No

Antineoplastic Agent, Miscellaneous

Patients with acute lymphoblastic leukemia (ALL) who require asparaginase in their treatment regimen, but have developed hypersensitivity to the native forms of asparaginase. Use as a single agent; should only be undertaken when multiagent chemotherapy is judged to be inappropriate for the patient.

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 or a history of pancreatitis; patients who have had significant hemorrhagic events associated with prior asparaginase therapy; previous serious allergic reactions, such as generalized urticaria, bronchospasm, laryngeal edema, hypotension, or other unacceptable adverse reactions to pegaspargase.

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered

Hypersensitivity reactions to pegaspargase, including life-threatening anaphylaxis, may occur during therapy, especially in patients with known hypersensitivity to the other forms of asparaginase. As a routine precaution, keep patients under observation for 1 hour with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, oxygen, I.V. steroids) available.

Use caution when treating patients with pegaspargase in combination with hepatotoxic agents, especially when liver dysfunction is present

Overall, the adult patients had a somewhat higher incidence of asparaginase toxicities, except for hypersensitivity reactions, than the pediatric patients

Cardiovascular: Edema

Central nervous system: Pain

Dermatologic: Urticaria, erythema

Gastrointestinal: Pancreatitis (sometimes fulminant and fatal); increased serum amylase and lipase

Hepatic: Elevations of AST/ALT and bilirubin (direct and indirect); jaundice, ascites and hypoalbuminemia, fatty changes in the liver, liver failure

Local: Induration, tenderness

Neuromuscular & skeletal: Arthralgia

Respiratory: Bronchospasm, dyspnea

Miscellaneous: Hypersensitivity: Acute or delayed anaphylaxis, edema of the lips

>5%:

Central nervous system: Fever, chills, malaise

Dermatologic: Rash

Gastrointestinal: Emetic potential: Mild (>5%)

Hepatic: ALT increase

Respiratory: Dyspnea or bronchospasm

1% to 5%:

Cardiovascular: Hypotension, tachycardia, thrombosis

Central nervous system: Chills

Dermatologic: Lip edema

Endocrine & metabolic: Hyperglycemia requiring insulin (3%)

Gastrointestinal: Abdominal pain, pancreatitis (1%)

Hematologic: Decreased anticoagulant effect, disseminated intravascular coagulation, decreased fibrinogen, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia, increased thromboplastin

Myelosuppressive effects:

WBC: Mild

Platelets: Mild

Onset (days): 7

Nadir (days): 14

Recovery (days): 21

Local: Injection site hypersensitivity

Respiratory: Dyspnea

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:

Aspirin, dipyridamole, heparin, warfarin, NSAIDs: Imbalances in coagulation factors have been noted with the use of pegaspargase - use with caution

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)

Avoid excessive agitation; do not shake; refrigerate at 2°C to 8°C (36°F to 46°F); single-use vial; discard unused portions

Standard I.M. dilution: Usually no >2 mL/injection site

Standard I.V. dilution: Dose/100 mL NS or D₅W; stable for 48 hours at room temperature

Pegaspargase is a modified version of the enzyme L-asparaginase; the L-asparaginase used in the manufacture of pegaspargase is derived from Escherichia coli

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: 5.73 days

Elimination: Clearance unaffected by age, renal function, or hepatic function; asparaginase was measurable for at least 15 days following initial treatment with pegaspargase

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

Children: I.M., I.V.:

Body surface area <0.6 m²: 82.5 international units/kg every 14 days

Body surface area greater than or equal to 0.6 m²: 2500 international units/m² every 14 days

Adults: I.M., I.V.: 2500 international units/m² every 14 days

Hemodialysis: Significant drug removal is unlikely based on physiochemical characteristics

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

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

Drowsiness is common

May cause pancytopenia; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

This drug can only be given I.M. or I.V. Make note of scheduled return dates. Inform prescriber if you are using any other medications that may increase risk of bleeding. Possibility of hypersensitivity reactions includes anaphylaxis. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) and nutrition (small frequent meals may help if you experience nausea, vomiting, or loss of appetite). Frequent mouth care may help reduce the incidence of mouth sores. You may experience dizziness, drowsiness, syncope, or blurred vision (use caution when driving or engaging in tasks that require alertness until response to drug is known). You may experience increased sweating, decreased sexual drive, or cough. Report immediately chest pain or heart palpitations; difficulty breathing or constant cough; rash, hives, or swelling of lips or mouth; or abdominal pain. Report swelling of extremities or sudden weight gain; burning, pain, or redness at infusion site; persistent fever or chills; unusual bruising or bleeding; twitching or tremors; pain on urination; or persistent nausea or diarrhea. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Do not filter solution; 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, preservative free: 750 units/mL

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

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

Holle LM, "Pegaspargase: An Alternative?" Ann Pharmacother, 1997, 31(5):616-24.

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

Muss HB, Spell N, Scudiery D, et al, "A Phase II Trial of PEG-L-Asparaginase in the Treatment of Non-Hodgkin's Lymphoma," Invest New Drugs, 1990, 8(1):125-30.