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pegaspargase
Pegaspargase is a pegylated form of L-asparaginase. It hydrolyzes extracellular L-asparagine, an amino acid that appears to be essential for protein synthesis by some tumour cells, which are unable to synthesize asparagine. Pegylation does not change L-asparaginase's enzymatic properties, but affects its pharmacokinetics and immunogenicity. Pegaspargase is less immunogenic than asparaginase derived from E. coli or Erwinia chrysanthemi; however, cross-hypersensitivity (including anaphylaxis) can occur. Pegaspargase has immunosuppressive activity.
| Bioavailability |
82% (after first IM dose), 98% (after repeat IM dosing) |
| T max |
5 days (single IM dose); 1.25 h (single IV dose) |
| Cross blood brain barrier? |
Distribution in to the CSF is reported to be similar to L-asparaginase (minimal). |
Degraded by enzymes distributed ubiquitously in tissues.
| Active metabolites | None known |
| Inactive metabolites | Yes |
Half-life appeared to be unaffected by dose, age, sex, BSA, renal or hepatic function. Pegaspargase is not excreted renally. Terminal half-life was shorter in hypersensitive patients than in non-hypersensitive patients, which may be due to the formation of high levels of anti-drug antibodies
| Half-life |
IM: 5.8 days; IV: 5.3 days |
- Acute lymphoblastic leukemia
Refer to the product monograph for a full list of approved indications.
Other Uses:
- Extranodal natural killer/T-cell lymphoma (ENKTL)
Emetogenic Potential:
Extravasation Potential: None
The following adverse events were reported from clinical trials (including pediatric patients) with pegaspargase and post-marketing reports. The list also includes severe or life-threatening events reported with other asparaginase formulations.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial thromboembolism (1 to <10%) | E | |||
| Hypotension (3%) (severe) | I | ||||
| Venous thromboembolism (3%) (including CNS) | E | ||||
| Dermatological | Rash (5%) (severe skin disorders) | E | |||
| Gastrointestinal | Abdominal pain (≥10%) | E | |||
| Diarrhea (≥10%) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (1 to <10%) | E | ||||
| Nausea, vomiting (1 to <10%) | I | ||||
| General | Fever (may be severe) | I | |||
| Hematological | Fibrinogen decreased (1 to <10%; also ↑ PT, aPTT ± bleeding; may be severe, including CNS) | E | |||
| Myelosuppression (1 to <10%; ± infection) | E | ||||
| Hepatobiliary | ↑ LFTs (≥10%) (may be severe with hepatic failure) | E | |||
| Pancreatitis (≥10%) (2% severe, including hemorrhagic or necrotizing) | E D | ||||
| Hypersensitivity | Hypersensitivity (10%) (in asparaginase-naive patients; may be severe) | I | |||
| Immune | Antibody response (antibody formation; 2-11%) | E D | |||
| Metabolic / Endocrine | Hyperglycemia (≥10%) (5% severe) | E | |||
| Hyperlipidemia (1 to <10%) | E | ||||
| Hyperuricemia (during periods of active cell lysis) | I | ||||
| Musculoskeletal | Musculoskeletal pain (1 to <10%) | E | |||
| Nervous System | Cognitive disturbance (1 to <10%) | E | |||
| Peripheral neuropathy (7%) (severe) | E | ||||
| Posterior reversible leukoencephalopathy syndrome (PRES) (rare) | E | ||||
| Seizure (1 to <10%) | E | ||||
| Tremor (rare) | E | ||||
| Renal | Nephrotoxicity (rare) | 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)
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g. some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
Severe hepatotoxicity has been described when used in combination with other hepatotoxic agents and in debilitated patients . Asparaginase treatment may increase pre-existing liver impairment from underlying liver disease or caused by prior therapy. Liver abnormalities usually resolve after the end of therapy and some reversal may occur during the course of treatment.
Asparaginase or hepatic impairment may produce decreased levels of factors V, VII, VIII, IX, X and fibrinogen, and possibly contribute to coagulation disorders. Increased fibrinolytic activity has also been observed.
Hemorrhagic and thrombotic cardiovascular or neurologic events occur in approximately 1-2% of patients receiving asparaginase. These generally occur after a few weeks of l-asparaginase therapy, and may occur after therapy is completed.
Cognitive dysfunction may include mild to severe lethargy, drowsiness, depression, confusion, hallucination, agitation, seizures or personality changes. They are seen during the first day of therapy and resolve within a few days to a week after drug discontinuation.
Pancreatitis can occur during or after therapy, and can be fatal. It may be present despite normal serum amylase concentrations.
Hyperglycemia has been observed, which appears to be potentiated by prednisone. Transient diabetes mellitus may develop. Insulin may be required for severe hyperglycemia, but it is usually reversible when the drug is discontinued. Glucose intolerance may be irreversible.
Severe hypersensitivity reactions may occur with pegaspargase. There is a higher risk in patients with known hypersensitivity to other forms of L-asparaginase.
Antibodies to pegaspargase have been observed. Patients with hypersensitivity reactions to asparaginase were more likely to have antibodies than those who did not have reactions. Hypersensitivity reactions are associated with increased asparaginase clearance, and higher antibody levels may lead to decreased asparaginase activity.
May be given either by intravenous or intramuscular injection.
Numerous dosing schedules exist. Refer to protocol by which the patient is being treated.
Usually used in combination with other cytotoxic drugs.
Thromboprophylaxis may be considered.
Premedications (prophylaxis for infusion reaction)
Give 30-60 minutes before administration:
- Acetaminophen (e.g. 500 mg PO)
- H1-receptor blocker (e.g. diphenhydramine 50 mg PO)
- H2-receptor blocker (e.g. famotidine 20 mg IV)
- Corticosteroid (e.g. hydrocortisone 100 mg IV)
- 2000 units/m² q14-21 days
- 2500 units/m2 q21 days (SMILE or DDGP)
Consider monitoring trough serum L-asparaginase activity measured before the next pegaspargase administration. A switch to a different L-asparaginase preparation could be considered if L-asparaginase activity failed to reach target levels. Consult with a hematology expert.
Dosage with Myelosuppression: No dose adjustment required.
- Myelosuppression is not increased when used with other antileukemic drugs.
Dosage with Other Toxicity:
| Toxicity | Action |
| Thrombotic or hemorrhagic events |
Hold; restart when resolved if appropriate . Discontinue for severe events. |
| Suspected pancreatitis | Hold, investigate and if confirmed, discontinue. |
| Bilirubin 2.5-4 x ULN and/or AST/ALT 5-20 x ULN* | Hold; restart if resolved to bilirubin ≤1.5 x ULN and LFTs ≤3 x ULN |
| Bilirubin >4 x ULN and/or AST/ALT >20 x ULN* | Discontinue |
| Severe hypersensitivity reactions, anaphylaxis | Discontinue |
| RPLS / PRES | |
| Other grade 4 organ/ non-hematologic |
*Adapted from Stock et al, 2011.
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
IV Pegaspargase:
|
Grade |
Re-challenge | |
|
1 |
|
No specific recommendations available |
|
2 |
Restart: After symptom resolution, restart by reducing the infusion rate by 50%. |
|
|
3 or 4 |
|
Permanently discontinue. (Do not re-challenge.) |
Not formally studied in patients with hepatic impairment. May increase pre-existing liver impairment. There is an increased risk of hepatic effects (e.g. ↑ LFTs or bilirubin) among patients > 18 years of age.
| Hepatic Impairment | LFTs | Starting dose |
| Mild | bilirubin ≤ 3 x ULN ± AST/ALT ≤ 10 x ULN | No information found |
| Moderate | ||
| Severe |
bilirubin > 3 x ULN ± AST/ALT > 10 x ULN | Contraindicated |
Not formally studied in patients with renal impairment. Pegaspargase is not excreted renally; no dose adjustment is required.
There are limited data available for patients > 65 years.
Refer to protocol by which the patient is being treated. There is very limited information on safety and efficacy of pegaspargase in children < 1 year of age.
Risk of medication error: The 3 asparaginase formulations (pegaspargase, E. coli asparaginase, Erwinia asparaginase) are not Interchangeable. Confirm the formulation carefully against the regimen used before prescribing, dispensing and administration.
- May be given either IV or IM
- For IV administration, dilute the dose in 100 NS or D5W and infuse over 1 to 2 hours.
- The IM injection volume should not exceed 3 mL in adults (or 2 mL in children/adolescents) per injection site; divide the dose and give at several injection sites for higher injection volumes.
- Refrigerate unused vials (2 to 8ºC). Do not freeze or shake. Protect from light.
- anaphylactic or severe hypersensitivity reactions to the active substance or to any of the excipients
- known serious allergic reactions to pegaspargase
- patients with known serious thrombosis or serious hemorrhagic events with previous L-asparaginase therapy
- patients who have or had pancreatitis (including hemorrhagic)
- severe hepatic impairment (bilirubin > 3 times upper limit of normal [ULN]; transaminases > 10 times ULN).
- Avoid live and attenuated live vaccines.
- Pegaspargase may worsen pre-existing liver impairment.
- Use with caution in diabetic patients.
- Risk of severe hypersensitivity reactions is higher in patients with known hypersensitivity to other forms of asparaginase.
- Patients should use caution when driving or using machinery as fatigue, drowsiness or confusion have been reported with treatment.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Mutagenicity:
Unknown
-
Embryotoxicity:
Yes
-
Teratogenicity:
Yes
Pegaspargase is contraindicated in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose. Since an indirect interaction between oral contraceptives and pegaspargase cannot be excluded, females should use a method other than oral contraceptives.
-
Breastfeeding:
Contraindicated
L-asparaginase is found in animal milk.
-
Fertility effects:
Unknown
Formal interaction studies have not been conducted with pegaspargase. Pegaspargase may interfere with enzymatic metabolism of other medications, especially in the liver.
The following also includes interactions reported with other formulations of asparaginase:
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Hepatotoxic drugs (e.g. imatinib) | ↑ hepatotoxicity | Additive | Monitor liver function, use with caution |
| Neurotoxic drugs (e.g. vincristine) | ↑ risk of neurotoxicity | Additive | Monitor for toxicity, use with caution |
| Drugs requiring hepatic enzyme metabolism | May ↑ toxicity of these agents | Asparaginase may interfere with enzymatic detoxification | Caution |
| Methotrexate | ↓ effect of both drugs when asparaginase given immediately before or concurrently with methotrexate; Enhanced effect of both drugs when asparaginase given after methotrexate | Suppression of asparagine concentrations or cell replication | refer to protocol by which patient is being treated |
| Cytarabine | ↓ effect of asparaginase when asparaginase given immediately before or concurrently with cytarabine; Enhanced effect of asparaginase when asparaginase given after cytarabine | Suppression of asparagine concentrations or cell replication | Refer to protocol by which patient is treated |
| Immunosuppressants (i.e., cyclosporine, tacrolimus, sirolimus) | ↑immunosuppression, risk of lymphoproliferation | Additive | Caution |
| Phenytoin | ↑ risk of seizures | ↓ phenytoin uptake; risk of ↑ toxicity or ↓ efficacy of cytotoxics due to metabolism induction | Use other anticonvulsant alternatives |
| Prednisone | ↑hyperglycemia | Additive | Monitor |
| Vincristine and/or prednisone | Immediately preceding or simultaneous vincristine and/or prednisone treatment can ↑ pegaspargase toxicity and ↑ risk of anaphylactic reactions | Unknown | refer to protocol by which patient is being treated |
| Anticoagulants, including NSAIDs, ASA | ↑ risk of bleeding | Changes in coagulation by asparaginase | Use with caution |
| Serum thyroxine-binding globulin | ↓ total serum thyroxine concentration | ↓ synthesis of thyroxine-binding globulin in liver | Delay measurement until 4 weeks after end of asparaginase therapy |
| Live and attenuated live vaccines | ↑ risk of severe infections | immunosuppressive activity of asparaginase | Avoid. Vaccinations with live vaccines should be given at least 3 months after the end of the entire treatment protocol |
| Oral contraceptives | May ↓ efficacy of oral contraceptives (reported with pegaspargase) | May impair hepatic clearance of oral contraceptives due to asparaginase's hepatotoxic effects | Use alternative contraception method |
| Glucocorticoids | Osteonecrosis has been observed in children > 10 years of age, higher incidence in girls | Possible complication from hypercoagulability | Caution |
| Glucocorticoids | ↑ effects on fibrinogen and ATIII decreases (reported with pegaspargase) | Unknown | refer to protocol by which patient is treated |
| Highly protein-bound drugs | ↑ toxicity of these drugs (reported with pegaspargase) | Decreased serum proteins | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests, 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 and as clinically indicated, more frequent if concurrent use of drugs with pro-coagulant/anticoagulant effects |
Blood glucose, especially in patients known to be diabetic |
Baseline and as clinically indicated |
CBC |
Baseline and as clinically indicated |
Hypersensitivity reactions |
For 1 hour after administration |
Trough serum L-asparaginase level |
Before the next dose (refer to local protocols) |
Clinical toxicity assessment for tumour lysis syndrome, infection, hypersensitivity reactions, GI, rash, pancreatitis, thromboembolism/bleeding, neurologic effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Cholesterol and triglycerides |
As clinically indicated |
Urinary glucose |
Baseline and as clinically indicated |
Ammonia levels |
As clinically indicated |
High Cost Therapy Funding Program ()
- Pegaspargase (Inpatient) - Adult Acute Lymphoblastic Leukemia (ALL) Lymphoblastic Lymphoma Mixed or Biphenotypic Leukemia
- Pegaspargase - Newly Diagnosed Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
- Pegaspargase - Relapsed or Refractory Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
- Pegaspargase (Outpatient) - Adult Acute Lymphoblastic Leukemia (ALL) Lymphoblastic Lymphoma Mixed or Biphenotypic Leukemia
- Pegaspargase - Extranodal Natural Killer/T-cell Lymphoma
Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations. Clin Pharmacokinet 2005; 44(4): 367-93.
Heo YA, Syed YY, Keam SJ. Pegaspargase: A review in acute lymphoblastic leukaemia. Drugs 2019 May;79(7):767-77.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 935-8, 1207-10.
Prescribing information: Oncaspar® (pegaspargase). Servier Pharmaceuticals (USA), November 2021.
Product Monograph: Kidrolase® (asparaginase). Jazz Pharmaceuticals, December 18, 2017.
Product Monograph: Erwinase® (Erwinia asparaginase). Jazz Pharmaceuticals, July 20, 2016.
Product Monograph: Oncaspar® (pegaspargase) . Servier Canada., November 2021.
Silverman LB, Stevenson KE, Athale UH, et al. Results of The DFCI ALL consortium protocol 05-001 for children and adolescents with newly diagnosed ALL. Blood 2013;122(21):838.
Stock W, Luger SM, Advani AS. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-59.
Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011;52(12):2237-53.
August 2022 Updated Indications, Adverse Effects, Dosing, Special precautions, Interactions, Monitoring sections
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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