AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Asparaginase (Erwinia chrysanthemi)

Molecular Formula:

• C₁₅₄₆H₂₅₁₀N₄₃₂O₄₇₆S₉ (monomer)

Asparaginase (Erwinia chrysanthemi), an asparaginase enzyme derived from Erwinia chrysanthemi (formerly Erwinia carotovora ; also known as Pectobacterium chrysanthemi ), is an antineoplastic agent.1,6

Acute Lymphocytic Leukemia

Acute Lymphocytic Leukemia and Hypersensitivity to Escherichia coli-derived Asparaginase

Asparaginase (Erwinia chrysanthemi) is used as a component of combination chemotherapy for the treatment of acute lymphocytic (lymphoblastic) leukemia (ALL) in patients who are hypersensitive to E. coli -derived asparaginase preparations.1,4,7,8,9 Asparaginase (Erwinia chrysanthemi) has been designated an orphan drug by the US Food and Drug Administration (FDA) for this use.2 For additional information on other asparaginase preparations and the treatment of ALL, see Pegaspargase 10:00.

The current indication for asparaginase (Erwinia chrysanthemi) is based on an open-label, noncomparative safety and clinical pharmacology study in patients on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue pegaspargase therapy because of hypersensitivity reactions and received asparaginase (Erwinia chrysanthemi) by IM injection.1 Additional information on the safety and efficacy of asparaginase (Erwinia chrysanthemi) is available from an open-label, noncomparative study evaluating the pharmacokinetics of the drug administered by IV infusion.1

In the study evaluating IM asparaginase (Erwinia chrysanthemi) therapy, patients received 25,000 units/m² of the drug by IM injection on a Monday, Wednesday, and Friday schedule for 2 weeks (total of 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.1,3 The primary outcome measure was the proportion of patients who achieved sustained asparaginase activity at a level predicted to result in clinical efficacy (i.e., serum trough asparaginase activity of 0.1 units/mL or greater, which has been demonstrated to correlate with asparagine depletion [asparagine concentration of less than 0.4 mcg/mL]).1,3 Of the 58 patients enrolled in the study, 48 were evaluated for the primary outcome measure based on availability of pharmacokinetic samples; the median age of patients in the study was 11 years (range: 2-18 years of age).1 The proportion of patients who achieved serum trough asparaginase activity of 0.1 units/mL or greater was 100% at either 48 hours (35 of 35 patients) or 72 hours (13 of 13 patients) following the third dose of asparaginase (Erwinia chrysanthemi).1 Because some clinicians suggest that serum trough asparaginase activity of 0.4 units/mL or greater is a better predictor of clinical efficacy, an exploratory analysis was performed using this outcome measure.1,3 The proportion of patients who achieved serum trough asparaginase activity of 0.4 units/mL or greater was 80% at 48 hours (28 of 35 patients) and 38% at 72 hours (5 of 13 patients) following the third dose of asparaginase (Erwinia chrysanthemi).1,3

In the study evaluating IV asparaginase (Erwinia chrysanthemi) therapy, patients received 25,000 units/m² of the drug by IV infusion over 60 minutes on a Monday, Wednesday, and Friday schedule for up to 30 weeks.1 The primary outcome measure was the proportion of patients who achieved serum trough asparaginase activity of 0.1 units/mL or greater at 48 hours after the fifth dose.1 Of the 30 patients enrolled in the study, 24 were evaluated for the primary outcome measure based on availability of pharmacokinetic samples; the median age of patients enrolled in the study was 7 years (range: 1-17 years).1 The proportion of patients who achieved serum trough asparaginase activity of 0.1 units/mL or greater was 83% (20 of 24 patients) at 48 hours after the fifth dose and 43% (9 of 21 patients) at 72 hours after the sixth dose of asparaginase (Erwinia chrysanthemi).1 The proportion of patients who achieved serum trough asparaginase activity of 0.4 units/mL or greater was 29% (7 of 24 patients) at 48 hours after the fifth dose and 0% (0 of 21 patients) at 72 hours after the sixth dose of asparaginase (Erwinia chrysanthemi).1

Asparaginase (Erwinia chrysanthemi) is administered by IM injection or IV infusion.1

Asparaginase (Erwinia chrysanthemi) should be administered in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis.1 (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.) In patients receiving asparaginase (Erwinia chrysanthemi) by IV infusion, consideration should be given to monitoring serum trough asparaginase activity and, if desired asparaginase concentrations are not achieved, switching to IM administration.1 (See Acute Lymphocytic Leukemia and Hypersensitivity to Escherichia coli-derived Asparaginase under Uses: Acute Lymphocytic Leukemia.)

Asparaginase (Erwinia chrysanthemi) lyophilized powder for injection should be inspected visually for foreign particulate matter and discoloration prior to reconstitution and discarded if either is present.1

Asparaginase (Erwinia chrysanthemi) sterile lyophilized powder for injection is reconstituted by adding 1 or 2 mL of sterile, preservative-free 0.9% sodium chloride injection to a vial labeled as containing 10,000 units of asparaginase (Erwinia chrysanthemi) to provide a solution containing 10,000 or 5000 units/mL, respectively.1 Based on the indicated dosage of asparaginase (Erwinia chrysanthemi), the appropriate number of vials of the drug should be reconstituted.1 During reconstitution, the sterile, preservative-free 0.9% sodium chloride injection should be injected slowly against the inner wall of the vial and should not be forcefully injected directly onto or into the powder.1 The contents of the vial should be dissolved by gently mixing or swirling the vial; the vial should not be shaken or inverted.1 The reconstituted solution should be clear and colorless and should be discarded if any visible particles or protein aggregates are present.1 The appropriate dose of asparaginase (Erwinia chrysanthemi) should be withdrawn from the vial into a polypropylene syringe within 15 minutes of reconstitution.1 Unused portions of the injection should be discarded and should not be saved for later administration.1 The reconstituted solution should be administered within 4 hours or discarded and should not be frozen or refrigerated.1

For IM administration, the manufacturer recommends that not more than 2 mL of reconstituted asparaginase (Erwinia chrysanthemi) solution be administered at any one injection site; if the total volume exceeds 2 mL, the dose should be divided and administered at separate sites.1

For IV infusion, the appropriate volume of reconstituted asparaginase (Erwinia chrysanthemi) solution should be further diluted in 0.9% sodium chloride injection and infused over 1-2 hours.1 The reconstituted solution should be injected slowly into an IV infusion bag containing 100 mL of 0.9% sodium chloride injection at room temperature.1 The bag should not be shaken or squeezed.1 IV solutions of asparaginase (Erwinia chrysanthemi) should not be infused simultaneously through the same IV line with other drugs.1

Asparaginase (Erwinia chrysanthemi) lyophilized powder for injection in unopened vials and cartons should be stored at 2-8°C and protected from light.1

Procedures for proper handling and disposal of antineoplastic drugs should be followed when preparing or administering asparaginase preparations.11,41

Dosage

Dosage of asparaginase (Erwinia chrysanthemi) is expressed in international units (IU, units) and must be individualized according to body surface area.1 Clinicians should consult published protocols for the dosage of asparaginase (Erwinia chrysanthemi) and other chemotherapeutic agents and the method and sequence of administration.

Acute Lymphocytic Leukemia

Acute Lymphocytic Leukemia and Hypersensitivity to Escherichia coli-derived Asparaginase

When asparaginase (Erwinia chrysanthemi) is substituted for a dose of pegaspargase, the recommended dosage of asparaginase (Erwinia chrysanthemi) is 25,000 units/m² administered by IM injection or IV infusion 3 times weekly (Monday, Wednesday, Friday) for 6 doses for each planned dose of pegaspargase.1

When asparaginase (Erwinia chrysanthemi) is substituted for a dose of native (nonconjugated) asparaginase (Escherichia coli) (no longer commercially available in the US), the recommended dosage of asparaginase (Erwinia chrysanthemi) is 25,000 units/m² administered by IM injection or IV infusion for each scheduled dose of native asparaginase (Escherichia coli).1

Dosage Modification for Toxicity and Contraindications to Continued Therapy

Anaphylaxis and Allergic Reactions

Asparaginase (Erwinia chrysanthemi) therapy should be discontinued in patients with serious allergic reactions.1

Thrombosis and Hemorrhage

Asparaginase (Erwinia chrysanthemi) therapy should be withheld in patients experiencing thrombotic or hemorrhagic events until the symptoms resolve; after resolution, therapy may be resumed.1 (See Cautions: Contraindications.)

Pancreatitis

Asparaginase (Erwinia chrysanthemi) therapy should be discontinued permanently in patients who experience severe pancreatitis.1 (See Pancreatitis under Cautions: Warnings/Precautions.) In patients with mild pancreatitis, the drug should be withheld until the signs and symptoms resolve and amylase concentrations return to normal; after resolution, therapy may be resumed.1

Special Populations

The manufacturer makes no specific dosage recommendations for patients with hepatic or renal impairment.1 Safety and efficacy of asparaginase (Erwinia chrysanthemi) have not been established in geriatric patients.1

Contraindications

Asparaginase (Erwinia chrysanthemi) is contraindicated in patients with a history of serious pancreatitis, serious thrombosis, or serious hemorrhagic events associated with prior asparaginase therapy or a history of serious hypersensitivity reactions (including anaphylaxis) to asparaginase (Erwinia chrysanthemi).1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious (grade 3 or 4) hypersensitivity reactions, including anaphylaxis, have occurred in 5% of patients receiving asparaginase (Erwinia chrysanthemi) in clinical studies.1 Systemic allergic reactions have occurred in 14% of patients receiving the drug in clinical studies.1 In one small series, allergic reactions to asparaginase (Erwinia chrysanthemi) were reported in 33% of patients switching to asparaginase (Erwinia chrysanthemi) following clinical hypersensitivity to native (nonconjugated) asparaginase (Escherichia coli) (no longer commercially available in the US).6,7,8,9

Asparaginase (Erwinia chrysanthemi) should be administered in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis.1 If a serious hypersensitivity reaction occurs, asparaginase (Erwinia chrysanthemi) therapy should be discontinued and appropriate therapy should be initiated.1

Pancreatitis

Pancreatitis has been reported in 4% of patients receiving asparaginase (Erwinia chrysanthemi) in clinical studies.1 Grade 3 or 4 pancreatitis has been reported in approximately 1% of patients receiving the drug in clinical studies.1 Patients experiencing symptoms compatible with pancreatitis should be evaluated to establish a diagnosis.1 In patients with severe or hemorrhagic pancreatitis associated with abdominal pain for longer than 72 hours and amylase concentrations 2 or more times the upper limit of normal (ULN), asparaginase (Erwinia chrysanthemi) therapy should be discontinued.1 Severe pancreatitis is a contraindication to continued asparaginase (Erwinia chrysanthemi) therapy.1 In patients with mild pancreatitis, asparaginase (Erwinia chrysanthemi) therapy should be withheld until the signs and symptoms resolve and amylase concentrations return to normal; after resolution, therapy may be resumed.1

Hyperglycemia

Glucose intolerance, sometimes irreversible, has been reported in 5% of patients receiving asparaginase (Erwinia chrysanthemi) in clinical studies.1 Hyperglycemia was grade 3 or 4 in approximately 3% of patients receiving the drug in clinical studies.1 Glucose concentrations should be monitored at baseline and periodically during therapy.1 Insulin therapy should be administered as necessary in patients with hyperglycemia.1

Thrombosis and Hemorrhage

Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been associated with both E. coli - and Erwinia chrysanthemi -derived asparaginase therapy.1 Grade 3 or 4 thrombosis and hemorrhage each have been reported in less than 1% of patients receiving asparaginase (Erwinia chrysanthemi) in clinical studies.1 Coagulation proteins (i.e., antithrombin III, fibrinogen, protein C activity, protein S activity) were decreased in most patients after 2 weeks of IM asparaginase (Erwinia chrysanthemi) therapy.1 Asparaginase (Erwinia chrysanthemi) therapy should be withheld in patients experiencing thrombotic or hemorrhagic events until the symptoms resolve; after resolution, therapy may be resumed.1

Fetal/Neonatal Morbidity and Mortality

There are no available data on use of asparaginase (Erwinia chrysanthemi) in pregnant women to evaluate the drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes.1 However, results of animal studies suggest that the drug may cause fetal harm if administered to pregnant women.1 In animal reproduction studies, IM administration of asparaginase (Erwinia chrysanthemi) during the period of organogenesis resulted in maternal toxicity and fetal abnormalities (partially undescended thymic tissue) in rats at doses of approximately 0.5 times the maximum recommended human dose (MRHD) and embryofetal mortality and gross structural abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, delayed ossification) in rabbits at doses of approximately 0.005 times the MRHD.1

Pregnancy should be avoided during asparaginase (Erwinia chrysanthemi) therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of asparaginase (Erwinia chrysanthemi) therapy.1 Women of childbearing potential should be advised to use effective methods of contraception while receiving asparaginase (Erwinia chrysanthemi) and for at least 3 months after the last dose.1 Concomitant use of oral contraceptives and asparaginase (Erwinia chrysanthemi) should be avoided.1 (See Drug Interactions: Oral Contraceptives.) Patients should be apprised of the potential fetal hazard if asparaginase (Erwinia chrysanthemi) is used during pregnancy or if the patient becomes pregnant while receiving the drug.1

Immunogenicity

There is potential for immunogenicity with the use of therapeutic proteins such as asparaginase (Erwinia chrysanthemi).1 Antibodies to asparaginase (Erwinia chrysanthemi) have been detected in patients receiving the drug.1 The presence of anti-drug antibodies is associated with a higher risk of hypersensitivity reactions in patients receiving the drug by IV infusion compared with those receiving the drug by IM injection.1 In patients receiving asparaginase (Erwinia chrysanthemi) by IM injection, anti-drug antibodies were detected in 6 of 56 patients (11%) and 1 of these patients experienced a hypersensitivity reaction.1 In patients receiving the drug by IV infusion, anti-drug antibodies were detected in 4 of 30 patients (13%) and 3 of these patients experienced a hypersensitivity reaction.1 None of these patients had neutralizing antibodies.1

Specific Populations

Pregnancy

Asparaginase (Erwinia chrysanthemi) may cause fetal harm if administered to pregnant women based on animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether asparaginase (Erwinia chrysanthemi) is distributed into milk.1 The effects of the drug on nursing infants and on milk production also are unknown.1 Because of the potential for serious adverse reactions to asparaginase (Erwinia chrysanthemi) in nursing infants, women should be advised to discontinue nursing during asparaginase (Erwinia chrysanthemi) therapy and for at least 3 months after the last dose.1

Pediatric Use

Safety and efficacy of asparaginase (Erwinia chrysanthemi) as a component of combination chemotherapy for the treatment of acute lymphocytic (lymphoblastic) leukemia (ALL) have been established in pediatric patients 1 year of age and older who were hypersensitive to E. coli -derived asparaginase.1 (See Acute Lymphocytic Leukemia and Hypersensitivity to Escherichia coli-derived Asparaginase under Uses: Acute Lymphocytic Leukemia.)

Geriatric Use

Safety and efficacy of asparaginase (Erwinia chrysanthemi) have not been established in geriatric patients.1

Common Adverse Effects

Adverse effects reported in 1% or more of patients receiving asparaginase (Erwinia chrysanthemi) include systemic hypersensitivity reactions, hyperglycemia, aminotransferase abnormalities, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain or discomfort, and diarrhea.1

No formal drug interaction studies have been performed with asparaginase (Erwinia chrysanthemi) to date.1

Oral Contraceptives

Asparaginase-induced hepatotoxicity may impair hepatic clearance of oral contraceptives.41 Since there is a potential for an indirect interaction between asparaginase (Erwinia chrysanthemi) and oral contraceptives, concomitant use of asparaginase (Erwinia chrysanthemi) and oral contraceptives is not recommended.1

Description

Asparaginase (Erwinia chrysanthemi) catalyzes the deamidation of the amino acid asparagine to aspartic acid and ammonia, resulting in reduced concentrations of circulating asparagine.1 Because of a lack of asparagine synthetase, some leukemic cells cannot synthesize asparagine and depend on an exogenous source of the amino acid for protein synthesis and cell survival.1,8,10 Because normal cells are able to synthesize asparagine, they are less affected by asparaginase-induced depletion of the amino acid.1,10

The half-life of asparaginase (Erwinia chrysanthemi) reportedly is approximately 15.6 hours following IM administration and appears to be shorter than that of native (nonconjugated) asparaginase (Escherichia coli) (no longer commercially available in the US) or pegaspargase (conjugate of monoethoxy polyethylene glycol [mPEG] and E. coli -derived asparaginase).1,4,5,6 Following IV infusion, the half-life is approximately 7.5 hours; this difference in half-life is reflected in the proportion of patients achieving sustained serum trough asparaginase activity of at least 0.1 or 0.4 units/mL.1 (See Acute Lymphocytic Leukemia and Hypersensitivity to Escherichia coli-derived Asparaginase under Uses: Acute Lymphocytic Leukemia.) Asparaginase (Erwinia chrysanthemi) is antigenically distinct from asparaginase (Escherichia coli).6

Advice to Patients

Risk of hypersensitivity reactions, including the possibility of anaphylaxis.1 Importance of informing patients of the symptoms of allergic reactions, including anaphylaxis, and instructing them to immediately contact clinicians if such symptoms occur.1

Risk of pancreatitis.1 Importance of immediately informing clinicians if abdominal pain occurs.1

Risk of glucose intolerance.1 Importance of informing clinicians if excessive thirst or any increase in the volume or frequency of urination occurs.1

Risk of thrombosis and hemorrhage.1 Importance of immediately informing clinicians if headache, arm or leg swelling, shortness of breath, or chest pain occurs.1

Risk of fetal harm.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Necessity of advising women of reproductive potential that they should use effective methods of contraception while receiving the drug and for at least 3 months after the last dose.1 Importance of advising women that concomitant use of asparaginase (Erwinia chrysanthemi) and oral contraceptives is not recommended.1

Importance of advising women to avoid breast-feeding while receiving asparaginase (Erwinia chrysanthemi) and for at least 3 months after the last dose.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.

1. Jazz Pharmaceuticals, Inc. Erwinaze^® (asparaginase Erwinia chrysanthemi ) lyophilized powder for injection prescribing information. Palo Alto, CA; 2019 Dec.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2012 Apr 23. [Web]

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 125359Orig1s000: Summary review. From FDA website. Accessed 2012 Apr 23. [Web]

4. Childhood acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2012 May 18. [Web]

5. Asselin BL, Whitin JC, Coppola DJ et al. Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol . 1993; 11:1780-6. [PubMed 8355045]

6. Vrooman LM, Supko JG, Neuberg DS et al. Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer . 2010; 54:199-205. [PubMedCentral][PubMed 19672973]

7. Pieters R, Hunger SP, Boos J et al. L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer . 2011; 117:238-49. [PubMed 20824725]

8. van den Berg H. Asparaginase revisited. Leuk Lymphoma . 2011; 52:168-78. [PubMed 21281233]

9. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol . 2010; 32:554-63. [PubMed 20724951]

10. Lundbeck Inc. Elspar^® (asparaginase Escherichia coli ) intravenous or intramuscular prescribing information. Deerfield, IL; 2010 Apr.

11. Lundbeck Inc. Elspar^® material safety data sheet. Deerfield, IL; 2010 Apr 1.

41. Les Laboratoires Servier. Oncaspar^® (pegasparase) summary of product characteristics. Suresnes, France; 2019 Nov 25.