Erwinia asparaginase is an anticancer (chemotherapeutic) drug that is used to treat acute lymphoblastic leukemia in combination with other chemotherapeutic drugs.

Erwinia asparaginase Uses:

• Acute lymphoblastic leukemia:

  • Used in treatment (in combination with other chemotherapy) of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to E. coli-derived asparaginase.

Erwinia asparaginase Dose in adults

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

Erwinia asparaginase Dose in the treatment of Acute lymphoblastic leukemia (ALL): IM, IV:

• As a substitute for pegaspargase:
  • 25,000 units per m² thrice in a weak  (Mon, Wed, Fri) for 6 doses for each planned pegaspargase dose
• As a substitute for asparaginase (E. coli):
  • 25,000 units per m² for each scheduled asparaginase (E. coli) dose.

Erwinia asparaginase Dose in Childrens

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

Erwinia asparaginase Dose in the treatment of Acute lymphoblastic leukemia (ALL):

• Children and Adolescents:

  • As a substitute for pegaspargase:
    • IM, IV: 25,000 units per m²  per dose thrice in a weak (Mon, Wed, Fri) for 6 doses for each planned pegaspargase dose
  • As a substitute for asparaginase (E. coli):
    • IM, IV: 25,000 units per m² per dose for each scheduled asparaginase (E. coli) dose

Erwinia asparaginase Dose in the treatment of Acute lymphoblastic leukemia (ALL) induction:

• Canadian labeling:

  • Infants, Children, and Adolescents <14 years:

    • IM: 6,000 units per m² 3 thrice in a weak for 9 doses beginning day 4 of week 1 (in combination with allopurinol,  methotrexate, vincristine, prednisone, and daunorubicin)

Erwinia asparaginase Dosage adjustment for toxicity:

• Manufacturer's labeling:

  • Children and Adolescents:

    • Hemorrhagic or thrombotic event:
      • Stops the 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):
        • Stops the treatment; further use is contraindicated.
      • Serious hypersensitivity:
        • Discontinue treatment.

The following adjustments have also been recommended for asparaginase products:

• Older Adolescents:

  • Hyperammonemia-related fatigue:
    • Continue therapy for grade 2 toxicity.
    • If grade 3 toxicity occurs, reduce dose by 25 percent;
    • resume full dose when toxicity ≤ grade 2 (make up for missed doses).
    • If grade 4 toxicity occurs, reduce dose by 50 percent;
    • 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 the 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 edema, bronchospasm, hypotension, or need for parenteral intervention.
    • If wheezing or another symptomatic bronchospasm with or without angioedema, hypotension, urticaria, and/or life-threatening hypersensitivity reactions occur, discontinue asparaginase.
  • Hypertriglyceridemia:
    • If serum triglyceride level less than 1,000 mg/dL, continue asparaginase but monitor closely for pancreatitis.
    • If triglyceride level longer than 1,000 mg per dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
  • Pancreatitis:
    • Asymptomatic amylase or lipase longer than thrice  ULN (chemical pancreatitis) or radiologic abnormalities only:
      • Continue asparaginase and monitor levels closely.
    • Symptomatic amylase or lipase longer than thrice time ULN:
      • Hold asparaginase until enzyme levels stabilize or are declining.
    • Symptomatic pancreatitis or clinical pancreatitis (abdominal pain with amylase or lipase longer than thrice time  ULN for more than 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 or 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 or less than 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 or less than grade 1 and until acute toxicity and clinical signs, resolve and coagulant replacement therapy is stable or completed.

Pregnancy Risk Factor C

• In animal reproduction studies, adverse events were noted.

Use of Erwinia paraginase during breastfeeding

• The manufacturer suggests that the mother decide whether to stop breastfeeding or discontinue using the drug.
• This is in consideration of the risk of serious adverse reactions in breastfed babies.
• It is unknown if breast milk contains asparaginase Erwinia.

Erwinia asparaginase Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments.

Erwinia asparaginase Dose in Liver disease:

• Manufacturer's labeling doesn't provide any dosage adjustments; however, the following adjustments have been recommended for other asparaginase products for hepatotoxicity during treatment:
  • 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 products.
  • Direct bilirubin >5 mg/dL:
    • Discontinue asparaginase; do not substitute other asparaginase products;
    • Do not make up for missed doses.

Common Side Effects of Erwinia asparaginase:

• Hypersensitivity:

  • Hypersensitivity reaction includes
    • Anaphylaxis
    • Urticaria

Less Common Side Effects of Erwinia asparaginase:

• Cardiovascular:

  • Thrombosis includes
    • Pulmonary embolism and cerebrovascular accident

• Endocrine & metabolic:

  • Abnormal transaminase
  • Decreased glucose tolerance
  • Hyperglycemia

• Gastrointestinal:

  • Vomiting
  • Pancreatitis
  • Abdominal pain
  • Diarrhea
  • Nausea
  • Mucositis

• Local:

  • Injection site reaction

• Miscellaneous:

  • Fever

Contraindications to Erwinia asparaginase:

• History of severe hypersensitivity reactions, including anaphylaxis of asparaginase or any component of its formulation
• Grave thrombosis
• A history of severe pancreatitis or hemorhagic events that were related to prior asparaginase therapy.

Canadian labeling: Additional contraindications not in the US labeling

• Women who may or are pregnant

Warnings and precautions

• Glucose intolerance

  • During treatment, monitor glucose levels (baseline, periodic)
  • Clinical trials showed that 5 percent of patients had glucose intolerance. This could be irreversible.
  • May need insulin administration.

• Hypersensitivity reactions

  • During treatment, hypersensitivity reactions must be treated immediately.
  • In clinical trials, 5 percent of patients experienced severe hypersensitivity reactions (grades 3 and 4), which included anaphylaxis.
  • If you have severe hypersensitivity reactions, discontinue use and seek appropriate treatment.

• Pancreatitis

  • Clinical trials have shown that 4 percent of patients with pancreatitis were diagnosed.
  • Mild pancreatitis: Do not start treatment until symptoms subside. Amylase levels will return to normal. Treatment may be resumable after resolution.
  • Assess immediately for symptoms that suggest pancreatitis.
  • For severe or hemorhagic pancreatitis, characterized by abdominal pain lasting more than 72 hours and amylase >=2x ULN, discontinue use.
  • If severe pancreatitis has been diagnosed, further use is not recommended.

• Hemorrhage and thrombosis:

  • Asparaginase formulations have been linked to serious thrombotic events such as sagittal sinus embolism and pulmonary embolism.
  • If you have a thrombotic episode, discontinue treatment. You may resume treatment once the problem is resolved.
  • For hemorhagic events, discontinue
  • You may be able to resume treatment if you have resolved any hemorhagic or serious thrombosis.
  • After intramuscular treatment for 2 weeks, there were decreases in fibrinogen and protein C activity as well as antithrombin III.

Erwinia asparaginase: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC with differential,
• triglycerides,
• amylase and lipase,
• 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, thrombosis, symptoms of pancreatitis, or hemorrhage.

How to administer Erwinia asparaginase?

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 injections for volumes of more than 2 mL.

IV:

• Infuse over 1 to 2 hours;
• Do not infuse other medications through the same IV line.

Mechanism of action of Erwinia asparaginase:

• Asparaginase is responsible for the reduction of asparagine levels by converting it to ammonia and aspartic acid.
• Leukemia cells lack the ability to synthesize asparagine and lack asparagine synthetase. 
• Cytotoxicity is specific to leukemic cell lines because asparaginase decreases the exogenous source of asparagine for the leukemic.

Half-life elimination:

• IM: ~16 hours;
• IV: ~7.5 hours

International Brand Names of Erwinia asparaginase:

• WErwinase
• Erwinaze

Erwinia asparaginase Brand Names in Pakistan:

There is no brand available in Pakistan.