PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 mL Vial Carton. NDC 72694-515-01ASPARLAS(TM)calaspargase pegol-mknlInjection3750 units/5 mL(750 units/mL)For Intravenous InfusionOnlyOne single-dose vial.Discard unused portion.Must dilute before use.Rx ONLYSERVIER. PRINCIPAL DISPLAY PANEL 5 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and effectiveness of ASPARLAS in the treatment of ALL have been established in pediatric patients month to 17 years (no data for the age group 1 month old). Use of ASPARLAS in these age groups is supported by evidence from an adequate and well-controlled trial with additional safety from second trial. The trials included 208 children with ALL or lymphoblastic lymphoma treated with ASPARLAS; there were 19 infants (1 month to 2 years old), 128 children (2 years to 12 years old), and 61 adolescents (12 years to 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups [see Adverse Reactions (6.1), Clinical Studies (14)].

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics. Calaspargase pegol-mknl pharmacodynamic (PD) response was assessed through measurement of plasma and cerebrospinal fluid (CSF) asparagine concentrations via an LC-MS/MS assay.Asparagine concentrations in plasma (N=41) were maintained below the assay limit of quantification for more than 18 days following single dose of ASPARLAS 2,500 U/m2 during the induction phase. Mean CSF asparagine concentrations decreased from pretreatment concentration of 0.8 ug/mL (N=10) to 0.2 ug/mL on Day (N=37) and remained decreased at 0.2 ug/mL (N=35) 25 days after the administration of single dose of ASPARLAS 2,500 U/m2 in the induction phase.

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Hypersensitivity [see Warnings and Precautions (5.1)].Pancreatitis [see Warnings and Precautions (5.2)].Thrombosis [see Warnings and Precautions (5.3)].Hemorrhage [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)].. Hypersensitivity [see Warnings and Precautions (5.1)].. Pancreatitis [see Warnings and Precautions (5.2)].. Thrombosis [see Warnings and Precautions (5.3)].. Hemorrhage [see Warnings and Precautions (5.4)] . Hepatotoxicity [see Warnings and Precautions (5.5)].. The most common (incidence >= 10%) grade >= adverse reactions were elevated transaminase, bilirubin increased, pancreatitis and abnormal clotting studies. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Servier Pharmaceuticals LLC at 1-800-807-6124 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Study DFCI 11-001The safety of ASPARLAS was investigated in Study DFCI 11-001, an open-label, randomized, active-controlled multicenter clinical trial that treated 237 children and adolescents with newly-diagnosed ALL or lymphoblastic lymphoma, with ASPARLAS 2,500 U/m2 (n=118) or pegaspargase 2,500 U/m2 (n=119) as part of Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. The median age on enrollment was years (range, 1-20) years. The majority of patients were male (62%) and white (70%). Most patients were considered standard risk (SR, 59%) and had B-cell lineage ALL (87%).The median number of doses during the study was 11 doses for ASPARLAS (administered every three weeks) and 16 doses for pegaspargase (administered every two weeks). The median duration of exposure was months for both ASPARLAS and pegaspargase.There was fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with pancreatic pseudocyst).Table summarizes the incidence of selected Grades >=3 adverse reactions that occurred in or more patients receiving ASPARLAS. Because not all grade and adverse reactions were collected prospectively, only grade and adverse events are presented in Table 2.Table 2: Selected Grades >= Adverse Reactions in Patients Receiving ASPARLAS With Multi-Agent Chemotherapy (Study DFCI 11-001)ASPARLAS or pegaspargase were administered as component of multi-agent chemotherapy regimens. Adverse ReactionGrouped 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; Diarrhea: Colitis, Diarrhea, Enterocolitis, Neutropenic colitis; Hypersensitivity: Anaphylactic reaction, Drug hypersensitivity, Hypersensitivity; Embolic and thrombotic events SMQ: Device related thrombosis, Disseminated intravascular coagulation, Embolism, Intracardiac thrombus, Intracranial venous sinus thrombosis, Pulmonary embolism, Superior sagittal sinus thrombosis, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Sepsis: Bacterial sepsis, Sepsis; Dyspnea: Hypoxia, Respiratory failure; 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; Pneumonia: Lung infection, Pneumonia, Pneumonitis; Arrhythmia: Atrioventricular block complete, Sinus tachycardia, Ventricular arrhythmia; Cardiac failure: Ejection fraction decreased, Left ventricular dysfunction. ASPARLAS2,500 U/m2 N=118Pegaspargase2,500 U/m2 N=119Grades >=3n (%)Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grades >=3n (%) Elevated transaminase61 (52)79 (66)Bilirubin increased24 (20)30 (25)Pancreatitis21 (18)29 (24)Abnormal clotting studies17 (14)25 (21)Diarrhea10 (9)6 (5)Hypersensitivity9 (8)8 (7)Embolic and thrombotic events9 (8)10 (8)Sepsis6 (5)7 (6)Dyspnea5 (4)1 (1)Hemorrhages5 (4)5 (4)Fungal infection4 (3)3 (3)Pneumonia4 (3)8 (7)Arrhythmia2 (2)1 (1)Cardiac failure2 (2)1 (1)In the subgroup of patients with B-cell lineage ALL, the complete remission rate in the ASPARLAS arm was 98% (95/97), compared to 99% in the pegaspargase arm; the Kaplan-Meier estimates of overall survival of the treatment arms were comparable.. Study AALL07P4The safety of ASPARLAS was also evaluated in Study AALL07P4, an open-label, randomized, active-controlled, multicenter clinical trial that treated patients with newly-diagnosed high-risk B-precursor ALL using ASPARLAS 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68), or pegaspargase 2,500 U/m2 (n=52), as component of an augmented Berlin-Frankfurt-Munster (BFM) therapy regimen. The median age was 11 years (range to 26 years); the median duration of exposure was months for both ASPARLAS and pegaspargase. In this study, the induction mortality of patients treated with ASPARLAS was 2.8% (3 out of 111); there were no induction deaths among 52 patients treated with pegaspargase.. 6.2Immunogenicity. As with all therapeutic proteins, there is 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 to ASPARLAS in the studies described below with the incidence of antibodies in other studies or to other asparaginase products may be misleading.Immunogenicity was assessed using enzyme linked immunosorbent assays (ELISA) in Study DFCI 11-001. Of 98 evaluable patients treated with ASPARLAS, 15 (15%) patients developed new or an increased titer of anti-drug antibodies (ADA) during treatment; 14 of these 15 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, mutagenicity, and impairment of fertility studies have not been conducted with calaspargase pegol-mknl.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism 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 ASPARLAS 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 reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.. 12.2Pharmacodynamics. Calaspargase pegol-mknl pharmacodynamic (PD) response was assessed through measurement of plasma and cerebrospinal fluid (CSF) asparagine concentrations via an LC-MS/MS assay.Asparagine concentrations in plasma (N=41) were maintained below the assay limit of quantification for more than 18 days following single dose of ASPARLAS 2,500 U/m2 during the induction phase. Mean CSF asparagine concentrations decreased from pretreatment concentration of 0.8 ug/mL (N=10) to 0.2 ug/mL on Day (N=37) and remained decreased at 0.2 ug/mL (N=35) 25 days after the administration of single dose of ASPARLAS 2,500 U/m2 in the induction phase.. 12.3Pharmacokinetics. Calaspargase pegol-mknl pharmacokinetics (PK) were assessed through measurement of plasma asparaginase activity via coupled enzymatic assay.The plasma asparaginase activity pharmacokinetics were characterized in 43 patients (1 to 26 years) with newly diagnosed high risk B-precursor ALL treated with multidrug backbone therapy. Table summarizes the plasma asparaginase activity pharmacokinetic parameters after single dose of ASPARLAS 2,500 U/m2 in the induction phase.Table 3: Plasma Asparaginase Activity Pharmacokinetic Parameters After Single Dose of ASPARLAS 2,500 U/m2 in Patients with ALL in Study AALL07P4ParameterArithmetic Mean (%CV)N=43General Cmax (U/mL)1.62 (23.0) AUC0-25day (dayU/mL)16.9 (23.2)N= 42 evaluable subjects. AUC0- (dayU/mL)Tmax generally near end of 1 hour calaspargase pegol-mknl intravenous (IV) infusion. 25.5 (30.4) Absorption Tmax (h) 1.17 (1.05, 5.47)Median (10th, 90th percentiles). Distribution Vss (L)2.96 (84.3) Elimination t1/2 (day) Plasma asparaginase activity pharmacokinetics are nonlinear following ASPARLAS administration. 16.1 (51.9) Clearance (L/day)0.147 (76.1) Specific PopulationsThe impact of renal and hepatic impairment on the PK of calaspargase pegol-mknl is unknown.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. 14.1Acute Lymphoblastic Leukemia. The determination of efficacy was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL using ASPARLAS 2500 U/m2 intravenously every weeks. The pharmacokinetics of ASPARLAS were studied when used in combination with multiagent chemotherapy in 124 patients with cell lineage acute lymphoblastic leukemia (ALL). Among these patients, the median age was 11.5 years (range - 26); 62 (50%) were male, 102 (82%) white, (5%) Asian, (4%) Black or African American, (2%) Native Hawaiian or Pacific Islander and (7%) other or unknown. The results showed that 123 (99%, 95% CI: 96% 100%) of the 124 patients maintained NSAA 0.1 U/mL at weeks 6, 12, 18, 24 and 30.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Study DFCI 11-001The safety of ASPARLAS was investigated in Study DFCI 11-001, an open-label, randomized, active-controlled multicenter clinical trial that treated 237 children and adolescents with newly-diagnosed ALL or lymphoblastic lymphoma, with ASPARLAS 2,500 U/m2 (n=118) or pegaspargase 2,500 U/m2 (n=119) as part of Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. The median age on enrollment was years (range, 1-20) years. The majority of patients were male (62%) and white (70%). Most patients were considered standard risk (SR, 59%) and had B-cell lineage ALL (87%).The median number of doses during the study was 11 doses for ASPARLAS (administered every three weeks) and 16 doses for pegaspargase (administered every two weeks). The median duration of exposure was months for both ASPARLAS and pegaspargase.There was fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with pancreatic pseudocyst).Table summarizes the incidence of selected Grades >=3 adverse reactions that occurred in or more patients receiving ASPARLAS. Because not all grade and adverse reactions were collected prospectively, only grade and adverse events are presented in Table 2.Table 2: Selected Grades >= Adverse Reactions in Patients Receiving ASPARLAS With Multi-Agent Chemotherapy (Study DFCI 11-001)ASPARLAS or pegaspargase were administered as component of multi-agent chemotherapy regimens. Adverse ReactionGrouped 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; Diarrhea: Colitis, Diarrhea, Enterocolitis, Neutropenic colitis; Hypersensitivity: Anaphylactic reaction, Drug hypersensitivity, Hypersensitivity; Embolic and thrombotic events SMQ: Device related thrombosis, Disseminated intravascular coagulation, Embolism, Intracardiac thrombus, Intracranial venous sinus thrombosis, Pulmonary embolism, Superior sagittal sinus thrombosis, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Sepsis: Bacterial sepsis, Sepsis; Dyspnea: Hypoxia, Respiratory failure; 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; Pneumonia: Lung infection, Pneumonia, Pneumonitis; Arrhythmia: Atrioventricular block complete, Sinus tachycardia, Ventricular arrhythmia; Cardiac failure: Ejection fraction decreased, Left ventricular dysfunction. ASPARLAS2,500 U/m2 N=118Pegaspargase2,500 U/m2 N=119Grades >=3n (%)Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grades >=3n (%) Elevated transaminase61 (52)79 (66)Bilirubin increased24 (20)30 (25)Pancreatitis21 (18)29 (24)Abnormal clotting studies17 (14)25 (21)Diarrhea10 (9)6 (5)Hypersensitivity9 (8)8 (7)Embolic and thrombotic events9 (8)10 (8)Sepsis6 (5)7 (6)Dyspnea5 (4)1 (1)Hemorrhages5 (4)5 (4)Fungal infection4 (3)3 (3)Pneumonia4 (3)8 (7)Arrhythmia2 (2)1 (1)Cardiac failure2 (2)1 (1)In the subgroup of patients with B-cell lineage ALL, the complete remission rate in the ASPARLAS arm was 98% (95/97), compared to 99% in the pegaspargase arm; the Kaplan-Meier estimates of overall survival of the treatment arms were comparable.. Study AALL07P4The safety of ASPARLAS was also evaluated in Study AALL07P4, an open-label, randomized, active-controlled, multicenter clinical trial that treated patients with newly-diagnosed high-risk B-precursor ALL using ASPARLAS 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68), or pegaspargase 2,500 U/m2 (n=52), as component of an augmented Berlin-Frankfurt-Munster (BFM) therapy regimen. The median age was 11 years (range to 26 years); the median duration of exposure was months for both ASPARLAS and pegaspargase. In this study, the induction mortality of patients treated with ASPARLAS was 2.8% (3 out of 111); there were no induction deaths among 52 patients treated with pegaspargase.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. ASPARLAS is contraindicated in patients with:History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy [see Warnings and Precautions (5.1)];History of serious thrombosis during previous L-asparaginase therapy [see Warnings and Precautions (5.3)];History of serious pancreatitis during previous L-asparaginase therapy [see Warnings and Precautions (5.2)];History of serious hemorrhagic events during previous L-asparaginase therapy [see Warnings and Precautions (5.4)];Severe hepatic impairment [see Warnings and Precautions (5.5)].. History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy [see Warnings and Precautions (5.1)];. History of serious thrombosis during previous L-asparaginase therapy [see Warnings and Precautions (5.3)];. History of serious pancreatitis during previous L-asparaginase therapy [see Warnings and Precautions (5.2)];. History of serious hemorrhagic events during previous L-asparaginase therapy [see Warnings and Precautions (5.4)];. Severe hepatic impairment [see Warnings and Precautions (5.5)].. History of serious hypersensitivity reactions to pegylated L-asparaginase. (4)History of serious thrombosis during L-asparaginase therapy. (4)History of serious pancreatitis related to previous L-asparaginase treatment. (4)History of serious hemorrhagic events during previous L-asparaginase therapy. (4)Severe hepatic impairment. (4). History of serious hypersensitivity reactions to pegylated L-asparaginase. (4). History of serious thrombosis during L-asparaginase therapy. (4). History of serious pancreatitis related to previous L-asparaginase treatment. (4). History of serious hemorrhagic events during previous L-asparaginase therapy. (4). Severe hepatic impairment. (4).

DESCRIPTION SECTION.

11DESCRIPTION. Calaspargase pegol-mknl contains an asparagine specific enzyme derived from Escherichia coli, as conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol (mPEG) with succinimidyl carbonate (SC) linker. The SC linker is chemically stable carbamate bond between the mPEG moiety and the lysine groups of L-asparaginase.L-asparaginase is tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 31 to 39 molecules of SC-PEG are linked to L-asparaginase; the molecular weight of each SC-PEG molecule is about kDa. The activity of ASPARLAS is expressed in units (U). ASPARLAS injection is supplied as clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered saline, pH 7.3 that requires dilution prior to intravenous infusion. Each vial of ASPARLAS contains 3,750 units in mL of solution. Each milliliter contains 750 units of calaspargase pegol-mknl; 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.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. Recommended Dosage: 2,500 units/m2 intravenously no more frequently than every 21 days. (2.1)See Full Prescribing Information for important details regarding dosing modifications and preparation and administration. (2.2, 2.3, 2.4). Recommended Dosage: 2,500 units/m2 intravenously no more frequently than every 21 days. (2.1). See Full Prescribing Information for important details regarding dosing modifications and preparation and administration. (2.2, 2.3, 2.4). 2.1Recommended Dosage. The recommended dose of ASPARLAS is 2,500 units/m2 given intravenously no more frequently than every 21 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 ASPARLAS 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 ModificationsAdverse ReactionSeverityGrade is mild, grade is moderate, grade is severe, and grade is life-threatening ActionInfusion Reaction/ Hypersensitivity Reaction [see Warnings and Precautions (5.1)]Grade 1Reduce the infusion rate by 50%Grade 2Interrupt the infusion of ASPARLASTreat the symptomsWhen symptoms resolve, resume the infusion and reduce the infusion rate by 50%Grade to 4Discontinue ASPARLAS permanentlyThrombosis [see Warnings and Precautions (5.2)] Uncomplicated deep vein thrombosisHold ASPARLAS.Treat with appropriate antithrombotic therapyUpon resolution of symptoms consider resuming ASPARLAS, while continuing antithrombotic therapy.Severe or life-threatening thrombosisDiscontinue ASPARLAS permanently.Treat with appropriate antithrombotic therapy.Pancreatitis [see Warnings and Precautions (5.3)] Grades to 4Hold ASPARLAS for elevations in lipase or amylase >3 ULN until enzyme levels stabilize or are decliningDiscontinue ASPARLAS permanently if clinical pancreatitis is confirmed.Hemorrhage [see Warnings and Precautions (5.5)] Grade to 4Hold ASPARLAS.Evaluate for coagulopathy and consider clotting factor replacement as needed.Resume ASPARLAS with the next scheduled dose if bleeding is controlled.Hepatotoxicity [see Warnings and Precautions (5.6)] Total bilirubin more than times to no more than 10 times the upper limit of normalHold ASPARLAS until total bilirubin is <= 1.5 times the upper limit of normalTotal bilirubin more than 10 times the upper limit of normalDiscontinue ASPARLAS and do not make up for missed doses. Reduce the infusion rate by 50%. Interrupt the infusion of ASPARLAS. Treat the symptoms. When symptoms resolve, resume the infusion and reduce the infusion rate by 50%. Discontinue ASPARLAS permanently. Hold ASPARLAS.. Treat with appropriate antithrombotic therapy. Upon resolution of symptoms consider resuming ASPARLAS, while continuing antithrombotic therapy.. Discontinue ASPARLAS permanently.. Treat with appropriate antithrombotic therapy.. Hold ASPARLAS for elevations in lipase or amylase >3 ULN until enzyme levels stabilize or are declining. Discontinue ASPARLAS permanently if clinical pancreatitis is confirmed.. Hold ASPARLAS.. Evaluate for coagulopathy and consider clotting factor replacement as needed.. Resume ASPARLAS with the next scheduled dose if bleeding is controlled.. Hold ASPARLAS until total bilirubin is <= 1.5 times the upper limit of normal. Discontinue ASPARLAS and do not make up for missed doses. 2.4 Preparation and Administration. ASPARLAS is 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. Do not administer if ASPARLAS has been shaken or vigorously agitated, frozen, or stored at room temperature for more than 48 hours.Dilute ASPARLAS in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP using sterile/aseptic technique. Discard any unused portion left in vial.After dilution, administer immediately into running infusion of either 0.9% sodium chloride or 5% dextrose, respectively.Administer the dose over period of hour.Do not infuse other drugs through the same intravenous line during administration of ASPARLAS.The diluted solution may be stored for up to hours at room temperature (15C to 25C [59F to 77F]) or refrigerated at 2C to 8C (36F to 46F) for up to 24 hours.Protect from light. Do not shake or freeze.. Dilute ASPARLAS in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP using sterile/aseptic technique. Discard any unused portion left in vial.. After dilution, administer immediately into running infusion of either 0.9% sodium chloride or 5% dextrose, respectively.. Administer the dose over period of hour.. Do not infuse other drugs through the same intravenous line during administration of ASPARLAS.. The diluted solution may be stored for up to hours at room temperature (15C to 25C [59F to 77F]) or refrigerated at 2C to 8C (36F to 46F) for up to 24 hours.. Protect from light. Do not shake or freeze.

DOSAGE FORMS & STRENGTHS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential. ASPARLAS can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing is recommended in females of reproductive potential prior to initiating ASPARLAS.. ContraceptionAdvise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with ASPARLAS and for at least months after the last dose.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. ASPARLAS (calaspargase pegol mknl) injection is supplied as clear, colorless, preservative-free sterile solution in single-dose vial containing 3,750 units of calaspargase pegol-mknl per mL solution (NDC 72694-515-01).. Store ASPARLAS refrigerated at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not shake or freeze product. Unopened vials may be stored at room temperature (15C to 25C [59F to 77F]) for no more than 48 hours.

IMMUNOGENICITY.

6.2Immunogenicity. As with all therapeutic proteins, there is 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 to ASPARLAS in the studies described below with the incidence of antibodies in other studies or to other asparaginase products may be misleading.Immunogenicity was assessed using enzyme linked immunosorbent assays (ELISA) in Study DFCI 11-001. Of 98 evaluable patients treated with ASPARLAS, 15 (15%) patients developed new or an increased titer of anti-drug antibodies (ADA) during treatment; 14 of these 15 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).

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. ASPARLAS is an asparagine specific enzyme indicated as component of multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age month to 21 years. (1.1). 1.1Acute Lymphoblastic Leukemia. ASPARLAS is indicated as component of multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age month to 21 years.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. HypersensitivityInform patients on the possibility of serious allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms [see Warnings and Precautions (5.1)].. PancreatitisInstruct patients on the signs and symptoms of pancreatitis and to seek immediate medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.2)].Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination [see Dosage and Administration (2.2)].. ThombosisInstruct patients on the risk of thrombosis and to seek medical advice immediately if they experience severe headache, arm or leg swelling, shortness of breath, or chest pain [see Warnings and Precautions (5.3)].. HemorrhageAdvise patients to report any unusual bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.4)].. HepatotoxicityAdvise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.5)].. PregnancyAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of 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 ASPARLAS and for months after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with ASPARLAS and for at least months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2Lactation. Risk SummaryThere are no data on the presence of calaspargase pegol-mknl 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 ASPARLAS and for months after the last dose.

MECHANISM OF ACTION SECTION.

12.1Mechanism 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 ASPARLAS 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 reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.

NONCLINICAL TOXICOLOGY SECTION.

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

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Calaspargase pegol-mknl pharmacokinetics (PK) were assessed through measurement of plasma asparaginase activity via coupled enzymatic assay.The plasma asparaginase activity pharmacokinetics were characterized in 43 patients (1 to 26 years) with newly diagnosed high risk B-precursor ALL treated with multidrug backbone therapy. Table summarizes the plasma asparaginase activity pharmacokinetic parameters after single dose of ASPARLAS 2,500 U/m2 in the induction phase.Table 3: Plasma Asparaginase Activity Pharmacokinetic Parameters After Single Dose of ASPARLAS 2,500 U/m2 in Patients with ALL in Study AALL07P4ParameterArithmetic Mean (%CV)N=43General Cmax (U/mL)1.62 (23.0) AUC0-25day (dayU/mL)16.9 (23.2)N= 42 evaluable subjects. AUC0- (dayU/mL)Tmax generally near end of 1 hour calaspargase pegol-mknl intravenous (IV) infusion. 25.5 (30.4) Absorption Tmax (h) 1.17 (1.05, 5.47)Median (10th, 90th percentiles). Distribution Vss (L)2.96 (84.3) Elimination t1/2 (day) Plasma asparaginase activity pharmacokinetics are nonlinear following ASPARLAS administration. 16.1 (51.9) Clearance (L/day)0.147 (76.1) Specific PopulationsThe impact of renal and hepatic impairment on the PK of calaspargase pegol-mknl is unknown.

PREGNANCY SECTION.

8.1Pregnancy. Risk SummaryBased on published literature studies with L-asparaginase in pregnant animals, ASPARLAS can cause fetal harm when administered to pregnant woman. There are no available data on ASPARLAS use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to times the maximum recommended human doses did not result in adverse developmental outcomes. Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring (see Data). Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.. Data. Animal DataIn an embryofetal development study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 U/kg (0.2, 0.6 and times the maximum recommended human dose, respectively, based on AUC) to pregnant rats during the period of organogenesis. Maternal toxicity of decreased body weight and food consumption was seen at all dose levels resulting in reductions in gravid uterine and placental weights, and slight reductions in fetal body weights. No evidence of structural abnormalities or embryo-fetal mortality were observed in this study at any of the doses tested. Published literature studies in which pregnant rabbits were administered L-asparaginase suggested harm to the animal offspring.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Recommended Premedication (2.2)12/2021Dosage and Administration, Recommended Monitoring and Dosage Modifications for Adverse Reactions (2.3)12/2021.

SPL UNCLASSIFIED SECTION.

1.1Acute Lymphoblastic Leukemia. ASPARLAS is indicated as component of multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age month to 21 years.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1Pregnancy. Risk SummaryBased on published literature studies with L-asparaginase in pregnant animals, ASPARLAS can cause fetal harm when administered to pregnant woman. There are no available data on ASPARLAS use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to times the maximum recommended human doses did not result in adverse developmental outcomes. Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring (see Data). Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.. Data. Animal DataIn an embryofetal development study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 U/kg (0.2, 0.6 and times the maximum recommended human dose, respectively, based on AUC) to pregnant rats during the period of organogenesis. Maternal toxicity of decreased body weight and food consumption was seen at all dose levels resulting in reductions in gravid uterine and placental weights, and slight reductions in fetal body weights. No evidence of structural abnormalities or embryo-fetal mortality were observed in this study at any of the doses tested. Published literature studies in which pregnant rabbits were administered L-asparaginase suggested harm to the animal offspring.. 8.2Lactation. Risk SummaryThere are no data on the presence of calaspargase pegol-mknl 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 ASPARLAS and for months after the last dose.. 8.3Females and Males of Reproductive Potential. ASPARLAS can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing is recommended in females of reproductive potential prior to initiating ASPARLAS.. ContraceptionAdvise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with ASPARLAS and for at least months after the last dose.. 8.4Pediatric Use. The safety and effectiveness of ASPARLAS in the treatment of ALL have been established in pediatric patients month to 17 years (no data for the age group 1 month old). Use of ASPARLAS in these age groups is supported by evidence from an adequate and well-controlled trial with additional safety from second trial. The trials included 208 children with ALL or lymphoblastic lymphoma treated with ASPARLAS; there were 19 infants (1 month to 2 years old), 128 children (2 years to 12 years old), and 61 adolescents (12 years to 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups [see Adverse Reactions (6.1), Clinical Studies (14)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Hypersensitivity: Observe patients for one hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions. (5.1)Pancreatitis: Discontinue ASPARLAS in patients with pancreatitis. Monitor blood glucose (5.2)Thrombosis: Discontinue ASPARLAS for severe or life-threatening thrombosis. (5.3)Hemorrhage: Discontinue ASPARLAS for severe or life-threatening hemorrhage. Evaluate for etiology and treat. (5.4)Hepatotoxicity: Monitor for toxicity through recovery from cycle. Discontinue ASPARLAS for severe liver toxicity. (5.5). Hypersensitivity: Observe patients for one hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions. (5.1). Pancreatitis: Discontinue ASPARLAS in patients with pancreatitis. Monitor blood glucose (5.2). Thrombosis: Discontinue ASPARLAS for severe or life-threatening thrombosis. (5.3). Hemorrhage: Discontinue ASPARLAS for severe or life-threatening hemorrhage. Evaluate for etiology and treat. (5.4). Hepatotoxicity: Monitor for toxicity through recovery from cycle. Discontinue ASPARLAS for severe liver toxicity. (5.5). 5.1Hypersensitivity. Grade and hypersensitivity reactions including anaphylaxis have been reported in clinical trials with ASPARLAS with an incidence between to 21% [see Contraindications (4), Adverse Reactions (6.1)]. Hypersensitivity reactions observed with other asparaginases include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritus and rash [see Adverse Reactions (6.1)].Premedicate patients 30-60 minutes prior to administration of ASPARLAS. [see Dosage and Administration (2.2)]. Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer ASPARLAS in clinical setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.4)] and observe patients for hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions.. 5.2Pancreatitis. Cases of pancreatitis have been reported in clinical trials with ASPARLAS with an incidence between 12 to 16% [see Adverse Reactions (6.1)]. Hemorrhagic or necrotizing pancreatitis have been reported with other asparaginases.Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Assess serum amylase and/or lipase levels to identify early signs of pancreatic inflammation. Discontinue ASPARLAS if pancreatitis is suspected; if pancreatitis is confirmed, do not resume ASPARLAS [see Dosage and Administration (2.4)].. 5.3Thrombosis. Serious thrombotic events, including sagittal sinus thrombosis, have been reported in clinical trials with ASPARLAS with an incidence of to 12%. Discontinue ASPARLAS in patients experiencing serious thrombotic events [see Dosage and Administration (2.4), Adverse Reactions (6.1)].. 5.4Hemorrhage. Hemorrhage associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia have been reported in patients receiving ASPARLAS [see Adverse Reactions (6.1)]. Evaluate patients with signs and symptoms of hemorrhage with coagulation parameters including PT, PTT, fibrinogen. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy [see Dosage and Administration (2.4)].. 5.5 Hepatotoxicity. Hepatotoxicity and abnormal liver function, including elevations of transaminase, bilirubin (direct and indirect), reduced serum albumin, and plasma fibrinogen can occur. Evaluate bilirubin and transaminases at least weekly, during cycles of treatment that include ASPARLAS through weeks after the last dose of ASPARLAS. In the event of serious liver toxicity, discontinue treatment with ASPARLAS and provide supportive care [see Dosage and Administration (2.4), Contraindications (4), Adverse Reactions (6.1)].