Pegaspargase

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, Diarrhea, Enterocolitis, Neutropenic colitis; Hemorrhages SMQ (excludes laboratory terms): Disseminated intravascular coagulation, Epistaxis, Hematoma, Hemorrhage intracranial, Melena, Esophageal ulcer hemorrhage, Small intestinal hemorrhage, Upper gastrointestinal hemorrhage; Fungal infection: Fungal infection, Hepatic infection fungal, Respiratory tract infection fungal, Splenic infection fungal, Systemic candida. ONCASPAR 2500 IU/m 2 N=119 Grade ≥3 Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. n (%) Elevated transaminase 79 (66) Febrile neutropenia 48 (40) Hypertriglyceridemia 36 (30) Hypoalbuminemia 33 (28) Bilirubin increased 30 (25) Hyperglycemia 29 (24) Pancreatitis 29 (24) Abnormal clotting studies 25 (21) Embolic and thrombotic events 10 (8) Hypersensitivity 8 (7) Pneumonia 8 (7) Sepsis 7 (6) Diarrhea 6 (5) Hemorrhages 5 (4) Fungal Infection 3 (3) 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 [see Clinical Studies (14.2) ] . 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 3 ). 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%). Allergic Reactions Allergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria. Among 58 ONCASPAR-treated patients enrolled in Study CCG-1962, 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 4 ). 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 a 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 4 ). Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to ONCASPAR (see Table 4 ). Table 4. Incidence of Clinical Allergic Reactions, Overall and by Severity Grade Patient Status Toxicity Grade, n (%) Total 1 2 3 4 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) 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other asparaginase products may be misleading. In Study CCG-1962, 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). In study CCG-1962, there is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions or altered pharmacokinetics (i.e., loss of asparaginase activity). In Study DFCI 11-001, of the 100 evaluable patients treated with ONCASPAR, 19 (19%) patients developed anti-drug antibodies (ADA) during treatment; 18 of these 19 patients were positive for anti-PEG antibodies. The presence of ADA correlated with the occurrence of hypersensitivity reactions. There is insufficient information to determine whether the development of antibodies is associated with altered pharmacokinetics (i.e., loss of asparaginase activity). 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ONCASPAR. 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. Blood and lymphatic system disorders: Coagulopathy. Gastrointestinal disorders : Hepatic impairment, pancreatic cyst, pancreatitis. Hepatic: Veno-occlusive disease. Immune system disorders: Anaphylactic shock, hypersensitivity reaction. Investigations: Blood cholesterol increased. Metabolism and nutrition disorders: Hyperglycemia, hyperammonemia. Musculoskeletal and connective tissue disorders: Osteonecrosis. Vascular disorders: Hemorrhage including central nervous system hemorrhage, thrombosis including superior sagittal sinus thrombosis.

12.3 Pharmacokinetics Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity after intramuscular (IM, CCG-1962) and intravenous (IV, AALL07P4) administration of 2,500 International Units/m 2 in patients with ALL. Absorption The mean maximum asparaginase activity (C max ) was reached at approximately 1 IU/mL (n=45-52) on Day 5 after a single IM injection. The mean half-life of absorption from the IM site was 1.7 days. The relative bioavailability was 82% following the first IM dose and 98% following repeat dosing. The mean C max and the area under the curve (AUC 0-inf ) was 1.6 IU/mL and 16.6 IU/mL*day, respectively, after a single IV infusion (n=47) during the induction phase. Distribution The mean volume of distribution at steady state was estimated to be 1.86 L/m 2 after a single IM injection and approximately 2 L after a single IV infusion based on non-compartmental analysis. Elimination The mean elimination half-life was approximately 5.8 days following a single IM injection and 5.3 days following a single IV infusion. The clearance was 0.17 L/m 2 /day and 0.2 L/day, respectively, for a single IM and IV dose. Specific Populations The impact of renal and hepatic impairment on the pharmacokinetics of ONCASPAR is unknown.