ASPARAGINASE

ASPARAGINASe
(a-spar'a-gi-nase)
Colaspase, Elspar, Kidrolase A, L-asparaginase
Classifications: antineoplastic enzyme; antimetabolite;
Therapeutic: antineoplastic
; antimetabolite
Pregnancy Category: C

Availability

10,000 IU vial

Action

A highly toxic drug with a low therapeutic index. Catalyzes asparagine to aspartic acid and ammonia, thus depleting extracellular supply of an amino acid essential to synthesis of DNa and other nucleoproteins.

Therapeutic Effect

Reduced availability of asparagine causes death of tumor cells, since unlike normal cells, tumor cells are unable to synthesize their own supply. Resistance to cytotoxic action develops rapidly, and it is not an effective treatment for solid tumors.

Uses

Primarily in combination regimens with other antineoplastic agents to treat acute lymphocytic leukemia (ALL).

Unlabeled Uses

Other leukemias, lymphosarcoma, and (intraarterially) treatment of hypoglycemia due to pancreatic islet cell tumor.

Contraindications

Hypersensitivity to Escherichia coli protein; history of or existing pancreatitis; chickenpox (existing or recent illness or exposure), herpetic infection; pregnancy (category C), lactation.

Cautious Use

Liver impairment; diabetes mellitus; anticoagulation therapy, coagulopathy; infections; history of urate calculi or gout; antineoplastic or radiation therapy.

Route & Dosage

Induction Agent
Adult: IV (sole agent) 200 IU/kg/d for 28 d, inject over at least 30 min into running IV OR 1000 IU/kg/d for days 22–32 (along with prednisone and vincristine)
Child: IV 1000 U/kg/d x10 d starting day 22 (along with prednisone and vincristine)

Desensitization Protocol
Adult/Child: IV Schedule begins with 1 IU, then double the dose q10min until the accumulated total matches the planned dose. See package insert for detailed dosing.

Administration

Intravenous
  • An intradermal skin test is usually performed prior to initial dose and when drug is readministered after an interval of a week or more; allergic reactions are unpredictable.
  • Observe test site for at least 1 h for evidence of positive reaction (wheal, erythema). A negative skin test, however, does not preclude possibility of an allergic reaction.
  • Administer test dose and IV infusion under constant supervision by clinician experienced in cancer chemotherapy.
  • Use only clear solutions.

PREPARE: IV Infusion: ?? Reconstitute with sterile water or with 0.9% NaCl.??Each 10,000 IU vial is diluted with 5 mL of diluent to yield 2000 IU/mL.??Shake vial well to promote dissolution of powder. Avoid vigorous shaking. Ordinary shaking does not inactivate the enzyme or cause foaming of content. 

ADMINISTER: IV Infusion: ??Further dilute reconstituted solution with NS or D5W by administration into tubing of an already free flowing infusion of one of these solutions.??Give over a period of not less than 30 min.??Use a 5-mm filter to remove gelatinous fiber-like particles that can develop in solutions on standing. 

  • Store sealed vial of lyophilized powder below 8° C (46° F) unless otherwise directed by manufacturer. Store reconstituted solutions and solutions diluted for IV infusion at 2°–8° C (36°–46° F) for up to 8 h; then discard.

Adverse Effects (≥1%)

Body as a Whole: Hypersensitivity (Skin rashes, urticaria, respiratory distress, anaphylaxis), chills, fever, fatal hyperthermia, perspiration, weight loss. CNS: Depression, fatigue, lethargy, drowsiness, confusion, agitation, hallucinations, dizziness, Parkinson-like syndrome with tremor and progressive increase in muscle tone. GI: Severe vomiting, nausea, anorexia, abdominal cramps, diarrhea, acute pancreatitis, liver function abnormalities. Urogenital: Uric acid nephropathy, azotemia, proteinuria, renal failure. Hematologic: Reduced clotting factors (especially V, VII, VIII, IX), decreased circulating platelets and fibrinogen, leukopenia. Metabolic: Hyperglycemia, glycosuria, polyuria, hypoalbuminemia, hypocalcemia, hyperuricemia. Other: Flank pain, infections.

Diagnostic Test Interference

Asparaginase may interfere with thyroid function tests: decreased total serum thyroxine and increased thyroxine-binding globulin index; pretreatment values return within 4 wk after drug is discontinued.

Interactions

Drug: Decreased hypoglycemic effects of sulfonylureas, insulin; increased potential for toxicity if asparaginase is given concurrently or immediately before corticosteroids, vincristine; blocks antitumor effect of methotrexate if given concurrently or immediately before it.

Pharmacokinetics

Distribution: Into intravascular space (80%) and lymph; low levels in CSF, pleural and peritoneal fluids. Elimination: Small amounts found in urine. Half-Life: 8–30 h.

Nursing Implications

Assessment & Drug Effects

  • Have immediately available: Personnel, drugs, and equipment for treating allergic reaction (which may range from urticaria to anaphylactic shock) whenever drug is administered, including skin testing.
  • Monitor for S&S and be alert to evidence of hypersensitivity or anaphylactoid reaction (see Appendix F) during drug administration. Anaphylaxis usually occurs within 30–60 min after dose has been given and is more likely with intermittent administrations, particularly at intervals of ≥7 d.
  • Monitor I&O and maintain adequate fluid intake.
  • Evaluate CNS function (general behavior, emotional status, level of consciousness, thought content, motor function) before and during therapy.
  • Note: Toxicity potential is increased when giving drug immediately before a course of prednisone and vincristine; toxicity appears less when given after these drugs.
  • Lab tests: Periodic serum amylase, serum calcium blood glucose, coagulation factors, ammonia and uric acid levels, hepatic and renal function tests, peripheral blood counts, and bone marrow function; liver function tests at least twice weekly during therapy.
  • Monitor diabetics for loss of glycemic control.
  • Monitor for and report S&S of hyperammonemia: anorexia, vomiting, lethargy, weak pulse, depressed temperature, irritability, asterixis, seizures, coma.
  • Anticipate possible prolonged or exaggerated effects of concurrently given drugs or their toxicity because of potential serious hepatic dysfunction that reduces enzymatic detoxification of other drugs. Report incidence promptly.
  • Watch for neurotoxic reaction (25% of patients) which usually appears within the first few days of therapy. It is manifested by tiredness and changing levels of consciousness (ranging from confusion to coma).
  • Note: Protect from infection during first several days of treatment when circulating lymphoblasts decrease markedly and leukocyte counts may fall below normal. Report promptly S&S of infection: chill, fever, aches, sore throat.
  • Report sudden severe abdominal pain with nausea and vomiting, particularly if these symptoms occur after medication is discontinued (may indicate pancreatitis).

Patient & Family Education

  • Note: Therapeutic response will most likely be accompanied by some toxicity in all patients; toxicity is reportedly greater in adults than in children.
  • Notify physician of continued loss of weight or onset of foot and ankle swelling.
  • Notify physician without delay if nausea or vomiting makes it difficult to take all prescribed medication.
  • Report onset of unusual bleeding, bruising, petechiae, melena, skin rash or itching, yellowed skin and sclera, joint pain, puffy face, or dyspnea.
  • Do not drive or operate equipment that requires alertness and skill. Exercise caution with potentially hazardous activities. These effects can continue several weeks after last dose of the drug.

Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug

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