a, 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 a 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 1 hour after administration. discontinue asparlas in patients with serious hypersensitivity reactions. 5.2 pancreatitis cases of pancreatitis have been reported in clinical trials with asparlas with an incidence between 12 and 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) ] . 5.3 thrombosis serious thrombotic events, including sagittal sinus thrombosis, have been reported in clinical trials with asparlas with an incidence of 9 to 12%. discontinue asparlas in patients experiencing serious thrombotic events [see dosage and administration (2.3) , adverse reactions (6.1) ] . 5.4 hemorrhage 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 (2.3) ] . 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 6 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 (2.3) , contraindications (4) , adverse reactions (6.1) ] .

fy 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 asparlas treat the symptoms when symptoms resolve, resume the infusion and reduce the infusion rate by 50% grade 3 to 4 discontinue asparlas permanently pancreatitis [see warnings and precautions (5.2) ] grades 3 to 4 hold asparlas for elevations in lipase or amylase >3 × upper limit of normal (uln) until enzyme levels stabilize or are declining discontinue asparlas permanently if clinical pancreatitis is confirmed thrombosis [see warnings and precautions (5.3) ] uncomplicated deep vein thrombosis hold asparlas treat with appropriate antithrombotic therapy upon resolution of symptoms consider resuming asparlas, while continuing antithrombotic therapy severe or life-threatening thrombosis discontinue asparlas permanently treat with appropriate antithrombotic therapy hemorrhage [see warnings and precautions (5.4) ] grade 3 to 4 hold 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 (5.5) ] total bilirubin more than 3 times to no more than 10 times the uln hold asparlas until total bilirubin is ≤1.5 times the uln total bilirubin more than 10 times the uln discontinue asparlas and do not make up for missed doses 2.4 preparation and administration asparlas 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. 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 a vial. after dilution, administer immediately into a running infusion of either 0.9% sodium chloride or 5% dextrose, respectively. administer the dose over a period of 1 hour. do not infuse other drugs through the same intravenous line during administration of asparlas. the diluted solution may be stored for up to 4 hours at room temperature (15°c to 25°c [59°f to 77°f]) or refrigerated at 2°c to 8°c (36°f to 46°f) for up to 24 hours. protect from light. do not shake or freeze.

1 the 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/m 2 (n=118) or pegaspargase 2,500 u/m 2 (n=119) as part of a dana-farber cancer institute (dfci) all consortium backbone therapy. the median age on enrollment was 5 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 8 months for both asparlas and pegaspargase. there was 1 fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst). table 2 summarizes the incidence of selected grades ≥3 adverse reactions that occurred in 2 or more patients receiving asparlas. because not all grade 1 and 2 adverse reactions were collected prospectively, only grade 3 and 4 adverse events are presented in table 2. table 2: selected grades ≥3 adverse reactions in patients receiving asparlas with multi-agent chemotherapy (study dfci 11-001) asparlas or pegaspargase were administered as a component of multi-agent chemotherapy regimens. 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; 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. asparlas 2,500 u/m 2 n=118 pegaspargase 2,500 u/m 2 n=119 grades ≥3 n (%) grading is based on the common terminology criteria for adverse events (ctcae) v4.0. grades ≥3 n (%) elevated transaminase 61 (52) 79 (66) bilirubin increased 24 (20) 30 (25) pancreatitis 21 (18) 29 (24) abnormal clotting studies 17 (14) 25 (21) diarrhea 10 (9) 6 (5) hypersensitivity 9 (8) 8 (7) embolic and thrombotic events 9 (8) 10 (8) sepsis 6 (5) 7 (6) dyspnea 5 (4) 1 (1) hemorrhages 5 (4) 5 (4) fungal infection 4 (3) 3 (3) pneumonia 4 (3) 8 (7) arrhythmia 2 (2) 1 (1) cardiac failure 2 (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 aall07p4 the 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/m 2 (n=43) or 2,100 u/m 2 (n=68), or pegaspargase 2,500 u/m 2 (n=52), as a component of an augmented berlin-frankfurt-münster (bfm) therapy regimen. the median age was 11 years (range, 1-26 years); the median duration of exposure was 7 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. 6.2 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 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).

2 to 4% and 15 to 20%, respectively. data animal data in an embryo-fetal development study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 u/kg (0.2, 0.6 and 1 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. 8.2 lactation risk summary there 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 3 months after the last dose. 8.3 females and males of reproductive potential asparlas can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . pregnancy testing pregnancy testing is recommended in females of reproductive potential prior to initiating asparlas. contraception advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with asparlas and for at least 3 months after the last dose. 8.4 pediatric use the safety and effectiveness of asparlas in the treatment of all have been established in pediatric patients 1 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 a 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) ] .

velopment study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 u/kg (0.2, 0.6 and 1 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.

n day 4 (n=37) and remained decreased at 0.2 µg/ml (n=35) 25 days after the administration of a single dose of asparlas 2,500 u/m 2 in the induction phase. 12.3 pharmacokinetics calaspargase pegol-mknl pharmacokinetics (pk) were assessed through measurement of plasma asparaginase activity via a 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 a multidrug backbone therapy. table 3 summarizes the plasma asparaginase activity pharmacokinetic parameters after a single dose of asparlas 2,500 u/m 2 in the induction phase. table 3: plasma asparaginase activity pharmacokinetic parameters after a single dose of asparlas 2,500 u/m 2 in patients with all in study aall07p4 parameter arithmetic mean (%cv) n=43 general c max (u/ml) 1.62 (23.0) auc 0-25day (day∙u/ml) 16.9 (23.2) n=42 evaluable subjects. auc 0∞ (day∙u/ml) t max generally near end of a 1 hour calaspargase pegol-mknl intravenous (iv) infusion. 25.5 (30.4) absorption t max (h) 1.17 (1.05, 5.47) median (10 th , 90 th percentiles). distribution vss (l) 2.96 (84.3) elimination t 1/2 (day) plasma asparaginase activity pharmacokinetics are nonlinear following asparlas administration. 16.1 (51.9) clearance (l/day) 0.147 (76.1) specific populations the impact of renal and hepatic impairment on the pk of calaspargase pegol-mknl is unknown.

vss (l) 2.96 (84.3) elimination t 1/2 (day) plasma asparaginase activity pharmacokinetics are nonlinear following asparlas administration. 16.1 (51.9) clearance (l/day) 0.147 (76.1) specific populations the impact of renal and hepatic impairment on the pk of calaspargase pegol-mknl is unknown.

s to report any unusual bleeding or bruising to their healthcare provider [see warnings and precautions (5.4) ] . hepatotoxicity advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see warnings and precautions (5.5) ] . 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 asparlas and for 3 months after the last dose [see use in specific populations (8.3) ]. lactation advise women not to breastfeed during treatment with asparlas and for at least 3 months after the last dose [see use in specific populations (8.2) ] .