Pegaspargase (Monograph)

Brand name: Oncaspar
Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: (Monomethoxypolyethylene glycol succinimidyl)74-l-asparaginase
CAS number: 130167-69-0

Medically reviewed by Drugs.com on Apr 17, 2024. Written by ASHP.

Introduction

Antineoplastic agent; conjugate of monomethoxy polyethylene glycol (mPEG) and Escherichia coli-derived asparaginase.^{1 2 3 5 6}

Uses for Pegaspargase

Acute Lymphocytic (Lymphoblastic) Leukemia (ALL)

Component of combination chemotherapy for first-line treatment of childhood and adult ALL.^{1 7 23 26} Used in induction and/or intensification (consolidation) regimens prior to maintenance therapy;^{1 7 22 23 25 26} CNS-directed therapy also required.^{7 8 9 30 31 32 46}

Component of combination chemotherapy for treatment of ALL in patients who are hypersensitive to native (nonconjugated) forms of asparaginase.^{1 2 3 4 5 6 8}

In childhood ALL, combination therapy with an asparaginase preparation, a corticosteroid (dexamethasone or prednisone), and vincristine, with or without an anthracycline (daunorubicin or doxorubicin), is used as an induction regimen.^{7 46} Some clinicians reserve 4-drug induction regimens for those with high-risk childhood ALL,^{7 8 33 46} while others use such regimens for all patients with childhood ALL regardless of presenting features.^{7 46} Multiple-drug induction regimens produce complete remission in ≥95% of children with ALL.^{7 33 46}

Because pegaspargase has similar efficacy and toxicity as asparaginase (Escherichia coli)^{7 22 25} but requires less frequent administration, many clinicians have preferred pegaspargase;^{7 44} with asparaginase (Escherichia coli) no longer commercially available in the US, pegaspargase has become a core component in most first-line combination chemotherapeutic regimens for childhood ALL.^{7 44} More recently, calaspargase pegol, an E. coli-derived asparaginase that is administered less frequently than pegaspargase, also has become commercially available in the US for childhood and young adult ALL.^{7 43 47} Asparaginase (Erwinia chrysanthemi) may be used in patients who are hypersensitive to E. coli-derived asparaginase preparations.^{7 34 35 36 37 38}

In adults, induction regimens typically include an anthracycline, vincristine, and prednisone; some regimens also add other drugs (e.g., an asparaginase preparation, cyclophosphamide).^{26 28 30} Such induction regimens produce complete remission in about 60–90% of adults with ALL.^{26 28 30 33}

Adolescents and young adults appear to have better outcomes with use of pediatric-based treatment regimens for ALL instead of traditional adult treatment regimens.^{7 45}

Related/similar drugs

methotrexate, imatinib, doxorubicin, mercaptopurine, Gleevec, Sprycel

Pegaspargase Dosage and Administration

General

• Monitor patients for hypersensitivity reactions for 1 hour after administration of pegaspargase; be prepared to provide immediate treatment.¹ (See Hypersensitivity Reactions under Cautions.)

• Monitor bilirubin, aminotransferase, and glucose concentrations and perform clinical examinations at least weekly until patient recovers from the treatment cycle.¹

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{40 41}

Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IM injection or IV infusion.¹ Has been administered by sub-Q^{† [off-label]} injection.²⁶

Discard injection or diluted solutions that appear discolored or cloudy or contain particulate matter.¹ (See Storage under Stability.)

Injection contains no preservative.¹ Vials are for single use only; discard any unused portion.¹

IM Administration

Administer undiluted by IM injection.¹

Do not give >2 mL at one injection site.¹

IV Administration

Administer by IV infusion.¹

Do not administer simultaneously through the same IV line with other drugs.¹

Dilution

For IV infusion, dilute pegaspargase dose in 100 mL of 0.9% sodium chloride injection or 5% dextrose injection.¹

Immediately use diluted solutions.¹ If immediate use not possible, store diluted solutions at 2–8°C and use within 48 hours of preparation.¹

Protect diluted solution from direct sunlight.¹

Rate of Administration

Administer over 1–2 hours into tubing of a free-flowing IV infusion of 0.9% sodium chloride injection or 5% dextrose injection.¹

Dosage

Dosage expressed in international units (IU, units).¹

Pediatric Patients

ALL

IM or IV

2500 units/m² administered no more frequently than every 14 days.¹ Consult published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.

Therapy Interruption for Toxicity

If an adverse reaction occurs, modify treatment accordingly.¹ See Table 1.

Adults

ALL

IM or IV

Adults ≤21 years of age: 2500 units/m² administered no more frequently than every 14 days.¹

Adults >21 years of age: 2000 units/m² administered no more frequently than every 14 days.¹

Consult published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.

Therapy Interruption for Toxicity

If an adverse reaction occurs, modify treatment accordingly.¹ Recommendations for treatment modification for toxicity in pediatric patients also apply to adults (see Table 1).¹

Prescribing Limits

Pediatric Patients

ALL

IM or IV

Manufacturer recommends administering no more frequently than every 14 days.¹ Consult specific clinical protocols for prescribing limits for alternative dosages.

Adults

ALL

IM or IV

Manufacturer recommends administering no more frequently than every 14 days.¹ Consult specific clinical protocols for prescribing limits for alternative dosages.

Special Populations

Geriatric Patients

No specific dosage recommendations.¹ (See Geriatric Use under Cautions.)

Cautions for Pegaspargase

Contraindications

• History of serious thrombosis associated with prior asparaginase therapy.¹

• History of pancreatitis, including pancreatitis associated with prior asparaginase therapy.^{1 12 19} (See Pancreatitis under Cautions.)

• History of serious hemorrhagic events associated with prior asparaginase therapy.^{1 12 19}

• History of serious allergic reactions, including anaphylaxis, to pegaspargase or any ingredient in the formulation.¹

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions^{1 5 6 12 13 15 16 19 25} (e.g., acute anaphylaxis,^{1 5 12 13 19} bronchospasm,^{1 5 12 19} hypotension,¹ angioedema,¹ lip swelling,¹ eye swelling,¹ urticaria,^{12 16 19} chills,^{12 16 18 19} dyspnea,¹ erythema,¹ pruritus,¹ rash,^{1 12 16 19} local erythema or swelling^{12 19} ) reported; discontinue the drug in patients with serious allergic reactions.¹

Probability of a previously hypersensitive or nonhypersensitive patient completing 8 doses of pegaspargase therapy without developing a therapy-limiting hypersensitivity reaction in clinical studies was 77 or 95%, respectively.^{19 21}

Monitor patients for 1 hour after administration of the drug;^{1 19} appropriate resuscitative equipment and agents (e.g., antihistamine, epinephrine, oxygen, IV corticosteroid) should be readily available.^{1 3 12 19}

Thrombotic Events

Serious thrombotic events^{1 18 19} (e.g., sagittal sinus thrombosis,^{1 12} central venous catheter thrombosis,^{23 29} stroke^{25 29} ) reported; discontinue the drug in patients with serious thrombotic events.¹

Pancreatitis

Pancreatitis,^{1 12 13 15 17 19} including fatal cases of hemorrhagic or necrotizing pancreatitis, reported;^{1 19} impairment of pancreatic function^{1 12 13 15 17 19} reported frequently.^{1 12 13 15 17 19}

Measure serum amylase and/or lipase concentrations to confirm early signs of pancreatic inflammation.¹ If pancreatitis suspected, withhold pegaspargase therapy; if confirmed, permanently discontinue drug.¹

Hyperglycemia

Glucose intolerance, sometimes irreversible, reported.¹

Mild to severe hyperglycemia^{1 12 13 15 17 23} may occur in patients receiving pegaspargase.¹ Hyperglycemia requiring insulin therapy^{1 12 15 19} may occur.¹

Monitor serum glucose concentrations.¹

Coagulopathy

Coagulopathy,^{15 16 29} sometimes severe, reported.¹

Evaluate coagulation parameters (including fibrinogen concentration, PT, and PTT) in patients with signs or symptoms of hemorrhage.¹ Consider the need for appropriate clotting factor replacement therapy in patients with severe or symptomatic coagulopathy.¹

Hepatic Effects

Hyperbilirubinemia^{1 23} and elevated ALT and AST concentrations^{1 12 16 17 19} reported frequently.¹

Hepatotoxicity,¹ jaundice,^{12 16 21} and abnormal liver function test results²¹ (e.g., hyperbilirubinemia [direct and indirect],^{1 12 16} hypofibrinogenemia,¹ hypoalbuminemia^{21 29} possibly associated with peripheral edema^{6 12 16 17} ) may occur.

Monitor bilirubin and aminotransferase concentrations at least weekly during treatment cycles including pegaspargase and for ≥6 weeks after the last dose.¹ If serious hepatotoxicity occurs, discontinue pegaspargase and provide supportive care.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal findings.¹ Studies in pregnant rabbits administered L-asparaginase or deprived of dietary asparagine suggest asparagine depletion may harm animal offspring.¹

Confirm pregnancy status prior to initiating pegaspargase therapy.¹ Avoid pregnancy during therapy.¹ Women of childbearing potential should use effective methods of contraception, including a barrier method, while receiving pegaspargase and for ≥3 months after last dose.¹ Avoid concomitant use of oral contraceptives and pegaspargase.¹ (See Specific Drugs under Interactions.) If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Immunogenicity

Antibodies to pegaspargase may develop.^{1 22} Clinical implications of antibody development (e.g., effect on pharmacokinetics, risk of allergic reactions, or efficacy) not fully established.¹

Specific Populations

Pregnancy

May cause fetal harm.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether pegaspargase distributes into human milk or has any effects on milk production or on the nursing infant.¹ Women should not breast-feed during therapy and for ≥3 months after last dose.¹

Pediatric Use

Safety and efficacy for treatment of ALL in pediatric patients supported by evidence of efficacy as first-line treatment from one adequate and well-controlled clinical trial, evidence of efficacy in patients with hypersensitivity to asparaginase from 4 adequate and well-controlled clinical trials, and safety data from 7 clinical trials.¹ In these trials, 26 infants, 165 children, and 39 adolescents received pegaspargase 2500 units/m².¹

Adult Use

Known asparaginase toxicity (e.g., pancreatic dysfunction, hepatic toxicity, thromboembolism, but not hypersensitivity reactions) reportedly is greater in adults than in children.^{17 19 44 45} However, in young adults, treatment outcomes appear to be better with pediatric-based treatment regimens for ALL than with traditional adult treatment regimens.^{7 45}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.¹

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics of pegaspargase not established.¹

Renal Impairment

Effect of renal impairment on pharmacokinetics of pegaspargase not established.¹

Common Adverse Effects

Grade 3 or 4 reactions: Hypoalbuminemia, elevated serum aminotransferase concentrations, febrile neutropenia, hypertriglyceridemia, hyperglycemia, hyperbilirubinemia, pancreatitis, clotting study abnormalities, embolic and thrombotic events, hypersensitivity reactions.¹

No apparent difference in adverse effects following IV versus IM administration.⁷

Drug Interactions

No formal drug interaction studies to date.¹

Specific Drugs

Pegaspargase Pharmacokinetics

Absorption

Bioavailability

Relative bioavailability following IM injection is 82% following initial dose and 98% with repeat dosing.¹

Following a single 2500-unit/m² IM dose, mean absorption half-life from injection site was 1.7 days.¹

Plasma Concentrations

Serum trough asparaginase activity of ≥0.1 units/mL correlates with asparagine depletion in CSF and serum; has been established as a surrogate measure of asparaginase efficacy.^{44 45 47}

Following a single 2500-unit/m² IM dose of pegaspargase, mean peak asparaginase concentration of approximately 1 unit/mL achieved on day 5.¹

Plasma asparaginase concentrations >0.1 units/mL in >90% of samples for approximately 20 days in pediatric patients receiving single IM pegaspargase doses of 2500 unit/m² during induction therapy and during both phases of delayed intensification therapy.¹

Following a single 2500-unit/m² IV dose of pegaspargase, mean peak plasma asparaginase concentration was 1.6 units/mL.^{1 42}

Peak serum asparaginase activity averaged 1 unit/mL in adults receiving a single IV dose of pegaspargase 2000 units/m² during induction therapy.²³

Distribution

Extent

Asparaginase does not appear to cross blood-brain barrier; however, CSF asparagine depletion occurs as a result of plasma asparagine depletion following treatment.⁴⁸

Not known whether pegaspargase is distributed into milk.¹

Elimination

Half-life

Approximately 5.8 days following IM administration in pediatric patients.¹

Approximately 5.3 days following IV administration in pediatric patients and young adults.^{1 42}

7 days following IV administration in adults.²³

Stability

Storage

Parenteral

Injection

2–8°C in original carton.¹ Do not store at room temperature (15–25°C) for >48 hours.¹ Do not freeze; protect from light.¹

Diluted solution: If immediate use not possible, store at 2–8°C and use within 48 hours of preparation.¹ Do not freeze; protect from direct sunlight.¹

Compatibility

Parenteral

Solution Compatibility1

Actions

• Inactivates the amino acid asparagine, which is required by tumor cells to synthesize protein, RNA, and DNA.^{1 24}

• Breaks down extracellular asparagine into aspartic acid and ammonia, which causes depletion of asparagine and kills leukemic cells.^{1 24 26}

• Less immunogenic and longer acting (i.e., possesses a longer plasma half-life) than native (nonconjugated) E. coli-derived asparaginase.^{1 22 24}

• Risk of serious hypersensitivity reactions, including anaphylaxis; importance of patients being monitored for 1 hour after pegaspargase administration.^{1 19} Importance of immediately informing clinician if symptoms of serious allergic reactions (e.g., swelling, difficulty breathing) occur.¹

• Risk of pancreatitis.¹ Importance of immediately informing clinicians if severe abdominal pain occurs.¹

• Risk of hyperglycemia and glucose intolerance.¹ Importance of immediately informing clinician if excessive thirst or any increase in the volume or frequency of urination occurs.¹

• Risk of thrombosis.¹ Importance of immediately informing clinician if severe headache, arm or leg swelling, shortness of breath, or chest pain occurs.¹

• Importance of informing clinician if any unusual bleeding or bruising occurs.¹

• Importance of immediately informing clinician if jaundice, severe nausea or vomiting, or easy bruising or bleeding occurs.¹

• Risk of fetal harm.¹ Importance of women informing clinicians if they are or plan to become pregnant.¹ Necessity of advising women of reproductive potential that they should use effective methods of contraception while receiving the drug and for ≥3 months after the last dose.¹ Importance of advising women that concomitant use of pegaspargase and oral contraceptives is not recommended.¹

• Importance of advising women to avoid breast-feeding while receiving pegaspargase and for ≥3 months after the last dose.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹⁹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Frequently asked questions

• How does Asparlas (calaspargase pegol-mknl) compare to Oncaspar (pegaspargase)?

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