Systemic Therapy Program
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Cancer Type

Document Type

Drug Monographs
Treatment Regimens
Scientific Name:
ASPARAGINASE
Brand Name(s):
Kidrolase®

Drug Monograph

Pharmacology

Mechanism of Action

Contains 1-asparaginase amidohydrolase type EC-2, which inhibits protein synthesis by hydrolyzing asparagine to aspartatic acid and ammonia. Leukemic cells, especially lymphoblasts, require exogenous asparagine; normal cells can synthesize asparagine. Asparaginase is cycle specific for the G1 phase of the cell cycle.  Asparaginase extracted from E.coli or erwinia sp.; erwinia source asparaginase limited to patient with allergy to E.coli proteins.

Pharmacokinetics

Oral Absorption:
no
Distribution:
most of an IV dose remains in the plasma, IM injection yields a much larger volume of distribution (plasma levels about 50% lower than with I.V.);
Excretion in breast-milk: unknown.
cross blood brain barrier?  Minimal
Vd: 245 ±28 mL/kg (IM); 63 ±7 mL/kg (IV)     PPB: low
Metabolism:
systemic; major route of elimination, possible mechanisms include proteolysis of the enzyme and/or removal by an organ other than the kidney (eg, reticuloendothelial system)
Metabolite(s): active- none known; inactive- yes
Excretion:
Reticuloendothelial system; minimal excretion into urine and bile
Urine: trace
t½: 27-32 hours (E. coli, IM); 16 hours (Erwinia, IM); 7-8 hours (I.V.)
Cl: no information

Side Effects

IMMEDIATE ONSET (hours to days)

anaphylaxis (6-43% allergic reactions, 1% mortality)
• nausea and vomiting
• increased uric acid levels (hyperuricemia)

EARLY ONSET  (days to weeks)

• liver problems (elevated liver function tests, parenchymal necrosis)
• blood clotting problems (1-2%, coagulopathy)
• low WBC, RBC, platelets (myelosuppression)
central nervous system problems (21-60%, depression, confusion, personality
   changes)
• kidney problems (toxic nephropathy)
• high blood glucose levels (hyperglycemia)
• inflammation of pancreas (pancreatitis)

DELAYED/LATE ONSET  (weeks to years)

• inflammation of pancreas (pancreatitis)
• liver problems (hepatic necrosis)
• blood clotting problems (1-2%, coagulopathy)
central nervous system problems (21-60%, depression, confusion, personality
   changes)

Therapeutics

Approved Indications

• Acute lymphocytic leukemia
• Acute myeloblastic leukemia
• Acute myelomonocytic leukemia
• Chronic lymphocytic leukemia
• Hodgkin’s disease
• Melanosarcoma

OTHER ONCOLOGY USES (Not Approved)
• Non-Hodgkin’s lymphoma

Routes

• Intramuscular - (preferred, maximum 2 mL per site)
• Intermittent IV  (in 50-150 mL D5W over 15-30 minutes)
• Subcutaneous

Administration

• Given as an IM injection (preferred route) (concentration of 2000 IU/mL- may increase to 10,000IU/mL for specified regimens or clinical trials)
• Mix in 100mL minibag  (5% Dextrose, Normal Saline) or slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline); Infuse over at least 30 minutes
• Hypersensitivity reactions (frequent): May occur with any dose including the first, but appear to be more common with multiple prior doses. Reactions typically present within ½-2hours following administration. Clinical manifestations of hypersensitivity (Type I - immediate) may include pruritus, dyspnea, agitation, urticaria, swelling at the injection site, angioedema, rash, abdominal pain, laryngospasm, nasal stuffiness, bronchospasm, hypotension and may progress to life threatening anaphylaxis. Respiratory support equipment, epinephrine, antihistamines, corticosteroids and physician support must be readily available.

IV Compatibility

Normal saline, dextrose 5% (discard if cloudy), sterile water for injection.

Dosing

IM and IV doses are equivalent.
Induction:
• daily (usual method and less likely to cause adverse effects):
• 6,000-10,000 IU/m2/day x 6-14 days
• 200-1000 IU/kg/day IM/IV x 28 days; may continue additional 14 days if remission not achieved
• tiw (= 3 times per week): 400 IU/kg - 400 IU/kg - 600 IU/kg MWF x 28 days; may continue additional 14 days if remission not achieved

Reinduction:
• q1w: 3,000 IU/m²/day IV x 5 days

Pediatric:
Intramuscular:
• tiw (= 3 times per week): 6,000 IU/m² x 9 doses (some protocols use 200 IU/kg for children <3 years of age)
• q7-10d: 10,000 IU/m²/day IV
• q1w: 25,000 IU/m²/day IM

Dose Adjustment Criteria

Hepatic failure:
Treatment should be discontinued if hepatic failure develops.
(Suggested action)

Antiemetic Risk

LOW RISK (Less than 10% of patients)
• No routine antiemetic pre-chemotherapy or post-chemotherapy

Contraindications

• Known hypersensitivity to asparaginase • Pregnancy and breast feeding • History of pancreatitis

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Observation for hypersensitivity reaction during and for 30 minutes after injection (emergency treatment readily available)
• Intradermal skin test prior to first dose and other doses if more than 1 week between doses.

SUGGESTED CRITERIA
• Baseline & periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels (serum proteins may be added if indicated)]
• Baseline & periodic serum amylase levels & serum glucose levels

Hypersensitivity/Allergy
0. None
1. Transient rash, fever <38oC
2. Urticaria, fever > 38oC, mild bronchospasm
3. Serum sickness, bronchospasm, requires parenteral medications
4. Anaphylaxis
Rated In Response To Patient Reaction

Extravasation Hazard

None

Significant Interactions

Cytarabine, etoposide, methotrexate, prednisone, vincristine (give asparaginase last on treatment day), serum thyroxine-binding globulin, cyclophosphamide, mercaptopurine, prednisone.

Product Information

Commercial Product Description

Vials of 10,000IU Asparaginase for reconstitution with 4mL Sterile Water for Injection- Keep refrigerated. Kidrolase removed from Canadian Market; Asparaginase Erwinia never released. Available on a case-by-case basis through Special Access Program, Health Canada (call 613-941-2108 /e-mail EDR_Drugs-BPA@hc-sc.gc.ca.

Pharmaceutical Considerations

Injection:
10,000 IU vial. Storage in the refrigerator is recommended. One reference [Vogenberg] states that intact asparaginase Kidrolase vials are stable for at least 48 hours at room temperature while another [King] states that they are stable for 1 year at room temperature. Intact asparaginase Erwinia vials should be refrigerated but are stable for 6 weeks at room temperature.
Reconstitute powder with 4 mL SWI or NS to a final concentration of 2,500 IU/mL. For IM injection, Trissel recommends reconstitution with 2 mL NS to give a final concentration of 5,000 IU/mL. For IM injections of high dose therapy (10,000 IU), the 10,000 IU vial can be reconstituted with 0.5 mL of NS to give a final concentration of 20,000 IU/mL. If >2mL solution is need, prepare in 2 syringes for injection into 2 different sites. To avoid foaming, rotate gently; do not shake.

Reconstituted solution for injection:
Kidrolase® solution maintains potency for 14 days when refrigerated and for 7 days at room temperature; storage in the refrigerator is recommended. Cloudy solutions should be discarded. Small numbers of gelatinous fibres may develop in Kidrolase solution on standing. Filtering through a 5 micron filter will remove the fibres with no loss of potency, but filtration through a 0.2 micron filter may result in some loss of potency.

Diluted solution for infusion:
Kidrolase is stable in D5W or NS for up to 8 hours, provided that the solution remains clear. Suitable volumes of D5W or NS for dilution are 50-150 mL. Loss of activity and denaturation may occur outside pH range of 6-7.5.
It is recommended that asparaginase not be mixed with other drugs.

Handling Risk Level

Pregnancy CPOSSIBLE HAZARDOUS DRUG
FDA Pregnancy Risk Factor C

  • Consider handling this drug using precuations outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANLDING RISK LEVEL:

HAZARD RISK LEVEL 3
FDA Pregnancy Risk Factor C
• Consider handling this drug using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

CCNS Provincial Formulary Status- Intermediate Level • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs Pharmacare Formulary Status- Formulary (red) NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety