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Pegaspargase

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (Monomethoxypolyethylene glycol succinimidyl)74-l-asparaginase
CAS Number: 130167-69-0
Brands: Oncaspar

Medically reviewed by Drugs.com on Apr 27, 2020. Written by ASHP.

Introduction

Antineoplastic agent; conjugate of monomethoxy polyethylene glycol (mPEG) and Escherichia coli-derived asparaginase.

Uses for Pegaspargase

Acute Lymphocytic (Lymphoblastic) Leukemia (ALL)

Component of combination chemotherapy for first-line treatment of childhood and adult ALL. Used in induction and/or intensification (consolidation) regimens prior to maintenance therapy; CNS-directed therapy also required.

Component of combination chemotherapy for treatment of ALL in patients who are hypersensitive to native (nonconjugated) forms of asparaginase.

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. Some clinicians reserve 4-drug induction regimens for those with high-risk childhood ALL, while others use such regimens for all patients with childhood ALL regardless of presenting features. Multiple-drug induction regimens produce complete remission in ≥95% of children with ALL.

Because pegaspargase has similar efficacy and toxicity as asparaginase (Escherichia coli) but requires less frequent administration, many clinicians have preferred pegaspargase; 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. 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. Asparaginase (Erwinia chrysanthemi) may be used in patients who are hypersensitive to E. coli-derived asparaginase preparations.

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

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

Pegaspargase Dosage and Administration

General

  • Monitor patients for hypersensitivity reactions for 1 hour after administration of pegaspargase; be prepared to provide immediate treatment. (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.

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IM injection or IV infusion. Has been administered by sub-Q injection.

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

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

IM Administration

Administer undiluted by IM injection.

Do not give >2 mL at one injection site.

IV Administration

Administer by IV infusion.

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

Dilution

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

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

Protect diluted solution from direct sunlight.

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.

Dosage

Dosage expressed in international units (IU, units).

Pediatric Patients

ALL
IM or IV

2500 units/m2 administered no more frequently than every 14 days. 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. See Table 1.

Table 1. Therapy Interruption for Pegaspargase Toxicity

Adverse Reaction and Severity

Modification

Infusion Reaction or Hypersensitivity Reaction

Grade 1

Reduce infusion rate by 50%

Grade 2

Interrupt therapy and treat symptoms; when symptoms resolve, resume infusion at reduced rate of 50%

Grade 3 or 4

Permanently discontinue therapy

Hemorrhage

Grade 3 or 4

Withhold therapy and evaluate for presence of coagulopathy; consider whether clotting factor replacement is needed; if bleeding is controlled, resume therapy with next scheduled dose

Pancreatitis

Grade 3 or 4

For lipase or amylase concentrations >3 times the ULN, withhold therapy until enzyme concentrations stabilize or decline; permanently discontinue therapy if pancreatitis is confirmed

Thromboembolism

Uncomplicated DVT

Withhold therapy and initiate appropriate antithrombotic therapy; when symptoms resolve, may consider resuming therapy while continuing antithrombotic therapy

Severe or life-threatening thrombosis

Permanently discontinue therapy and initiate appropriate antithrombotic therapy

Hepatotoxicity

Total bilirubin concentration >3 times to ≤10 times the ULN

Withhold therapy until total bilirubin concentrations ≤1.5 times the ULN

Total bilirubin concentration >10 times the ULN

Discontinue therapy; do not make up for missed doses

Adults

ALL
IM or IV

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

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

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. Recommendations for treatment modification for toxicity in pediatric patients also apply to adults (see Table 1).

Prescribing Limits

Pediatric Patients

ALL
IM or IV

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

Special Populations

Geriatric Patients

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

Cautions for Pegaspargase

Contraindications

  • History of serious thrombosis associated with prior asparaginase therapy.

  • History of pancreatitis, including pancreatitis associated with prior asparaginase therapy. (See Pancreatitis under Cautions.)

  • History of serious hemorrhagic events associated with prior asparaginase therapy.

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

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., acute anaphylaxis, bronchospasm, hypotension, angioedema, lip swelling, eye swelling, urticaria, chills, dyspnea, erythema, pruritus, rash, local erythema or swelling ) reported; discontinue the drug in patients with serious allergic reactions.

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.

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

Thrombotic Events

Serious thrombotic events (e.g., sagittal sinus thrombosis, central venous catheter thrombosis, stroke ) reported; discontinue the drug in patients with serious thrombotic events.

Pancreatitis

Pancreatitis, including fatal cases of hemorrhagic or necrotizing pancreatitis, reported; impairment of pancreatic function reported frequently.

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

Hyperglycemia

Glucose intolerance, sometimes irreversible, reported.

Mild to severe hyperglycemia may occur in patients receiving pegaspargase. Hyperglycemia requiring insulin therapy may occur.

Monitor serum glucose concentrations.

Coagulopathy

Coagulopathy, sometimes severe, reported.

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

Hepatic Effects

Hyperbilirubinemia and elevated ALT and AST concentrations reported frequently.

Hepatotoxicity, jaundice, and abnormal liver function test results (e.g., hyperbilirubinemia [direct and indirect], hypofibrinogenemia, hypoalbuminemia possibly associated with peripheral edema ) may occur.

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

Fetal/Neonatal Morbidity and Mortality

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

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

Immunogenicity

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

Specific Populations

Pregnancy

May cause fetal harm. (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. Women should not breast-feed during therapy and for ≥3 months after last dose.

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. In these trials, 26 infants, 165 children, and 39 adolescents received pegaspargase 2500 units/m2.

Adult Use

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

Geriatric Use

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

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics of pegaspargase not established.

Renal Impairment

Effect of renal impairment on pharmacokinetics of pegaspargase not established.

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.

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

Interactions for Pegaspargase

No formal drug interaction studies to date.

Specific Drugs

Drug

Interaction

Comment

Methotrexate

Decreased effectiveness of methotrexate during the period of pegaspargase suppression of protein synthesis and cell replication

Oral contraceptives

Possible indirect interaction (asparaginase-induced hepatotoxicity may impair hepatic clearance of oral contraceptives)

Avoid concomitant use

Pegaspargase Pharmacokinetics

Absorption

Bioavailability

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

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

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.

Following a single 2500-unit/m2 IM dose of pegaspargase, mean peak asparaginase concentration of approximately 1 unit/mL achieved on day 5.

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.

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

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

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.

Not known whether pegaspargase is distributed into milk.

Elimination

Half-life

Approximately 5.8 days following IM administration in pediatric patients.

Approximately 5.3 days following IV administration in pediatric patients and young adults.

7 days following IV administration in adults.

Stability

Storage

Parenteral

Injection

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

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

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Actions

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

  • Breaks down extracellular asparagine into aspartic acid and ammonia, which causes depletion of asparagine and kills leukemic cells.

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

Advice to Patients

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

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

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

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

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

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

  • Risk of fetal harm. Importance of women informing clinicians if they are or plan to become pregnant. 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. Importance of advising women that concomitant use of pegaspargase and oral contraceptives is not recommended.

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

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

  • Importance of informing patients of other important precautionary information. (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.

Pegaspargase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

750 units/mL

Oncaspar

Baxalta

AHFS DI Essentials™. © Copyright 2021, Selected Revisions April 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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