Pegaspargase

12.1 Mechanism of Action L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of ONCASPAR is thought to be based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.

1 INDICATIONS AND USAGE ONCASPAR is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for treatment of pediatric and adult patients with: First-line acute lymphoblastic leukemia ( 1.1 ) Acute lymphoblastic leukemia and hypersensitivity to asparaginase ( 1.2 ) 1.1 First Line Acute Lymphoblastic Leukemia (ALL) ONCASPAR ® is indicated as a component of a multi-agent chemotherapeutic regimen for the first-line treatment of pediatric and adult patients with ALL. 1.2 Acute Lymphoblastic Leukemia and Hypersensitivity to Asparaginase ONCASPAR is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with ALL and hypersensitivity to native forms of L-asparaginase.

2 DOSAGE AND ADMINISTRATION Administered intramuscularly or intravenously no more frequently than every 14 days. ( 2.1 ) Patients ages 21 years and younger: 2,500 International Units/m 2 . ( 2.1 ) Patients ages over 21 years: 2,000 International Units/m 2 . ( 2.1 ) For intramuscular administration, limit the volume at a single injection site to 2 mL; if greater than 2 mL, use multiple injection sites. ( 2.3 ) For intravenous administration, give over a period of 1 to 2 hours in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP through an infusion that is already running. ( 2.3 ) Do not administer ONCASPAR if drug has been frozen, stored at room temperature for more than 48 hours, or shaken or vigorously agitated. ( 16 ) 2.1 Recommended Dosage Patients 21 Years of Age or Younger The recommended dose of ONCASPAR for patients up to and including 21 years of age is 2,500 International Units/m 2 intramuscularly or intravenously no more frequently than every 14 days. Patients More Than 21 Years of Age The recommended dose of ONCASPAR for adult patients more than 21 years of age is 2,000 International Units/m 2 intramuscularly or intravenously no more frequently than every 14 days. 2.2 Recommended Premedication Premedicate patients with acetaminophen, an H-1 receptor blocker (such as diphenhydramine), and an H-2 receptor blocker (such as famotidine) 30-60 minutes prior to administration of ONCASPAR to decrease the risk and severity of both infusion and hypersensitivity reactions [see Warnings and Precautions (5.1) ] . 2.3 Recommended Monitoring and Dosage Modifications for Adverse Reactions Monitor patients at least weekly, with bilirubin, transaminases, glucose and clinical examinations until recovery from the cycle of therapy. If an adverse reaction should occur, modify treatment according to Table 1. Table 1. Dosage Modifications Adverse Reaction Severity Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening. Action Infusion Reaction/Hypersensitivity Reaction [see Warnings and Precautions (5.1) ] Grade 1 Reduce the infusion rate by 50% Grade 2 Interrupt the infusion of ONCASPAR Treat the symptoms When symptoms resolve, resume the infusion and reduce the infusion rate by 50% Grade 3 to 4 Discontinue ONCASPAR permanently Thrombosis [see Warnings and Precautions (5.2) ] Uncomplicated deep vein thrombosis Hold ONCASPAR Treat with appropriate antithrombotic therapy Upon resolution of symptoms consider resuming ONCASPAR, while continuing antithrombotic therapy Severe or life-threatening thrombosis Discontinue ONCASPAR permanently Treat with appropriate antithrombotic therapy Pancreatitis [see Warnings and Precautions (5.3) ] Grades 3 to 4 Hold ONCASPAR for elevations in lipase or amylase >3 × ULN until enzyme levels stabilize or are declining Discontinue ONCASPAR permanently if clinical pancreatitis is confirmed Hemorrhage [see Warnings and Precautions (5.5) ] Grade 3 to 4 Hold ONCASPAR Evaluate for coagulopathy and consider clotting factor replacement as needed Resume ONCASPAR with the next scheduled dose if bleeding is controlled Hepatotoxicity [see Warnings and Precautions (5.6) ] Total bilirubin more than 3 times to no more than 10 times the ULN Hold ONCASPAR until total bilirubin is ≤1.5 times the ULN Total bilirubin more than 10 times the ULN Discontinue ONCASPAR and do not make up for missed doses 2.4 Preparation and Administration Administer ONCASPAR in a healthcare setting with appropriate medical support and resuscitation equipment to manage hypersensitivity reactions, should they occur [see Warnings and Precautions (5.1) ] . ONCASPAR is a clear and colorless solution. Visually inspect parenteral drug products for particulate matter, cloudiness, or discoloration prior to administration. If any of these are present, discard the vial. When ONCASPAR is administered intramuscularly: Limit the volume at a single injection site to 2 mL. If the volume to be administered is greater than 2 mL, use multiple injection sites. When ONCASPAR is administered intravenously: Dilute ONCASPAR with 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, using aseptic technique. After dilution, administer immediately into a running infusion of either 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP, respectively. Administer over a period of 1-2 hours. Do not infuse other drugs through the same intravenous line during administration of ONCASPAR. The diluted solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours. Protect infusion bags from direct sunlight. ONCASPAR does not contain a preservative. Use only one dose per vial; discard unused product.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Anaphylaxis and serious hypersensitivity reactions [see Warnings and Precautions (5.1) ] Thrombosis [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.3) ] Glucose intolerance [see Warnings and Precautions (5.4) ] Hemorrhage [see Warnings and Precautions (5.5) ] Hepatotoxicity, including VOD [see Warnings and Precautions (5.6) ] The most common (>5%) grade > 3 adverse reactions with ONCASPAR are hypoalbuminemia, elevated transaminase, febrile neutropenia, hypertriglyceridemia, hyperglycemia, bilirubin increased, pancreatitis, abnormal clotting studies, embolic and thrombotic events, hypersensitivity, sepsis, and infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals, at 1-800-807-6124 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. The most common grade 3 and 4 adverse reactions (>5%) included: hypoalbuminemia, elevated transaminase, febrile neutropenia, hypertriglyceridemia, hyperglycemia, bilirubin increased, pancreatitis, abnormal clotting studies, embolic and thrombotic events, hypersensitivity, sepsis, and infections. First-Line Treatment of Acute Lymphoblastic Leukemia (ALL) Study CCG-1962 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 race. 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. In Study CCG-1962, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase induced adverse reactions and for grade 3 and 4 nonhematologic 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 2: Table 2. Incidence of Selected Grades 3 and 4 Adverse Reactions in Study CCG-1962 ONCASPAR (n=58) Native E. coli L-Asparaginase (n=59) Infection 3 (5%) 3 (5%) 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%) Allergic Reactions to Asparaginase 1 (2%) 0 The safety of ONCASPAR was investigated in Study DFCI 11-001, an open label, randomized, active-controlled multicenter clinical trial that included 119 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma treated with ONCASPAR in combination with the Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. The median age on enrollment was 4 years (range, 1-18 years). The majority of patients were male (60%) and white (75%). Most patients were considered standard risk ALL (59%) and had B-cell lineage ALL (87%). The median number of doses of ONCASPAR during the study was 16 doses (one dose during induction therapy then administered every two weeks during post induction therapy). The median duration of exposure to ONCASPAR was 8 months. Table 3 summarizes the incidence of selected Grades ≥3 adverse reactions that occurred in 2 or more patients receiving ONCASPAR. Because not all grade 1 and 2 adverse reactions were collected prospectively, only grade 3 and 4 adverse reactions are presented in Table 3. Table 3. Incidence of Selected Grades ≥3 Adverse Reactions in Patients Receiving ONCASPAR With Multi-Agent Chemotherapy in Study DFCI 11-001 Adverse Reaction Grouped terms: Elevated transaminase : Alanine aminotransferase increased, Aspartate aminotransferase increased; Pancreatitis : Amylase increased, Lipase increased, Pancreatic necrosis, Pancreatitis, Pancreatitis relapsing; Bilirubin increased : Bilirubin conjugated increased, Blood bilirubin increased; Abnormal clotting studies : Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; Febrile neutropenia : Febrile neutropenia; Embolic and thrombotic events : Embolism, Pulmonary embolism, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Hypersensitivity : Hypersensitivity, Anaphylactic reaction, Drug hypersensitivity; Pneumonia: Lung infection, Pneumonia, Pneumonitis; Sepsis: Bacterial sepsis, Sepsis; Diarrhea : Colitis, Diarrhe

7 DRUG INTERACTIONS 7.1 Glucocorticoids Pegaspargase may increase the risk of glucocorticoid-induced toxicities, including osteonecrosis through a potential increase in exposure of dexamethasone [see Adverse Reactions (6.3) ] .