Rylaze Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes .................................................................................................. 2

Table of Contents .................................................................................................................. 2

Part 1: Healthcare Professional Information........................................................................... 4

1. 1.

   Indications ................................................................................................................. 4

   1.1. Pediatrics ................................................................................................................ 4

   1.2. Geriatrics ................................................................................................................ 4

2. 2. Contraindications ....................................................................................................... 4
3. 4.

   Dosage and Administration ........................................................................................ 4

   4.2. Recommended Dose and Dosage Adjustment ....................................................... 4

   4.4. Administration ........................................................................................................ 6

4. 5. Overdose ................................................................................................................... 6
5. 6. Dosage Forms, Strengths, Composition, and Packaging ............................................... 6
6. 7.

   Warnings and Precautions .......................................................................................... 7

   Driving and Operating Machinery ....................................................................................... 7

   Endocrine and Metabolism ................................................................................................. 7

   Hematologic ........................................................................................................................ 7

   Hepatic/Biliary/Pancreatic .................................................................................................. 8

   Immune ............................................................................................................................... 8

   Reproductive Health ........................................................................................................... 9

   7.1. Special Populations ................................................................................................. 9

   7.1.1. Pregnancy ....................................................................................................... 9

   7.1.2. Breastfeeding ............................................................................................... 10

   7.1.3. Pediatrics ..................................................................................................... 10

   7.1.4. Geriatrics ..................................................................................................... 10

7. 8.

   Adverse Reactions .................................................................................................... 10

   8.1. Adverse Reaction Overview .................................................................................. 10

   8.2. Clinical Trial Adverse Reactions ............................................................................ 11

   8.3. Less Common Clinical Trial Adverse Reactions ..................................................... 13

   8.5. Post-Market Adverse Reactions ............................................................................ 14

8. 9.

   Drug Interactions ..................................................................................................... 14

   9.2. Drug Interactions Overview .................................................................................. 14

   9.3. Drug-Behaviour Interactions ................................................................................. 14

   9.4. Drug-Drug Interactions ......................................................................................... 14

   9.5. Drug-Food Interactions ......................................................................................... 14

   9.6. Drug-Herb Interactions ......................................................................................... 14

   9.7. Drug-Laboratory Test Interactions........................................................................ 14

9. 10.

   Clinical Pharmacology .............................................................................................. 14

   10.1. Mechanism of Action ........................................................................................ 14

   10.2. Pharmacodynamics ........................................................................................... 15

   10.3. Pharmacokinetics .............................................................................................. 15

   10.4. Immunogenicity ................................................................................................ 16

10. 11. Storage, Stability, and Disposal ................................................................................. 16

Part 2: Scientific Information ............................................................................................... 17

1. 13. Pharmaceutical Information ..................................................................................... 17
2. 14.

   Clinical Trials ............................................................................................................ 18

   14.1. Clinical Trials by Indication ............................................................................... 18

3. 16. Non-Clinical Toxicology ............................................................................................ 19

Patient Medication Information .......................................................................................... 21

Part 1: Healthcare Professional Information

1. Indications

RYLAZE (crisantaspase recombinant) 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 year or older who have developed hypersensitivity to E. coli-derived asparaginase.

1.1. Pediatrics

Pediatrics (1 to < 17 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of RYLAZE in pediatric patients 1 year of age or older has been established. Therefore, Health Canada has authorized an indication for pediatric use [see 14 Clinical Trials].

1.2. Geriatrics

Geriatrics (> 65 years of age): Clinical studies of RYLAZE did not include sufficient number of patients 65 years of age and older to determine whether they respond differently from younger patients.

2. Contraindications

RYLAZE is contraindicated in patients with a history of:

• Serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis [see 7 Warnings and Precautions, Immune].
• Serious pancreatitis during previous asparaginase therapy [see 7 Warnings and Precautions, Pancreatic].
• Serious thrombosis during previous asparaginase therapy [see 7 Warnings and Precautions, Hematologic].
• Serious hemorrhagic events during previous asparaginase therapy [see 7 Warnings and Precautions, Hematologic].
• RYLAZE is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

4. Dosage and Administration

4.2. Recommended Dose and Dosage Adjustment

Recommended Dosage

The recommended dosage of RYLAZE is 25 mg/m² on Monday and Wednesday and 50 mg/m² on Friday, administered intramuscularly, for a total of six doses to replace each planned dose of pegaspargase.

Recommended Monitoring and Dosage Adjustment for Adverse Reactions

Monitor patient’s bilirubin, transaminases, glucose, and clinical examinations prior to treatment every 2-3 weeks and as indicated clinically during treatment with RYLAZE. If results are abnormal, monitor patients until recovery from the cycle of therapy. If an adverse reaction occurs, modify treatment according to Table 1.

Table 1: Dosage Adjustments

* Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

4.4. Administration

RYLAZE solution should only be administered by intramuscular injection.

Administer RYLAZE in a clinical setting with resuscitation equipment and other medical support available to appropriately manage anaphylactic reactions.

Visually inspect parenteral drug products for particulate matter, cloudiness, or discoloration prior to administration. If any of these are present, discard the vial. RYLAZE does not contain a preservative.

Use aseptic technique when administering RYLAZE.

• Do not shake the vial.
• Determine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed.
• Withdraw the indicated injection volume of RYLAZE into the syringe(s) for injection.
• Limit the volume of RYLAZE at a single injection site to 2 mL. If the volume to be administered is greater than 2 mL, use multiple injection sites.
• Discard any remaining unused RYLAZE in the single-use vial.

• Administer RYLAZE within 4 hours of syringe preparation.

  • Rotate injection sites.
  • Do not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.
• If needed, store the syringe(s) at room temperature for up to 4 hours. The syringe does not need to be protected from light during storage.

5. Overdose

There is no specific antidote for an overdose with RYLAZE. If overdose occurs, patients should be treated supportively with appropriate monitoring as necessary.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 2: Dosage Forms, Strengths, and Composition

RYLAZE is a clear to opalescent, colourless to slightly yellow, preservative-free sterile solution supplied in single-use vials.

Description

Each carton of RYLAZE contains 3 single-use vials.

7. Warnings and Precautions

The safety of RYLAZE described in the Warnings and Precautions reflect exposure to RYLAZE at various dosages, including cumulative dosages higher than the recommended and used in combination with chemotherapy in 167 patients in study JZP458-201 (Study data cut-off date was 19^th July 2021). These patients received a median of 4 courses of RYLAZE (range: 1-15 courses); 65% of patients received at least four courses.

Driving and Operating Machinery

Based on the adverse reactions of RYLAZE there may be a minor influence on the ability to drive and use machines [see 8.1 Adverse Reactions, Adverse Reaction Overview].

Endocrine and Metabolism

Hyperglycemia was reported in 16% of patients receiving RYLAZE in clinical trials, and it was severe in 4% of patients [see 8 Adverse Reactions]. Monitor glucose levels in patients at baseline and periodically during treatment. Treat hyperglycemia as medically indicated.

Hematologic

Thrombosis

Thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported in 4% of patients following treatment with RYLAZE, and it was severe in 2% of patients.

Discontinue RYLAZE for a thrombotic event and administer appropriate antithrombotic therapy. Consider resumption of treatment with RYLAZE only if the patient had an uncomplicated thrombosis [see 4.2 Dosage and Administration, Recommended Dose and Dosage Adjustment].

Hemorrhage

Bleeding was reported in 26% of patients treated with RYLAZE, and it was severe in 2% of patients. Most commonly observed reactions were contusion (11%) and nose bleeding (9%).

In patients treated with L-asparaginase class products, hemorrhage may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy [see 4.2 Dosage and Administration, Recommended Dose and Dosage Adjustment].

Hepatic/Biliary/Pancreatic

Pancreatic

Pancreatitis was reported in 7% of patients treated in clinical trials of RYLAZE and was severe in 6% of patients [see 8 Adverse Reactions]. Hemorrhagic or necrotizing pancreatitis have been reported with asparaginase class products.

Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue RYLAZE in patients with severe or hemorrhagic pancreatitis. In the case of mild pancreatitis, withhold RYLAZE until the signs and symptoms subside and amylase and/or lipase levels return to normal. After resolution of mild pancreatitis, treatment with RYLAZE may be resumed [see 4.2 Dosage and Administration, Recommended Dose and Dosage Adjustment].

Immune

Hypersensitivity reactions after the use of RYLAZE occurred in 29% of patients in clinical trials, and it was severe in 6% of patients [see 8 Adverse Reactions]. The most commonly observed reaction was maculopapular rash (8%) and rash (7%), and no patients experienced severe maculopapular rash or rash. Anaphylactic reaction was observed in 2% of patients.

Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus.

Because of the risk of serious allergic reactions, administer RYLAZE in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis [see 4.4 Dosage and Administration, Administration]. Discontinue RYLAZE in patients with serious hypersensitivity reactions [see 4.2 Dosage and Administration, Recommended Dose and Dosage Adjustment].

Reproductive Health

Nonclinical studies were not conducted to evaluate the potential effects of RYLAZE on reproductive health. However, published data with other asparaginases indicate that RYLAZE can cause embryonic and fetal harm when administered to a pregnant woman [see 7.1.1 Warnings and Precautions, Pregnant Women and 16 Non-Clinical Toxicology].

Pregnancy Testing

Pregnancy testing in females of reproductive potential is recommended prior to starting treatment with RYLAZE.

Contraception

Advise females of reproductive potential to avoid becoming pregnant while receiving RYLAZE due to the risks to the fetus. Females should use effective contraceptive methods during treatment and for 3 months after the last dose. Since an indirect interaction between oral contraception and RYLAZE cannot be ruled out, a method of contraception other than oral contraceptives should be used in females of reproductive potential.

• Fertility

Nonclinical studies were not conducted to evaluate the potential effects of RYLAZE on fertility. Nonclinical reports of impaired fertility following asparaginase treatment were not identified in the literature. [see 16 Non-Clinical Toxicology].

• Teratogenic risk

Nonclinical studies were not conducted to evaluate the potential teratogenicity of RYLAZE. However, published data with other asparaginases indicate that RYLAZE can cause embryonic and fetal harm when administered to a pregnant woman [see 16 Non-Clinical Toxicology].

7.1. Special Populations

7.1.1. Pregnancy

There are no data on the use of RYLAZE in pregnant women. However, published data with other asparaginases indicates that RYLAZE can cause embryonic and fetal harm when administered to a pregnant woman. RYLAZE should not be used during pregnancy, unless the clinical condition of the woman requires treatment and justifies the potential risk to the fetus.

If the medicinal product is used during pregnancy, or if the patient becomes pregnant while receiving RYLAZE, the woman should be informed of the potential risk to the fetus.

7.1.2. Breastfeeding

It is not known whether RYLAZE is excreted in human milk. Because of the potential for serious adverse reactions in breastfeeding children, advise women not to breastfeed during treatment with RYLAZE and for 2 weeks after the last dose.

7.1.3. Pediatrics

Pediatrics (1 to < 17 years of age): The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients 1 year to < 17 years of age who have developed hypersensitivity to pegaspargase. Use of RYLAZE in these age groups is supported by evidence from a single arm open label study in adults and pediatric patients. The trial included 112 pediatric patients, including 2 infants (1 year to < 2 years old), 79 children (2 years to < 12 years old), and 31 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 year of age.

7.1.4. Geriatrics

Geriatrics (> 65 years of age): Clinical studies of RYLAZE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The safety of RYLAZE was evaluated in a cohort of 51 patients from study JZP458-201 who received RYLAZE intramuscularly at a dosage of 25 mg/m² on Monday and Wednesday and 50 mg/m² on Friday for a total of 6 doses to replace each planned dose of pegaspargase [see 14 Clinical Trials]. RYLAZE was administered as a component of multi-agent chemotherapy.

The study population included patients with a median age of 10 years (range, 1 to 25 years); the majority of patients were male (61%) and white (65%). The patients received a median of 4 courses of RYLAZE (range: 1-11 courses).

The most common adverse reactions (in ≥ 20% of patients) were anemia, thrombocytopenia, neutropenia, nausea, vomiting, decreased appetite, febrile neutropenia, stomatitis, abdominal pain, diarrhea, fatigue, headache, hypokalemia, transaminase increased, white blood cell count decreased and pyrexia. The most common Grade 3 or higher adverse reactions (in ≥ 5% of patients) were neutropenia, thrombocytopenia, anemia, febrile neutropenia, white blood cell count decreased, lymphocyte count decreased, sepsis, hypokalemia, pancreatitis, transaminase increased, activated partial thromboplastin time prolonged, decreased appetite, dehydration, and nausea.

Serious adverse reactions occurred in 59% of patients. The most common serious adverse reactions (in ≥ 3% of patients) were febrile neutropenia, pyrexia, sepsis, dehydration, pancreatitis, acute kidney injury, bacteremia, decreased appetite, dysarthria, enterocolitis infectious, hypotension, muscular weakness, stomatitis, vomiting, and weight decreased.

Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RYLAZE. Adverse reactions resulting in permanent discontinuation included pancreatitis (8%) and hypersensitivity (2%).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Table 3: Non-hematologic Adverse Reactions (≥ 5% incidence) in Patients Receiving RYLAZE as a Component of Multi-Agent Chemotherapy (Study JZP458-201)^a

Grading is based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

a Hematologic adverse reactions are not included in the table. Patients received RYLAZE as a component of various multi-agent chemotherapy regimens in an uncontrolled trial making causality unclear.

b RYLAZE was administered intramuscularly at a dosage of 25 mg/m² on Monday and Wednesday and 50 mg/m² on Friday. RYLAZE was administered as a component of multi-agent chemotherapy.

c The analysis data cut-off date was 19^th July, 2021.

*Adverse drug reaction ‘Abdominal pain’ is a combined term of ‘Abdominal pain’ and ‘Abdominal pain upper’; ‘Bilirubin increased’ is a combined term of ‘Blood bilirubin increased’ and ‘Bilirubin conjugated increased’; ‘Fatigue’ is a combined term of ‘Fatigue’ and ‘Asthenia’; ‘Pancreatitis’ is a combined term of ‘Pancreatitis’ and ‘Pancreatitis acute’; ‘Transaminase increased’ is a combined term of ‘Transaminase increased’, ‘Alanine aminotransferase increased’ and ‘Aspartate aminotransferase increased’.

8.3. Less Common Clinical Trial Adverse Reactions

Less common adverse drug reactions that occurred in the JZP458-201 Study (N=167) treated with RYLAZE included:

Immune: anaphylactic reaction, drug hypersensitivity

Investigations: blood fibrinogen decreased

Metabolism and nutrition: hyperammonaemia

Nervous system: superior sagittal sinus thrombosis

Respiratory, thoracic and mediastinal: pulmonary embolism

8.5. Post-Market Adverse Reactions

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: Sinusoidal obstruction syndrome (SOS)/Veno-occlusive disease (VOD).

9. Drug Interactions

9.2. Drug Interactions Overview

No formal drug interaction studies have been conducted with RYLAZE.

9.3. Drug-Behaviour Interactions

The interaction of RYLAZE with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

Interactions with other drugs have not been established

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established

10. Clinical Pharmacology

10.1. Mechanism of Action

RYLAZE catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The mechanism of action of RYLAZE is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.

10.2. Pharmacodynamics

RYLAZE exposure-response relationships and the time course of pharmacodynamic response are unknown.

10.3. Pharmacokinetics

The pharmacokinetics (PK) of RYLAZE were determined based on serum asparaginase activity (SAA).

Sparse PK SAA samples were collected from patients with ALL/LBL who developed hypersensitivity or silent inactivation to long-acting E. coli-derived asparaginases, and a population PK approach was used to characterize the PK of RYLAZE. Patients received 6 doses of RYLAZE at 3 different dosages, including the recommended dosage, 25 mg/m² administered intramuscularly on Monday and Wednesday and 50 mg/m² on Friday, as a replacement for each dose of pegaspargase remaining on their original treatment plan [see 14 Clinical Trials]. Table 4 summarizes the PK parameters from the population PK analysis in the target patient population.

Table 4: Summary of RYLAZE Pharmacokinetic Parameters based on SAA in Patients in Study JZP458-201

a T_max reported as median and range.

b CL/F: apparent clearance; V/F: apparent volume of distribution.

Absorption:

The median T_max of RYLAZE is 13.7 hours. The mean absolute bioavailability for IM administration is 37% in healthy subjects. The maximum SAA (C_max) and area under the SAA-time curve (AUC) increase proportionally over a dosage range from 12.5 to 50 mg/m².

Distribution:

The mean (%CV) apparent volume of distribution of RYLAZE is 2.16 (93.6) L.

Metabolism:

RYLAZE is expected to be metabolized into small peptides by catabolic pathways.

Elimination:

The mean (%CV) apparent clearance of RYLAZE is 0.5 (87.4) L/hour and the apparent half-life following intramuscular administration is 19.1 hours (3.97).

Special Populations and Conditions:

No study has been conducted to evaluate the impact of renal and hepatic impairment on the pharmacokinetics of RYLAZE.

10.4. Immunogenicity

All therapeutic proteins have the 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 incidence of antibodies with the incidences of antibodies in other studies or to other products may be misleading.

The incidence of ADA and subsequent effects on pharmacokinetics, pharmacodynamics, safety, or effectiveness have not been established.

As with all L-asparaginase class products, there is a potential for immunogenicity with RYLAZE.

1. 11. Storage, Stability, and Disposal

Store RYLAZE refrigerated at 2°C to 8°C in the original carton to protect from light. Do not shake or freeze product. Discard unused product in accordance with local requirements. Do not use beyond expiration date printed on the carton or vial.

In-use storage period: administer within 4 hours of preparing syringe(s). The syringe(s) should be stored at room temperature and does not need to be protected from light before use.

If partial vial is used, do not save, or reuse the unused drug for later administration. Discard unused product.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: crisantaspase recombinant

Chemical name: L-asparaginase

Molecular formula and molecular mass: crisantaspase recombinant is a non-disulfide bonded, tetrameric crisantaspase (L-asparaginase) enzyme consisting of 4 identical polypeptide subunits with a combined molecular weight of 140 kDa; each individual subunit has a molecular weight of 35 kDa.

Table 5: Physicochemical properties

14. Clinical Trials

14.1. Clinical Trials by Indication

Treatment of Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients

Table 6: Summary of patient demographics for clinical trials in adults and pediatric patients with ALL or LBL who developed hypersensitivity to E. coli-derived asparaginases.

*Over two weeks (total of 6 doses) to replace each scheduled dose of pegaspargase.

The safety and efficacy of RYLAZE was assessed in study JZP458-201, a Phase 2/3, open-label, multicenter trial in adult and pediatric patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who had developed hypersensitivity to E. coli-derived asparaginase. Patients received RYLAZE at various dosages administered intramuscularly every Monday, Wednesday, and Friday for a total of 6 doses to replace each planned dose of pegaspargase.

In the ongoing study JZP458-201, 137 patients received at least one dose of RYLAZE. The median age was 10 years (range, 1 to 25 years); 59% were male, 41% were female, 69% were white, 13% were Black/African American, 4% were Asian and 10% were other or unknown race. A total of 34% were Hispanic or Latino. One hundred nineteen (87%) patients had experienced a hypersensitivity reaction to pegaspargase, 7 patients (5%) reported silent inactivation and 11 (8%) patients had experienced an allergic reaction with inactivation.

The determination of efficacy was based on a demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL.

Table 7: Proportion (95% CI) with NSAA levels ≥ 0.1 U/mL by Simulation

MW=Monday, Wednesday

MWF=Monday, Wednesday, Friday

16. Non-Clinical Toxicology

General toxicology

In a GLP-compliant study, RYLAZE was administered IV once daily to groups of rats (n=10/sex/group) for up to 14 days at doses of 0, 4.6, 15.2, and 45.6 mg/kg (0, 27.6, 91.2, and 273.6 mg/m², respectively). Recovery animals (n=5/sex/group) were included in the control and high dose groups. At the highest dose (273.6 mg/m²), significant clinical observations on Day 6 required interruption of dosing and initiation of the 2-week recovery or euthanasia. Hematology changes indicative of decreased hematopoiesis, increased glycemia and blood urea nitrogen, and decreased serum protein and liver enzymes were noted. Microscopic findings of decreased cellularity in the femoral bone marrow, decreased splenic red pulp, extramedullary hematopoiesis, decreased lymphocytes in the thymus and the spleen, and secretory depletion in the pancreas were also reported. Observations in the recovery animals (control and high dose) suggested these findings were reversible. At lower doses (≤ 91.2 mg/m²), dose-related effects as described above were also observed but were lower in magnitude, incidence, or severity and not considered adverse. The no-observed-adverse-effect level (NOAEL) was determined to be 91.2 mg/m², which provided exposure multiples of 24- and 10-fold based on the anticipated human C_max and AUC_0-336h at the proposed human dose of IM 25/25/50 mg/m² MWF. The incidence of ADA induction to RYLAZE was 0% (0/30 animals) in the control group, 45% (9/20) at 27.6 mg/m², 5% (1/20) at 91.2 mg/m², and 20% (6/30, all from the recovery animals) at 273.6 mg/m².

Genotoxicity

No studies have been performed to evaluate the mutagenicity of RYLAZE.

Carcinogenicity

No studies have been performed to evaluate the carcinogenicity of RYLAZE.

Reproductive and developmental toxicology

No studies have been performed to evaluate the potential reproductive and developmental toxicity of RYLAZE. RYLAZE mechanism of action is to catalyze the conversion of asparagine to aspartic acid and ammonia thereby resulting in profound depletion of circulating asparagine levels. Studies demonstrating the requirement for asparagine during normal pregnancy and fetal development in animals have been previously published, along with reports of abortion, stunted growth, malformations, and developmental delays effects of asparagine depletion in pregnant and nursing animals and their offspring when exposed to E. coli-derived and Erwinia-derived asparaginases.