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Asparaginase (Erwinia)

Pronunciation

(a SPEAR a ji nase er WIN i ah)

Index Terms

  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Crisantaspase
  • L-asparaginase (Erwinia)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intramuscular:

Erwinaze: 10,000 units (1 ea)

Brand Names: U.S.

  • Erwinaze

Pharmacologic Category

  • Antineoplastic Agent, Enzyme
  • Antineoplastic Agent, Miscellaneous

Pharmacology

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

Use: Labeled Indications

Acute lymphoblastic leukemia: Treatment (in combination with other chemotherapy) of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to E. coli-derived asparaginase

Contraindications

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 U.S. labeling): Women who are or may become pregnant

Dosing: Adult

Note: If administering IV, consider monitoring nadir serum asparaginase activity (NSAA) levels; if desired levels are not achieved, change to IM administration.

Acute lymphoblastic leukemia (ALL): IM, IV:

As a substitute for pegaspargase: 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): 25,000 units/m2 for each scheduled asparaginase (E. coli) dose

Dosing: Pediatric

Note: If administering IV, consider monitoring nadir serum asparaginase activity (NSAA) levels; if desired levels are not achieved, change to IM administration.

Acute lymphoblastic leukemia (ALL): Children ≥1 year and Adolescents: IM, IV: Refer to adult dosing.

ALL induction: Canadian labeling (not in the US labeling): Children <14 years: IM: 6,000 units/m2 3 times weekly for 9 doses beginning day 4 of week 1 (in combination with vincristine, prednisone, methotrexate, and daunorubicin)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

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 (Stock 2011):

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.

Dosing: Adjustment for Toxicity

Hemorrhagic or thrombotic event: Discontinue treatment; may resume treatment upon symptom resolution.

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.

The following adjustments have also been recommended for asparaginase products (Stock 2011):

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 <1000 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.

Reconstitution

Reconstitute each vial with 1 mL of preservative free sodium chloride 0.9% (NS) to obtain a concentration of 10,000 units/mL, or with 2 mL preservative free NS to obtain a concentration of 5,000 units/mL. Gently direct the NS down the wall of the vial (do not inject forcefully into or onto the powder). Dissolve by gently swirling or mixing; do not shake or invert the vial. Resulting reconstituted solution should be clear and colorless and free of visible particles or protein aggregates. Within 15 minutes of reconstitution, withdraw appropriate volume for dose into a polypropylene syringe. If administering intravenously, slowly inject the appropriate volume of reconstituted solution into a NS 100 mL infusion bag; do not shake or squeeze the bag. Administer within 4 hours of reconstitution.

Particulate matter has been observed in some asparaginase Erwinia batches (US batch 178K) and a possibility remains that released vials from this batch may contain particulate matter. Carefully inspect each vial and quarantine any vials in which particulate matter is observed. If particulate matter is not observed, use a standard 5‐micron filter needle to withdraw reconstituted product from the vial, then discard the filter needle and replace it with an appropriate needle prior to administration; the drug should then be administered by intramuscular administration only (Frey 2016).

In regions where the UK product is utilized or imported, particulate matter has been observed in batches CAMR-174, 178K, and 179G; a 5 micron filter needle should be utilized when withdrawing reconstituted solution from vial in these batches (replace with a new needle prior to addition to IV bag or prior to IM or SubQ administration).

Administration

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.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Within 15 minutes of reconstitution, withdraw appropriate volume for dose into a polypropylene syringe. Do not freeze or refrigerate reconstituted solution; discard if not administered within 4 hours.

Drug Interactions

Dexamethasone (Systemic): Asparaginase (Erwinia) may increase the serum concentration of Dexamethasone (Systemic). This is thought to be due to an asparaginase-related decrease in hepatic proteins responsible for dexamethasone metabolism. Monitor therapy

Adverse Reactions

Frequency of adverse reactions is for both IM and IV routes unless specified.

>10%: Hypersensitivity: Hypersensitivity reaction (14% [IV: ≤37%]; grades 3/4: 4%; includes anaphylaxis, urticaria)

1% to 10%:

Cardiovascular: Thrombosis (2% [IV: ≤7%]; grades 3/4: ≤1%; includes pulmonary embolism and cerebrovascular accident)

Endocrine & metabolic: Hyperglycemia (4% [IV: ≤17%]; grades 3/4: 4%), abnormal transaminase (4%), decreased glucose tolerance (4%)

Gastrointestinal: Nausea (3% [IV: ≤20%]), vomiting (3% [IV: ≤17%]), pancreatitis (4%; grades 3/4: <1%), abdominal pain (1%), diarrhea (1%), mucositis (1%)

Local: Injection site reaction (3%)

Miscellaneous: Fever (4%)

<1% (Limited to important or life-threatening): Acute renal failure, anorexia, bone marrow depression (rare), changes in serum lipids, disseminated intravascular coagulation, hemorrhage, hepatomegaly, hyperammonemia, hyperbilirubinemia, malabsorption syndrome, seizure, transient ischemic attacks, weight loss

Warnings/Precautions

Concerns related to adverse effects:

• Glucose intolerance: In clinical trials, 5% of patients experienced glucose intolerance; may be irreversible. Monitor glucose levels (baseline and periodic) during treatment. May require insulin administration.

• Hypersensitivity reactions: Serious hypersensitivity reactions (grade 3 and 4), including anaphylaxis, have occurred in 5% of patients in clinical trials. Immediate treatment for hypersensitivity reactions should be available during treatment. Discontinue for serious hypersensitivity reactions (and administer appropriate treatment).

• Pancreatitis: Pancreatitis has been reported in 4% of patients in clinical trials. Promptly evaluate with symptoms suggestive of pancreatitis. For mild pancreatitis, withhold treatment until signs and symptoms subside and amylase levels return to normal; may resume after resolution. Discontinue for severe or hemorrhagic pancreatitis characterized by abdominal pain >72 hours and amylase ≥2 x ULN. Further use is contraindicated if severe pancreatitis is diagnosed.

• Thrombosis and hemorrhage: Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported with asparaginase formulations. Discontinue for thrombotic event, may resume treatment after resolution. Decreases in fibrinogen, protein C activity, protein S activity, and antithrombin III have been noted following a 2-week treatment course administered intramuscularly. Discontinue for hemorrhagic event; may resume treatment after resolution (contraindicated with history of serious thrombosis or hemorrhagic event with prior asparaginase treatment).

Other warnings/precautions:

• Medication error prevention: Do not interchange Erwinia asparaginase for E. coli asparaginase or pegaspargase; ensure the proper formulation, route of administration, and dose prior to administration.

Monitoring Parameters

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 (NSAA) levels. Monitor for symptoms of hypersensitivity, symptoms of pancreatitis, thrombosis, or hemorrhage.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, nausea, vomiting, injection site irritation, mouth sores, or abdominal pain. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, coughing up blood, shortness of breath, severe headache, bruising, or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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