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Elspar

Generic Name: Asparaginase
Class: Antineoplastic Agents
VA Class: AN900
CAS Number: 9015-68-3

Warning(s)

Special Alerts:

In August 2012, Lundbeck announced that it would be discontinuing the sale of Asparaginase (Escherichia coli) (Elspar) in the US by the end of December 2012. Access to other forms of asparaginase (e.g., pegaspargase, Asparaginase [Erwinia chrysanthemi]) is not affected. Patients should consult with healthcare providers to discuss other available treatment options that may be appropriate. For additional information, please refer to the Dear Healthcare Professional letter available on the FDA's website at .

Introduction

Antineoplastic agent; enzyme derived from Escherichia coli.108 a

Uses for Elspar

Acute Lymphocytic Leukemia (ALL)

Component of combination chemotherapeutic regimens for the treatment of ALL.107 108 109 110 111 112 114 122 123 124 Used in induction and/or intensification (consolidation) regimens.109 110 122 123 124 (See Special Alerts.)

In non-high-risk childhood ALL, combination therapy with an asparaginase preparation, a corticosteroid (dexamethasone or prednisone), and vincristine is used as an induction regimen.109 Intensive induction regimens with ≥4 drugs, including an asparaginase preparation, an anthracycline (e.g., daunorubicin), a corticosteroid, and vincristine, with or without cyclophosphamide, may improve event-free survival but cause greater toxicity.107 109 111 Some clinicians reserve 4- or 5-drug regimens for patients with high-risk childhood ALL;107 109 111 others elect to use such regimens for all patients with childhood ALL regardless of presenting features.109

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Either asparaginase (Escherichia coli) or pegaspargase may be used as the asparaginase component in first-line combination chemotherapeutic regimens for childhood ALL;108 113 138 139 however, many clinicians prefer pegaspargase during both induction and postinduction phases because of similar efficacy and toxicity as asparaginase (Escherichia coli) but less frequent administration.109 Asparaginase (Erwinia chrysanthemi) may be used in patients hypersensitive to E. coli-derived asparaginase (asparaginase [Escherichia coli] or pegaspargase).109 137 138 139 140 141

In adults, induction regimens typically include an anthracycline, vincristine, and prednisone; some regimens also add other drugs (e.g., an asparaginase preparation, cyclophosphamide).110 122 123 130 142

Acute Myeloid Leukemia (AML)

Used in conjunction with high-dose cytarabine as post-induction intensification therapy for AML in patients without a suitable donor for allogeneic bone marrow transplant.117 118 (See Special Alerts.)

Non-Hodgkin’s Lymphoma

Used in combination with other antineoplastic agents for treatment of non-Hodgkin’s lymphoma (e.g., lymphoblastic lymphoma).107 110 120 (See Special Alerts.)

Elspar Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.143

Hypersensitivity Reactions

  • Monitor patients for hypersensitivity reactions for 1 hour after administration of asparaginase; be prepared to provide immediate treatment.108 (See Sensitivity Reactions under Cautions.)

Administration

Administer by IM injection, IV infusion, or sub-Q injection.108 123 126 130

Discard solutions that appear cloudy, discolored, or contain precipitates.108

Vials are for single use only; discard any unused portion.108

Avoid vigorous shaking; may cause foaming and difficulty removing entire contents of vial.121

IM Administration

Administer by IM injection.108

Do not give >2 mL at one injection site.108

Reconstitution

For IM injection, add 2 mL of 0.9% sodium chloride injection to a vial containing 10,000 units of asparaginase to provide a solution containing 5000 units/mL.108

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.108

Filter gelatinous fiber-like particles that develop in standing solutions through a 5-mcm filter during administration.108

Reconstitution

Add 5 mL of 0.9% sodium chloride injection or sterile water to a vial containing 10,000 units of asparaginase to provide a solution containing 2000 units/mL.108

Rate of Administration

Administer over ≥30 minutes into the tubing of a freely flowing IV solution of 0.9% sodium chloride or 5% dextrose injection.108

Dosage

Dosage expressed in terms of international units (IU, units).108 (See Special Alerts.)

Consult published protocols for optimum dosage and administration sequence of drugs in combination regimens.a

Pediatric Patients

ALL

Discontinue if pancreatitis, serious allergic reaction, or serious thrombotic reaction occurs.108

Induction Therapy
IM or IV

Manufacturer recommends 6000 units/m2 3 times a week.108

Adults

ALL

Discontinue if pancreatitis, serious allergic reaction, or serious thrombotic reaction occurs.108

Induction Therapy
IM

Manufacturer recommends 6000 units/m2 3 times a week.108

Linker regimen: 6000 units/m2 daily on days 17–28 (total of 12 doses) during 4-week induction phase.122

IV

Manufacturer recommends 6000 units/m2 3 times a week.108

Sub-Q

Larson regimen: 6000 units/m2 for 6 doses (days 5, 8, 11, 15, 18, and 22) during 4-week induction phase.123

Intensification (Consolidation) Phase
IM

Linker regimen: 12,000 units/m2 for 6 doses (days 2, 4, 7, 9, 11, and 14) during cycles 1, 3, 5, and 7 (of a total of 9 cycles administered approximately monthly).122

Sub-Q

Larson regimen: 6000 units/m2 for 4 doses (days 15, 18, 22, and 25) during each of two 4-week early intensification periods.123

Special Populations

No special population dosage recommendations at this time.108

Cautions for Elspar

Contraindications

  • History of serious thrombosis associated with prior asparaginase therapy.108

  • History of pancreatitis with prior asparaginase therapy.108 (See Pancreatitis under Cautions.)

  • History of serious hemorrhagic events associated with prior asparaginase therapy.108

  • History of serious allergic reactions to asparaginase derived from E. coli.108

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Potential for severe sensitivity reactions (e.g., anaphylaxis).108 116 117 126 129 Risk of hypersensitivity reactions increases upon reexposure to the drug;108 a more common with IV than with IM administration.116 125 126

If severe hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., antihistamine, epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).108

Intradermal sensitivity testing has limited value in predicting hypersensitivity; false-positive and false-negative results occur.126

Thrombotic Effects

Thrombotic events (e.g., sagittal sinus thrombosis,101 108 cerebral infarction,101 thrombosis associated with a central venous catheter,122 superficial and deep-vein thrombosis,101 123 130 132 pulmonary embolism123 130 ) have been reported;108 discontinue the drug in patients with serious thrombotic events.108

Coagulopathy

Coagulopathy (e.g., prolonged PT and PTT; decreased fibrinogen, protein C, protein S, and antithrombin III), sometimes severe,108 a and CNS hemorrhage reported.100 101 102 108 121 Alterations in coagulation factors may predispose individuals to bleeding and/or thrombosis.100 101 102 103 108

Perform coagulation tests (e.g., PT, PTT, fibrinogen) at baseline and periodically during and following therapy.108 In patients with severe or symptomatic coagulopathy, initiate treatment with fresh frozen plasma to replace coagulation factors.108

Pancreatitis

Pancreatitis (sometimes fulminant and fatal) reported.108 a

Evaluate patients with abdominal pain for pancreatitis; discontinue the drug in patients with pancreatitis.108

Hyperglycemia

Glucose intolerance, sometimes irreversible, reported.108

Possible hyperglycemia;108 133 monitor blood glucose concentrations.108

Hepatic Effects

Hepatotoxicity (including fulminant hepatic failure) and abnormal liver function (e.g., elevated AST, ALT, alkaline phosphatase, and bilirubin [direct and indirect]; decreased serum albumin and plasma fibrinogen) may occur; may be fatal in some patients.108 a Fatty changes in liver documented on biopsy or autopsy.108 a

Hyperbilirubinemia and elevated ALT and AST occur frequently.108

Evaluate hepatic enzymes and bilirubin prior to and periodically during therapy.108

Adequate Patient Monitoring

Perform coagulation tests (e.g., fibrinogen concentrations, PT, PTT) at baseline and periodically during and following therapy.108

Monitor serum glucose concentrations.108

Evaluate hepatic enzymes and bilirubin prior to and periodically during therapy.108

Renal Effects

Azotemia, usually prerenal, occurs frequently.108 a

Discontinue at first sign of renal failure.a

Immunologic Effects

Antibodies to asparaginase may develop.108 Antibody-positive patients more likely to experience a hypersensitivity reaction.108 Hypersensitivity reactions associated with increased clearance of asparaginase.108 (See Sensitivity Reactions under Cautions.)

Clinical implications of antibody formation not fully established, but higher levels of antibody associated with decreased asparaginase activity.108 129 In several studies, development of a hypersensitivity reaction did not appear to alter outcome of treatment for ALL; most patients who required discontinuance of the drug were switched to another formulation (Erwinia-derived asparaginase) to complete treatment.129 130

Specific Populations

Pregnancy

Category C.108

Lactation

Not known whether asparaginase is distributed into milk; discontinue nursing or the drug.108

Pediatric Use

Efficacy of combination chemotherapeutic regimens containing asparaginase established in pediatric patients with ALL.108 109

Adult Use

Toxicity of asparaginase generally is greater in adults than in children.116 117 122 a

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.108

Common Adverse Effects

Allergic reactions,108 116 117 126 129 azotemia,108 a pancreatitis,105 106 108 116 a coagulopathy,108 a hyperglycemia,108 133 CNS thrombosis,101 108 liver function abnormalities (e.g., hyperbilirubinemia, elevated transaminases).108 a

Interactions for Elspar

No formal drug interaction studies to date.108

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Methotrexate

Possible decreased effectiveness of methotrexate during period of asparagine suppressiona

Prednisone

Possible increased hyperglycemia133 a

Tests for thyroid function

Decreased serum concentration of thyroxine-binding globulin104

Values return to pretreatment levels within 4 weeks of asparaginase discontinuance104

Vincristine

Possible reduction in hepatic clearance of vincristine135 a

Cumulative neuropathy136 a and disturbances of erythropoiesis if asparaginase and vincristine administered concomitantlya

Manufacturer of vincristine recommends administration of asparaginase 12–24 hours after vincristine135

Consult published protocols for sequence of administration of chemotherapeutic agents in combination regimensa

Elspar Pharmacokinetics

Absorption

Bioavailability

Not absorbed from GI tract after oral administration; must be given parenterally.a

Peak plasma concentration attained 14–24 hours after IM administration.108 144

Distribution

Extent

Following IV administration, apparent volume of distribution is slightly higher than plasma volume.108

Not known whether asparaginase is distributed into milk.108

Crosses blood-brain barrier to a minimal extent.108

Elimination

Half-life

8–30 hours after IV administration.108 a

34–49 hours after IM administration.108 144

Stability

Storage

Parenteral

Powder for Injection

2–8°C.108

Store reconstituted solutions at 2–8°C; discard after 8 hours or sooner if solution becomes cloudy.108

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Ringer, injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Methotrexate sodium

Sodium bicarbonate

Actions

  • Inactivates the amino acid asparagine, which is required by tumor cells to synthesize DNA and essential proteins.108 a

  • Resistance to cytotoxic effects of asparaginase develops rapidly.a

  • No apparent cross-resistance between asparaginase and other available antineoplastic agents.a

  • Large foreign protein; therefore, is antigenic and may cause antibody production and varying degrees of hypersensitivity.108 a

Advice to Patients

  • Risk of hypersensitivity reactions, including the possibility of anaphylaxis; importance of patients being monitored for 1 hour after asparaginase administration.108 Importance of immediately informing clinicians if symptoms of serious allergic reactions (e.g., swelling, difficulty breathing) occur.108

  • Risk of pancreatitis.108 Importance of immediately informing clinicians if severe abdominal pain occurs.108

  • Risk of glucose intolerance.108 Importance of informing clinicians if excessive thirst or any increase in the volume or frequency of urination occurs.108

  • Risk of thrombosis.108 Importance of immediately informing clinicians if severe headache, seizures, mental status changes, arm or leg swelling, shortness of breath, or chest pain occurs.108

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.108

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.108

  • Importance of informing patients of other important precautionary information.108 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

In August 2012, Lundbeck announced that it would be discontinuing the sale of Asparaginase (Escherichia coli) (Elspar) in the US by the end of December 2012. (See Special Alerts.)

Asparaginase (Escherichia coli)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

10,000 units

Elspar

Lundbeck

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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101. Priest JR, Ramsay NKC, Steinherz PG et al. A syndrome of thrombosis and hemorrhage complicating l-asparaginase therapy for childhood acute lymphoblastic leukemia. J Pediatr. 1982; 100:984-9. [IDIS 157208] [PubMed 6953221]

102. Lederman GS. Stroke due to treatment with l-asparaginase in an adult. N Engl J Med. 1982; 307:1643. [IDIS 161589] [PubMed 7144855]

103. Priest JR, Ramsay NKC, Bennett AJ et al. The effect of l-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia. J Pediatr. 1982; 100:990-5. [IDIS 157209] [PubMed 6953222]

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135. Hospira Inc. Vincristine sulfate (for injection) prescribing information. Lake Forest, IL; 2007 Dec.

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a. AHFS drug information 2013. McEvoy GK, ed. Asparaginase Escherichia coli. Bethesda, MD: American Society of Health-System Pharmacists; 2013.

HID. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011.

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