Advanced Breast Cancer: Learn about treatment options.

Oncaspar

Generic Name: Pegaspargase
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (Monomethoxypolyethylene glycol succinimidyl)74-l-asparaginase
CAS Number: 130167-69-0

Introduction

Antineoplastic agent; conjugate of polyethylene glycol (PEG) and Escherichia coli-derived asparaginase.1 2 3 5 6

Uses for Oncaspar

Acute Lymphocytic Leukemia (ALL)

Component of combination chemotherapy for first-line treatment of ALL.1 7 Used in induction and/or intensification (consolidation) regimens.1 7 22 23 25 26

Component of combination chemotherapy for treatment of ALL in patients who are hypersensitive to native (nonconjugated) forms of asparaginase.1 2 3 4 5 6 8

Slideshow: Fact or Fiction? The Top 15 Osteoarthritis Myths

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.7 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.7 8 Some clinicians reserve 4- or 5-drug regimens for patients with high-risk childhood ALL;7 8 others elect to use such regimens for all patients with childhood ALL regardless of presenting features.7

Either pegaspargase or asparaginase (Escherichia coli) (no longer commercially available in the US) may be used as the asparaginase component in first-line combination chemotherapeutic regimens for childhood ALL;1 35 36 39 however, many clinicians prefer pegaspargase during both induction and postinduction phases because of similar efficacy and toxicity as asparaginase (Escherichia coli)22 25 but less frequent administration.7 Asparaginase (Erwinia chrysanthemi) may be used in patients hypersensitive to E. coli-derived asparaginase (asparaginase [Escherichia coli] or pegaspargase).7 34 35 36 37 38

In adults, induction regimens typically include an anthracycline, vincristine, and prednisone; some regimens also add other drugs (e.g., an asparaginase preparation, cyclophosphamide).26 28 30

Oncaspar Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1 40

Hypersensitivity Reactions

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

Administration

Administer by IM injection or IV infusion.1 May be administered by sub-Q injection.26

Discard injection or diluted solutions that appear discolored or cloudy, contain particulate matter, may have been frozen (even if there is no change in the appearance of the solution), or have been shaken or vigorously agitated.1 21 Discard injections stored at room temperature (15–25°C) for >48 hours.1

Injection contains no preservative.1 Vials are for single use only; discard any unused portion.1

IM Administration

Administer undiluted by IM injection every 14 days.1

Do not give >2 mL at one injection site.1

IV Administration

Administer by IV infusion.1

Dilution

For IV infusion, dilute pegaspargase dose in 100 mL of sodium chloride injection or 5% dextrose injection.1

Immediately use diluted solutions.1 If immediate use not possible, store diluted solutions at 2–8°C and complete administration within 48 hours of preparation.1

Protect diluted solution from direct sunlight.1

Rate of Administration

Administer over 1–2 hours into tubing of a free-flowing IV infusion solution.1

Dosage

Dosage expressed in international units (IU, units).1 Each mL of undiluted pegaspargase injection contains 750 units of the enzyme.1

Consult published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.

Pediatric Patients

ALL

Discontinue if pancreatitis, serious allergic reaction, or serious thrombotic event occurs.1

Induction Therapy
IM or IV

2500 units/m2 no more frequently than every 14 days.1

While the optimum duration of induction remission regimen remains to be established, a 28-day, 1- or 2-dose regimen has been evaluated.1 4 21 22 23

Intensification Treatment Phase
IM or IV

2500 units/m2 has been given at various dosing intervals.1 22 25 Administer no more frequently than every 14 days.1

Adults

ALL

Discontinue if pancreatitis, serious allergic reaction, or serious thrombotic event occurs.1

Induction Therapy
IM or IV

2500 units/m2 no more frequently than every 14 days.1

While the optimum duration of induction remission regimen remains to be established, a 28-day, 1- or 2-dose regimen has been evaluated.1 4 21 22 23

Sub-Q

2000 units/m2 (maximum 3750 units) has been administered on days 5 and 22 of a 4-week induction phase.26 28

Intensification Treatment Phase
IM or IV

2500 units/m2 has been given at various dosing intervals.1 Administer no more frequently than every 14 days.1

Sub-Q

2000 units/m2 has been administered on days 15 and 43 of an 8-week early intensification treatment phase.26

Prescribing Limits

Pediatric Patients

ALL
IM or IV

Manufacturer recommends administering no more frequently than every 14 days.1 Consult specific clinical protocols for prescribing limits for alternative dosages.

Adults

ALL
IM or IV

Manufacturer recommends administering no more frequently than every 14 days.1 Consult specific clinical protocols for prescribing limits for alternative dosages.

Special Populations

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Oncaspar

Contraindications

  • History of serious thrombosis associated with prior asparaginase therapy.1

  • History of pancreatitis associated with prior asparaginase therapy.1 (See Pancreatitis under Cautions.)

  • Clinically important hemorrhagic events associated with prior asparaginase therapy.1 12 19

  • History of serious allergic reactions (e.g., urticaria, systemic rash, bronchospasm, laryngeal edema, local erythema or swelling, hypotension) to pegaspargase.1 12 19

Warnings/Precautions

General Considerations

Carefully weigh potential benefits against possible risks and apprise patient of the risks.1 19

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions1 5 6 12 13 15 16 19 25 (e.g., acute anaphylaxis,1 5 12 13 19 bronchospasm,1 5 12 19 hypotension,1 laryngeal edema,1 urticaria,1 12 16 19 chills,12 16 18 19 rash,1 12 16 19 local erythema or swelling1 12 19 ) reported;19 discontinue the drug in patients with serious allergic reactions.1

Probability of a previously hypersensitive or nonhypersensitive patient completing 8 doses of pegaspargase therapy without developing a therapy-limiting hypersensitivity reaction in clinical studies was 77 or 95%, respectively.19 21

Monitor patients for 1 hour after administration of the drug;1 19 appropriate resuscitative equipment and agents (e.g., antihistamine, epinephrine, oxygen, IV corticosteroid) should be readily available.1 3 12 19

Coagulopathy

Coagulopathy,15 16 29 sometimes severe, reported.1

Perform coagulation tests (e.g., fibrinogen levels, PT, PTT) at baseline and periodically during and following therapy.1 In patients with severe or symptomatic coagulopathy, initiate treatment with fresh frozen plasma to replace coagulation factors.1

Hyperglycemia

Glucose intolerance, sometimes irreversible, reported.1

Mild to severe hyperglycemia1 12 13 15 17 23 may occur in patients receiving pegaspargase.1 Hyperglycemia requiring insulin therapy1 12 15 19 occurred in 3% of patients receiving pegaspargase in clinical trials.1

Pancreatitis

Pancreatitis1 12 13 15 17 19 (sometimes fulminant and fatal) reported;1 19 impairment of pancreatic function1 12 13 15 17 19 reported frequently.1 12 13 15 17 19

Evaluate patients with abdominal pain for pancreatitis; discontinue the drug in patients with pancreatitis.1

Thrombotic Events

Thrombotic events1 18 19 (e.g., sagittal sinus thrombosis,1 12 central venous catheter thrombosis,23 29 stroke25 29 ) have been reported; discontinue the drug in patients with serious thrombotic events.1

Hepatic Effects

Hyperbilirubinemia1 23 and elevated ALT and AST concentrations1 12 16 17 19 reported frequently.1

Jaundice12 16 21 and hypoalbuminemia,21 29 which may be associated with peripheral edema,6 12 16 17 may occur.

Immunogenicity

Antibodies to pegaspargase may develop.1 22 Clinical implications of antibody development (e.g., effect on pharmacokinetics, risk of allergic reactions, or efficacy) not fully established.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether pegaspargase is distributed into milk; discontinue nursing or the drug.1 12 19

Pediatric Use

Safety and efficacy evaluated in a randomized trial involving children 1–9 years of age receiving pegaspargase as first-line therapy for standard-risk ALL.1 In addition, safety and efficacy evaluated in children with ALL and hypersensitivity to asparaginase.1

Adult Use

Known asparaginase toxicity (except for hypersensitivity reactions) reportedly is greater in adults than in children.1 17 19

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Hypersensitivity reactions,1 5 6 12 13 15 16 19 25 coagulopathy,1 15 16 29 hyperglycemia,1 elevated serum transaminase concentrations,1 12 16 17 19 hyperbilirubinemia,1 23 pancreatitis,1 12 13 15 17 19 CNS thrombosis.1 22 No apparent difference in adverse effects following IV versus IM administration.7

Interactions for Oncaspar

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comment

Methotrexate

Decreased effectiveness of methotrexate during the period of pegaspargase suppression of protein synthesis and cell replication21

Oncaspar Pharmacokinetics

Distribution

Extent

Distributes into CSF (reportedly reducing CSF asparagine concentrations to a similar extent as asparaginase (Escherichia coli).1

Not known whether pegaspargase is distributed into milk.1

Elimination

Half-life

Approximately 5.8 days following IM administration in pediatric patients.1

7 days following IV administration in adults.23

1.4–5 and 2.5–8.9 days following IM administration in patients with relapsed ALL previously hypersensitive and non-hypersensitive to asparaginase (Escherichia coli), respectively.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Do not store at room temperature (15–25°C) for >48 hours.1 Do not freeze; protect from light.1

Discard any unused portion.1

Diluted solution: If immediate use not possible, store at 2–8°C and complete administration within 48 hours of preparation.1 Do not freeze; protect from direct sunlight.1

Actions

  • Inactivates the amino acid asparagine, which is required by tumor cells to synthesize protein, RNA, and DNA.1 24

  • Breaks down extracellular asparagine into aspartic acid and ammonia, which causes depletion of asparagine and kills leukemic cells.1 24 26

  • Less immunogenic and longer acting (i.e., possesses a longer plasma half-life) than native (nonconjugated) E. coli-derived asparaginase.1 22 24

Advice to Patients

  • Risk of hypersensitivity reactions, including the possibility of life-threatening anaphylaxis; importance of patients being monitored for 1 hour after pegaspargase administration.1 19 Importance of immediately informing clinicians if symptoms of serious allergic reactions (e.g., swelling, difficulty breathing) occur.1

  • Risk of pancreatitis.1 Importance of immediately informing clinicians if severe abdominal pain occurs.1

  • Risk of glucose intolerance.1 Importance of informing clinicians if excessive thirst or any increase in the volume or frequency of urination occurs.1

  • Risk of thrombosis.1 Importance of immediately informing clinicians if severe headache, arm or leg swelling, shortness of breath, or chest pain occurs.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.19

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Pegaspargase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

750 units/ mL

Oncaspar

Sigma-Tau

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 1, 2012. 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

1. Sigma-Tau Pharmaceuticals, Inc. Oncaspar (pegaspargase) intravenous or intramuscular injection prescribing information. Gaithersburg, MD; 2011 May.

2. Kurtzberg J. A new look at Peg-l-asparaginase and other asparaginases in hematological malignancies. Cancer Invest. 1994; 12(Suppl 1):59.

3. 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.

4. Kurtzberg J, Ettinger LJ, Fisher A et al. Multicenter study of PEG-L-asparaginase treatment of children with ALL. ASHP Midyear Clinical Meeting Abstract. 1992; 27:369E. Abstract.

5. Ho DH, Brown NS, Yen A et al. Clinical pharmacology of polyethylene glycol-l-asparaginase. Drug Metab Dispos. 1986; 14:349-52. [IDIS 216912] [PubMed 2872037]

6. Keating MJ, Holmes R, Lerner S et al. L-Asparaginase and PEG asparaginase—past, present, and future. Leuk Lymphoma. 1993; 10(Suppl):153-7. [PubMed 8481665]

7. Childhood acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2012 May 18.

8. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

9. Kebriaei P, Champlin R, De Lima M et al. Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA et al, eds. DeVita, Hellman, and Rosenberg's cancer: principles and practice of oncology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

10. Cao SG, Zhao Q, Ding ZT et al. Chemical modification of enzyme molecules to improve their characteristcs. Ann N Y Acad Sci. 1990; 613:460-7. [PubMed 2075996]

11. Weiss RB. Hypersensitivity reactions. Semin Oncol. 1992; 5:458-77.

12. Rhone-Poulenc Rorer Pharmaceuticals Inc. Product information form for American Hospital Formulary Service: Oncaspar (pegaspargase). Collegeville, PA: 1994 Jan.

13. Anon. Pegaspargase for acute lymphoblastic leukemia. Med Lett Drugs Ther. 1995; 37:23-4. [PubMed 7877556]

14. Kawashima K, Takeshima H, Higashi Y et al. High efficacy of monomethoxypolyethylene glycol-conjugated l-asparginase (peg2-asp) in two patients with hematological malignancies. Leuk Res. 1991; 15:525-30. [PubMed 1861535]

15. Capizzi RL. Asparaginase revisited. Leuk Lymph. 1993; 10(Suppl):147-50.

16. Ettinger LJ, Kurtzberg J, Vote PA et al. An open-label, multicenter study of polyethylene glycol-L-asparaginase for the treatment of acute lymphoblastic leukemia. Cancer. 1995; 75:1176-81. [IDIS 342636] [PubMed 7850718]

17. Ettinger AR. Pegaspargase (Oncaspar). J Pediatr Oncol Nurs. 1995; 12:46-8. [PubMed 7893462]

18. Wada H, Imamura I, Sako M et al. Antitumor enzyme: polyethylene glycol-modified asparaginase. Ann N Y Acad Sci. 1990; 613:95-108. [PubMed 2076022]

19. Rhone-Poulenc Rorer Pharmaceuticals Inc. Oncaspar (pegaspargase) comprehensive product profile. 1994 Dec.

20. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

21. Enzon. Oncaspar (PEG-L-asparaginase) prescribing information. Piscataway, NJ; 1998 Nov 5.

22. 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; 99:1986-94. [PubMed 11877270]

23. Douer D, Yampolsky H, Cohen LJ et al. Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood. 2007; 109:2744-50. [PubMed 17132721]

24. Apostolidou E, Swords R, Alvarado Y et al. Treatment of acute lymphoblastic leukaemia: a new era. Drugs. 2007; 67:2153-71. [PubMed 17927282]

25. Silverman LB, Gelber RD, Dalton VK et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood. 2001; 97:1211-8. [PubMed 11222362]

26. Wetzler M, Sanford BL, Kurtzberg J et al. Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007; 109:4164-7. [PubMed 17264295]

27. Armstrong JK, Hempel G, Koling S et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007; 110:103-11. [PubMed 17516438]

28. 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]

29. Enzon Pharmaceuticals, Bridgewater, NJ: Personal communication.

30. Adult acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2012 May 10.

31. Margolin JF, Rabin KR, Poplack DG. Leukemias and lymphomas of childhood. In: DeVita VT Jr, Lawrence TS, Rosenberg SA et al, eds. DeVita, Hellman, and Rosenberg's cancer: principles and practice of oncology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

32. 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]

33. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006; 354:166-78. [PubMed 16407512]

34. EUSA Pharma (USA), Inc. Erwinaze (asparaginase Erwinia chrysanthemi) intramuscular injection prescribing information. Langhorne, PA; 2011 Nov.

35. Pieters R, Hunger SP, Boos J et al. L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. 2011; 117:238-49. [PubMed 20824725]

36. van den Berg H. Asparaginase revisited. Leuk Lymphoma. 2011; 52:168-78. [PubMed 21281233]

37. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010; 32:554-63. [PubMed 20724951]

38. Vrooman LM, Supko JG, Neuberg DS et al. Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2010; 54:199-205. [PubMed 19672973]

39. Lundbeck Inc. Elspar (asparaginase Escherichia coli) intravenous or intramuscular prescribing information. Deerfield, IL; 2010 Apr.

40. Lundbeck Inc. Elspar material safety data sheet. Deerfield, IL; 2010 Apr 1.

Hide
(web3)