Rylaze Drug Information

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.

• 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)

Pregnancy Risk Summary Based on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to a pregnant woman. There are no available data on RYLAZE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemi to pregnant rats and rabbits during organogenesis resulted in structural abnormalities and embryo-fetal mortality ( see Data ) at exposures below those in patients at the recommended human dose.

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 reproductive and developmental toxicity studies have not been conducted with RYLAZE. In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 3, 6, or 12 mg/m 2 ) and rabbits (at 0.12, 0.30, or 0.48 mg/m 2 ). In rats given 12 mg/m 2 (approximately 0.48 times the maximum recommended human dose), maternal toxicity of decreased body weight gain was observed, as was a fetal finding of increased incidence of partially undescended thymic tissue.

In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m 2 (approximately 0.02 times the maximum recommended human dose). Increased post-implantation loss, a decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of ≥ 0.12 mg/m 2 (approximately 0.005 times the maximum recommended human dose).

Pediatric Use The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients 1 month to < 17 years who have developed hypersensitivity to a long-acting E. coli -derived asparaginase. Use of RYLAZE in these age groups is supported by evidence from an adequate and well-controlled study in adults and pediatric patients. The trial included 139 pediatric patients, including 2 infants (1 month to < 2 years), 99 children (2 years to < 12 years old), and 38 adolescents (12 years to < 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups.

The safety and effectiveness of RYLAZE have not been established in pediatric patients younger than 1 month of age.

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