Asparaginase

Trade Names:
Elspar
- Powder for injection, lyophilized 10,000 units

Pharmacology

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Asparaginase contains the enzyme L-asparagine amidohydrolase. In a significant number of patients with acute leukemia, the malignant cells depend on exogenous asparagine for survival. Administration of asparaginase hydrolyzes serum asparagine to nonfunctional aspartic acid and ammonia, depriving tumor cells of a required amino acid. Tumor cell proliferation is blocked.

Pharmacokinetics

Absorption

T _max is 14 to 24 h.

Distribution

Vd is approximately 70% to 80% of the estimated plasma volume.

Elimination

Trace amounts found in urine.

T _½ is 8 to 30 h.

T _½ is 39 to 49 h.

Indications and Usage

Combination therapy for acute lymphocytic leukemia (ALL). Do not use as the sole induction agent unless combination therapy is deemed inappropriate.

ALL. Do not use as the sole induction agent unless combination therapy is deemed inappropriate.

Contraindications

Anaphylactic reactions to asparaginase; pancreatitis or a history of pancreatitis.

Dosage and Administration

IV Give over 30 min through the side arm of an already running infusion of sodium chloride injection or dextrose 5% injection. The drug has little tendency to cause phlebitis when given IV.

IM Limit the volume at a single injection site to 2 mL. For a volume greater than 2 mL, use 2 injection sites.

One of the following combination regimens is recommended for ALL in children.

40 mg/m ² /day PO in 3 divided doses for 15 days, followed by tapering of the dosage as follows: 20 mg/m ² for 2 days, 10 mg/m ² for 2 days, 5 mg/m ² for 2 days, 2.5 mg/m ² for 2 days, and then discontinue.

2 mg/m ² IV once weekly on days 1, 8, and 15. The maximum single dose should not exceed 2 mg.

1,000 units/kg/day IV for 10 successive days beginning on day 22. When remission is obtained, institute appropriate maintenance therapy. Do not use asparaginase as part of a maintenance regimen. Asparaginase has been used in other combination regimens. Administering the drug IV concurrently with or immediately before a course of vincristine and prednisone may be associated with increased toxicity.

40 mg/m ² /day PO in 3 divided doses for 28 days (the total daily dose to the nearest 2.5 mg), then gradual discontinuation over 14 days.

1.5 mg/m ² IV weekly for 4 doses, on days 1, 8, 15, and 22. The maximum single dose should not exceed 2 mg.

6,000 units/m ² IM on days 4, 7, 10, 13, 16, 19, 22, 25, and 28. When remission is obtained, institute appropriate maintenance therapy. Do not use asparaginase as part of a maintenance regimen

IV Use asparaginase as the sole induction agent only when a combined regimen is inappropriate because of toxicity or other specific patient-related factors, or in cases refractory to other therapy. Administer 200 units/kg/day IV for 28 days. Complete remissions are of short duration, 1 to 3 mo.

General Advice

• IM
• Reconstitute by adding sodium chloride injection 2 mL to the 10,000 unit vial. Use the resulting solution within 8 h and only if clear.

• IV
• Reconstitute the 10,000 unit vial with 5 mL sterile water for injection or with sodium chloride injection. This solution may be used for direct IV administration within 8 h following reconstitution. For administration by infusion, dilute solutions with sodium chloride injection or dextrose 5% injection. Infuse within 8 h and only if clear.
• Filtration through a 5 micron filter during administration will remove the particles with no loss of potency.

Storage/Stability

Store at 2° to 8°C (36° to 46°F). Store reconstituted solution at 2° to 8°C (36° to 46°F); discard after 8 h or sooner if cloudy.

Drug Interactions

Asparaginase may diminish or abolish methotrexate's effect on malignant cells. Do not use methotrexate with, or following asparaginase, while asparagine levels are below normal. Asparaginase may augment corticosteroid-induced hyperglycemia.

IV administration may be associated with increased toxicity.

Laboratory Test Interactions

May interfere with the interpretation of thyroid function tests by producing a rapid and marked reduction in serum concentrations of thyroxine-binding globulin within 2 days after the first dose.

Adverse Reactions

CNS

Depression; confusion; hallucinations; headache; Parkinson-like syndrome.

Dermatologic

Rashes.

Endocrine

Hyperglycemia.

GI

Moderate potential for nausea, vomiting. Pancreatitis, sometimes fulminant, and acute hemorrhagic pancreatitis have occurred, both may be fatal; fatty changes in the liver; elevation of LFTs.

Hematologic

Hypofibrinogenemia; decreased synthesis of clotting factors and antithrombin III.

Hypersensitivity

Acute anaphylactoid reactions are common; discontinuation of therapy and administration of fluids, corticosteroids, antihistamines, or pressors may be required.

Renal

Azotemia, usually prerenal; transient proteinuria.

Miscellaneous

Chills; fever; weight loss (usually mild); fatal hyperthermia; hypoglycemia.

Precautions

Pregnancy

Category C .

Lactation

Discontinue breast-feeding or the drug.

Children

Toxicity is reported to be greater in adults than in children.

ALL dosage adjustments

Patients who have received a course of therapy, if treated again, have an increased risk of hypersensitivity reactions. Therefore, repeat treatment only when the benefit of such therapy is weighed against the increased risk.

Hematologic

Bone marrow depression, leukopenia, thrombosis, and clotting factors depressed; increase in blood ammonia during the conversion of asparagine to aspartic acid by the enzyme.

Patient Information

• Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
• Advise patient, family, or caregiver that medication will be used in combination with other agents to achieve maximum benefit possible.
• Review dosing schedule with patient, family, or caregiver.
• Advise patient, family, or caregiver that skin tests may be used prior to administration of medication.
• Advise patient, family, or caregiver to carefully follow instructions for supplemental therapies designed to protect the kidneys from excessive uric acid (eg, increased fluid intake, allopurinol, urinary alkalinizing agents).
• Advise patient, family, or caregiver to immediately report any of the following to health care provider: rash; hives; difficulty breathing; fever, chills, or other signs of infection; sore throat.
• Advise patient, family, or caregiver to report any of the following to health care provider: persistent nausea, vomiting, or appetite loss; persistent stomach pain; unusual bruising or bleeding.
• Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.

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