No

Antineoplastic Agent, Miscellaneous

Treatment of acute lymphocytic leukemia, lymphoma; used for induction therapy

C

Clinical effects on the fetus: Based on limited reports in humans, the use of asparaginase does not seem to pose a major risk to the fetus when used in the 2nd and 3rd trimesters, or when exposure occurs prior to conception in either females or males. Because of the teratogenicity observed in animals and the lack of human data after 1st trimester exposure, asparaginase should be used cautiously, if at all, during this period.

Pancreatitis (active or any history of), hypersensitivity to asparaginase or any component; if a reaction occurs to Elspar®, obtain Erwinia L-asparaginase and use with caution

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered; monitor for severe allergic reactions; risk for hypersensitivity increases with successive doses

Only administer in hospital setting

Monitor blood pressure every 15 minutes for 1 hour

Administer a small test dose first; the intradermal skin test is commonly given prior to the initial injection, using a dose of 0.1 mL of 20 unit/mL dilute solution (~2 units); the skin test site should be observed for at least 1 hour for a wheal or erythema; note that a negative skin test does not preclude the possibility of an allergic reaction; desensitization should be performed in patients who have been found to be hypersensitive by the intradermal skin test or who have received previous courses of therapy with the drug

Have epinephrine, diphenhydramine, and hydrocortisone at the bedside

Have a running I.V. in place

A physician should be readily accessible

Avoid administering at night

>10%:

Immediate effects: Fever, chills, nausea, and vomiting occur in 50% to 60% of patients

Gastrointestinal: Pancreatitis: Occurs in <15% of patients, but may progress to severe hemorrhagic pancreatitis

Emetic potential: Moderate (30% to 60%)

Renal: Prerenal azotemia

Miscellaneous: Hypersensitivity effects: Hypersensitivity and anaphylactic reactions occur in ~10% to 40% of patients and can be fatal; this reaction is more common in patients receiving asparaginase alone or by I.V. administration; hypersensitivity appears rarely with the first dose and more commonly after the second or third treatment; hypersensitivity may be treated with antihistamines and/or steroids; if an anaphylactic reaction occurs, a change in treatment to the Erwinia preparation may be made, since this preparation does not share antigenic cross-reactivity with the E. coli preparation; note that allergic reactions to the Erwinia preparation may also occur and ultimately develop in 5% to 20% of patients

1% to 10%:

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Mouth sores

<1%: Hypotension, leg vein thrombosis, chills, malaise, disorientation, drowsiness, seizures, and coma which may be due to elevated NH₄ levels; hyperthermia, drowsiness, fever, hallucinations, rash, pruritus, urticaria, transient diabetes mellitus, weight loss, inhibition of protein synthesis will cause a decrease in production of albumin, insulin (resulting in hyperglycemia), serum lipoprotein, antithrombin III, and clotting factors II, V, VII, VIII, IX, and X; the loss of the later two proteins may result in either thrombotic or hemorrhagic events; these protein losses occur in 100% of patients; increased serum bilirubin, AST/ALT, alkaline phosphatase, and possible decrease in mobilization of lipids, azotemia, laryngeal spasm, coughing

Myelosuppressive effects: Myelosuppression is uncommon

WBC: Mild

Platelets: Mild

Onset (days): 7

Nadir (days): 14

Recovery (days): 21

Symptoms of overdose include nausea, diarrhea

Decreased effect: Methotrexate: Asparaginase terminates methotrexate action by inhibition of protein synthesis and prevention of cell entry into the S phase

Increased toxicity:

Vincristine and prednisone: An increase in toxicity has been noticed when asparaginase is administered with VCR and prednisone

Cyclophosphamide (decreases metabolism)

Mercaptopurine (increases hepatotoxicity)

Vincristine (increases neuropathy)

Prednisone (increases hyperglycemia)

Intact vials of powder should be refrigerated (<8°C); lyophilized powder should be reconstituted with 1-5 mL sterile water for I.V. administration or NS for I.M. use, reconstituted solutions are stable 1 week at room temperature; shake well but not too vigorously; use of a 5 micron in-line filter is recommended to remove fiber-like particles in the solution (not 0.2 micron filter - has been associated with some loss of potency)

Usually no >2 mL/injection site, however, contact RN first to clarify administration route.

Standard I.V. dilution: Dose/50-250 mL NS or D₅W

Stable for 8 hours at room temperature or refrigeration

Some malignant cells (ie, lymphoblastic leukemia cells and those of lymphocyte derivation) must acquire the amino acid asparagine from surrounding fluid such as blood, whereas normal cells can synthesize their own asparagine. Asparaginase is an enzyme that deaminates asparagine to aspartic acid and ammonia in the plasma and extracellular fluid and therefore deprives tumor cells of the amino acid for protein synthesis.

Absorption: Not absorbed from GI tract, therefore, requires parenteral administration; I.M. administration produces peak blood levels 50% lower than those from I.V. administration (I.M. may be less immunogenic)

Distribution: V_d: 4-5 L/kg; 70% to 80% of plasma volume; does not penetrate the CSF

Metabolism: Systemically degraded, only trace amounts are found in the urine

Half-life: 8-30 hours

Elimination: Clearance unaffected by age, renal function, or hepatic function

Refer to individual protocols; dose must be individualized based upon clinical response and tolerance of the patient

Asparaginase is available from two different microbiological sources: One is from Escherichia coli and the other is from Erwinia carotovora; the Erwinia is restricted to patients who have sustained allergic reactions to the E. coli preparation

I.M., I.V.: 6000 units/m² every other day for 3-4 weeks or daily doses of 1000-20,000 units/m² for 10-20 days; other induction regimens have been utilized

Hemodialysis: Significant drug removal is unlikely based on physiochemical characteristics

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics

Desensitization should be performed before administering the first dose of asparaginase to patients who developed a positive reaction to the intradermal skin test or who are being retreated; one schedule begins with a total of 1 unit given I.V. and doubles the dose every 10 minutes until the total amount given in the planned dose for that day

Asparaginase Desensitization:

Injection No. 1: Dose = 1 int units; Accumulated total dose = 1

Injection No. 2: Dose = 2 int units; Accumulated total dose = 3

Injection No. 3: Dose = 4 int units; Accumulated total dose = 7

Injection No. 4: Dose = 8 int units; Accumulated total dose = 15

Injection No. 5: Dose =16 int units; Accumulated total dose = 31

Injection No. 6: Dose = 32 int units; Accumulated total dose = 63

Injection No. 7: Dose = 64 int units; Accumulated total dose = 127

Injection No. 8: Dose = 128 int units; Accumulated total dose = 255

Injection No. 9: Dose = 256 int units; Accumulated total dose = 511

Injection No. 10: Dose = 512 int units; Accumulated total dose = 1023

Injection No. 11: Dose = 1024 int units; Accumulated total dose = 2047

Injection No. 12: Dose = 2048 int units; Accumulated total dose = 4095

Injection No. 13: Dose = 4096 int units; Accumulated total dose = 8191

Injection No. 14: Dose = 8192 int units; Accumulated total dose = 16,383

Injection No. 15: Dose = 16,384 int units; Accumulated total dose = 32,767

Injection No. 16: Dose = 32,768 int units; Accumulated total dose = 65,535

Injection No. 17: Dose = 65,536 int units; Accumulated total dose = 131,071

Injection No. 18: Dose = 131,072 int units; Accumulated total dose = 262,143

For example, if a patient was to receive a total dose of 4000 units, he/she would receive injections 1 through 12 during the desensitization

Vital signs during administration, CBC, urinalysis, amylase, liver enzymes, prothrombin time, renal function tests, urine dipstick for glucose, blood glucose, uric acid

thyroxine and thyroxine-binding globulin

Rare reports of depression, disorientation, and hallucinations

None reported; may cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

This medication can only be given I.M. or I.V. It is vital to maintain good hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) and good nutritional status (small frequent meal may help). You may experience acute gastric disturbances (eg, nausea or vomiting); frequent mouth care or lozenges may help or antiemetic may be prescribed. Report any respiratory difficulty, skin rash, or acute anxiety immediately. Report unusual fever or chills, confusion, agitation, depression, yellowing of skin or eyes, unusual bleeding or bruising, unhealed sores, or vaginal discharge. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Consult prescriber if breast-feeding.

Appropriate agents for maintenance of an adequate airway and treatment of a hypersensitivity reaction (antihistamine, epinephrine, oxygen, I.V. corticosteroids) should be readily available. Be prepared to treat anaphylaxis at each administration; monitor for onset of abdominal pain and mental status changes.

Injection:

10,000 units/vial ( Erwinia)

Asselin BL, Whitin JC, Coppola DJ, et al, "Comparative Pharmacokinetic Studies of Three Asparaginase Preparations," J Clin Oncol, 1993, 11(9):1780-6.

Capizzi RL, "Asparaginase Revisited," Leukemia & Lymphoma, 1993, 10(Suppl):147-50.

Clavell LA, Gelber RD, Cohen HJ, et al, "Four-Agent Induction and Intensive Asparaginase Therapy for Treatment of Childhood Acute Lymphoblastic Leukemia," N Engl J Med, 1986, 315(11):657-63.

Ettinger LJ, Ettinger AG, Avramis VI, et al, "Acute Lymphoblastic Leukemia: A Guide to Asparaginase and Pegaspargase Therapy," BioDrugs, 1997, 7:30-9.

Gallagher MP, Marshall RD, and Wilson R, "Asparaginase as a Drug for Treatment of Acute Lymphoblastic Leukemia," Essays Biochem, 1989, 24:1-40.

Haskell CM, "L-Asparaginase: Human Toxicology and Single Agent Activity in Nonleukemic Neoplasms," Cancer Treatment Reports, 1981, 65(Suppl 4): 57-9.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Keating MJ, Holmes R, Lerner S, et al, "L-Asparaginase and PEG Asparaginase - Past, Present, and Future," Leukemia & Lymphoma, 1993, 10(Suppl):153-7.

Nesbit M, Chard R, Evans A, et al, "Evaluation of Intramuscular Versus Intravenous Administration of L-Asparaginase in Childhood Leukemia," Am J Pediatr Hematol Oncol, 1979, 1(1):9-13.

Ortega JA, Nesbit ME Jr, and Donaldson MH, "L-Asparaginase, Vincristine, and Prednisone for Induction of First Remission in Acute Lymphocytic Leukemia," Cancer Res, 1977, 37(2):535-40.