Asparaginase Erwinia chrysanthemi

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# Overview
Asparaginase Erwinia chrysanthemi is an Asparaginase antineoplastic agent that is FDA approved for the treatment of acute lymphoblastic leukemia (ALL) as a component of a multi-agent chemotherapeutic regimen for patients who have developed hypersensitivity to E. coli-derived asparaginase.   Common adverse reactions include Diarrhea, elevated levels of transaminase & lactic acid dehydrogenase, fever, injection site reaction.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Acute Lymphoblastic Leukemia (ALL)
- As a component of a multi-agent chemotherapeutic regimen for patients who have developed hypersensitivity to E. coli-derived asparaginase.
- The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m2 administered intramuscularly or intravenously three times a week (Monday/Wednesday/Friday) for six doses.
- The recommended dose is 25,000 International Units/m2 administered intramuscularly or intravenously for each scheduled dose of native E. coli asparaginase within a treatment.
- When administering asparaginase erwinia chrysanthemi intravenously, consider monitoring nadir (pre-dose) serum asparaginase activity (NSAA) levels and switching to intramuscular administration if desired NSAA levels are not achieved.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Asparaginase Erwinia Chrysanthemi in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Asparaginase Erwinia Chrysanthemi in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Acute Lymphoblastic Leukemia (ALL)
- As a component of a multi-agent chemotherapeutic regimen for patients who have developed hypersensitivity to [[Escherichia coli
- The recommended dose for each planned dose of pegaspargase is 25,000 International Units/m2 administered intramuscularly or intravenously three times a week (Monday/Wednesday/Friday) for six doses.
- The recommended dose is 25,000 International Units/m2 administered intramuscularly or intravenously for each scheduled dose of native E. coli asparaginase within a treatment.
- When administering asparaginase erwinia chrysanthemi intravenously, consider monitoring nadir (pre-dose) serum asparaginase activity (NSAA) levels and switching to intramuscular administration if desired NSAA levels are not achieved.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Asparaginase Erwinia Chrysanthemi in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Asparaginase Erwinia Chrysanthemi in pediatric patients.

# Contraindications
- History of serious hypersensitivity reactions to asparaginase erwinia chrysanthemi, including anaphylaxis
- History of serious pancreatitis with prior L-asparaginase therapy
- History of serious thrombosis with prior L-asparaginase therapy
- History of serious hemorrhagic events with prior L-asparaginase therapy

# Warnings

### Hypersensitivity Reactions
- Grade 3 and 4 hypersensitivity reactions after the use of asparaginase erwinia chrysanthemi have occurred in 5% of patients in clinical trials.
- Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis.
- If a serious hypersensitivity reaction occurs, discontinue asparaginase erwinia chrysanthemi and initiate appropriate therapy.

### Pancreatitis
- Pancreatitis has been reported in 4% of patients in clinical trials.
- Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis.
- Discontinue asparaginase erwinia chrysanthemi for severe or hemorrhagic pancreatitis manifested by abdominal pain > 72 hours and amylase elevation  2.0 x ULN.
- Severe pancreatitis is a contraindication to additional asparaginase administration. *In the case of mild pancreatitis, hold asparaginase erwinia chrysanthemi until the signs and symptoms subside and amylase levels return to normal.
- After resolution, treatment with asparaginase erwinia chrysanthemi may be resumed.

### Glucose Intolerance
- Glucose intolerance has been reported in 5% of patients receiving asparaginase erwinia chrysanthemi in clinical trials. In some cases glucose intolerance may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.

### Thrombosis and Hemorrhage
Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism have been reported with both E. coli and Erwinia-derived L-asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2-week course of asparaginase erwinia chrysanthemi by intramuscular administration: fibrinogen, protein C activity, protein S activity, and anti-thrombin III. Discontinue asparaginase erwinia chrysanthemi for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with asparaginase erwinia chrysanthemi may be resumed.

# Adverse Reactions

## Clinical Trials Experience
Because clinical trials are conducted under controlled, but widely varying conditions, adverse reaction rates observed in clinical trials of asparaginase erwinia chrysanthemi cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
The data presented below are based on information collected from Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial (intramuscular administration), the asparaginase erwinia chrysanthemi Master Treatment Protocol (EMTP), an expanded access program (both intramuscular, intravenous, and other or unknown administration), and Study 2, a single-arm, multi-center, open-label, pharmacokinetic (PK) study trial of intravenous administration of asparaginase erwinia chrysanthemi.
Study 1 enrolled 58 patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. Patients received 6 doses of asparaginase erwinia chrysanthemi 25,000 International Units/m2 intramuscularly on a Monday, Wednesday, and Friday schedule as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The Study 1 population included patients with a median age of 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. In Study 1, the number of asparaginase erwinia chrysanthemi courses ranged from 1 to 9. In this study, 76% (44 of 58) completed all planned therapy. Fourteen (24%) patients stopped therapy prior to completion; seven due to allergic reactions, five due to physician or patient choice, one due to disease progression, and one due to discontinuation during frontline protocol. All other chemotherapy was continued according to the patients prescribed treatment regimen.
Study 2 enrolled 30 patients  following allergy to native E. coli asparaginase or pegaspargase. Patients received asparaginase erwinia chrysanthemi 25,000 International Unit/m2/dose, administered by intravenous infusion on a Monday, Wednesday, and Friday schedule (6 doses) as a replacement for doses remaining on their original treatment plan. The Study 2 population included patients with a median age of 7 years (1 to 17 years); 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native or Indian).
The EMTP trial enrolled 1368 patients with ALL or lymphoblastic lymphoma who received asparaginase erwinia chrysanthemi after developing systemic hypersensitivity to an E. coli-derived asparaginase. Of these 1368 patients, safety data were received for 940 patients with a median age of 9 years (0 to 76 years), 63% were male, 91% with leukemia, 3% with lymphoma, and 6% with unknown disease information. Patients received asparaginase erwinia chrysanthemi according to several schedules, and treatment center specifications with doses that ranged from 20,000 to 25,000 International Units/m2. The route of administration was intramuscular n=852, intravenous n=29, other or unknown n=59. In the EMTP trial, the planned number of doses of asparaginase erwinia chrysanthemi ranged from 3 to 48 doses. Seventy-eight percent of patients (693 of 893) were able to receive all planned doses to complete their prescribed treatment regimen.
In Study 1 and Study 2, safety information was prospectively and systematically collected. In Study 1, all Grades of adverse events were reported for the following adverse events of special interest: allergy, pancreatitis, coagulopathy (hemorrhage, thrombosis or infarct), hyperbilirubinemia, hyperglycemia, hyperlipidemia, ketoacidosis, and CNS events (hemorrhage, thrombosis or infarction, and cerebral venous thrombosis) and only Grade 3 and 4 events were reported for other adverse events. In Study 2 all adverse events of all Grades were prospectively collected. In the EMTP trial, safety data were derived from case report forms that collected adverse event information. The forms specifically requested information on occurrence of allergic reactions, thrombotic events, hemorrhagic events, hepatobiliary disorders, pancreatic disorders, and hyperglycemia.
The incidence of non-hematologic, non-infectious, adverse events (all Grades) in Study 1, Study 2, and the EMTP trial is provided in Table 1.
The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with asparaginase erwinia chrysanthemi in Study 1, Study 2 and EMTP trial is provided in Table 2.

### Immunogenicity
As with most therapeutic proteins, patients may develop anti-drug antibodies (ADA) to asparaginase erwinia chrysanthemi.
In a study with asparaginase erwinia chrysanthemi treatment by intramuscular administration (Study 1), 6 of 56 (11%) patients treated with asparaginase erwinia chrysanthemi developed antibodies to asparaginase erwinia chrysanthemi. Of these 6 ADA positive patients, one experienced a hypersensitivity reaction during Study 1 (2%, 1 of 56). None of these 6 patients had neutralizing antibodies.
In a study with asparaginase erwinia chrysanthemi treatment by intravenous administration (Study 2), 4 of 30 (13.3%) patients treated with asparaginase erwinia chrysanthemi developed anti-asparaginase erwinia chrysanthemi antibodies. Of these 4 patients who developed anti-asparaginase erwinia chrysanthemi antibodies, 3 experienced hypersensitivity reactions (10%, 3 of 30) during the study. None of these 4 patients had neutralizing antibodies.
The presence of ADA to asparaginase erwinia chrysanthemi is associated with a higher risk of hypersensitivity reactions in patients who received asparaginase erwinia chrysanthemi through intravenous infusion compared to intramuscular administration of asparaginase erwinia chrysanthemi.
Immunogenicity assay are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to asparaginase erwinia chrysanthemi with the incidence of antibodies to other products may be misleading.

## Postmarketing Experience
There is limited information regarding Asparaginase Erwinia chrysanthemi Postmarketing Experience in the drug label.

# Drug Interactions
- No formal drug interaction studies between asparaginase erwinia chrysanthemi and other drugs have been performed.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- here are no adequate and well-controlled studies of asparaginase erwinia chrysanthemi in pregnant women.
- In embryofetal development studies in rats and rabbits, asparaginase Erwinia chrysanthemi produced embryofetal toxicities and fetal abnormalities.
Asparaginase erwinia chrysanthemi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

### Animal Data
- In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 500, 1000, or 2000 IU/kg) and rabbits (at 10, 25, and 40 IU/kg). In rats given 2000 IU/kg (approximately 50% of the recommended human dose, adjusted for body surface area), maternal toxicity of decreased body weight gain was observed, as well as a fetal finding of increased incidence of partially undescended thymic tissue.
- In rabbits, maternal toxicity consisting of decreased body weight was observed at 40 IU/kg (approximately 2% of the recommended human dose, adjusted for body surface area). *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 10 IU/kg (approximately 0.5% of the recommended human dose, adjusted for body surface area).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Asparaginase Erwinia chrysanthemi in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Asparaginase Erwinia chrysanthemi during labor and delivery.

### Nursing Mothers
- It is not known whether asparaginase erwinia chrysanthemi is secreted in human milk. *Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from asparaginase erwinia chrysanthemi, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- See clinical studies

### Geriatic Use
- The safety and efficacy of asparaginase erwinia chrysanthemi has not been studied in geriatric patients.

### Gender
There is no FDA guidance on the use of Asparaginase Erwinia chrysanthemi with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Asparaginase Erwinia chrysanthemi with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Asparaginase Erwinia chrysanthemi in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Asparaginase Erwinia chrysanthemi in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Asparaginase Erwinia chrysanthemi in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Asparaginase Erwinia chrysanthemi in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intramuscular
- Intravenous
- For intramuscular use, limit the volume of reconstituted asparaginase erwinia chrysanthemi at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites.
- For intravenous use, infuse asparaginase erwinia chrysanthemi in 100 mL of normal saline over 1 hour.
- Do not infuse other intravenous drugs through the same intravenous line while infusing asparaginase erwinia chrysanthemi.

### Monitoring
- Monitor glucose levels in patients at baseline and periodically during treatment.

# IV Compatibility
1. Visually inspect the asparaginase erwinia chrysanthemi powder for foreign particulate matter and discoloration prior to reconstitution. Discard vial if present.
2. Reconstitute the contents of each vial by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride (0.9%) injection (USP) against the inner vial wall.
3. Do not forcefully inject solution for reconstitution directly onto or into the powder. When reconstituted with 1 mL the resultant concentration is 10,000 International Units per mL. When reconstituted with 2 mL the resultant concentration is 5,000 International Units per mL.
4. Dissolve contents by gentle mixing or swirling. Do not shake or invert vial.
5. When reconstituted, asparaginase erwinia chrysanthemi should be a clear, colorless solution. Inspect the solution after reconstitution and discard if any visible particles or protein aggregates are present.
6. Calculate the dose needed and the volume needed to obtain the calculated dose.
7. Withdraw the volume containing the calculated dose from the vial into a polypropylene syringe within 15 minutes of reconstitution. For intravenous use, slowly inject the reconstituted asparaginase erwinia chrysanthemi into an IV infusion bag containing 100 mL of normal saline acclimatized to room temperature. Do not shake or squeeze the IV bag.
8. If partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.
9. Do not freeze or refrigerate reconstituted solution and administer within 4 hours or discard

# Overdosage
- There are no known cases of overdose with asparaginase erwinia chrysanthemi.

# Pharmacology
There is limited information regarding Asparaginase Erwinia chrysanthemi Pharmacology in the drug label.

## Mechanism of Action
Asparaginase Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of asparaginase erwinia chrysanthemi is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of amino acid asparagine for their protein metabolism and survival.

## Structure
Aasparaginase Erwinia chrysanthemi contains an asparagine specific enzyme derived from Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The activity of asparaginase erwinia chrysanthemi is expressed in terms of International Units.

## Pharmacodynamics
There is limited information regarding Asparaginase Erwinia chrysanthemi Pharmacodynamics in the drug label.

## Pharmacokinetics
Based on a population PK model, the mean (%CV) half-life of intravenous asparaginase erwinia chrysanthemi was 7.51 (23.9%) hours in contrast to a mean (%CV) half-life of 15.6 (20%) hours reported for intramuscular asparaginase erwinia chrysanthemi. These differences in PK between intravenous and intramuscular asparaginase erwinia chrysanthemi are reflected in the proportion of patients with 2-day and 3-day nadir serum asparaginase activity (NSAA) levels of asparaginase Erwinia chrysanthemi  0.1 or 0.4 IU/mL.
Following administration of asparaginase erwinia chrysanthemi 25,000 International Units/m2 intramuscularly to 48 ALL patients aged  2 years to  18 years in Study 1 on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients who completed Course 1 achieved NSAA levels  0.1 International Units/mL at either 48 hours (n=35) or 72 hours (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had nadir serum asparaginase activity levels  0.4 International Units/mL.
Following intravenous administration of asparaginase erwinia chrysanthemi 25,000 International Units/m2 to 24 evaluable patients (aged  1 year to  17 years) in Study 2 on a Monday, Wednesday, and Friday schedule, 83% (20/24) and 43% (9/21) of patients who completed Course 1 achieved NSAA levels  0.1 International Units/mL at 48 hours post-dose 5 and 72 hours post dose 6, respectively. Twenty-nine percent (7/24) of those evaluated at 48 hours and no patients (0/21) evaluated at 72 hours had nadir serum asparaginase activity levels  0.4 International Units/mL

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term carcinogenicity studies in animals have been performed with asparaginase Erwinia chrysanthemi. No studies that assess the mutagenic potential of asparaginase Erwinia chrysanthemi have been conducted.
In a fertility and early embryonic development study in rats, asparaginase Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 2000 IU/kg (approximately 50% of the recommended human dose, when adjusted for total body surface area) every other day for a total of 35 doses. Findings in males included decreased sperm count at doses of more than 500 IU/kg (approximately 12% of the recommended human dose).

# Clinical Studies
The safety and efficacy of asparaginase erwinia chrysanthemi was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial.  Additional safety data were obtained in the asparaginase erwinia chrysanthemi Master Treatment Protocol (EMTP), an expanded access program. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions.  The main outcome measure was determination of the proportion of patients who achieved a serum trough asparaginase level greater than or equal to 0.1 International Units/mL.  Serum trough asparaginase activity  0.1 International Units/mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 M) and to serum levels that predict clinical efficacy.   Patients received asparaginase erwinia chrysanthemi 25,000 International Units/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.
Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in Course 1.  The median age was 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino.
Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the pre-specified trough asparaginase activity level of  0.1 International Units/mL at 48 or 72 hours following the third dose. Results for the main outcome measure and for an exploratory analysis using a higher cut-off (trough serum asparaginase activity levels  0.4 International Units/mL are presented in Table 3.
The safety and efficacy of intravenous administration were determined in Study 2 by characterizing the PK of a 25,000 International Units/m2 asparaginase erwinia chrysanthemi dose given 3 days per week on a Monday, Wednesday, and Friday schedule for up to 30 weeks. This open-label, single-arm, multicenter PK study enrolled 30 patients. The main outcome measure was determination of the proportion of patients with 2-day NSAA levels (48-hour levels taken after the fifth dose)  0.1 International Unit/mL in the first 2 weeks of asparaginase erwinia chrysanthemi treatment.
Of the thirty patients enrolled, 24 were evaluable for the main outcome measure based on the pharmacokinetic samples in Course 1. The median age was 7 years (1-17 years), 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native, or Indian).
In Study 2, serum asparaginase activity of asparaginase Erwinia chrysanthemi was determined in 24 evaluable patients (aged  1 year to 17 years) following intravenous administration of asparaginase erwinia chrysanthemi 25,000 International Units/m2. Five minutes after the 60-minute infusion in Course 1, the mean asparaginase activity level was 12.65  3.16 International Unit/mL post-dose 1 and 12.11  3.11 International Unit/mL post dose 4. The main study objective was met with an asparaginase activity level of  0.1 International Units/mL 48 hours after the fifth dose observed in 83% of patients. The 72-hour post dose 6 asparaginase activity level of  0.1 International Unit/mL was the secondary endpoint, with 43% of patients achieving this endpoint. Results are presented in Table 3

# How Supplied
- Asparaginase erwinia chrysanthemi is a sterile, white lyophilized powder supplied in a clear 3 mL glass vial.
- Each carton of asparaginase erwinia chrysanthemi (NDC 57902-249-05) contains 5 vials.
- Each single vial (NDC 57902-249-01) contains 10,000 International Units asparaginase Erwinia chrysanthemi.

## Storage
- Store unused or unopened vials and cartons at 36F to 46F (2C to 8C).
- Protect from light.
- Do not use asparaginase erwinia chrysanthemi after the expiration date on the vial.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Instruct patients on the risk of allergic reactions, including anaphylaxis.
- Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical advice immediately if they experience such symptoms.
- Instruct patients on the risk of pancreatitis and to seek medical advice immediately if they experience abdominal pain.
- Instruct patients on the risk of hyperglycemia and glucose intolerance.
- Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination.
- Instruct patients on the risk of thrombosis and hemorrhage and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain.

# Precautions with Alcohol
Alcohol-Asparaginase Erwinia Chrysanthemi interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Erwinaze

# Look-Alike Drug Names
There is limited information regarding Asparaginase Erwinia chrysanthemi Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price