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Pegaspargase

Pronunciation

(peg AS par jase)

Index Terms

  • L-asparaginase with Polyethylene Glycol
  • PEG - ASP
  • PEG - asparaginase
  • PEG - L - asparaginase
  • PEGLA
  • Polyethylene Glycol-L-asparaginase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection [preservative free]:

Oncaspar: 750 units/mL (5 mL)

Brand Names: U.S.

  • Oncaspar

Pharmacologic Category

  • Antineoplastic Agent, Enzyme
  • Antineoplastic Agent, Miscellaneous

Pharmacology

Pegaspargase is a modified version of L-asparaginase, conjugated with polyethylene glycol. In leukemic cells, asparaginase hydrolyzes L-asparagine to ammonia and L-aspartic acid, leading to depletion of asparagine. Leukemia cells, especially lymphoblasts, require exogenous asparagine; normal cells can synthesize asparagine. Asparagine depletion in leukemic cells leads to inhibition of protein synthesis and apoptosis. Asparaginase is cycle-specific for the G1 phase of the cell cycle.

Absorption

Not absorbed from the GI tract; therefore, requires parenteral administration; IM: Slow

Distribution

Apparent Vd: Plasma volume: IM: Children: 1.5 L/m2; IV: Adults (asparaginase naive): 2.4 L/m2 (Douer 2007)

Metabolism

Systemically degraded

Excretion

Clearance is unaffected by age, renal function, or hepatic function; not detected in urine

Onset of Action

Asparagine depletion: IM: Within 4 days

Time to Peak

IM: 3 to 4 days

Duration of Action

Asparagine depletion: IV (in asparaginase naive adults): 2 to 4 weeks (Douer 2007); IM: ~21 days

Half-Life Elimination

IM: Children: 5.8 days; Adults: 5.5-6 days; 3.2 ± 1.8 days in patients who previously had a hypersensitivity reaction to native L-asparaginase

IV: Adults (asparaginase naive): 7 days (Douer 2007)

Use: Labeled Indications

Acute lymphoblastic leukemia and hypersensitivity to asparaginase: Treatment of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to native forms of L-asparaginase (as a component of a multiagent chemotherapy regimen)

Acute lymphoblastic leukemia, first-line: First-line treatment of ALL (as a component of a multiagent chemotherapy regimen)

Contraindications

History of serious allergic reactions to pegaspargase or any component of the formulation; history of any of the following with prior L-asparaginase treatment: serious thrombosis, pancreatitis, and/or serious hemorrhagic events

Dosing: Adult

Acute lymphoblastic leukemia (ALL): IM, IV: 2500 units/m2 (as part of a combination chemotherapy regimen), do not administer more frequently than every 14 days

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Acute lymphoblastic leukemia (ALL): IM, IV: Refer to adult dosing.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

There are no initial dosage adjustments provided in the manufacturer’s labeling. The following adjustments have been recommended (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 it 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 pegaspargase and resume when direct bilirubin <2 mg/dL; consider switching to alternate asparaginase product.

Direct bilirubin >5 mg/dL: Discontinue pegaspargase; do not substitute other asparaginase products; do not make up for missed doses.

Dosing: Adjustment for Toxicity

The following adjustments have 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 pegaspargase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold pegaspargase (and corticosteroids) until blood glucose is controlled with insulin; resume pegaspargase 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 pegaspargase. Replace pegaspargase with asparaginase (Erwinia).

Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue pegaspargase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold pegaspargase 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 pegaspargase and monitor levels closely.

Clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue pegaspargase.

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 pegaspargase 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 pegaspargase 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.

Reconstitution

IV: Dilute in 100 mL NS or D5W.

Administration

Have available appropriate agents for maintenance of an adequate airway and treatment of a hypersensitivity reaction (antihistamine, epinephrine, oxygen, IV corticosteroids). Be prepared to treat anaphylaxis at each administration.

IM: Must only be administered as a deep intramuscular injection into a large muscle. Do not exceed 2 mL per injection site; use multiple injection sites for IM injection volume >2 mL.

IV: Administer over 1 to 2 hours through a running IV infusion line; do not administer IV push.

Compatibility

Stable in NS, D5W.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake; protect from light. Discard vial if previously frozen, stored at room temperature for >48 hours, excessively shaken/agitated, or if cloudy, discolored, or if precipitate is present. If not used immediately, solutions for infusion should be protected from light, refrigerated at 2°C to 8°C (36°F to 46°F) and used within 48 hours (including administration time).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pegloticase: May diminish the therapeutic effect of Pegaspargase. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Hepatic: Increased serum transaminases (ALT, AST; grades 3/4: 3% to 11%)

Hypersensitivity: Hypersensitivity reaction (grades 3/4: 1%, includes anaphylaxis, bronchospasm, erythema, hives, hypotension, laryngeal edema, skin rash, swelling, urticaria; relapsed acute lymphoblastic leukemia [ALL] with no prior asparaginase hypersensitivity: 10%; relapsed ALL with prior asparaginase hypersensitivity: 32%)

1% to 10%:

Cardiovascular: Thrombosis (4%)

Central nervous system: Cerebral thrombosis (or hemorrhage of the brain: 2%; grades 3/4: 3%)

Endocrine & metabolic: Hyperglycemia (3% [some patients required insulin therapy]; grades 3/4: 5%)

Gastrointestinal: Pancreatitis (1%; grades 3/4: 2% [includes 3 deaths])

Hematologic: Blood coagulation disorder (grades 3/4: 2% to 7%; includes prolonged prothrombin time or partial thromboplastin time or decreased serum fibrogen)

Hepatic: Abnormal hepatic function tests (grades 3/4: 5%), hyperbilirubinemia (grades 3/4: 1% to 2%)

Immunologic: Hypersensitivity to L-asparaginase (grades 3/4: 2%)

<1%(Limited to important or life-threatening): Abdominal pain, anemia, arthralgia, bronchospasm, chest pain, coagulation time increased, colitis, confusion, constipation, deep vein thrombosis, disseminated intravascular coagulation, dizziness, dyspnea, emotional lability, endocarditis, facial edema, gastrointestinal pain, headache, hemorrhagic cystitis, hepatic failure, hyperuricemia, hypoglycemia, increased thirst, lip edema, liver steatosis, myalgia, night sweats, ostealgia, pancytopenia, paresthesia, purpura, renal failure, sagittal sinus thrombosis, seizure, septic shock, superficial venous thrombosis

Warnings/Precautions

Concerns related to adverse effects:

• Allergic reactions: Anaphylaxis and serious allergic reactions (eg, bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, urticaria) may occur; discontinue in patients with serious allergic reaction. The risk of serious allergic reactions is increased in patients with a history of hypersensitivity reactions to other L-asparaginase products. Observe patients for 1 hour after administration; equipment and immediate treatment for hypersensitivity reactions should be available during administration.

• Coagulopathy: Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia may occur. Severe or symptomatic coagulopathy may require treatment with fresh-frozen plasma. Use cautiously in patients with an underlying coagulopathy or previous hematologic complications from asparaginase. Monitor coagulation parameters at baseline and periodically during and after therapy.

• Glucose intolerance: May cause glucose intolerance; irreversible in some cases. Use with caution in patients with diabetes mellitus and hyperglycemia. Monitor serum glucose.

• Hepatotoxicity: Altered liver function tests (eg, increased AST, ALT, alkaline phosphatase, bilirubin [direct and indirect], and decreased serum albumin, plasma fibrinogen) may occur with therapy. Use with caution in patients with pre-existing hepatic impairment. Monitor liver function tests at baseline and periodically during treatment.

• Pancreatitis: May occur; promptly evaluate patients with abdominal pain. The manufacturer recommends discontinuing pegaspargase if pancreatitis occurs during treatment. May consider continuing therapy for asymptomatic chemical pancreatitis (amylase or lipase >3 times ULN) or only radiologic abnormalities; monitor closely for rising amylase and/or lipase levels (Stock 2011). Discontinue permanently for clinical pancreatitis (eg, vomiting, severe abdominal pain) with amylase/lipase elevation >3 times ULN for >3 days and/or development of a pancreatic pseudocyst. Avoid alcohol use (Stock 2011).

• Thrombotic events: Serious thrombotic events, including sagittal sinus thrombosis may occur; discontinue with serious thrombotic event. Anticoagulation prophylaxis during therapy may be considered in some patients (Farge 2013).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Medication error prevention: Do not interchange pegaspargase for asparaginase (E. coli) or asparaginase (Erwinia); ensure the proper asparaginase formulation, route of administration, and dose prior to administration.

Monitoring Parameters

CBC with differential, platelets, amylase/lipase, liver function tests (baseline and periodically during treatment), fibrinogen, PT, PTT (coagulation parameters [baseline and periodically during and after treatment]), renal function tests; urine glucose, blood glucose; triglycerides; vital signs during administration; monitor for onset of abdominal pain; observe for allergic reaction (for 1 hour after administration); signs/symptoms of thrombosis or bleeding

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with pegaspargase.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of pancreatitis, signs of hyperglycemia, signs of hepatic impairment, injection site irritation, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, angina, edema of extremities, extremity discoloration, painful extremities, hemoptysis, dyspnea, severe headache, ecchymosis, hemorrhaging, vision changes, or illogical thinking (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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