Dosage guidance:
Safety: To decrease the risk and severity of infusion and hypersensitivity reactions, premedicate 30 to 60 minutes prior to pegaspargase administration with acetaminophen, an H1 antagonist (eg, diphenhydramine), and an H2 antagonist (eg, famotidine).
Clinical considerations: Consider thromboprophylaxis with low molecular weight heparin (LMWH) during induction and intensification phases of asparaginase therapy, particularly in patients at high risk for venous thromboembolism; withhold LMWH for platelet count <30,000/mm3 (Ref). Patients should avoid alcohol use to help prevent pancreatitis (Ref).
Acute lymphoblastic leukemia, as first-line treatment or in patients with hypersensitivity to native asparaginase:
≤21 years of age: IM, IV: 2,500 units/m2 (as part of a multi-agent combination chemotherapy regimen); do not administer more frequently than every 14 days.
>21 years of age: IM, IV: 2,000 units/m2 (as part of a multi-agent combination chemotherapy regimen); do not administer more frequently than every 14 days.
There are no dosage adjustments provided in the manufacturer’s labeling.
Hepatic impairment prior to treatment initiation:
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.
Severe impairment: Use is contraindicated.
Hepatotoxicity during treatment:
Total bilirubin >3 to 10 times ULN: Withhold pegaspargase until total bilirubin levels decrease to ≤1.5 times ULN.
Total bilirubin >10 times ULN: Discontinue pegaspargase and do not make up for missed doses.
Serious hepatotoxicity, including hepatic sinusoidal obstruction syndrome, also known as veno-occlusive disease: Discontinue pegaspargase and provide appropriate supportive care.
The following off-label adjustments have also been recommended:
ALT/AST >3 to 5 times ULN: Continue therapy (Ref).
ALT/AST >5 to 20 times ULN: Delay next dose until transaminases <3 times ULN (Ref).
ALT/AST >20 times ULN: Discontinue therapy if it takes longer than 1 week for transaminases to return to <3 times ULN (Ref).
Direct bilirubin <3 mg/dL: Continue therapy (Ref).
Direct bilirubin 3.1 to 5 mg/dL: Hold pegaspargase and resume when direct bilirubin <2 mg/dL; consider switching to alternate asparaginase product (Ref).
Direct bilirubin >5 mg/dL: Discontinue pegaspargase; do not substitute other asparaginase products; do not make up for missed doses (Ref).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (Ref).
Adverse reaction |
Severitya |
Pegaspargase dosage modificationb |
---|---|---|
a Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening. | ||
b See additional adjustments recommended below. | ||
c In adults, for acute management of venous thromboembolism (VTE), consider low-molecular-weight heparin if severe thrombocytopenia (platelets <50,000/mm3) is anticipated; following resolution of severe thrombocytopenia, consider direct oral anticoagulants in the absence of relevant contraindications. For life-threatening VTE (eg, central venous thrombosis or central pulmonary embolism), consider short-term concurrent use of antithrombin concentrate until clinically stable and therapeutic anticoagulation is established. Antithrombin concentrate is suggested for antithrombin levels below 50% to 60%, with a suggested repletion target of 80% to 120%. Temporarily withhold asparaginase therapy for high-risk events (eg, central venous/sinus thrombosis, central pulmonary embolism, proximal deep vein thrombosis, arterial thrombosis); resume after thrombotic event is stabilized (ISTH [Zwicker 2020]). | ||
Hemorrhage |
Grade 3 or 4 |
Withhold pegaspargase. Evaluate for coagulopathy and consider clotting factor replacement as needed. Resume pegaspargase with the next scheduled dose if bleeding is controlled. |
Hypersensitivity/Infusion reaction |
Grade 1 |
Reduce pegaspargase infusion rate by 50%. |
Grade 2 |
Interrupt pegaspargase infusion and manage symptoms; when symptoms resolve, resume the infusion with the infusion rate decreased by 50%. | |
Grade 3 or 4 |
Permanently discontinue pegaspargase. | |
Pancreatitis |
Grade 3 or 4 |
Lipase or amylase >3 x ULN: Withhold pegaspargase until pancreatic enzyme levels stabilize or are declining. Confirmed clinical pancreatitis: Permanently discontinue pegaspargase. |
Thromboembolismc |
Uncomplicated deep vein thrombosis |
Withhold pegaspargase and treat with appropriate antithrombotic therapy. Upon resolution of symptoms, consider resuming pegaspargase while continuing antithrombotic therapy. |
Severe or life-threatening thrombosis |
Treat with appropriate antithrombotic therapy. Permanently discontinue pegaspargase. |
The following off-label adjustments have also been recommended:
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) (Ref).
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 (Ref).
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) (Ref).
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 (Ref).
Pancreatitis:
Asymptomatic amylase or lipase >3 times ULN (chemical pancreatitis) or radiologic abnormalities only: Continue pegaspargase and monitor closely for rising amylase and/or lipase levels or for development of symptomatic pancreatitis (Ref).
Clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue pegaspargase (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
Refer to adult dosing.
(For additional information see "Pegaspargase: Pediatric drug information")
Acute lymphoblastic leukemia (ALL): Infants, Children, and Adolescents: IM, IV: 2,500 units/m2/dose (as part of a combination chemotherapy regimen); do not administer more frequently than every 14 days
Dosing adjustment for toxicity: Infants, Children, and Adolescents:
Hemorrhage: Grade 3 or 4: Hold therapy, evaluate for coagulopathy, and consider clotting factor replacement as needed; if resolution (ie, bleeding controlled), resume therapy with the next scheduled dose
Hypersensitivity or infusion reactions:
Grade 1: Reduce infusion rate by 50%
Grade 2: Interrupt infusion and treat symptoms; after resolution of symptoms, resume infusion at 50% of previous rate
Grade 3 or 4: Discontinue permanently
Pancreatitis: Grade 3 or 4: If lipase or amylase >3 times ULN, hold therapy until enzyme levels stabilize or are declining. Discontinue permanently if clinical pancreatitis confirmed.
Thromboembolism:
Uncomplicated deep vein thrombosis (DVT): Hold therapy, evaluate and treat DVT with antithrombotic therapy; upon resolution of symptoms, may resume therapy with concomitant antithrombotic agent(s)
Severe or life-threatening thrombosis: Discontinue permanently; treat thrombosis with necessary medical management
The following additional adjustments have been recommended for other asparaginase products (Ref): Older Adolescents:
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 the asparaginase product (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold the asparaginase product (and corticosteroids) until blood glucose is controlled with insulin; resume the asparaginase product and do not make up for missed doses.
Hypertriglyceridemia: If serum triglyceride level <1 g/dL, continue the asparaginase product but monitor closely for pancreatitis. If triglyceride level >1 g/dL, hold the asparaginase product and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Infants, Children, and Adolescents:
Baseline (prior to therapy initiation):
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied)
Severe impairment: Use is contraindicated
Hepatotoxicity during therapy:
Total bilirubin >3 to 10 times ULN: Hold therapy until total bilirubin decreases to ≤1.5 times ULN
Total bilirubin >10 times ULN: Discontinue therapy and do not make up for missed doses
The following adjustments have also been recommended for other asparaginase products (Ref): Older adolescents:
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for pediatric patients.
>10%:
Hypersensitivity: Hypersensitivity reaction (first-line treatment of acute lymphoblastic leukemia [ALL]: 2% to 3%; relapsed ALL with no prior asparaginase hypersensitivity: 10%; relapsed ALL with prior asparaginase hypersensitivity: 32%)
Immunologic: Antibody development (induction: 2%; delayed intensification: 10% to 11%)
1% to 10%:
Cardiovascular: Thromboembolic complications (grades 3/4)
Endocrine & metabolic: Hyperglycemia (grades 3/4: 5%), hypertriglyceridemia (grades 3/4), hypoalbuminemia (grades 3/4)
Gastrointestinal: Pancreatitis (grades 3/4: 2%)
Hematologic & oncologic: Disorder of hemostatic components of blood (grades 3/4: 2%; including decreased serum fibrinogen, prolonged partial thromboplastin time, prolonged prothrombin time), febrile neutropenia (grades 3/4)
Hepatic: Hyperbilirubinemia (grades 3/4: 2%), increased serum alanine aminotransferase (grades 3/4: ≤3%), increased serum aspartate aminotransferase (grades 3/4: ≤3%)
Infection: Infection (grades 3/4: 5%), sepsis (grades 3/4)
Nervous system: Cerebral thrombosis (grades 3/4: 3%)
Postmarketing (all populations):
Cardiovascular: Thrombosis (including sagittal sinus thrombosis)
Endocrine & metabolic: Hyperammonemia, hypercholesterolemia
Gastrointestinal: Hemorrhagic pancreatitis, necrotizing pancreatitis
Hematologic & oncologic: Hemorrhage
Hepatic: Hepatic impairment
Hypersensitivity: Anaphylactic shock
Nervous system: Intracranial hemorrhage
Neuromuscular & skeletal: Osteonecrosis
Miscellaneous: Cyst (pancreatic)
History of serious hypersensitivity reactions (including anaphylaxis) to pegaspargase or any component of the formulation; history of serious thrombosis with prior L-asparaginase therapy; history of pancreatitis (including pancreatitis associated with prior L-asparaginase therapy); history of serious hemorrhagic events with prior L-asparaginase therapy; severe hepatic impairment.
Concerns related to adverse effects:
• Glucose intolerance: Pegaspargase may result in glucose intolerance (was irreversible in some cases).
• Hemorrhage: Increased PT, increased PTT, and hypofibrinogenemia may occur in patients receiving pegaspargase. Severe or symptomatic coagulopathy may require appropriate replacement therapy.
• Hepatotoxicity: Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of hepatic sinusoidal obstruction syndrome, also known as hepatic veno-occlusive disease, have been observed with pegaspargase when used in combination with chemotherapy (including during the induction portion of multiphase combination chemotherapy).
• Hypersensitivity: Anaphylaxis and serious hypersensitivity reactions may occur with pegaspargase. The risk of serious hypersensitivity reactions is increased in patients with known hypersensitivity to E. coli derived L-asparaginase products. Hypersensitivity reactions may include angioedema, lip swelling, eye swelling, hypotension, bronchospasm, dyspnea, erythema, pruritus, and rash.
• Pancreatitis: Pancreatitis may occur in patients receiving pegaspargase; hemorrhagic or necrotizing pancreatitis have been reported (sometimes fatal). Inform patients of the signs/symptoms of pancreatitis. Untreated pancreatitis may be fatal.
• Thrombotic events: Serious thrombotic events, including sagittal sinus thrombosis may occur with pegaspargase.
Other warnings/precautions:
• Administration route: In a study comparing IV pegaspargase to IM native E. coli asparaginase for post-induction treatment in children with ALL, 5-year disease-free survival did not differ and the overall frequency of asparaginase-related toxicities (including allergy, pancreatitis, and thrombotic or bleeding complications) did not differ between the IV pegaspargase and IM native E. coli asparaginase groups. The median nadir serum asparaginase activity was significantly higher in the IV pegaspargase group. Reported treatment-related anxiety was significantly lower (for both patients and guardians) in the group that received IV pegaspargase (Place 2015).
• Medication error prevention: Do not interchange pegaspargase for asparaginase (E. coli), asparaginase (Erwinia), asparaginase (Erwinia [recombinant]), or calaspargase pegol-mknl; ensure the proper asparaginase formulation, route of administration, and dose prior to administration.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection [preservative free]:
Oncaspar: 750 units/mL (5 mL)
No
Solution (Oncaspar Injection)
750 units/mL (per mL): $6,129.18
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Oncaspar: 750 units/mL (5 mL)
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. Observe for 1 hour after administration for signs of hypersensitivity.
IM: Must only be administered as a deep IM injection into a large muscle. Limit the injection volume to 2 mL per single 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 (of either NS or D5W, depending on which fluid was used in preparation of the diluted solution); do not administer IV push. Do not infuse other medications through the same IV line during pegaspargase administration.
Note : 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.
Parenteral:
IM: Administer as a deep IM injection into a large muscle. Limit the volume at a single injection site to 2 mL; for IM administration, if the volume to be administered is >2 mL, use multiple injection sites.
IV: Administer dose as an IV infusion over a period of 1 to 2 hours through a running IV infusion line (of either NS or D5W, depending on which fluid was used in preparation of the diluted solution). Do not administer IV push. Use of a 0.2 micron filter may result in some loss of potency. Do not infuse other medications through the same IV line during pegaspargase administration.
Acute lymphoblastic leukemia and hypersensitivity to asparaginase: Treatment of acute lymphoblastic leukemia (ALL) in pediatric and adult patients with hypersensitivity to native forms of L-asparaginase (as a component of a multiagent chemotherapy regimen).
Acute lymphoblastic leukemia, first-line treatment: First-line treatment of ALL (as a component of a multiagent chemotherapy regimen) in pediatric and adult patients.
Oncaspar may be confused with Asparlas, Elspar
Pegaspargase may be confused with asparaginase (E. coli), asparaginase (Erwinia), asparaginase (Erwinia [recombinant]), calaspargase pegol-mknl, peginesatide
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Hormonal Contraceptives: May enhance the thrombogenic effect of Asparaginase Products. Management: Consider discontinuing hormonal contraceptives and using an alternative contraceptive method in patients treated with asparaginase products. Risk D: Consider therapy modification
Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Risk C: Monitor therapy
Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Risk C: Monitor therapy
Evaluate pregnancy status prior to use in patients who could become pregnant. Effective nonhormonal contraception should be used during therapy and for 3 months after the last pegaspargase dose. Hormonal contraceptives may not be effective and are not recommended as a form of contraception.
Based on animal reproduction studies conducted with L-asparaginase, in utero exposure to pegaspargase may cause fetal harm.
It is not known if pegaspargase is present in breast milk.
Due to the potential for adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 month after the last pegaspargase dose.
CBC with differential, platelets (at least weekly during treatment). Assess amylase/lipase to identify/confirm early signs of pancreatic inflammation. Monitor LFTs (bilirubin, transaminases; baseline and at least weekly during treatment cycles; continue monitoring for at least 6 weeks after the last pegaspargase dose); for patients with abnormal LFTs after pegaspargase administration, more frequent monitoring of liver function and clinical signs/symptoms of hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD) is recommended. Monitor renal function tests, urine glucose, blood glucose (at least weekly during treatment); triglycerides; uric acid. Evaluate pregnancy status (prior to treatment in patients who could become pregnant). Evaluate coagulation parameters (fibrinogen, PT, PTT [baseline and periodically during and after treatment and in patients with signs/symptoms of hemorrhage]). Consider monitoring antithrombin III activity (Barreto 2017); consider weekly antithrombin levels during the course of asparaginase therapy (ISTH [Zwicker 2020]). Monitor patients frequently for signs/symptoms of hepatic SOS/VOD (may include rapid weight gain, fluid retention with ascites, hepatomegaly [may be painful], and rapid increase in bilirubin levels). Monitor vital signs during administration; monitor for onset of abdominal pain; observe for allergic reaction (for 1 hour after administration); monitor for signs/symptoms of thrombosis or bleeding.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Pegaspargase is a modified version of L-asparaginase, conjugated with monomethoxypolyethylene glycol (mPEG). In leukemic cells, asparaginase hydrolyzes L-asparagine to ammonia and L-aspartic acid, leading to depletion of asparagine. Leukemia cells require exogenous asparagine; normal cells can synthesize asparagine. Asparagine depletion in leukemic cells leads to inhibition of protein synthesis and apoptosis.
Onset: Mean maximum asparaginase activity: IM: On day 5 (following a single IM dose of 2,500 units/m2)
Duration: Asparagine depletion: IV (in asparaginase naive adults): 2 to 4 weeks (Douer 2007); IM: ~21 days.
Bioavailability: IM: 82% (first dose); 98% (repeat dosing).
Distribution: Vdss: 1.86 L/m2 (following a single IM dose of 2,500 units/m2); ~2 L (following a single IV dose of 2,500 units/m2); Asparaginase-naive adults: IV: 2.4 L/m2 (Douer 2007).
Metabolism: Systemically degraded.
Half-life elimination: ~5.8 days (following a single IM dose of 2,500 units/m2); ~5.3 days (following a single IV dose of 2,500 units/m2); Asparaginase-naive adults: IV: 7 days (Douer 2007).
Excretion: Clearance: 0.17 L/m2/day (following a single IM dose of 2,500 units/m2); 0.2 L/day (following a single IV dose of 2,500 units/m2).
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