Version May 2024
Dosage guidance:
Safety: To decrease the risk and severity of infusion and hypersensitivity reactions, premedicate 30 to 60 minutes prior to calaspargase pegol 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).
Acute lymphoblastic leukemia: Adults ≤21 years of age: IV: 2,500 units/m2 (as a part of a combination chemotherapy regimen); do not administer more frequently than every 21 days (Ref).
Trial-specific (DFCI 11-001) dosing details: Adults ≤21 years of age: IV: 2,500 units/m2 once on day 7 of induction phase. Beginning week 7 of multiphase treatment, 2,500 units/m2 every 3 weeks for 10 doses (30 consecutive weeks) (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Hepatic impairment prior to treatment 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 treatment:
Total bilirubin >3 to 10 times ULN: Withhold calaspargase pegol until total bilirubin levels decrease to ≤1.5 times ULN.
Total bilirubin >10 times ULN: Discontinue calaspargase pegol and do not make up for missed doses.
Serious hepatotoxicity, including hepatic sinusoidal obstruction syndrome, also known as veno-occlusive disease (VOD): Discontinue calaspargase pegol and provide appropriate supportive care.
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 |
Calaspargase pegol dosage modificationc |
|---|---|---|
|
a Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life threatening. | ||
|
b In adults, for acute management of venous thromboembolism (VTE), consider low molecular weight heparin (LMWH) 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, 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]). | ||
|
c See additional adjustments recommended for other asparaginase products below. | ||
|
d DVT = deep vein thrombosis. | ||
|
Hemorrhage |
Grade 3 or 4 |
Withhold calaspargase pegol. Evaluate for coagulopathy and consider clotting factor replacement, as needed. Resume calaspargase pegol with the next scheduled dose if bleeding is controlled. |
|
Hypersensitivity/ Infusion reaction |
Grade 1 |
Reduce calaspargase pegol infusion rate by 50%. |
|
Grade 2 |
Interrupt calaspargase pegol infusion and manage symptoms; when symptoms resolve, resume the infusion with the infusion rate decreased by 50%. | |
|
Grade 3 or 4 |
Permanently discontinue calaspargase pegol. | |
|
Pancreatitis |
Suspected pancreatitis |
Withhold calaspargase pegol. Confirmed clinical pancreatitis: Permanently discontinue calaspargase pegol. |
|
Grade 3 or 4 |
Lipase or amylase >3 × ULN: Withhold calaspargase pegol until pancreatic enzyme levels stabilize or are declining. | |
|
Thromboembolismb |
Uncomplicated DVTd |
Withhold calaspargase pegol and treat with appropriate antithrombotic therapy. Upon resolution of symptoms, consider resuming calaspargase pegol while continuing antithrombotic therapy. |
|
Severe or life-threatening thrombosis |
Treat with appropriate antithrombotic therapy. Permanently discontinue calaspargase pegol. | |
The following additional adjustments have been recommended for other asparaginase products:
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 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 (Ref).
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 (Ref).
(For additional information see "Calaspargase pegol: Pediatric drug information")
Note: To decrease the risk and severity of infusion and hypersensitivity reactions, premedicate 30 to 60 minutes prior to calaspargase pegol doses with acetaminophen, an H1 antagonist (eg, diphenhydramine), and an H2 antagonist (eg, famotidine).
Acute lymphoblastic leukemia (ALL): Infants, Children, and Adolescents: IV: 2,500 units/m2/dose administered no more frequently than every 21 days (as part of a combination chemotherapy regimen).
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. Withhold therapy if pancreatitis suspected; if confirmed then discontinue permanently.
Thromboembolism:
Uncomplicated deep vein thrombosis (DVT): Hold therapy, evaluate, and treat DVT with appropriate antithrombotic therapy; upon resolution of symptoms, consider resuming therapy while continuing 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 (Stock 2011): 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 dosing 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 dosing 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 adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported reactions are for combination therapy in children, adolescents, and young adults.
>10%:
Cardiovascular: Thrombosis (severe; including sagittal sinus thrombosis: 9% to 12%)
Gastrointestinal: Pancreatitis (12% to 16%)
Hematologic & oncologic: Disorder of hemostatic components of blood (grades ≥3: 14%)
Hepatic: Increased serum bilirubin (grades ≥3: 20%), increased serum transaminases (grades ≥3: 52%)
Hypersensitivity: Hypersensitivity reaction (grades 3/4: 7% to 21%; including anaphylaxis)
Immunologic: Antibody development (15%)
1% to 10%:
Cardiovascular: Cardiac arrhythmia (grades ≥3: 2%), heart failure (grades ≥3: 2%), thromboembolic complications (grades ≥3: 8%; including disseminated intravascular coagulation, intracranial venous sinus thrombosis, pulmonary embolism, sagittal sinus thrombosis [superior], venous thrombosis)
Gastrointestinal: Diarrhea (grades ≥3: 9%)
Hematologic & oncologic: Hemorrhage (grades ≥3: 4%)
Infection: Fungal infection (grades ≥3: 3%), sepsis (grades ≥3: 5%)
Respiratory: Dyspnea (grades ≥3: 4%), pneumonia (grades ≥3: 3%)
Postmarketing:
Hematologic & oncologic: Hypofibrinogenemia, prolonged partial thromboplastin time, prolonged prothrombin time
Hepatic: Hepatotoxicity (including hepatic sinusoidal obstruction syndrome)
History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy; history of serious pancreatitis, thrombosis, or hemorrhagic events during previous L-asparaginase therapy; severe hepatic impairment
Concerns related to adverse effects:
• Hemorrhage: Hemorrhage associated with increased PT, increased PTT, and hypofibrinogenemia have been reported in patients receiving calaspargase pegol. Consider appropriate clotting factor replacement therapy in patients with severe or symptomatic coagulopathy.
• Hepatotoxicity: Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of sinusoidal obstruction syndrome, also known as hepatic veno-occlusive disease (VOD), have occurred with calaspargase pegol therapy when used in combination with chemotherapy (including during the induction portion of multiphase combination chemotherapy).
• Hyperglycemia: Hyperglycemia has been reported with calaspargase pegol (Angiolillo 2014) and with other asparaginase products. Use with caution in patients with diabetes mellitus and hyperglycemia.
• Hyperlipidemia: Hyperlipidemia was reported in a small pharmacokinetic study; the incidence was higher in induction phase (Angiolillo 2014).
• Hypersensitivity: Grade 3 and 4 hypersensitivity reactions, including anaphylaxis, have been reported in clinical studies with calaspargase pegol. Hypersensitivity reactions observed with other asparaginase products have included angioedema, lip swelling, eye swelling, erythema, hypotension, bronchospasm, dyspnea, pruritus, and rash. Due to the risk of serious allergic reactions (eg, life-threatening anaphylaxis), administer calaspargase pegol in a clinical setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, oxygen, intravenous corticosteroids, and antihistamines).
• Pancreatitis: Cases of pancreatitis have been reported in clinical trials with calaspargase pegol. Hemorrhagic or necrotizing pancreatitis have been reported with other asparaginase products. Inform patients of the signs/symptoms of pancreatitis. Untreated pancreatitis may be fatal.
• Thrombosis: Serious thrombotic events, including sagittal sinus thrombosis (cerebral venous thrombosis), have been reported in clinical studies with calaspargase pegol.
Other warnings/precautions:
• Medication error prevention: Do not interchange calaspargase pegol for asparaginase (E. coli), asparaginase (Erwinia), asparaginase (Erwinia [recombinant]), or pegaspargase; 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, Intravenous [preservative free]:
Asparlas: 3750 units/5 mL (5 mL)
No
Solution (Asparlas Intravenous)
3750 unit/5 mL (per mL): $6,497.60
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IV: Infuse over 1 hour into a running infusion of either NS or D5W. Do not infuse other medications through the same intravenous line. Observe for 1 hour after infusion for signs of hypersensitivity.
Do not administer if solution has been shaken or vigorously agitated.
Note: To decrease the risk and severity of infusion and hypersensitivity reactions, premedicate 30 to 60 minutes prior to calaspargase pegol doses with acetaminophen, an H1 antagonist (eg, diphenhydramine), and an H2 antagonist (eg, famotidine).
Parenteral: IV: Do not administer if solution has been shaken or vigorously agitated. Administer IV over 1 hour into a running infusion of either NS or D5W; do not infuse with other drugs. Observe for 1 hour after infusion for signs of hypersensitivity.
Acute lymphoblastic leukemia: Treatment of acute lymphoblastic leukemia (ALL) (as part of a combination chemotherapy regimen) in pediatrics and adults 1 month to 21 years of age.
Asparlas may be confused with Elspar, Oncaspar
Calaspargase pegol may be confused with asparaginase (E. coli), asparaginase (Erwinia), asparaginase (Erwinia [recombinant]), certolizumab pegol, pegaspargase.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
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 Lexicomp 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 at least 3 months after the last calaspargase pegol dose.
Based on animal reproduction studies conducted with L-asparaginase, in utero exposure to calaspargase pegol may cause fetal harm.
It is not known if calaspargase pegol 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 3 months after the last calaspargase pegol dose.
Monitor bilirubin, ALT, and AST (prior to each dose and at least weekly during cycles of treatment that include calaspargase pegol; continue monitoring for at least 6 weeks after the last calaspargase pegol dose); for patients with abnormal liver function tests after calaspargase pegol 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 glucose (at least weekly until recovery from treatment cycle). Assess amylase/lipase to identify early signs of pancreatic inflammation. Evaluate pregnancy status (prior to treatment in patients who could become pregnant). Consider monitoring antithrombin III activity (Baretto 2017; Czogała 2017); consider weekly antithrombin levels during the course of asparaginase therapy (ISTH [Zwicker 2020]). Evaluate coagulation parameters (including PT, PTT, fibrinogen) in patients with signs/symptoms of hemorrhage. Observe for 1 hour after infusion for signs of hypersensitivity. 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 for signs/symptoms of hemorrhage, hepatotoxicity, pancreatitis, and thrombosis.
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.
Calaspargase pegol contains an E. coli-derived asparagine-specific enzyme, as a conjugate of L-asparaginase and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate linker which produces a stable bond between the mPEG component and the L-asparaginase lysine groups. L-asparaginase is an enzyme which catalyzes the deamidation of asparagine to aspartic acid and ammonia, reducing circulating levels of asparagine. Leukemic cells with low asparagine synthetase expression have a reduced ability to synthesize asparagine. L-asparaginase reduces the exogenous asparagine source for the leukemic cells, resulting in cytotoxicity towards leukemic cells.
Distribution: Vdss: 2.96 L
Half-life elimination: 16.1 days
Time to peak: 1.17 hours
Excretion: Clearance: 0.147 L/day
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