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calaspargase pegol
Calaspargase pegol contains an E.coli-derived L-asparaginase conjugated with monomethoxy polyethylene glycol via a succinimidyl carbonate linker that improves stability. L-asparagine reduces circulating levels of asparagine, which is essential for leukemic cells that are unable to synthesize asparagine, by catalyzing the conversion of L-asparagine to aspartic acid and ammonia. Therefore, the mechanism of action of calaspargase pegol is based on the depletion of plasma L-asparagine. This results in the inhibition of protein synthesis, DNA synthesis, and RNA synthesis of leukemic cells and subsequently in apoptosis.
| T max |
1.17 h |
Elimination is time-dependent. Asparaginase activity typically showed first a linear elimination, followed by a faster decline in asparaginase activity levels (non-linear).
Elimination pathways of calaspargase pegol is unknown.
| Half-life |
16.1 days |
- Acute lymphoblastic leukemia (ALL)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
Extravasation Potential: None
The following adverse events occurred in ≥ 5% of newly-diagnosed ALL or lymphoblastic lymphoma patients aged 1 to 21 years receiving calaspargase pegol as part of a Dana Farber Cancer Institute (DFCI) ALL Consortium backbone therapy in a randomized, open-label trial. Severe or life-threatening adverse effects may also be included from other sources and post-marketing.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (5%) | E | |||
| Thromboembolism (12%) (including CNS; may be severe) | E | ||||
| Gastrointestinal | Colitis (7%) (neutropenic) (severe) | E | |||
| Mucositis (25%) (severe) | E | ||||
| Hematological | Disseminated intravascular coagulation (<5%) | E | |||
| Fibrinogen decreased (22%) | E | ||||
| INR / prothrombin time increased (12%) | E | ||||
| Myelosuppression ± infection, bleeding (34%) (severe) | E | ||||
| Hepatobiliary | ↓ albumin (81%) (27% severe) | E | |||
| ↑ Amylase / lipase (18%) (15% severe) | E | ||||
| Hepatotoxicity (<5%) | E | ||||
| ↑ LFTs (79%) (49% severe) | E | ||||
| Pancreatitis (12%) (10% severe) | E | ||||
| Veno-occlusive disease (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (9%) (5% severe) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (46%) (↓ K, ↓ Na) (43% severe) | E | |||
| Hyperglycemia (34%) (24% severe) | E | ||||
| Hypoglycemia (31%) | E | ||||
| ↑ Triglycerides (28%) (21% severe) | E | ||||
| Nervous System | Confusion (<5%) | E | |||
| Encephalopathy (7%) | E | ||||
| Posterior reversible encephalopathy syndrome (PRES) (<5%) | E | ||||
| Seizure (5%) | E | ||||
| Renal | Renal failure (<5%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for calaspargase pegol include ↓ albumin, ↑ LFTs, abnormal electrolyte(s), hyperglycemia, myelosuppression ± infection, bleeding, hypoglycemia, ↑ triglycerides, mucositis, fibrinogen decreased and ↑ amylase / lipase.
Glucose intolerance has occurred in patients receiving asparaginase products and may be irreversible.
Anti-drug antibodies (ADA) were detected during clinical trials. The presence of ADA correlated with hypersensitivity reactions. There is insufficient information to determine whether antibodies are associated with loss of asparaginase activity.
Serious infections, including fatal cases of sepsis, have been reported.
Asparaginase products may worsen pre-existing liver impairment. There is an increased risk of hepatic effects (e.g. ↑ LFTs) in patients >18 years of age using asparaginase products.
Refer to protocol by which the patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Different asparaginase products are not interchangeable and dosing schedules are different. For example, giving calaspargase pegol at the same dose and frequency as pegaspargase may result in higher asparaginase activity exposures, which may increase toxicities.
Pre-medications (prophylaxis for infusion reactions)
To be given 30-60 minutes prior to calaspargase pegol administration:
- Acetaminophen
- H-1 receptor blocker (e.g. diphenhydramine)
- H-2 receptor blocker (e.g. famotidine)
- Optional: steroids may also be considered.
| Toxicity | Severity | Action |
| Thrombosis | Uncomplicated DVT |
Hold. Treat with appropriate antithrombotic therapy. Consider restart when symptoms resolve, while continuing antithrombotic therapy. |
| Severe or life- threatening |
Discontinue. Treat with appropriate antithrombotic therapy. |
|
| Hemorrhage | Grade 3 or 4 |
Hold. Evaluate for coagulopathy and consider clotting factor replacement as needed. If bleeding is controlled, restart with the next scheduled dose. |
| Pancreatitis | lipase or amylase >3 x ULN |
Hold until enzyme levels stabilize or decline. |
| Grade 3 or 4 | Discontinue if clinical pancreatitis is confirmed. | |
| ↑ bilirubin | >3 to 10 x ULN | Hold. Restart when bilirubin ≤1.5 x ULN. |
| >10 x ULN | Discontinue. |
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 |
|
|
| 2 |
|
|
| 3 or 4 |
|
|
Calaspargase pegol is contraindicated in patients with severe hepatic impairment.
The effects of hepatic impairment on the pharmacokinetics (PK) of calaspargase pegol are unknown.
The effects of renal impairment on the PK of calaspargase pegol are unknown.
No data available.
Calaspargase pegol has been shown in clinical trials to be safe and effective in children ≥1 year of age
Refer to product monograph for additional information.
Different asparaginase products are not interchangeable and dosing schedules are different. For example, giving calaspargase pegol at the same dose and frequency as pegaspargase may result in higher asparaginase activity exposures, which may increase toxicities.
- Calaspargase pegol is for intravenous infusion only.
- Dilute in 100 mL of NS or D5W prior to administration.
- After dilution, administer immediately into a running infusion of NS or D5W.
- Administer IV over 1 to 2 hours. Observe patient during and for at least 60 minutes after the infusion.
- Do not administer other drugs through the same IV line during calaspargase pegol infusion.
- Store unopened vials refrigerated at 2-8°C in the original carton to protect from light. Do not shake or freeze.
- Patients who are anaphylactic or have severe hypersensitivity to asparaginase (including pegylated L-asparaginase), to this drug or any of its components
- Patients who experience serious thrombosis, serious pancreatitis, or serious hemorrhagic events during previous L-asparaginase treatment
- Patients with severe hepatic impairment
- Live vaccines should not be given during treatment and for at least 3 months after the end of treatment.
- Exercise caution when driving or operating potentially dangerous machinery as calaspargase pegol may cause seizures, drowsiness, or confusion.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
Unknown
-
Fetotoxicity:
Documented in animals
-
Pregnancy:
Calaspargase pegol is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 3 months after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment and for 3 months after the last dose.
-
Fertility effects:
Unknown
No formal drug interaction studies have been conducted with calaspargase pegol.
A decrease in serum proteins caused by asparaginase products may increase the toxicity of other medications that are protein bound.
The following drug interactions have been observed with various asparaginase products.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Methotrexate (when given before asparaginase) | ↑ effect of both drugs | Synergistic effect | Caution |
| Methotrexate (when given after asparaginase) | ↓ effect of both drugs | Antagonistic effect | Caution |
| Cytarabine (when given before asparaginase) | ↑ effect of asparaginase | Synergistic effect | Caution |
| Cytarabine (when given after asparaginase) | ↓ effect of asparaginase | Antagonistic effect | Caution |
| Antineoplastic agents that are substrates for CYPs | Interference with metabolism and clearance of these substrates | Caution | |
| Neurotoxic products (e.g. vincristine, methotrexate) | ↑ risk of CNS toxicity | Additive | Monitor |
| Hepatotoxic drugs or drugs metabolized by the liver | ↑ risk of hepatotoxicity | Additive | Monitor liver function; use with caution, especially in patients with pre-existing hepatic impairment |
| Glucocorticoids (e.g. prednisolone, dexamethasone) | ↑ glucocorticoid exposure | Decreased glucocorticoid elimination | Monitor for glucocorticoid adverse effects |
| Glucocorticoids (e.g. prednisolone, dexamethasone) | ↑ risk of glucocorticoid-induced osteonecrosis in children > 10 years of age, higher incidence in girls | Unknown | Monitor |
| Drugs affecting coagulation (e.g. glucocorticoids, methotrexate, daunorubicin, warfarin, heparin, ASA, Dipyridamole, NSAIDs) | ↑ tendency to bleeding and/or thrombosis | Alter coagulation parameters | Caution. Monitor coagulation parameters, adjust procoagulant/anticoagulant dose if needed, and manage bleeding/thrombotic risk. |
| Oral contraceptives | May ↓ efficacy of oral contraceptives | Hepatic clearance of oral contraceptives may be reduced | Avoid concomitant use. Use alternative methods of contraception. |
| Live vaccines | ↑ risk of severe infections | Additive immunosuppressive effects of asparaginase, chemotherapy, and underlying condition | Avoid. Live vaccines should not be given during treatment and for at least 3 months after the end of treatment |
| Highly protein-bound drugs | ↑ risk of toxicity from these drugs | Decreased serum proteins | Caution |
| Immunosuppressants | ↑ risk of immunosuppression | Additive | Caution |
| Thyroid function tests | Test results can be affected | ↓ synthesis of thyroxine-binding globulin in liver | Delay measurement until 4 weeks after end of asparaginase therapy |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests, serum albumin |
Baseline, before each dose, and as clinically indicated |
Serum amylase, lipase levels |
Baseline, before each dose, and as clinically indicated |
Clotting profile (PT, aPTT, fibrinogen, ATIII) |
Baseline, before each dose, and as clinically indicated |
Blood and urine glucose levels |
Baseline, before each dose, and as clinically indicated |
CBC |
Baseline and as clinically indicated |
Uric acid levels, especially during induction |
Baseline and as clinically indicated |
Ammonia levels, in the presence of symptoms of hyperammonemia (e.g. nausea, vomiting, lethargy, irritation) |
Baseline and as clinically indicated |
Trough asparaginase activity levels |
Before the dose (refer to local protocol) |
Clinical toxicity assessment for hypersensitivity, tumour lysis syndrome, infection, bleeding, thrombosis, pancreatitis, GI and neurologic effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
High Cost Therapy Funding Program
- Calaspargase Pegol (Inpatient) - Relapsed or Refractory Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
- Calaspargase Pegol (Inpatient) - Newly Diagnosed Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
- Calaspargase Pegol (Outpatient) - Relapsed or Refractory Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
- Calaspargase Pegol (Outpatient) - Newly Diagnosed Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
CADTH. CADTH Reimbursement Recommendation: Calaspargase Pegol (Asparlas). Canadian Journal of Health Technologies. January 2024.
CADTH. CADTH Reimbursement Review: Calaspargase Pegol (Asparlas). Canadian Journal of Health Technologies. April 2024
National Cancer Institute. NCI Drug Dictionary. Accessed on November 2024. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug.
Prescribing Information: ASPARLAS® (calaspargase pegol-mknl) injection. Servier Pharmaceuticals LLC. December 2023
Product monograph. Asparlas (Calaspargase pegol). Servier Canada Inc. March 8, 2024.
Product monograph. ERWINASE® (Erwinia L-asparaginase). Jazz Pharmaceuticals France SAS. August 30, 2016.
Product monograph. KIDROLASE® (L-asparaginase). Jazz Pharmaceuticals France SAS. August 12, 2019.
Vrooman LM, Blonquist TM, Stevenson KE, et al. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505.
December 2024 New drug monograph
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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