Calaspargase Pegol-mknl (Monograph)

Brand name: Asparlas
Drug class: Antineoplastic Agents
Chemical name: [27-Alanine,64-aspartic acid,252-threonine,263-asparagine]-L-asparaginase 2 (EC 3.5.1.1, L-asparagine amidohydrolase II) Escherichia coli (strain K12) tetramer α4, carbamates with α-carboxy-ω-methoxypoly(oxyethylene)
Molecular formula: C₁₅₁₆H₂₄₂₃N₄₁₅O₄₉₂S₈
CAS number: 941577-06-6

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.

Uses for Calaspargase Pegol-mknl

Acute Lymphocytic (Lymphoblastic) Leukemia (ALL)

Component of combination chemotherapy for treatment of childhood and young adult ALL. Asparaginase preparations used in induction and/or intensification (consolidation) regimens prior to maintenance therapy; CNS-directed therapy (for prophylaxis of CNS involvement) also required.

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.

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.

Calaspargase Pegol-mknl Dosage and Administration

General

Monitor patients for hypersensitivity reactions for 1 hour after administration of calaspargase pegol; be prepared to provide immediate treatment. (See Hypersensitivity 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

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.

Injection concentrate must be diluted prior to administration.

Administer diluted solution into a running infusion of the same solution (0.9% sodium chloride injection or 5% dextrose injection) used for dilution.

Dilution

Injection concentrate should be clear and colorless. Do not use if cloudy or discolored or if particulate matter is present. Also do not use if injection concentrate has been shaken or vigorously agitated, frozen, or stored at room temperature for >48 hours.

Withdraw the calculated dose from the vial and dilute in 100 mL of 0.9% sodium chloride injection or 5% dextrose injection.

Discard any partially used vial.

Rate of Administration

Administer by IV infusion over 1 hour.

Dosage

Dosage expressed in units.

Pediatric Patients

ALL

IV

Pediatric patients ≥1 month of age: 2500 units/m² no more frequently than every 21 days. Consult published protocols for the dosage of calaspargase pegol and other chemotherapeutic agents and the method and sequence of administration.

Therapy Interruption for Toxicity

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

Table 1. Therapy Interruption for Calaspargase Pegol 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

IV

Adults ≤21 years of age: 2500 units/m² no more frequently than every 21 days. Consult published protocols for the dosage of calaspargase pegol and other chemotherapeutic agents and the method and sequence of administration.

Therapy Interruption for Toxicity

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

Prescribing Limits

Pediatric Patients

ALL

IV

Manufacturer recommends administering no more frequently than every 21 days.

Adults

ALL

IV

Manufacturer recommends administering no more frequently than every 21 days.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations. Contraindicated in patients with severe hepatic impairment. (See Hepatic Impairment under Cautions and also see Metabolism under Pharmacokinetics.)

Renal Impairment

Manufacturer makes no specific dosage recommendations. (See Renal Impairment under Cautions and also see Elimination Route under Pharmacokinetics.)

Cautions for Calaspargase Pegol-mknl

Contraindications

History of serious hypersensitivity reactions, including anaphylaxis, to pegylated asparaginase. (See Hypersensitivity under Cautions.)
History of serious thrombosis, pancreatitis, or hemorrhagic events during previous therapy with asparaginase.
Severe hepatic impairment.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Grade 3 or 4 hypersensitivity reactions, including anaphylaxis, reported with calaspargase pegol therapy. Other hypersensitivity reactions (e.g., angioedema, lip or eye swelling, erythema, hypotension, bronchospasm, dyspnea, pruritus, rash) also reported with other asparaginase preparations.

Administer calaspargase pegol in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, IV corticosteroids, antihistamines). Observe patients for 1 hour following infusion. If a serious hypersensitivity reaction occurs, discontinue the drug and initiate appropriate therapy. (See Dosage under Dosage and Administration.)

Pancreatitis

Pancreatitis reported with calaspargase pegol therapy. Hemorrhagic or necrotizing pancreatitis also reported with other asparaginase preparations.

Measure serum amylase and/or lipase concentrations to identify early signs of pancreatic inflammation. If pancreatitis is suspected, withhold calaspargase pegol therapy; if confirmed, permanently discontinue therapy. (See Dosage under Dosage and Administration.)

Thrombosis

Serious thrombotic events (e.g., sagittal sinus thrombosis) reported with calaspargase pegol therapy.

Discontinue the drug in patients experiencing serious thrombotic events. (See Dosage under Dosage and Administration.)

Hemorrhage

Hemorrhagic events associated with increased PT, increased PTT, and hypofibrinogenemia reported with calaspargase pegol therapy.

Evaluate coagulation parameters (e.g., PT, PTT, fibrinogen) in patients with signs and symptoms of hemorrhage. Consider the need for appropriate clotting factor replacement therapy in patients with severe or symptomatic coagulopathy. (See Dosage under Dosage and Administration.)

Hepatotoxicity

Hepatotoxicity and abnormal liver function, including elevations in aminotransferase and bilirubin (direct and indirect) concentrations and reduced serum albumin and plasma fibrinogen concentrations, can occur.

Monitor bilirubin and aminotransferase concentrations at least weekly during treatment cycles including calaspargase pegol and for 6 weeks after last dose. If serious hepatotoxicity occurs, discontinue calaspargase pegol and initiate supportive care. (See Dosage under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal findings. Studies in pregnant rabbits suggest that asparagine depletion may harm animal offspring.

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

Immunogenicity

Potential for immunogenicity. Although development of anti-drug antibodies reported, immunogenic potential of calaspargase pegol-mknl not fully established.

Specific Populations

Pregnancy

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

Lactation

Not known whether calaspargase pegol 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 1 month through 16 years of age supported by evidence from an adequate and well-controlled clinical trial and an additional safety trial in a total of 208 pediatric patients (19 infants, 128 children, 61 adolescents). No clinically meaningful differences in safety or serum trough asparaginase activity noted across age groups.

Geriatric Use

Safety and efficacy not established.

Hepatic Impairment

Effects of hepatic impairment on pharmacokinetics not established. (See Contraindications under Cautions.)

Renal Impairment

Effects of renal impairment on pharmacokinetics not established.

Common Adverse Effects

Elevated concentrations of aminotransferases and bilirubin, pancreatitis, abnormal clotting studies.

Drug Interactions

Specific Drugs

Drug	Interaction	Comments
Oral contraceptives	Possible indirect interaction (asparaginase-induced hepatotoxicity may impair hepatic clearance of oral contraceptives)	Avoid concomitant use

Calaspargase Pegol-mknl Pharmacokinetics

Absorption

Bioavailability

Following IV administration of calaspargase pegol-mknl, pharmacokinetics of plasma asparaginase activity are nonlinear.

Following IV administration of a single 2500-unit/m² dose, peak plasma concentration attained after approximately 1 hour, generally near the end of the 1-hour infusion. Steady-state concentrations achieved around the fourth dose.

Onset

Rapidly depletes plasma asparagine (i.e., concentrations below the lower limit of quantification within 5 minutes after the dose) in the induction phase.

Duration

Plasma asparagine concentrations remained less than the assay limit of quantification for >18 days following a single 2500-unit/m² dose.

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.

Steady-state serum trough asparaginase activity for calaspargase pegol-mknl 2500 units/m² every 3 weeks comparable to that for pegaspargase 2500 units/m² every 2 weeks.

Distribution

Extent

Not known whether calaspargase pegol is distributed into milk.

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

Elimination

Metabolism

Not metabolized by hepatic enzymes; expected to undergo proteolytic degradation.

Elimination Route

Unlikely to be renally filtered.

Half-life

Approximately 16 days; about 2.5–3 times longer than asparaginase activity half-life of pegaspargase.

Stability

Storage

Parenteral

Injection

2–8°C; if necessary, may store at 15–25°C for up to 48 hours. Store in original carton to protect from light. Do not shake or freeze.

Diluted solution: If immediate use not possible, store at 15–25°C for up to 4 hours or 2–8°C for up to 24 hours. Protect from light. Do not shake or freeze.

Compatibility

Parenteral

Solution Compatibility1

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Actions

Depletes 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.
Longer acting than pegaspargase. (See Plasma Concentrations and also Half-life under Pharmacokinetics.) E. coli-derived l-asparaginase is conjugated to mPEG via a succinimidyl carbonate (SC) linker in calaspargase pegol and via a succinimidyl succinate (SS) linker in pegaspargase; the SC linker creates a more stable molecule.

Advice to Patients

Risk of serious allergic reactions, including anaphylaxis. Importance of informing clinician immediately if symptoms of serious allergic reactions (e.g., angioedema, lip or eye swelling, hypotension, bronchospasm, dyspnea, rash) occur.
Risk of pancreatitis. Importance of informing clinician immediately if severe abdominal pain occurs.
Risk of hyperglycemia and glucose intolerance. Importance of informing clinician if excessive thirst or increased urinary volume or frequency occurs.
Risk of thrombosis. Importance of informing clinician immediately if severe headache, swelling of arms or legs, shortness of breath, or chest pain occurs.
Importance of informing clinician if any unusual bleeding or bruising occurs.
Importance of informing clinician immediately 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 calaspargase pegol and oral contraceptives is not recommended.
Importance of advising women to avoid breast-feeding while receiving calaspargase pegol 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.