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pegaspargase

( peg-AS-par-gase )
Funding:
New Drug Funding Program
  • Pegaspargase - Newly Diagnosed Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
  • Pegaspargase - Relapsed or Refractory Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
Other Name(s): Oncaspar®
Appearance:
A - Drug Name

pegaspargase

COMMON TRADE NAME(S):   Oncaspar®

 
B - Mechanism of Action and Pharmacokinetics

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.



Distribution
Cross blood brain barrier?

Distribution in to the CSF is reported to be similar to L-asparaginase (minimal).

Metabolism

Degraded by enzymes distributed ubiquitously in tissues.  

Active metabolites None known
Inactive metabolites Yes
Elimination

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:  5.5 to 7 days

 
C - Indications and Status
Health Canada Approvals:

Component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia



 
D - Adverse Effects

Emetogenic Potential:  

Minimal

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) E
Myelosuppression (1 to <10%; ± infection) E
Hepatobiliary ↑ LFTs (≥10%) (may be severe with hepatic failure) E
Pancreatitis (≥10%) (2% severe) 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
RPLS / 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. Rare cases of posterior reversible encephalopathy syndrome (PRES/RPLS) have been reported.

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.

 
E - Dosing

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.

 

 

 



Adults:

Dosing: 2000 units/m² q14 days

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 Toxicity:

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 
Suspected pancreatitis Hold, investigate and if confirmed, discontinue.
Grade 2 bilirubin ± grade 3 AST/ALT Hold; restart if resolved to ≤ grade 1 within 7 days; otherwise discontinue 
Severe hypersensitivity reactions, anaphylaxis  Discontinue
RPLS / PRES
Grade ≥3 bilirubin ± grade 4 AST/ALT    
Other grade 4 organ/ non-hematologic

 



Dosage with Hepatic Impairment:

Not formally studied in patients with hepatic impairment.  May increase pre-existing liver impairment. The following recommendations are based on literature.

Hepatic Impairment LFTs Action
Mild   Use with caution; no information found.
Moderate   
Severe  Grade ≥3 bilirubin ± AST/ALT > 10 x ULN Do not use


Dosage with Renal Impairment:

Not formally studied in patients with renal impairment.  Pegaspargase is not excreted renally; no dose adjustment is required.



Dosage in the elderly:

There are limited data available for patients > 65 years.



Children:

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.



 
F - Administration Guidelines

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  
  • IM route is preferred for smaller volumes.
  • 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. 
  • For IV administration, dilute the dose in 100 NS or D5W and infuse over 1 to 2 hours.
  • Refrigerate unused vials (2 to 8ºC).  Do not freeze or shake.
 
G - Special Precautions
Contraindications:

  • 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).

Other Warnings/Precautions:

  • 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.


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • 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
 
H - Interactions

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 ↑ hepatotoxicity Additive Monitor liver function, 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 ↑ 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
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Liver function tests

Baseline and as clinically indicated

Serum amylase, lipase levels

Baseline and as clinically indicated

Clotting profile (PT, aPTT, fibrinogen, ATIII)

Baseline and as clinically indicated

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

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



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

Cholesterol and triglycerides

As clinically indicated

Albumin levels

As clinically indicated

Urinary glucose

Baseline and as clinically indicated

Ammonia levels

As clinically indicated
 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Pegaspargase - Newly Diagnosed Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia
  • Pegaspargase - Relapsed or Refractory Pediatric ALL Lymphoblastic Lymphoma or Mixed_Biphenotypic Leukemia

 
K - References

Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations. Clin Pharmacokinet 2005; 44(4): 367-93.

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 935-8, 1207-10.

Product Monograph: Kidrolase® (asparaginase). Jazz Pharmaceuticals, December 18, 2017.

Product Monograph: Erwinase® (Erwinia asparaginase). Jazz Pharmaceuticals, July 20, 2016.

Product Monograph:  Oncaspar® (pegaspargase) .  Shire Pharma Canada Corp.  April 20, 2018.

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, 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.


October 2019 new full monograph

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

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