Asparaginase Erwinia Chrysanthemi (Recombinant)-Rywn

1 INDICATIONS AND USAGE RYLAZE is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli -derived asparaginase. RYLAZE is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli -derived asparaginase. ( 1 )

2 DOSAGE AND ADMINISTRATION There are two RYLAZE regimens that can be used to replace a long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hours • 25 mg/m 2 intramuscularly every 48 hours; When administered Monday/Wednesday/Friday • 25 mg/m 2 intramuscularly on Monday morning and Wednesday morning and 50 mg/m 2 intramuscularly on Friday afternoon. ( 2.1 ) 2.1 Recommended Dosage There are two RYLAZE regimens that can be used to replace a long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hours: • 25 mg/m 2 administered intramuscularly every 48 hours; When administered on a Monday/Wednesday/Friday schedule: • 25 mg/m 2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m 2 intramuscularly on Friday afternoon. Administer the Friday afternoon dose 53 to 58 hours after the Wednesday morning dose (e.g., 8:00 am on Monday and Wednesday, and 1:00 pm to 6:00 pm on Friday) [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . Table 1 shows the number of RYLAZE dosages recommended for the intended duration of treatment for replacement of one dose of calaspargase pegol products (3 weeks of asparaginase coverage) or one dose of pegaspargase products (2 weeks of asparaginase coverage). See the full prescribing information for the long-acting asparaginase product to determine the total duration of administration of RYLAZE as replacement therapy. Table 1: Recommended Duration of RYLAZE Dosing to Replace One Long-Acting Asparaginase Dose When RYLAZE is Administered: Recommended Duration of RYLAZE to Replace Calaspargase Pegol Products Recommended Duration of RYLAZE to Replace Pegaspargase Products 25 mg/m 2 intramuscular every 48 hours Replace one dose of calaspargase pegol products with 11 doses of RYLAZE Replace one dose of pegaspargase products with 7 doses of RYLAZE 25 mg/m 2 intramuscular on Monday morning and Wednesday morning, and 50 mg/m 2 intramuscular on Friday afternoon* Replace one dose of calaspargase pegol products with 9 doses of RYLAZE Replace one dose of pegaspargase products with 6 doses of RYLAZE *See bullet above for timing of 25/25/50 mg/m 2 dosing of RYLAZE. 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 RYLAZE to decrease the risk and severity of hypersensitivity reactions [see Warnings and Precautions ( 5.1 )] . 2.3 Recommended Monitoring and Dosage Modifications for Adverse Reactions Monitor patient’s bilirubin, transaminases, glucose, and clinical examinations prior to treatment every 2-3 weeks and as indicated clinically. If results are abnormal, monitor patients until recovery from the cycle of therapy. If an adverse reaction occurs, modify treatment according to Table 2. Table 2: Dosage Modifications Adverse Reaction Severity* Action Hypersensitivity Reaction [see Warnings and Precautions ( 5.1 )] Grade 2 • Treat the symptoms. Grade 3 to 4 • Discontinue RYLAZE permanently. Pancreatitis [see Warnings and Precautions ( 5.2 )] Grade 2 to 4 • Hold RYLAZE for elevations in lipase or amylase > 2 times the ULN**, or for symptomatic pancreatitis. • Resume treatment when lipase and amylase are < 1.5 times the ULN and symptoms are resolved. • Discontinue RYLAZE permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed. Thrombosis [see Warnings and Precautions ( 5.3 )] Uncomplicated thrombosis • Hold RYLAZE. • Treat with appropriate antithrombotic therapy. • Upon resolution of symptoms, consider resuming RYLAZE, while continuing antithrombotic therapy. Severe or life-threatening thrombosis • Discontinue RYLAZE permanently. • Treat with appropriate antithrombotic therapy. Hemorrhage [see Warnings and Precautions ( 5.4 )] Grade 3 to 4 • Hold RYLAZE. • Evaluate for coagulopathy and consider clotting factor replacement as needed. • Resume RYLAZE with the next scheduled dose if bleeding is controlled. Hepatotoxicity [see Warnings and Precautions ( 5.5 )] Total bilirubin > 3 times to ≤ 10 times the ULN • Hold RYLAZE until total bilirubin levels decrease to ≤ 1.5 times the ULN. Total bilirubin > 10 times the ULN • Discontinue RYLAZE and do not make up missed doses. * Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. ** Upper limit of normal 2.4 Preparation and Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering RYLAZE [see Warnings and Precautions ( 5.1 )] . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, cloudiness, or discoloration are present, discard the vial. • Use aseptic technique. • Determine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed based on the individual patient’s BSA. More than one vial may be needed for a full dose. • Withdraw the indicated injection volume of RYLAZE into the syringe for injection. o Do not shake the vial. o Limit the volume of RYLAZE at a single injection site to 2 mL. o If the volume to be administered is greater than 2 mL, divide the doses equally into multiple syringes, one for each injection site. o Discard the remaining unused RYLAZE in the single-dose vial. • Administer RYLAZE by intramuscular injection. o Rotate injection sites. o Do not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen. • If the prepared dose is not used immediately, store the syringe(s) at room temperature 15°C to 25°C (59°F to 77°F) for up to 8 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The syringe does not need to be protected from light during storage.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of the labeling: • Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] • Pancreatic Toxicity [see Warnings and Precautions ( 5.2 )] • Thrombosis [see Warnings and Precautions ( 5.3 )] • Hemorrhage [see Warnings and Precautions ( 5.4 )] • Hepatotoxicity, including VOD [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence > 20%) are abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals Ireland Limited at 1-800-520-5568 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of RYLAZE described in the WARNINGS AND PRECAUTIONS reflect exposure in 167 patients administered RYLAZE intramuscularly at various dosages when used in combination with chemotherapy in study JZP458-201 [see Clinical Studies ( 14 )] . These patients received a median of 4 courses of RYLAZE (range: 1-15 courses); 65% of patients received at least four courses. The safety of RYLAZE described below and in Table 3 was evaluated in study JZP458-201, a multi-cohort study. Patients received RYLAZE administered intramuscularly at dosages of 25 mg/m 2 on Monday, Wednesday, and Friday or 25 mg/m 2 on Monday and Wednesday, and 50 mg/m 2 on Friday, for 6 doses as a replacement for a single dose of pegaspargase as a component of multi-agent chemotherapy [see Clinical Studies ( 14 )] . The patients had a median age of 11 years (range: 1‑25 years); the majority of patients were male (57%) and White (68%). The patients received a median of 4 courses of RYLAZE (range: 1-14 courses); 65% of patients received at least four courses. A fatal adverse reaction (infection) occurred in 1 patient treated with the RYLAZE 25/25/25 mg/m 2 dosage. Serious adverse reactions occurred in 60% of patients who received the recommended dosages of RYLAZE. The most frequent nonhematological serious adverse reactions (in ≥ 5% of patients) were febrile neutropenia, infection, drug hypersensitivity, pyrexia, nausea, dehydration, stomatitis, acute kidney injury, pancreatitis, diarrhea, and viral infection. Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RYLAZE intramuscularly at the recommended dosages. Adverse reactions resulting in permanent discontinuation included pancreatitis (5%), drug hypersensitivity (4%), and infection (1%). All patients treated with the recommended dosages of RYLAZE as a component of multi-agent chemotherapy experienced neutropenia, anemia, or thrombocytopenia. The most common nonhematological adverse reactions (incidence > 20%) in patients were abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. Table 3 shows the common adverse reactions occurring in at least 15% of the patients. Table 3: Adverse Reactions (≥ 15% Incidence) in Patients Receiving RYLAZE as a Component of Multi-Agent Chemotherapy in Study JZP458-201 Adverse Reaction RYLAZE 25/25/25 mg/m 2 Intramuscular Dosage a (N = 33) RYLAZE 25/25/50 mg/m 2 Intramuscular Dosage a (N = 51) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Abnormal liver test* # 70 18 75 27 Musculoskeletal pain* 45 6 35 4 Nausea* 45 9 47 8 Fatigue* 36 18 22 18 Headache 36 0 22 0 Infection* b 36 15 27 17 Febrile neutropenia 30 30 27 27 Pyrexia 30 6 20 0 Hemorrhage* 24 0 27 6 Stomatitis 24 12 27 4 Abdominal pain* 21 0 25 2 Decreased appetite 21 6 27 6 Drug hypersensitivity* 21 6 24 2 Hyperglycemia 21 3 12 4 Diarrhea* 18 6 25 4 Tachycardia* 18 0 16 2 Cough 15 0 14 0 Dehydration 15 9 12 6 Insomnia 15 0 4 0 Peripheral neuropathy* 15 0 6 0 Pancreatitis* # 12 0 22 10 Hypokalemia 9 3 22 8 * Includes grouped terms: Abnormal liver test : alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased; Musculoskeletal pain : arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, pain in extremity; Nausea : nausea, vomiting; Fatigue : fatigue, asthenia; Infection : sepsis, upper respiratory tract infection, enterocolitis infectious, skin infection, bacteremia, paronychia, pneumonia, otitis externa, soft tissue infection, abdominal infection, conjunctivitis, device related infection, folliculitis, lymph gland infection, necrotizing fasciitis, perirectal abscess, peritonsillar abscess, sinusitis, subcutaneous abscess, wound infection; Drug hypersensitivity : drug hypersensitivity, rash, infusion related reaction, lip swelling, periorbital edema, throat irritation, urticaria, dry skin, eczema, erythema, hand dermatitis, rash maculo-papular, rash papular; Hemorrhage : contusion, epistaxis, catheter site hemorrhage, petechiae, hematochezia, menorrhagia, mouth hemorrhage, increased tendency to bruise, rectal hemorrhage; Abdominal pain : abdominal pain, abdominal pain upper; Diarrhea : diarrhea, colitis; Tachycardia : sinus tachycardia, tachycardia; Peripheral neuropathy : peripheral motor neuropathy, neuropathy peripheral, peripheral sensory neuropathy; Pancreatitis : pancreatitis, pancreatitis acute, amylase increased, lipase increased. *Includes adverse event terms and laboratory abnormalities Grading is based on Common Terminology Criteria for Adverse Events version 5.0. a RYLAZE was administered as a component of multi-agent chemotherapy regimens on a Monday, Wednesday, and Friday schedule. b Does not include the following fatal adverse reactions: infection (N=1). Clinically relevant adverse reactions in < 15% of patients who received RYLAZE in combination with chemotherapy included: Gastrointestinal disorders : Abdominal discomfort, abdominal distension, constipation, gastritis General disorders and administration site conditions : Infusion site reaction, injection site reaction, pain Infections and infestations : Viral infection, bacterial infection, fungal infection Investigations : Antithrombin III decreased, blood cholesterol increased, blood fibrinogen decreased, activated partial thromboplastin time prolonged Metabolism and nutrition disorders : Acidosis, hyperammonemia, hyperphosphatemia, hypertriglyceridemia, hypoglycemia Musculoskeletal and connective tissue disorders : Bone pain, muscular weakness, muscle spasms Nervous system disorders : Paresthesia, dizziness, gait disturbance, hyperammonemic encephalopathy Psychiatric disorders : Agitation, anxiety, irritability Respiratory, thoracic, and mediastinal disorders: Acute respiratory distress syndrome, pulmonary edema Renal and urinary disorders : Acute kidney injury Skin and subcutaneous disorders : Pruritus Vascular disorders : Hypertension, hypotension, thrombosis 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of RYLAZE. 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: Hepatic: Veno-occlusive disease (VOD)

12.3 Pharmacokinetics The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) after administration of RYLAZE in pediatric and young adult patients with ALL or LBL, unless otherwise specified. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (C max ) and area under the SAA-time curve (AUC) increase proportionally over a dosage range from 12.5 to 50 mg/m 2 (0.25 to 1 times the maximum approved recommended dose of 50 mg/m 2 ). The simulated exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn after administration of the approved recommended dosages in a virtual population are summarized in Table 4. Table 4: Simulated RYLAZE Pharmacokinetic Parameters Based on SAA PK Parameter Geometric Mean (%CV) After Last Dose 25 mg/m 2 Intramuscularly Every 48 Hours 25/25/50 mg/m 2 Intramuscularly Monday, Wednesday, Friday Last 25 mg/m 2 Wednesday morning dose Last 50 mg/m 2 Friday afternoon dose C max (U/mL) 2.3 (55%) 2.3 (54%) 4.1 (57%) C trough (U/mL) 0.46 (75%) 0.3 (75%) a 0.39 (87%) b a C trough at maximum interval of 58 hours after the last 25 mg/m 2 Wednesday morning dose. b C trough at maximum interval of 67 hours after the last 50 mg/m 2 Friday afternoon dose. Absorption The median (min, max) T max of asparaginase erwinia chrysanthemi (recombinant)-rywn after intramuscular administration is 12 (8, 24) hours. The mean absolute bioavailability after intramuscular administration is 37% in healthy subjects. Distribution The geometric mean (%CV) volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.37 L/m 2 (47%). Elimination The geometric mean (%CV) clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.17 L/hour/m 2 (42%) and the apparent half-life is 15.9 (11%) hours. Metabolism Asparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways. Specific Populations There were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1.4 to 25 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied. Body Surface Area The volume of distribution and clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m 2 ). Racial and Ethnic Groups Black or African American patients had 29% lower clearance which may increase SAA exposure compared to White and Asian patients. There were no clinically significant differences in clearance between Hispanic and Non-Hispanic patients.