeutic regimen.

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.

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 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.