Asparaginase erwinia chrysanthemi (recombinant)-rywn

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# Overview
Asparaginase erwinia chrysanthemi (recombinant)-rywn is an asparagine specific enzyme that is FDA approved for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in patients who are allergic to E. coli-derived asparaginase products, as a component of a chemotherapy regimen.   Common adverse reactions include musculoskeletal pain, febrile neutropenia, hypokalemia, abnormal liver test, abdominal pain, hypersensitivity, pyrexia, fatigue, nausea, infection, decreased appetite, stomatitis, hemorrhage, diarrhea, drug hypersensitivity, pancreatitis, and hyperglycemia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Treatment Options of Rylaze to replace a long-acting asparaginase product
- Option 1 is 25 mg/m2 administered intramuscularly every 48 hours.
- Option 2 is 25 mg/m2 intramuscularly in the mornings of Monday and Wednesday, and 50 mg/m2 intramuscularly in the afternoon on Friday. Friday dosage should be administered 53 to 58 hours after the Wednesday dose.
Table 1 summarizes Recommended Duration of Rylaze Dosing to Replace One Long-Acting Asparaginase Dose.
Recommended Pre-medication
- 30-60 minutes prior to Rylaze treatment, consider administering an H-1 receptor blocker, acetaminophen, and an H-2 receptor blocker to reduce severity and risk of hypersensitivity reactions.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Asparaginase erwinia chrysanthemi (recombinant)-rywn FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in pediatric patients.

# Contraindications
- Serious hypersensitivity reactions to Erwinia asparaginase
- If a patient experienced, during previous asparaginase therapy, serious pancreatitis.
- If a patient experienced, during previous asparaginase therapy, serious thrombosis.
- If a patient experienced, during previous asparaginase therapy, serious hemorrhagic events.

# Warnings
Hypersensitivity Reactions
- 29% of patients experienced hypersensitivity reactions in clinical trials when given Rylaze.
- 6% of patients experienced severe hypersensitivity reactions in clinical trials when given Rylaze.
- 2% of patients in clinical trials experienced anaphylaxis after intramuscular administration.
- 5% of patients in clinical trials had to discontinue treatment due to hypersensitivity reactions.
- 12 doses was the median number to the first recorded experience of a hypersensitivity reaction from a patient receiving Rylaze.
- Rash was the most common observed reaction.
- Blood pressure decrease, pruritus, eye swelling, angioedema, rash or erythema, dyspnea, lip swelling, bronchospasm, and urticaria are some of the many hypersensitivity reactions observed with L-asparaginase class products.
- If severe hypersensitivity reaction is observed, patients are advised to discontinue Rylaze treatment.
Pancreatitis
- 20% of patients experienced pancreatitis in clinical trials when given Rylaze.
- 8% of patients experienced severe pancreatitis in clinical trials when given Rylaze.
- 7% of patients experienced symptomatic pancreatitis in clinical trials when given Rylaze.
- 6% of patients experienced severe symptomatic pancreatitis in clinical trials when given Rylaze.
- 13% of patients had signs of elevated lipase or amylase without symptomatic pancreatitis.
- Necrotizing pancreatitis and hemorrhagic pancreatitis are observed with L-asparaginase class products.
- Advise patients about signs and symptoms associated with pancreatitis.
- Monitor patients lipase levels and serum amylase levels during Rylaze treatment.
- Advise patients with severe or hemorrhagic pancreatitis to discontinue Rylaze treatment.
- Withhold treatment of Rylaze in patients who experience mild pancreatitis till the signs/symptoms are gone as well as the return of amylase/lipase levels to 1.5 times the ULN.
Thrombosis
- 1% of patients experienced serious thrombotic events in clinical trials when given Rylaze.
- Advise patients who experience signs/symptoms associated with a thrombotic event to discontinue Rylaze treatment.
- If the patient experienced an uncomplicated thrombosis, the patient should be considered for Rylaze treatment.
Hemorrhage
- 25% of patients experienced bleeding in clinical trials when treated with Rylaze.
- 2% of patients experienced severe bleeding in clinical trials when treated with Rylaze.
- Nose bleed and bruising were most common observed reaction.
- For patients with severe or symptomatic coagulopathy, replacement therapy should be considered.
Hepatotoxicity
- 75% of patients experienced elevated bilirubin and/or transaminases in clinical trials when treated with Rylaze.
- 26% had Grade  3 elevations of bilirubin and/or transaminases in clinical trials when treated with Rylaze.
- 28% of patients experienced elevated bilirubin in clinical trials when treated with Rylaze.
- 2% had Grade  3 elevations of bilirubin in clinical trials when treated with Rylaze.
- 73% of patients experienced elevated transaminases in clinical trials when treated with Rylaze.
- 25% had Grade  3 elevations of transaminases in clinical trials when treated with Rylaze.
- Monitor bilirubin and transaminases levels in patients treated with Rylaze.
- Patients who experience serious liver toxicity should discontinue Rylaze treatment.

# Adverse Reactions

## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
Study JZP458-201
- 167 patients who received a median of 4 courses of Rylaze.
- Patients were either given 25 mg/m2 of Rylaze on Monday, Wednesday, and Friday or 25 mg/m2 on Monday and Wednesday, and 50 mg/m2 on Friday, for 6 doses as a replacement for a single dose of pegaspargase as a component of multi-agent chemotherapy.
- 11 years of age was the median age of the patient population.
- Patient population consisted mostly of males (57%) and Caucasian (68%).
- 1 patient experienced fatal adverse reaction during the study.
- 60% of patients in the study experienced serious adverse reactions.
- Drug hypersensitivity, pyrexia, nausea, dehydration, pancreatitis, diarrhea, viral infection, febrile neutropenia, infection,  stomatitis, and acute kidney injury were some of the serious adverse reactions reported by patients in the study.
- 10% of patients in the study had to discontinue Rylaze treatment.
- Infection, pancreatitis, and hypersensitivity are some of the adverse reactions reported by patients that led to Rylaze discontinuation.
- Anemia, neutropenia, or thrombocytopenia were symptoms reported by patients in the clinical study that received Rylaze as a component of multi-agent chemotherapy.
- Abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, diarrhea, pancreatitis, abnormal liver test, nausea, musculoskeletal pain, infection, hypokalemia, and stomatitis are the symptoms reported by patients that were the most common non-hematological adverse reactions.
Table 3 summarizes the common adverse reactions reported by patients when receiving Rylaze treatment
Rylaze in combination with chemotherapy
- < 15% of patients experienced clinically relevant adverse reactions.
- Infections and infestations, musculoskeletal and connective tissue disorders, skin and subcutaneous disorders, gastrointestinal disorders, psychiatric disorders, general disorders and administration site conditions, metabolism and nutrition disorders, nervous system disorders, vascular disorders, renal and urinary disorders, and respiratory, thoracic, and mediastinal disorders were observed in patients during the clinical trial.

## Postmarketing Experience
There is limited information regarding Asparaginase erwinia chrysanthemi (recombinant)-rywn Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Asparaginase erwinia chrysanthemi (recombinant)-rywn Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Rylaze can be harmful to the fetus, based on animal reproduction studies, when given to pregnant women. No studies have been conducted to look at if Rylaze causes major birth defects, miscarriage or adverse maternal or fetal outcomes in humans. Embryo-fetal mortality and structural abnormalities were observed in pregnant rabbits and rats given asparaginase Erwinia chrysanthemi. Maternal toxicity of decreased body weight gain and increased incidence of partially undescended thymic tissue of rat fetus was observed when pregnant rats were given 12 mg/m2 of asparaginase Erwinia chrysanthemi. Maternal toxicity of decreased body weight was seen in rabbits that received 0.48 mg/m2 of asparaginase Erwinia chrysanthemi.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Asparaginase erwinia chrysanthemi (recombinant)-rywn in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Asparaginase erwinia chrysanthemi (recombinant)-rywn during labor and delivery.

### Nursing Mothers
No current data has been done on the effects of Rylaze on the breastfed infant and the effects on milk production in women when treated with Rylaze. Advise nursing patients to not breastfeed until 1 week after the last dose of Rylaze due to the potential adverse reactions.

### Pediatric Use
Hypersensitivity was developed in pediatric patients 1 month to < 17 years when treated with Rylaze. Nadir serum asparaginase activity or safety differences were not clinically signifcant/meaningful across all age groups.

### Geriatic Use
There is no FDA guidance on the use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in geriatric settings.

### Gender
There is no FDA guidance on the use of Asparaginase erwinia chrysanthemi (recombinant)-rywn with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Asparaginase erwinia chrysanthemi (recombinant)-rywn with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in patients with hepatic impairment.

### Females of Reproductive Potential and Males
Advise females of reproductive potential to take a pregnancy test before start of Rylaze treatment. Rylaze can harm the fetus when administered into pregnant women. Advise females of reproductive potential to use effective non-hormonal contraceptive methods during  and for 3 months after the last dose of Rylaze treatment.

### Immunocompromised Patients
There is no FDA guidance one the use of Asparaginase erwinia chrysanthemi (recombinant)-rywn in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Preparation and Administration Instructions
- If anaphylactic reactions occur due to Rylaze treatment, seek medical support immediately.
- Discard vial of Rylaze if there is cloudiness, particulate matter, or discoloration.
- Use individual patients BSA to determine the number of Rylaze vials as well as the dose and total volume of Rylaze solution required for proper treatment.
- Prepare injection with the correct amount of Rylaze solution determined.
- Maximum amount of volume in syringe should be 2 mL.
- If greater than 2 mL is required, then equally distribute volume needed into multiple syringes for one injection spot.
- Use intramuscular injection to administer dosage into the patient
Rylaze solution prepared not for immediate use can either be placed for 8 hours at room temperature (15C to 25C) or for 24 hours refrigerated at 2C to 8C.

### Monitoring
Recommended Monitoring and Dosage Modifications for Adverse Reactions
- Every 2-3 weeks during Rylaze treatment, monitor patients glucose levels, bilirubin levels, clinical examinations, and transaminases levels.
Table 2 summarizes treatment modifications if patient continues to experience adverse reactions

# IV Compatibility
There is limited information regarding the compatibility of Asparaginase erwinia chrysanthemi (recombinant)-rywn and IV administrations.

# Overdosage
There is limited information regarding Asparaginase erwinia chrysanthemi (recombinant)-rywn overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- The conversion of the amino acid L-asparagine into aspartic acid and ammonia occurs due to the catalyze of the enzyme called Asparaginase erwinia chrysanthemi (recombinant)-rywn.

## Structure
There is limited information regarding Asparaginase erwinia chrysanthemi (recombinant)-rywn Structure in the drug label.

## Pharmacodynamics
- Time course of pharmacodynamic response of asparaginase erwinia chrysanthemi (recombinant)-rywn are unknown.
- Exposure-response relationships of asparaginase erwinia chrysanthemi (recombinant)-rywn are unknown.

## Pharmacokinetics
- Cmax and AUC increased over a dosage range from 12.5 to 50 mg/m2 proportionally  serum asparaginase activity.
Table 4 Summarizes the Data of Simulated Rylaze Pharmacokinetic Parameters Based on SAA
Absorption
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 12 hours was the median Tmax.
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 8 hours was the minimum Tmax.
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 24 hours was the maximum Tmax.
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 37% was the mean absolute bioavailability.
Distribution
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 1.37 L/m2 was the geometric mean volume.
Elimination
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 0.17 L/hour/m2  was the geometric mean clearance.
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, 15.9 hours is the apparent half-life.
Metabolism
- Catabolic pathways are expected to metabolize asparaginase erwinia chrysanthemi (recombinant)-rywn into small peptides.
Specific Populations
- For the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn, weight (9 to 131 kg), age (1.4 to 25 years), and sex after the dose was adjusted by BSA did not show clinically significant differences on patients.
- For asparaginase erwinia chrysanthemi (recombinant)-rywn, increasing BSA led to increases in clearance and volume of distribution.
- SAA exposure may increase in Black or African American patients compared to Asian and White patients.
- A 29% lower clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn was seen in Black or African American patients when compared to Asian and White patients.
Immunogenicity
- Antibodies of anti-asparaginase erwinia chrysanthemi (recombinant)-rywn were observed in 47% patients part of Study JZP458-201.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- For anti-asparaginase erwinia chrysanthemi (recombinant)-rywn, studies have not been conducted on mutagenesis, impairment of fertility, or carcinogenesis.
- Fertility was not impacted by asparaginase erwinia chrysanthemi (recombinant)-rywn for male or female rats given doses of up to 12 mg/m2.
- Sperm decrease was seen in male rats, but had no impact on fertility when administered asparaginase erwinia chrysanthemi (recombinant)-rywn.

# Clinical Studies
Study JZP458-201
- An open labeled, multi-cohort, multi-center trial that looked into a patient population of 225 patients with either LBL or ALL that have developed hypersensitivity to E. coli-derived asparaginase as a component of a multi-agent chemotherapeutic regimen.
- The patient population consisted of mostly males (61%) and Caucasian (69%).
- The study looked into the efficacy of Rylaze based on NSAA levels.
Table 5 summarizes Proportion (95% CI) with NSAA  0.1 U/mL by Simulation Data

# How Supplied
- An injection that contains vials with a colorless to slightly yellow and clear to opalescent solution.
- 10 mg/0.5 mL asparaginase erwinia chrysanthemi (recombinant)-rywn are stored in each single vial.
- 3 single-dose vials are found in each carton of Rylaze.

## Storage
- May refrigerate Rylaze vials from 2C to 8C.
- Protect vials from light by using original carton.
- Do not freeze or shake Rylaze vials.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Hypersensitivity
- Risks of allergic reactions such as anaphylaxis may occur.
- Advise patients to seek medical attention immediately if they experience an allergic reaction.
Pancreatitis
- Risk of severe abdominal pain may occur
- Advise patients to seek immediate medical attention if they experience signs associated with pancreatitis
Thrombosis
- Patients may experience shortness of breath, headache, chest pain, and arm or leg swelling
- Advise patients to seek immediate medical attention if they experience signs of thrombosis
Hemorrhage
- Advise patients to report to their doctor any signs or symptoms of bruising or unusual bleeding
Hepatotoxicity
- Advise patients to report to their doctors any signs of severe nausea or vomiting, jaundice, easy bruising, or easy bleeding
Pregnancy
- Advise patients about the potential risks to the fetus when taking Rylaze
- Advise female patients to report any signs or symptoms of pregnancy to their doctor
- Advise females of reproductive potential to use effective non-hormonal contraceptive methods during  and for 3 months after the last dose of Rylaze treatment
Lactation
- Advise female patients to neither nurse a fetus when taking Rylaze or until 1 week after last dose has been administered

# Precautions with Alcohol
Alcohol-Asparaginase erwinia chrysanthemi (recombinant)-rywn interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Rylaze

# Look-Alike Drug Names
There is limited information regarding Asparaginase erwinia chrysanthemi (recombinant)-rywn Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price