Asparaginase Erwinia Chrysanthemi (Recombinant)-Rywn

FDA Drug Information • Also known as: Rylaze

Brand Names: Rylaze
Dosage Form: INJECTION
Product Type: DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION Asparaginase erwinia chrysanthemi (recombinant)-rywn contains an asparagine specific bacterial enzyme (L-asparaginase). L-asparaginase is a tetrameric enzyme that consists of four identical 35 kDa subunits with a combined molecular weight of 140 kDa. The amino acid sequence is identical to native asparaginase Erwinia chrysanthemi (also known as crisantaspase). The activity of asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined as the amount of enzyme that catalyzes the conversion of 1μmol of L-asparagine per reaction minute, per mg of protein. Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by fermentation of a genetically engineered Pseudomonas fluorescens bacterium containing the DNA which encodes for asparaginase Erwinia chrysanthemi . RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection is supplied as a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intramuscular injection. Each 0.5 mL contains 10 mg asparaginase erwinia chrysanthemi (recombinant)-rywn and the inactive ingredients: polysorbate 80 (0.1 mg), sodium chloride (1.5 mg), sodium phosphate dibasic anhydrous (0.8 mg), sodium phosphate monobasic monohydrate (0.6 mg), and trehalose dihydrate (32.1 mg). Sodium hydroxide may be added during manufacture to adjust the pH. The pH is approximately 7.

What Is Asparaginase Erwinia Chrysanthemi (Recombinant)-Rywn Used For?

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 )

Dosage and Administration

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...

Side Effects (Adverse Reactions)

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...

Contraindications

4 CONTRAINDICATIONS RYLAZE 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 )

Pregnancy and Breastfeeding

8.1 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).

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection is supplied as a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution in single-dose vials. Each single-dose vial (NDC 68727-900-01) contains 10 mg/0.5 mL asparaginase erwinia chrysanthemi (recombinant)-rywn. Each carton of RYLAZE (NDC 68727-900-03) contains 3 single-dose vials. Store RYLAZE vials 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.