Class: Antineoplastic Agents
VA Class: AN900
CAS Number: 9015-68-3
Brands: Elspar
Introduction
Antineoplastic agent; enzyme derived from Escherichia coli.108 a
Uses for Asparaginase
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
In non-high-risk childhood ALL, combination therapy with asparaginase (or pegaspargase), a corticosteroid (dexamethasone or prednisone), and vincristine is used as an induction regimen.109 Intensive induction regimens with ≥4 drugs, including asparaginase (or pegaspargase), 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-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
In adults, induction regimens typically include an anthracycline, vincristine, and prednisone; some regimens also add other drugs (e.g., asparaginase, cyclophosphamide).110 122 123
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
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
Asparaginase Dosage and Administration
General
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
Dilution
For IV infusion, dilute dose in either 0.9% sodium chloride or 5% dextrose injection.121
Rate of Administration
Administer dose slowly (over ≥30 minutes) into the tubing of a freely flowing IV solution.108
Dosage
Dosage expressed in terms of international units (IU, units).108
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 Asparaginase
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 hepatic failure), liver disorder, and various liver function abnormalities (e.g., elevated AST, ALT, alkaline phosphatase, and bilirubin [direct and indirect]; decreased albumin and fibrinogen) reported;108 a may be fatal in some patients.a Fatty changes in liver documented on biopsy or autopsy.108 a
Hyperbilirubinemia and elevated ALT and AST occur frequently.108 Marked hypoalbuminemia with peripheral edema may occur.108 a
Hepatic abnormalities usually reversible on discontinuance of therapy;108 some reversal may occur with continued 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
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 Asparaginase
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 |
Asparaginase 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
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
Stability
Storage
Parenteral
Powder for Injection
2–8°C.108
Store reconstituted solutions and solutions diluted for IV infusion at 2–8°C; discard after 8 hours or sooner if solution becomes cloudy.108 121
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution CompatibilityHID
Compatible |
|---|
Ringer, injection, lactated |
Dextrose lcx2 5% in water |
Sodium chloride 0.9% |
Drug Compatibility
Compatible |
|---|
Methotrexate sodium |
Sodium bicarbonate |
ActionsActions
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 notifying a clinician if facial swelling, seizures, severe headache, arm or leg swelling, acute shortness of breath, chest pain, or severe abdominal pain occurs.108
Importance of immediately notifying a clinician of signs of glucose intolerance (e.g., increased volume or frequency of urination, excessive thirst).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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection | 10,000 units | Elspar | Lundbeck |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. 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
100. Cairo MS, Lazarus K, Gilmore RL et al. Intracranial hemorrhage and focal seizures secondary to use of l-asparaginase during induction therapy of acute lymphocytic leukemia. J Pediatr. 1980; 97:829-33. [IDIS 127909] [PubMed 6933231]
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]
104. Garnick MB, Larsen PR. Acute deficiency of thyroxine-binding globulin during l-asparaginase therapy. N Engl J Med. 1979; 301:252-3. [PubMed 109764]
105. Underwood TW, Frye CB. Drug-induced pancreatitis. Clin Pharm. 1993; 12:440-8. [IDIS 314327] [PubMed 8403815]
106. Mclean R, Martin S, Lan-Po-Tang PRL. Fatal case of l-asparaginase induced pancreatitis. Lancet. 1982; 2:1401-2.
107. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.
108. Lundbeck Inc. Elspar (asparaginase) prescribing information. Deerfield, IL; 2010 Feb.
109. Childhood acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2010 Feb 12.
110. Adult acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2009 Sep 10.
111. Poplack DG, Magrath IT, Kun LE et al. Leukemias and lymphomas of childhood. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: JB Lippincott; 1993:1792-1818.
112. Preti A, Kantarjian HM. Management of adult acute lymphocytic leukemia: present issues and key challenges. J Clin Oncol. 1994; 12:1312-22. [IDIS 331854] [PubMed 8201394]
113. Enzon. Oncaspar (pegaspargase) intravenous or intramuscular injection prescribing information. Bridgewater, NJ; 2006 Sep.
114. Keating MJ, Estey E, Kantarjian H. Acute leukemia. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: JB Lippincott; 1993:1938-64.
115. Kurtzberg J. A new look at PEG-L-asparaginase and other asparaginases in hematological malignancies. Cancer Invest. 1994; 12(Suppl 1):59.
116. Capizzi RL, Holcenberg JS. Asparaginase. In: Holland JF, Frei E, Bast RC Jr et al, eds. Cancer medicine. 3rd ed. Philadelphia: Lea & Febiger; 1993:796-805.
117. Childhood acute myeloid leukemia/other myeloid malignancies. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Aug 18.
118. Wells RJ, Woods WG, Lampkin BC et al. Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: a report from the Childrens Cancer Group. J Clin Oncol. 1993; 11:538-45. [PubMed 8445429]
119. Fragasso G, Pastore MR, Vicari A et al. Myocardial infarction in a patient with acute lymphoblastic leukemia during L-asparaginase therapy. Am J Hematol. 1995; 48:136-7. [PubMed 7847336]
120. Childhood non-Hodgkin lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Sep 9.
121. Ovation Pharmaceuticals. Elspar (asparaginase) prescribing information. Deerfield, IL; 2005 Dec.
122. Linker CA, Levitt LJ, O'Donnell M et al. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991; 78:2814-22. [PubMed 1835410]
123. Larson RA, Dodge RK, Burns CP 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; 85:2025-37. [PubMed 7718875]
124. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006; 354:166-78. [PubMed 16407512]
125. Nesbit M, Chard R, Evans A et al. Evaluation of intramuscular versus intravenous administration of L-asparaginase in childhood leukemia. Am J Pediatr Hematol Oncol. 1979; 1:9-13. [PubMed 295576]
126. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol. 2009; 102:179-87. [PubMed 19354063]
127. Ohnuma T, Holland JF, Freeman A et al. Biochemical and pharmacological studies with asparaginase in man. Cancer Res. 1970; 30:2297-305. [PubMed 4920133]
128. Evans WE, Tsiatis A, Rivera G et al. Anaphylactoid reactions to Escherichia coli and Erwinia asparaginase in children with leukemia and lymphoma. Cancer. 1982; 49:1378-83. [PubMed 7037164]
129. Woo MH, Hak LJ, Storm MC et al. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2000; 18:1525-32. [PubMed 10735901]
130. Larson RA, Fretzin MH, Dodge RK et al. Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia. Leukemia. 1998; 12:660-5. [PubMed 9593262]
131. Caruso V, Iacoviello L, Di Castelnuovo A et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. 2006; 108:2216-22. [PubMed 16804111]
132. Caruso V, Iacoviello L, Di Castelnuovo A et al. Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis. J Thromb Haemost. 2007; 5:621-3. [PubMed 17229043]
133. Lowas SR, Marks D, Malempati S. Prevalence of transient hyperglycemia during induction chemotherapy for pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2009; 52:814-8. [PubMed 19260096]
134. Sarris A, Cortes J, Kantarjian H et al. Disseminated intravascular coagulation in adult acute lymphoblastic leukemia: frequent complications with fibrinogen levels less than 100 mg/dl. Leuk Lymphoma. 1996; 21:85-92. [PubMed 8907274]
135. Hospira Inc. Vincristine sulfate (for injection) prescribing information. Lake Forest, IL; 2007 Dec.
136. Hildebrand J, Kenis Y, Mubashir BA et al. Vincristine neurotoxicity. N Engl J Med. 1972; 287:517.
137. EUSA Pharma (Europe). Products: Erwinase. Available from website. Accessed 2010 May 5.
a. AHFS drug information 2009. McEvoy GK, ed. Asparaginase. Bethesda, MD: American Society of Health-System Pharmacists; 2009: 935–8.
HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:176-7.
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