Asparaginase (E. coli)

• E. coli Asparaginase
• ASNase
• Asparaginase
• Elspar
• L-ASP
• L-asparaginase (E. coli)

• Elspar [DSC]

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

Use is contraindicated in patients with hepatic insufficiency. The following adjustments have been recommended 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.

Allergic reaction/hypersensitivity: Discontinue for severe reactions.

Neurotoxicity (posterior reversible encephalopathy syndrome; PRES): Interrupt therapy for suspected PRES; control blood pressure and closely monitor for seizure activity.

Pancreatitis: Discontinue permanently (per manufacturer).

Thrombotic event: Discontinue for serious reactions.

The following adjustments have also been recommended (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 <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.

Reconstitute each vial with 4 mL sterile water for injection; rotate gently, do not shake. For IM administration, the US manufacturer recommended reconstitution of the lyophilized powder with 2 mL NS to a concentration of 5000 units/mL; however, some institutions reconstitute with 1 mL NS for IM use, resulting in a concentration of 10,000 units/mL. Shake well, but not too vigorously. A 5 micron filter may be used to remove fiber-like particles in the solution (do not use a 0.2 micron filter; has been associated with loss of potency).

Standard IM dilution: 5,000 units/mL (10,000 units/mL has been used by some institutions)

Standard IV dilution: Dilute in 50 to 250 mL NS or D5W

May be administered IM (preferred for intermittent administration) or IV; has been administered SubQ (off-label route; Larson, 1995) in specific protocols. May administer corticosteroids 1 to 2 days prior to initiating reinduction therapy (to prevent hypersensitivity reaction). Observe patients for 1 hour after administration; have epinephrine, diphenhydramine, and hydrocortisone at the bedside. A physician should be readily accessible.

IM: Doses should be given as a deep intramuscular injection into a large muscle; volumes >2 mL should be divided and administered in 2 separate sites.

IV: Infuse over at least 30 minutes through the side arm of a NS or D5W infusion.

Dexamethasone (Systemic): Asparaginase (E. coli) 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