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Pronunciation

(a SPEAR a ji nase)

Generic Available (U.S.)

No

Index Terms

• E. coli Asparaginase
• Erwinia Asparaginase
• L-asparaginase

Prescribing and Access Restrictions

The Erwinia strain of asparaginase is no longer commercially available in the U.S., although may be obtained through clinical trials or on a compassionate use basis.

U.S. Brand Names

• Elspar®

Canadian Brand Names

• Kidrolase®

Pharmacologic Category

• Antineoplastic Agent, Miscellaneous

Pharmacologic Category Synonyms

• Chemotherapy Agent, Miscellaneous

Use: Labeled Indications

Treatment (in combination with other chemotherapy) of acute lymphoblastic leukemia (ALL)

Use: Unlabeled/Investigational

Treatment of lymphoblastic lymphoma

Pregnancy Risk Factor

C

Pregnancy Considerations

Decreased weight gain, resorptions, gross abnormalities, and skeletal abnormalities were observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed.

Lactation

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.

Contraindications

History of serious allergic reaction to asparaginase or any E. coli-derived L-asparaginase; history of serious thrombosis, pancreatitis, or serious hemorrhagic events with prior L-asparaginase treatment

Warnings/Precautions

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Allergic reactions: Severe allergic reactions may occur; monitor; immediate treatment for hypersensitivity reactions should be available during administration. Risk factors for allergic reactions include: I.V. administration, doses >6000-12,000 units/m², patients who have received previous cycles of asparaginase, and intervals of even a few days between doses. Up to 33% of patients who have an allergic reaction to E. coli asparaginase will also react to the Erwinia form or pegaspargase. A test dose may be administered prior to the first dose of asparaginase, or prior to restarting therapy after a hiatus of several days. False-negative rates of up to 80% to test doses of 2-50 units are reported. Desensitization may be performed in patients found to be hypersensitive by the intradermal test dose or who have received previous courses of therapy with the drug.

• Coagulopathy: Increased prothrombin time, partial thromboplastin time, and hypofibrinogenemia may occur; cerebrovascular hemorrhage has been reported; monitor coagulation parameters. Use with caution in patients with an underlying coagulopathy.

• Hyperglycemia: May cause hyperglycemia/glucose intolerance (may be irreversible); monitor blood glucose.

• Pancreatitis: May cause serious and possibly fatal pancreatitis; promptly evaluate patients with abdominal pain; discontinue permanently if pancreatitis develops.

• Thrombotic events: Serious thrombosis, including sagittal sinus thrombosis may occur; discontinue with serious thrombotic events.

• Tumor lysis syndrome: Appropriate measures must be taken to prevent tumor lysis syndrome and subsequent hyperuricemia and uric acid nephropathy; monitor, consider allopurinol, hydration and urinary alkalization.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with pre-existing hepatic impairment; may alter function.

Adverse Reactions

Note: Immediate effects: Fever, chills, nausea, and vomiting occur in 50% to 60% of patients.

>10%:

Central nervous system: Fatigue, fever, chills, depression, agitation, seizure (10% to 60%), somnolence, stupor, confusion, coma (25%)

Endocrine & metabolic: Hyperglycemia/glucose intolerance (10%)

Gastrointestinal: Nausea, vomiting (50% to 60%), anorexia, abdominal cramps (70%), acute pancreatitis (15%, may be severe in some patients)

Hematologic: Hypofibrinogenemia and depression of clotting factors V and VIII, variable decrease in factors VII and IX, severe protein C deficiency and decrease in antithrombin III (may be dose limiting or fatal)

Hepatic: Transaminases, bilirubin, and alkaline phosphatase increased (transient)

Hypersensitivity: Acute allergic reactions (fever, rash, urticaria, arthralgia, hypotension, angioedema, bronchospasm, respiratory distress, anaphylaxis (15% to 35%); may be dose limiting in some patients, may be fatal)

Renal: Azotemia (66%)

1% to 10%:

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Stomatitis

Miscellaneous: Allergic reaction (including anaphylaxis), antibody formation/immunogenicity (~25%)

<1%, postmarketing case reports, and/or frequency not defined: Acute renal failure, albumin decreased, cerebrovascular hemorrhage, cerebrovascular thrombosis, cough, disorientation, drowsiness, fatty liver, fibrinogen decreased, glucosuria, hallucinations, headache, hemorrhagic pancreatitis, hyper-/hypolipidemia, hyperthermia, hypocholesterolemia, hypotension, insulin-dependent diabetes, intracranial hemorrhage, irritability, ketoacidosis, laryngospasm, malabsorption syndrome, myelosuppression (mild–to-moderate anemia, leukopenia, and thrombocytopenia; onset: 7 days; nadir: 14 days; recovery: 21 days), pancreatic pseudocyst, Parkinsonian symptoms (including tremor and increased muscle tone), partial thromboplastin time increased, peripheral edema, polyuria, proteinuria, prothrombin time increased, pruritus, rash, renal insufficiency, serum ammonia increased, serum cholesterol decreased, sagittal sinus thrombosis, stroke (hemorrhagic and thrombotic), thrombosis, urticaria, venous thrombosis, weight loss

Drug Interactions

BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy

Dexamethasone: Asparaginase may increase the serum concentration of Dexamethasone. This is thought to be due to an asparaginase-related decrease in hepatic proteins responsible for dexamethasone metabolism. Risk C: Monitor therapy

Dexamethasone (Systemic): Asparaginase may increase the serum concentration of Dexamethasone (Systemic). This is thought to be due to an asparaginase-related decrease in hepatic proteins responsible for dexamethasone metabolism. Risk C: Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination

Storage

Intact vials of powder should be refrigerated at 2°C to 8°C (36°F to 48°F). Reconstituted solutions are stable 1 week refrigerated at 8°C (Stecher, 1999), although the manufacturer recommends use within 8 hours. Solutions for I.V. infusion are stable for 8 hours at room temperature or under refrigeration.

Reconstitution

For I.V. administration, reconstitute lyophilized powder with 5 mL sterile water for injection or NS. For I.M. administration, the manufacturer recommends reconstitution of the lyophilized powder with 2 mL NS to a concentration of 5000 units/mL; however, some institutions reconstitute with 1 mL NS for I.M. use, resulting in a concentration of 10,000 units/mL. Shake well, but not too vigorously. A 5 micron filter may be used to remove fiber-like particles in the solution (do not use a 0.2 micron filter; has been associated with loss of potency).

Standard I.M. dilution: 5000 units/mL (10,000 units/mL has been used by some institutions)

Standard I.V. dilution: Dilute in 50-250 mL NS or D₅W

Compatibility

Stable in D₅W, NS.

Y-site administration: Compatible: Methotrexate, sodium bicarbonate

Mechanism of Action

Asparaginase inhibits protein synthesis by hydrolyzing asparagine to aspartic acid and ammonia. Leukemia cells, especially lymphoblasts, require exogenous asparagine; normal cells can synthesize asparagine. Asparaginase is cycle-specific for the G₁ phase.

Pharmacodynamics/Kinetics

Absorption: I.M.: Produces peak blood levels 50% lower than those from I.V. administration

Distribution: V_d: 4-5 L/kg; 70% to 80% of plasma volume; <1% CSF penetration

Metabolism: Systemically degraded

Half-life elimination: I.M.: 39-49 hours; I.V.: 8-30 hours

Time to peak, plasma: I.M.: 14-24 hours

Dosage

Refer to individual protocols. Note: Dose, frequency, number of doses, and start date may vary by protocol and treatment phase.

Children:

I.V.:

6000 units/m²/dose 3 times/week for ~6-9 doses or

1000 units/kg/day for 10 days or

High-dose therapy (unlabeled dose): 10,000 units/m²/dose every ~3 days for ~4-8 doses

I.M.:

6000 units/m²/dose 3 times/week or 6000 units/m²/dose every ~3 days for ~6-9 doses

High-dose therapy (unlabeled dose): 10,000 units/m²/dose every ~3 days for ~4-8 doses or 25,000 units/m²/dose weekly for ~9 doses (generally used in high-risk continuation therapy)

Adults:

I.V.:

6000 units/m²/dose 3 times/week for ~6-9 doses or

1000 units/kg/day for 10 days or

High-dose therapy (unlabeled dose): 10,000 units/m²/day for ~3-12 doses

Single agent therapy (rare): 200 units/kg/day for 28 days

I.M.:

6000 units/m²/dose 3 times/week for ~6-9 doses or 6000 units/m²/dose every ~3 days for ~6-9 doses

High-dose therapy (unlabeled dose): 10,000 units/m²/day for ~3-12 doses

Test dose: A test dose is often recommended prior to the first dose of asparaginase, or prior to restarting therapy after a hiatus of several days. Most commonly, 0.1 mL of a 20 units/mL (2 units) asparaginase dilution is injected intradermally, and the patient observed for at least 1 hour. False-negative rates of up to 80% to test doses of 2-50 units are reported.

Some practitioners recommend an asparaginase desensitization regimen for patients who react to a test dose, or are being retreated following a break in therapy. Doses are doubled and given every 10 minutes until the total daily dose for that day has been administered. One schedule begins with a total of 1 unit given I.V. and doubles the dose every 10 minutes until the total amount given is the planned dose for that day. For example, if a patient was to receive a total dose of 4000 units, he/she would receive injections 1 through 12 during the desensitization. See table.

Dosage: Combination Regimens

Leukemia, acute lymphocytic:

Hyper-CVAD (Leukemia, Acute Lymphocytic)

Larson Regimen (ALL)

Linker Protocol (ALL)

PVA (POG 8602)

PVDA

Administration: I.M.

Doses should be given as a deep intramuscular injection into a large muscle; volumes >2 mL should be divided and administered in 2 separate sites

Administration: I.V.

Note: I.V. administration greatly increases the risk of allergic reactions and should be avoided if possible.

The following precautions should be taken when administering. Administer in 50-250 mL of D₅W over at least 30-60 minutes. The manufacturer recommends a test dose (0.1 mL of a dilute 20 unit/mL solution) prior to initial administration and when given after an interval of 7 days or more. Institutional policies vary. The skin test site should be observed for at least 1 hour for a wheal or erythema. Note that a negative skin test does not preclude the possibility of an allergic reaction. Desensitization may be performed in patients who have been found to be hypersensitive by the intradermal skin test or who have received previous courses of therapy with the drug. Have epinephrine, diphenhydramine, and hydrocortisone at the bedside. Have a running I.V. in place. A physician should be readily accessible.

Administration: Other

Has been administered SubQ in specific protocols

Administration: I.V. Detail

The intradermal skin test is commonly given prior to the initial injection, using a dose of 0.1 mL of 20 units/mL solution (~2 units). The skin test site should be observed for at least 1 hour for a wheal or erythema. Do not infuse through filter.

Gelatinous fiber-like particles may develop on standing. Filtration through a 5-micron filter during administration will remove the particles with no loss of potency.

pH: 7.4; 6.5-8 (active enzyme)

Monitoring Parameters

Vital signs during administration; CBC with differential, urinalysis, amylase, liver enzymes, coagulation parameters (baseline and periodic), renal function tests, urine dipstick for glucose, blood glucose, uric acid. Monitor for allergic reaction, be prepared to treat anaphylaxis at each administration; monitor for onset of abdominal pain and mental status changes.

Test Interactions

Decreased thyroxine and thyroxine-binding globulin

Patient Education

This medication can only be given I.M. or I.V. Report immediately any pain or burning at infusion/injection site, rash, chest pain, respiratory difficulty or chest tightness, difficulty swallowing, or sharp back pain. It is vital to maintain adequate hydration, unless instructed to restrict fluid intake, and good nutritional status. May cause acute nausea or vomiting. Report unusual fever or chills, changes in mentation (confusion, agitation, depression, stupor, seizures), yellowing of skin or eyes, unusual bleeding or bruising, unhealed sores, or vaginal discharge.

Additional Information

Some institutions recommended the following precautions for asparaginase administration: Parenteral epinephrine, diphenhydramine, and hydrocortisone available at bedside; freely running I.V. in place; physician readily accessible; monitor the patient closely for 30-60 minutes; avoid administering at night.

The E. coli and the Erwinia strains of asparaginase differ slightly in their gene sequencing, and have slight differences in their enzyme characteristics. Both are highly specific for asparagine and have <10% activity for the D-isomer. The E. coli form is more commonly used. The Erwinia variety is no longer commercially available in the U.S., although may be obtained through clinical trials or on a compassionate use basis.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Rare reports of depression, disorientation, and hallucinations

Mental Health: Effects on Psychiatric Treatment

May cause myelosuppression; use caution with clozapine and carbamazepine

Nursing: Physical Assessment/Monitoring

With each dose, patient should be monitored closely for acute hypersensitivity reactions (may occur in 10% to 35% of patients and can be fatal), hyperglycemia, CNS changes, nausea, or vomiting. In event of hypersensitivity or hyperglycemia, infusion should be stopped and prescriber notified immediately.

Oncology: Emetic Potential

Very low (<10%)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution:

Elspar®: 10,000 int. units

References

Avramis VI, Sencer S, Periclou AP, et al, “A Randomized Comparison of Native Escherichia Coli Asparaginase and Polyethylene Glycol Conjugated Asparaginase for Treatment of Children With Newly Diagnosed Standard-Risk Acute Lymphoblastic Leukemia: A Children's Cancer Group Study,” Blood, 2002, 99(6):1986-94.

Capizzi RL, “Asparaginase Revisited,” Leukemia & Lymphoma, 1993, 10(Suppl):147-50.

Duval M, Suciu S, Ferster A, et al, “Comparison of Escherichia Coli -Asparaginase With Erwinia-Asparaginase in the Treatment of Childhood Lymphoid Malignancies: Results of a Randomized European Organisation for Research and Treatment of Cancer − Children's Leukemia Group Phase 3 Trial,” Blood, 2002, 99(8):2734-9.

Ettinger LJ, Ettinger AG, Avramis VI, et al, “Acute Lymphoblastic Leukemia: A Guide to Asparaginase and Pegaspargase Therapy,” BioDrugs, 1997, 7:30-9.

Gallagher MP, Marshall RD, and Wilson R, “Asparaginase as a Drug for Treatment of Acute Lymphoblastic Leukemia,” Essays Biochem, 1989, 24:1-40.

Hoelzer D, Gökbuget N, Digel W, et al, “Outcome of Adult Patients With T-Lymphoblastic Lymphoma Treated According to Protocols for Acute Lymphoblastic Leukemia,” Blood, 2002; 99(12):4379-85.

Larson RA, Dodge RK, Burns P, et al, “A Five-Drug Remission Induction Regimen With Intensive Consolidation for Adults With Acute Lymphoblastic Leukemia: Cancer and Leukemia Group B Study 8811,” Blood, 1995, 85(8):2025-37.

Lazarus HM, Richards SM, Chopra R, et al, “Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia at Diagnosis: Results from the International ALL Trial MRC UKALL XII/ECOG E2993,” Blood, 2006, 108(2):465-72.

Morgan C, Tillett T, Braybrooke J, et al, “Management of Uncommon Chemotherapy-Induced Emergencies,” Lancet Oncol, 2011 [epub ahead of print].

Muller HJ and Boos J, “Use of L-Asparaginase in Childhood ALL,” Crit Rev Oncol Hematol, 1998, 28(2):97-113.

Pession A, Valsecchi MG, Masera G, et al, “Long-Term Results of a Randomized Trial on Extended Use of High Dose L-Asparaginase for Standard Risk Childhood Acute Lymphoblastic Leukemia,” J Clin Oncol, 2005, 23(28):7161-7.

Stecher AL, de Deus PM, Polikarpov I, et al, “Stability of L-Asparaginase: An Enzyme Used in Leukemia Treatment,” Pharm Acta Helv, 1999, 74(1):1-9.

International Brand Names

• Asparaginase medac (PL)
• Crasnitin (AT, CH, HN, PT)
• Elspar (BR, MX)
• Erwinase (DE, DK, FI, GB, GR, NL, NO, NZ, SE, SG)
• Kidrolase (AR, BG, CO, CZ, EG, FR, IL, PE, PL, UY)
• Laspar (ZA)
• Leunase (AU, BD, CL, HK, ID, IN, JP, KP, MY, PH, PK, TH, TW)
• Oncaspar (DE)
• Paronal (BE)

Lexi-Comp.com

Last full review/revision May 2011