ONCASPAR

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 [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; Transaminases increased; Bilirubin increased : Bilirubin conjugated increased, Blood bilirubin increased; Pancreatitis : Amylase increased, Lipase increased, Pancreatic necrosis, Pancreatitis, Pancreatitis relapsing; Abnormal clotting studies : Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; 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 postapproval 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. 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.

4 CONTRAINDICATIONS ONCASPAR is contraindicated in patients with a: History of serious hypersensitivity reactions, including anaphylaxis, to ONCASPAR or to any of the excipients [see Warnings and Precautions (5.1) ] . History of serious thrombosis with prior L-asparaginase therapy [see Warnings and Precautions (5.2) ] . History of pancreatitis, including pancreatitis related to prior L-asparaginase therapy [see Warnings and Precautions (5.3) ] . History of serious hemorrhagic events with prior L-asparaginase therapy [see Warnings and Precautions (5.5) ] . Severe hepatic impairment [see Warnings and Precautions (5.6) ] . History of serious hypersensitivity reactions to ONCASPAR. ( 4 ) History of serious thrombosis with prior L-asparaginase therapy. ( 4 ) History of pancreatitis with prior L-asparaginase therapy. ( 4 ) History of serious hemorrhagic events with prior L-asparaginase therapy. ( 4 ) Severe hepatic impairment. ( 4 )

11 DESCRIPTION Pegaspargase is a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase (L-asparagine amidohydrolase), an asparagine specific enzyme. L-asparaginase is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 69 to 82 molecules of mPEG are linked to L-asparaginase; the molecular weight of each mPEG molecule is about 5 kDa. ONCASPAR activity is expressed in International Units. ONCASPAR (pegaspargase) injection is supplied as a clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered saline, pH 7.3, for intramuscular use or for dilution prior to intravenous infusion. Each vial of ONCASPAR contains 3,750 International Units of pegaspargase in 5 mL of solution. Each milliliter contains 750 International Units of pegaspargase, dibasic sodium phosphate, USP (5.58 mg), monobasic sodium phosphate, USP (1.20 mg), and Sodium Chloride, USP (8.50 mg) in Water for Injection, USP.

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.

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.

10 OVERDOSAGE Three patients received 10,000 International Units/m 2 of ONCASPAR as an intravenous infusion. One patient experienced a slight increase in liver enzymes. A second patient developed a rash 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate. A third patient did not experience any adverse reactions. There is no specific antidote for ONCASPAR overdosage. In case of overdose, monitor patients closely for signs and symptoms of adverse reactions, and appropriately manage with symptomatic and supportive treatment.

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) ] .

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Pharmacodynamic activity was assessed through serial measurements of asparagine in sera and cerebrospinal fluid (CSF). In Study CCG-1962, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of ONCASPAR (2,500 International Units/m 2 ), one each during induction and two delayed intensification treatment phases [see Clinical Studies (14.1) ] . In Study AALL07P4, the pharmacodynamic response of pegaspargase was assessed in 47 evaluable patients with newly diagnosed high risk B-precursor ALL. Asparagine concentrations in plasma (N=42) were maintained below the assay limit of quantification for at least 11 days following a single dose of ONCASPAR 2,500 International Units/m 2 during the induction phase. CSF asparagine concentration was decreased from a mean pretreatment concentration of 0.6 µg/mL (N=20) to 0.2 µg/mL on Day 4 (N=41) and remained decreased at 0.2 µg/mL (N=39) 25 days after the administration of a single dose of ONCASPAR in the induction phase. 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.

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.

12.2 Pharmacodynamics Pharmacodynamic activity was assessed through serial measurements of asparagine in sera and cerebrospinal fluid (CSF). In Study CCG-1962, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of ONCASPAR (2,500 International Units/m 2 ), one each during induction and two delayed intensification treatment phases [see Clinical Studies (14.1) ] . In Study AALL07P4, the pharmacodynamic response of pegaspargase was assessed in 47 evaluable patients with newly diagnosed high risk B-precursor ALL. Asparagine concentrations in plasma (N=42) were maintained below the assay limit of quantification for at least 11 days following a single dose of ONCASPAR 2,500 International Units/m 2 during the induction phase. CSF asparagine concentration was decreased from a mean pretreatment concentration of 0.6 µg/mL (N=20) to 0.2 µg/mL on Day 4 (N=41) and remained decreased at 0.2 µg/mL (N=39) 25 days after the administration of a single dose of ONCASPAR in the induction phase.

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.

20221229

10

3 DOSAGE FORMS AND STRENGTHS Injection: 3,750 International Units/5 mL (750 International Units/mL) clear, colorless solution in a single-dose vial. Injection: 3,750 International Units/5 mL (750 International Units/mL) solution in a single-dose vial. ( 3 )

ONCASPAR Pegaspargase PEGASPARGASE PEGASPARGASE SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM SODIUM CHLORIDE WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity and impairment of fertility studies have not been conducted with pegaspargase.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity and impairment of fertility studies have not been conducted with pegaspargase.

BLA103411

ONCASPAR

Pegaspargase

72694-954

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 5 mL Vial Carton NDC 72694-954-01 ONCASPAR ® pagaspargase Injection 3750 International Units Per 5 mL (750 International Units Per mL) For intravenous or intramuscular use. Single-use vial. Discard unused portion. Rx ONLY SERVIER PRINCIPAL DISPLAY PANEL - 5 mL Vial Carton

ONCASPAR is a registered trademark of Servier IP UK LTD, a wholly owned, indirect subsidiary of Les Laboratoires Servier. Servier and the Servier logo are trademarks of Les Laboratoires Servier. Manufactured by: Servier Pharmaceuticals LLC, Boston, MA 02210 U.S. License No. 2125

17 PATIENT COUNSELING INFORMATION Anaphylaxis and Serious Hypersensitivity Reactions Inform patients of the possibility of serious allergic reactions, including anaphylaxis, and to seek immediate medical care for any swellings or difficulty breathing [see Warnings and Precautions (5.1) ] . Thrombosis Instruct patients on the risk of thrombosis and hemorrhage and to seek immediate medical attention if they experience severe headache, arm or leg swelling, shortness of breath, or chest pain [see Warnings and Precautions (5.2) ] . Pancreatitis Instruct patients on the signs and symptoms of pancreatitis and to seek immediate medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.3) ] . Glucose Intolerance Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to immediately report excessive thirst or increase in the volume or frequency of urination [see Warnings and Precautions (5.4) ] . Hemorrhage Advise patients to report any unusual bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.5) ] . Hepatotoxicity Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.6) ] . Pregnancy Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ONCASPAR and for 3 months after the last dose [see Use in Specific Populations (8.3) ] . Lactation Advise women not to breastfeed during treatment with ONCASPAR and for 1 month after the last dose [see Use in Specific Populations (8.2) ] .

14 CLINICAL STUDIES 14.1 First-Line Treatment of ALL Study CCG-1962 The safety and effectiveness of ONCASPAR was evaluated in an open label, multicenter, randomized, active controlled study (Study CCG-1962). In this study, 118 pediatric patients aged 1 to 9 years with previously untreated standard-risk ALL were randomized 1:1 to ONCASPAR or native E. coli L-asparaginase as part of combination therapy. ONCASPAR was administered intramuscularly at a dose of 2,500 International Units/m 2 on Day 3 of the 4 week induction phase and on Day 3 of each of two 8 week delayed intensification phases. Native E. coli L-asparaginase was administered intramuscularly at a dose of 6,000 International Units/m 2 three times weekly for 9 doses during induction and for 6 doses during each delayed intensification phase. The primary determination of effectiveness was based on demonstration of similar asparagine depletion (magnitude and duration) in the ONCASPAR and native E. coli L-asparaginase arms. The protocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤1 µM. The proportion of patients with this level of depletion was similar between the 2 study arms during all 3 phases of treatment at the protocol-specified time points. In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose of asparaginase in the treatment phase and remained low for approximately 3 weeks for both ONCASPAR and native E. coli L-asparaginase arms. Serum asparagine concentrations during the induction phase are shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensification phases are similar to the pattern of serum asparagine depletion in the induction phase. Figure 1. Mean (± Standard Error) Serum Asparagine Concentrations During Study CCG-1962 Induction Phase Note: ONCASPAR (2,500 International Units/m 2 intramuscular) was administered on Day 3 of the 4-week induction phase. Native E. coli L-asparaginase (6,000 International Units/m 2 intramuscular) was administered 3 times weekly for 9 doses during induction. CSF asparagine concentrations were determined in 50 patients during the induction phase. CSF asparagine decreased from a mean pre-treatment concentration of 3.1 µM to 1.7 µM on Day 4±1 and 1.5 µM at 25±1 days after administration of ONCASPAR. These findings were similar to those observed in the native E. coli L-asparaginase treatment arm. Concentrations of asparaginase activities greater than 0.1 International Units/mL were observed in over 90% of the samples from patients treated with ONCASPAR during Induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days. While the 3-year Event-Free Survival (EFS) for the ONCASPAR and native E. coli L-asparaginase study arms were similar and in the range of 80%, Study CCG-1962 was not designed to evaluate for differences in EFS rates. 14.2 Patients with ALL Hypersensitive to Asparaginase The safety and effectiveness of ONCASPAR was evaluated in 4 open label studies enrolling a total of 42 patients with multiply relapsed, acute leukemia [39 (93%) with ALL] with a history of prior clinical allergic reaction to asparaginase. Hypersensitivity to asparaginase was defined by a history of systemic rash, urticaria, bronchospasm, laryngeal edema, hypotension, or local erythema, urticaria, or swelling, greater than 2 centimeters, for at least 10 minutes following administration of any form of native E. coli L-asparaginase. All patients received ONCASPAR at a dose of 2,000 or 2,500 International Units/m 2 administered intramuscularly or intravenously every 14 days. Patients received ONCASPAR as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50% (95% confidence interval: 35%, 65%), based upon 36% complete remissions and 14% partial remissions. These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E. coli L-asparaginase-containing re-induction chemotherapy. Anti-tumor activity was also observed with single-agent ONCASPAR. Three responses (1 complete remission and 2 partial remissions) were observed in 9 adult and pediatric patients with relapsed ALL and hypersensitivity to native E. coli L-asparaginase. Figure 1

8.5 Geriatric Use Clinical studies of ONCASPAR did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.

8.4 Pediatric Use The safety and effectiveness of ONCASPAR in the treatment of ALL have been established in pediatric patients. Use of ONCASPAR in these age groups is supported by evidence of efficacy as first-line treatment from one adequate and well-controlled trial, and evidence of efficacy for treatment of patients with hypersensitivity to asparaginase from four adequate and well-controlled trials [see Clinical Studies (14.1) ] , and safety data from 7 total trials. The pediatric patients treated with ONCASPAR 2,500 International Units/m 2 on these trials included 26 infants (1 month to <2 years old), 165 children (2 years to <12 years old), and 39 adolescents (12 to 17 years old).

8.1 Pregnancy Risk summary Based on published literature studies with L-asparaginase in pregnant animals, ONCASPAR can cause fetal harm when administered to a pregnant woman. There are no available data on ONCASPAR use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published literature studies in pregnant animals suggest asparagine depletion may cause harm to the animal offspring (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with ONCASPAR to evaluate its effect on reproduction and fetal development. Published literature studies in which pregnant rabbits were administered L-asparaginase or pregnant rats were deprived of dietary asparagine suggested harm to the animal offspring.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk summary Based on published literature studies with L-asparaginase in pregnant animals, ONCASPAR can cause fetal harm when administered to a pregnant woman. There are no available data on ONCASPAR use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published literature studies in pregnant animals suggest asparagine depletion may cause harm to the animal offspring (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with ONCASPAR to evaluate its effect on reproduction and fetal development. Published literature studies in which pregnant rabbits were administered L-asparaginase or pregnant rats were deprived of dietary asparagine suggested harm to the animal offspring. 8.2 Lactation Risk summary There are no data on the presence of pegaspargase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONCASPAR and for 1 month after the last dose. 8.3 Females and Males of Reproductive Potential ONCASPAR can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Pregnancy testing is recommended in females of reproductive potential prior to initiating ONCASPAR. Contraception Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with ONCASPAR and for 3 months after the last dose. 8.4 Pediatric Use The safety and effectiveness of ONCASPAR in the treatment of ALL have been established in pediatric patients. Use of ONCASPAR in these age groups is supported by evidence of efficacy as first-line treatment from one adequate and well-controlled trial, and evidence of efficacy for treatment of patients with hypersensitivity to asparaginase from four adequate and well-controlled trials [see Clinical Studies (14.1) ] , and safety data from 7 total trials. The pediatric patients treated with ONCASPAR 2,500 International Units/m 2 on these trials included 26 infants (1 month to <2 years old), 165 children (2 years to <12 years old), and 39 adolescents (12 to 17 years old). 8.5 Geriatric Use Clinical studies of ONCASPAR did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING ONCASPAR (pegaspargase) injection is supplied as a sterile, clear, colorless, preservative-free solution in Type I single-dose vial containing 3,750 International Units of pegaspargase per 5 mL (750 International Units per mL) solution (NDC 72694-954-01). Store ONCASPAR refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not shake or freeze product . Unopened vials may be stored at room temperature (15°C to 25°C [59°F to 77°F]) for no more than 48 hours.

Store ONCASPAR refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not shake or freeze product . Unopened vials may be stored at room temperature (15°C to 25°C [59°F to 77°F]) for no more than 48 hours.