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adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in other sections of the label: • Anaphylaxis and serious allergic reactions [see Warnings and Precautions ( 5.1 )] • Serious thrombosis [see Warnings and Precautions ( 5.2 )] • Pancreatitis [see Warnings and Precautions ( 5.3 )] • Glucose intolerance [see Warnings and Precautions ( 5.4 )] • Coagulopathy [see Warnings and Precautions ( 5.5 )] • Hepatotoxicity and abnormal liver function [see Warnings and Precautions ( 5.6 )] The most common adverse reactions with Oncaspar ® are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to Oncaspar ® . Most common adverse reactions (≥ 2%) are allergic reactions (including anaphylaxis), central nervous system (CNS) thrombosis, coagulopathy, elevated transaminases, hyperbilirubinemia, hyperglycemia, and pancreatitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc. at 1-888-393-4584 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, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. First-Line ALL The data presented below are derived from 2 studies in patients with standard-risk ALL who received Oncaspar ® as a component of first-line multi-agent chemotherapy. Study 1 was a randomized (1:1), active-controlled study that enrolled 118 patients, with a median age of 4.7 years (1.1-9.9 years), of whom 54% were males and 65% White, 14% Hispanic, 8% Black, 8% Asian, and 6% other. Of the 59 patients in Study 1 who were randomized to Oncaspar ® , 48 patients (81%) received all 3 planned doses of Oncaspar ® , 6 (10%) received 2 doses, 4 (7%) received 1 dose, and 1 patient (2%) did not receive the assigned treatment. Study 2 is an ongoing, multi-factorial design study in which all patients received Oncaspar ® as a component of various multi-agent chemotherapy regimens; interim safety data are available for 2,770 patients. Study participants had a median age of 4 years (1-10 years), and were 55% male, 68% White, 18% Hispanic, 4% Black, 3% Asian, and 7% other. Per protocol, the schedule of Oncaspar ® varied by treatment arm, with intermittent doses of Oncaspar ® for up to 10 months. In Study 1, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase-induced adverse reactions and for grade 3 and 4 non-hematologic adverse reactions according to the Children’s Cancer Group (CCG) Toxicity and Complication Criteria. The per-patient incidence, by treatment arm, for these selected adverse reactions occurring at a severity of grade 3 or 4 are presented in Table 1 below: TABLE 1 STUDY 1: PER-PATIENT INCIDENCE OF SELECTED GRADE 3 AND 4 ADVERSE REACTIONS Oncaspar ® (n=58) Native E. coli L-Asparaginase (n=59) Abnormal Liver Tests 3 (5%) 5 (8%) Elevated Transaminases Aspartate aminotransferase, alanine aminotransferase. 2 (3%) 4 (7%) Hyperbilirubinemia 1 (2%) 1 (2%) Hyperglycemia 3 (5%) 2 (3%) Central Nervous System Thrombosis 2 (3%) 2 (3%) Coagulopathy Prolonged prothrombin time or partial thromboplastin time; or hypofibrinogenemia. 1 (2%) 3 (5%) Pancreatitis 1 (2%) 1 (2%) Clinical Allergic Reactions to Asparaginase 1 (2%) 0 Previously Treated ALL Adverse reaction information was obtained from 5 clinical trials that enrolled a total of 174 patients with relapsed ALL who received Oncaspar ® as a single agent or in combination with multi-agent chemotherapy. The toxicity profile of Oncaspar ® in patients with previously treated relapsed ALL is similar to that reported above with the exception of clinical allergic reactions (see Table 2 ). The most common adverse reactions of Oncaspar ® were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to Oncaspar ® treatment were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%). 6.2 Allergic Reactions Allergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria. First-Line ALL Among 58 Oncaspar ® -treated patients enrolled in Study 1, clinical allergic reactions were reported in 2 patients (3%). One patient experienced a grade 1 allergic reaction and the other grade 3 hives; both occurred during the first delayed intensification phase of the study (see Table 2 ). Previously Treated ALL Among 62 patients with relapsed ALL and prior hypersensitivity reactions to asparaginase, 35 patients (56%) had a history of clinical allergic reactions to native Escherichia (E.) coli L-asparaginase, and 27 patients (44%) had history of clinical allergic reactions to both native E. coli and native Erwinia L-asparaginase. Twenty (32%) of these 62 patients experienced clinical allergic reactions to Oncaspar ® (see Table 2 ). Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to Oncaspar ® (see Table 2 ). TABLE 2 INCIDENCE OF CLINICAL ALLERGIC REACTIONS, OVERALL AND BY SEVERITY GRADE Toxicity Grade, n (%) Patient Status 1 2 3 4 Total Previously Hypersensitive Patients (n=62) 7 (11) 8 (13) 4 (6) 1 (2) 20 (32) Non- Hypersensitive Patients (n=112) 5 (4) 4 (4) 1 (1) 1 (1) 11 (10) First Line (n=58) 1 (2) 0 1 (2) 0 2 (3) 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product. In Study 1, Oncaspar ® -treated patients were assessed for evidence of binding antibodies using an enzyme-linked immunosorbent assay (ELISA) method. The incidence of protocol-specified “high-titer” antibody formation was 2% in Induction (n=48), 10% in Delayed Intensification 1 (n=50), and 11% in Delayed Intensification 2 (n=44). There is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions, altered pharmacokinetics, or loss of anti-leukemic efficacy. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Oncaspar ® with the incidence of antibodies to other products may be misleading.