Version May 2024
Note: Erwinaze has been discontinued in the United States for >1 year.
Note: Do not substitute asparaginase (Erwinia) for asparaginase (Erwinia [Recombinant]), or vice versa; the products are different and dosing differs. Consider thromboprophylaxis with low-molecular-weight heparin (LMWH) during induction and intensification phases of asparaginase therapy, particularly in patients at high risk for venous thromboembolism; withhold LMWH for platelet count <30,000/mm3 (Ref). If administering asparaginase (Erwinia) IV, consider monitoring nadir serum asparaginase activity (NSAA) levels; if desired levels are not achieved, change to IM administration.
Acute lymphoblastic leukemia:
As a substitute for pegaspargase: IM, IV: 25,000 units/m2 3 times weekly (Mon, Wed, Fri) for 6 doses for each planned pegaspargase dose.
As a substitute for asparaginase (E. coli): IM, IV: 25,000 units/m2 for each scheduled asparaginase (E. coli) dose.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended for other asparaginase products for hepatotoxicity during treatment (Ref):
ALT/AST >3 to 5 times ULN: Continue therapy.
ALT/AST >5 to 20 times ULN: Delay next dose until transaminases <3 times ULN.
ALT/AST >20 times ULN: Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times ULN.
Direct bilirubin <3 mg/dL: Continue therapy.
Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin <2 mg/dL; consider switching to alternate asparaginase product.
Direct bilirubin >5 mg/dL: Discontinue asparaginase; do not substitute other asparaginase products; do not make up for missed doses.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
Hemorrhagic or thrombotic event: Discontinue treatment; may resume treatment upon symptom resolution.
Hyperglycemia: May require insulin administration.
Pancreatitis:
Mild pancreatitis: Withhold treatment until signs and symptoms subside and amylase levels return to normal; may resume after resolution.
Severe or hemorrhagic pancreatitis (abdominal pain >72 hours and amylase ≥2 x ULN): Discontinue treatment; further use is contraindicated.
Serious hypersensitivity reaction: Discontinue treatment and administer appropriate treatment (immediate therapy for hypersensitivity reactions should be available during treatment).
The following adjustments have also been recommended for asparaginase products (Ref):
Hyperammonemia-related fatigue: Continue therapy for grade 2 toxicity. If grade 3 toxicity occurs, reduce dose by 25%; resume full dose when toxicity ≤ grade 2 (make up for missed doses). If grade 4 toxicity occurs, reduce dose by 50%; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
Hyperglycemia: Continue therapy for uncomplicated hyperglycemia. If hyperglycemia requires insulin therapy, hold asparaginase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold asparaginase (and corticosteroids) until blood glucose is controlled with insulin; resume asparaginase and do not make up for missed doses.
Hypersensitivity reactions: May continue dosing for urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention. If wheezing or other symptomatic bronchospasm with or without urticaria, angioedema, hypotension, and/or life-threatening hypersensitivity reactions occur, discontinue asparaginase.
Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue asparaginase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
Pancreatitis:
Asymptomatic amylase or lipase >3 times ULN (chemical pancreatitis) or radiologic abnormalities only: Continue asparaginase and monitor levels closely.
Symptomatic amylase or lipase >3 times ULN: Hold asparaginase until enzyme levels stabilize or are declining.
Symptomatic pancreatitis or clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue asparaginase.
Thrombosis and bleeding, CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Hemorrhage: Discontinue therapy; do not withhold therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Thrombosis and bleeding, non-CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 or 4 toxicity occurs, withhold therapy until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed. Do not withhold therapy for abnormal laboratory findings without clinical correlate.
For acute management of venous thromboembolism (VTE), consider low-molecular-weight heparin if severe thrombocytopenia (platelets <50,000/mm3) is anticipated; following resolution of severe thrombocytopenia, consider direct oral anticoagulants in the absence of relevant contraindications. For life-threatening VTE (eg, central venous thrombosis, central pulmonary embolism), consider short-term concurrent use of antithrombin concentrate until clinically stable and therapeutic anticoagulation is established. Antithrombin concentrate is suggested for antithrombin levels below 50% to 60%, with a suggested repletion target of 80% to 120%. Temporarily withhold asparaginase therapy for high-risk events (eg, central venous/sinus thrombosis, central pulmonary embolism, proximal deep vein thrombosis, arterial thrombosis); resume after thrombotic event is stabilized (Ref).
Hemorrhage: If grade 2 bleeding in conjunction with hypofibrinogenemia occurs, withhold therapy until bleeding ≤ grade 1. Do not withhold therapy for abnormal laboratory findings without clinical correlate. For grade 3 or 4 bleeding, withhold therapy until bleeding ≤ grade 1 and until acute toxicity and clinical signs resolve and coagulant replacement therapy is stable or completed.
(For additional information see "Erwinia asparaginase (United States and Canada: Not available): Pediatric drug information")
Note: Erwinaze has been discontinued in the United States for >1 year. If administering IV, consider monitoring nadir serum asparaginase activity (NSAA) levels; if desired levels are not achieved, change to IM administration. Antiemetics may be recommended to prevent nausea and vomiting; in pediatrics, IV doses ≥20,000 units/m2 are associated with a high emetic potential (Ref).
Acute lymphoblastic leukemia:
Acute lymphoblastic leukemia: Children and Adolescents:
As a substitute for pegaspargase: IM, IV: 25,000 units/m2/dose 3 times weekly (Mon, Wed, Fri) for 6 doses for each planned pegaspargase dose
As a substitute for asparaginase (E. coli): IM, IV: 25,000 units/m2/dose for each scheduled asparaginase (E. coli) dose
Acute lymphoblastic leukemia: Canadian labeling: Infants, Children, and Adolescents <14 years: IM: 6,000 units/m2 3 times weekly for 9 doses beginning day 4 of week 1 (in combination with allopurinol, vincristine, prednisone, methotrexate, and daunorubicin)
Dosage adjustment for toxicity:
Manufacturer's labeling: Children and Adolescents:
Hemorrhagic or thrombotic event: Discontinue treatment; may resume treatment upon symptom resolution.
Pancreatitis:
Mild pancreatitis: Withhold treatment until signs and symptoms subside and amylase returns to normal; may resume after resolution.
Severe or hemorrhagic pancreatitis (abdominal pain >72 hours and amylase ≥2 x ULN): Discontinue treatment; further use is contraindicated.
Serious hypersensitivity: Discontinue treatment.
The following adjustments have also been recommended for asparaginase products (Ref): Older Adolescents:
Hyperammonemia-related fatigue: Continue therapy for grade 2 toxicity. If grade 3 toxicity occurs, reduce dose by 25%; resume full dose when toxicity ≤ grade 2 (make up for missed doses). If grade 4 toxicity occurs, reduce dose by 50%; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
Hyperglycemia: Continue therapy for uncomplicated hyperglycemia. If hyperglycemia requires insulin therapy, hold asparaginase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold asparaginase (and corticosteroids) until blood glucose is controlled with insulin; resume asparaginase and do not make up for missed doses.
Hypersensitivity reactions: May continue dosing for urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention. If wheezing or other symptomatic bronchospasm with or without urticaria, angioedema, hypotension, and/or life-threatening hypersensitivity reactions occur, discontinue asparaginase.
Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue asparaginase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
Pancreatitis:
Asymptomatic amylase or lipase >3 times ULN (chemical pancreatitis) or radiologic abnormalities only: Continue asparaginase and monitor levels closely.
Symptomatic amylase or lipase >3 times ULN: Hold asparaginase until enzyme levels stabilize or are declining.
Symptomatic pancreatitis or clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue asparaginase.
Thrombosis and bleeding, CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Hemorrhage: Discontinue therapy; do not withhold therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.
Thrombosis and bleeding, non-CNS:
Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 or 4 toxicity occurs, withhold therapy until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed. Do not withhold therapy for abnormal laboratory findings without clinical correlate.
Hemorrhage: If grade 2 bleeding in conjunction with hypofibrinogenemia occurs, withhold therapy until bleeding ≤ grade 1. Do not withhold therapy for abnormal laboratory findings without clinical correlate. For grade 3 or 4 bleeding, withhold therapy until bleeding ≤ grade 1 and until acute toxicity and clinical signs resolve and coagulant replacement therapy is stable or completed.
All patients: There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended for other asparaginase products for hepatotoxicity during treatment (Ref):
Older Adolescents:
ALT/AST >3 to 5 times ULN: Continue therapy.
ALT/AST >5 to 20 times ULN: Delay next dose until transaminases <3 times ULN.
ALT/AST >20 times ULN: Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times ULN.
Direct bilirubin <3 mg/dL: Continue therapy.
Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin <2 mg/dL; consider switching to alternate asparaginase product.
Direct bilirubin >5 mg/dL: Discontinue asparaginase; do not substitute other asparaginase products; do not make up for missed doses.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Hyperglycemia
Gastrointestinal: Nausea, vomiting
Hepatic: Increased serum transaminases
Hypersensitivity: Hypersensitivity reaction
Immunologic: Antibody development
1% to 10%:
Cardiovascular: Thrombosis
Endocrine & metabolic: Decreased glucose tolerance
Gastrointestinal: Abdominal distress, abdominal pain, diarrhea, pancreatitis, stomatitis
Hematologic & oncologic: Hemorrhage
Hepatic: Hyperbilirubinemia
Hypersensitivity: Local hypersensitivity reaction
Miscellaneous: Fever
<1%: Anaphylaxis, hyperammonemia
Frequency not defined: Cardiovascular: Cerebrovascular accident
Postmarketing: Pulmonary embolism, sagittal sinus thrombosis
History of serious hypersensitivity reactions, including anaphylaxis to asparaginase (Erwinia) or any component of the formulation; history of serious pancreatitis, serious thrombosis, or serious hemorrhagic events with prior asparaginase treatment.
Canadian labeling: Additional contraindications (not in the US labeling): Patients who are or could become pregnant.
Concerns related to adverse effects:
• Glucose intolerance: In clinical trials, 5% of patients experienced glucose intolerance; may be irreversible.
• Hypersensitivity reactions: Serious hypersensitivity reactions (grade 3 and 4), including anaphylaxis, have occurred in 5% of patients in clinical trials.
• Pancreatitis: Pancreatitis has been reported in 4% of patients in clinical trials.
• Thrombosis and hemorrhage: Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported with asparaginase formulations. Decreases in fibrinogen, protein C activity, protein S activity, and antithrombin III have been noted following a 2-week treatment course administered intramuscularly.
Other warnings/precautions:
• Medication error prevention: Do not interchange asparaginase (Erwinia) for asparaginase (Erwinia [Recombinant]), asparaginase (Escherichia coli), calaspargase pegol, or pegaspargase; ensure the proper formulation, route of administration, and dose prior to administration.
Erwinaze has been discontinued in the United States for >1 year.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Injection:
Erwinase: 10,000 units (1 ea [DSC])
Erwinaze: 10,000 units (1 ea [DSC])
No
Solution (reconstituted) (Erwinase Injection)
10000 unit (per each): $4,837.01
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Injection:
Erwinase: 10,000 units ([DSC])
IM: The volume of each single injection site should be limited to 2 mL; use multiple injections for volumes >2 mL.
IV: Infuse over 1 to 2 hours; do not infuse other medications through the same IV line.
Asparaginase (Erwinia) should be administered in a setting with resuscitation equipment and agents necessary to manage anaphylaxis.
Parenteral: Note: Vials from certain batches should only be administered intramuscularly or require the use of a 0.2-micron filter if administered intravenously.
IM: The volume of each single injection site should be limited to 2 mL; use multiple injection sites for volumes >2 mL.
IV: Infuse over 1 or 2 hours; do not infuse other medications through the same IV line; some product lots may require use of a 0.2-micron filter; refer to manufacturer for batch-specific information. Note: Some product lots not for IV administration; refer to manufacturer for batch-specific information.
Antiemetics may be recommended to prevent nausea and vomiting; in pediatrics, IV doses ≥20,000 units/m2 are associated with a high emetic potential (Ref).
Acute lymphoblastic leukemia: Treatment (in combination with other chemotherapy) of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to E. coli-derived asparaginase.
Asparaginase (Erwinia) may be confused with asparaginase (Erwinia [Recombinant]), asparaginase (Escherichia coli), calaspargase pegol, pegaspargase.
Erwinaze may be confused with Asparlas, Elaprase, Elspar, Oncaspar, Rylaze.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Asparaginase is available as asparaginase (Erwinia), asparaginase (Erwinia [Recombinant]), and asparaginase (Escherichia coli). Use caution when selecting the asparaginase formulation, as dosing and administration vary between the products.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Hormonal Contraceptives: May enhance the thrombogenic effect of Asparaginase Products. Management: Consider discontinuing hormonal contraceptives and using an alternative contraceptive method in patients treated with asparaginase products. Risk D: Consider therapy modification
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 3 months after the last dose of asparaginase (Erwinia); use of oral contraceptives is not recommended.
Based on data from animal reproduction studies, in utero exposure to asparaginase (Erwinia) may cause fetal harm.
It is not known if asparaginase Erwinia chrysanthemi is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 3 months after the last dose of asparaginase (Erwinia).
CBC with differential, amylase, lipase, triglycerides, liver enzymes, blood glucose (baseline and periodically during treatment), coagulation parameters; for IV administration, consider monitoring nadir serum asparaginase activity levels. Consider monitoring antithrombin levels weekly during the course of asparaginase treatment (ISTH [Zwicker 2020]). Monitor for symptoms of hypersensitivity, symptoms of pancreatitis (promptly evaluate with symptoms suggestive of pancreatitis), thrombosis, or hemorrhage. Evaluate pregnancy status prior to use in patients who could become pregnant.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Asparaginase catalyzes the deamidation of asparagine to aspartic acid and ammonia, reducing circulating levels of asparagine. Leukemia cells lack asparagine synthetase and are unable to synthesize asparagine. Asparaginase reduces the exogenous asparagine source for the leukemic cells, resulting in cytotoxicity specific to leukemic cells.
Half-life elimination: IM: ~16 hours (Asselin 1993; Avramis 2005); IV: ~7.5 hours
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