Cerezyme

Generic Name: Imiglucerase
Class: Enzymes
Chemical Name: 495-L-Histidineglucosylceramidase (human placenta isoenzyme protein moiety)
Molecular Formula: C2532H3843N671O711S16
CAS Number: 154248-97-2

Introduction

Biosynthetic (recombinant DNA origin) form of human β-glucocerebrosidase (glucosylceramidase).1 4 6 7

Uses for Cerezyme

Gaucher’s Disease

Long-term enzyme replacement therapy in adults and pediatric patients with confirmed diagnosis of nonneuronopathic (type 1) Gaucher’s disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly, or splenomegaly (designated an orphan drug by FDA for this use).1 9 31

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Role of imiglucerase therapy in patients with neuronopathic forms of Gaucher’s disease (type 2 or 3) not established31 (designated an orphan drug by FDA for this use).9

Cerezyme Dosage and Administration

General

  • Individualize dosage and/or frequency of administration according to disease severity and individual requirements and response.1 17

Administration

IV Administration

Administer by IV infusion.1

May be administered using an inline, low protein-binding, 0.2-mcm particulate filter as slight flocculation (evidenced by thin translucent fibers) may occasionally occur after dilution.1 31

Reconstitution

Determine number of vials to be reconstituted based on patient weight.1

Reconstitute appropriate number of vials containing 200 or 400 units of imiglucerase lyophilized powder with 5.1 or 10.2 mL of sterile water for injection, respectively, to provide a solution containing 40 units of imiglucerase per mL.1

Dilution

Use strict aseptic technique since drug product contains no preservative.a

Withdraw appropriate dose from reconstituted vials and dilute with 0.9% sodium chloride injection to a final volume of 100–200 mL.a

Rate of Administration

Administer over 1–2 hours.1

Dosage

Pediatric Patients

Gaucher’s Disease
IV

Children and adolescents 2–16 years of age: Initially, dosage ranges from 2.5 units/kg 3 times weekly to 60 units/kg every 2 weeks.1

Increase or decrease dosage and/or frequency of administration according to disease severity and patient response and convenience.1 17

Individual doses occasionally may be increased or decreased slightly to avoid wasting a partially used vial, as long as the total monthly dosage is not altered substantially.1

Clinical improvement in hematologic and visceral manifestations generally occurs within the first year of therapy;17 response to skeletal manifestations may require 2–3 years of therapy.17

Failure to respond within 6 months may indicate the need for increased dosages.17 31

Adults

Gaucher’s Disease
IV

Adults >16 years of age: Initially, dosage ranges from 2.5 units/kg 3 times weekly to 60 units/kg every 2 weeks.1

Increase or decrease dosage and/or frequency of administration according to disease severity and patient response and convenience.1 17

Individual doses occasionally may be increased or decreased slightly to avoid wasting a partially used vial, as long as the total monthly dosage is not altered substantially.1

Clinical improvement in hematologic and visceral manifestations generally occurs within the first year of therapy;17 response to skeletal manifestations may require 2–3 years of therapy.17

Failure to respond within 6 months may indicate the need for increased dosages.17 31

Cautions for Cerezyme

Contraindications

  • No known contraindications.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, hypotension) reported during or shortly after IV infusion; anaphylactoid reactions reported in <1% of patients.1

Carefully reevaluate therapy if substantial clinical evidence of hypersensitivity develops.1 Use with caution in patients who have exhibited manifestations of hypersensitivity reactions.1 Further therapy can generally be administered successfully following a decrease in infusion rate and pretreatment with antihistamines and/or corticosteroids.1

Antibody Formation

Development of IgG antibodies to imiglucerase reported in approximately 15% of patients, usually within the first 6 months of therapy and rarely after 12 months of therapy.1 (See Distribution: Special Populations and Elimination: Special Populations under Pharmacokinetics.)

Possible increased risk of hypersensitivity reactions in patients with detectable IgG antibodies.1 (See Hypersensitivity Reactions under Cautions.) Use with caution in patients who have developed antibodies to the drug; monitor periodically for imiglucerase IgG antibodies during the first year of therapy.1

Cross-hypersensitivity

Use with caution in patients previously treated with alglucerase who developed antibodies or exhibited hypersensitivity reactions to alglucerase.a

General Precautions

Pulmonary Hypertension and Pneumonia

Pulmonary hypertension and pneumonia reported rarely; however, no causal relationship with the drug established.1

Evaluate patients with respiratory symptoms in the absence of fever for the presence of pulmonary hypertension.1

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether imiglucerase is distributed into milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in children <2 years of age, although the drug has been used in this age group.1

Common Adverse Effects

Children 2–12 years of age: Dyspnea, fever, nausea, vomiting, flushing, coughing.1

Adolescents >12–16 years of age and adults >16 years of age: Headache, pruritus, rash.1

Cerezyme Pharmacokinetics

Absorption

Onset

Steady-state enzymatic activity reached in 30 minutes during a 1-hour IV infusion.1

Distribution

Extent

Volume of distribution ranges from 0.09–0.15 L/kg.1

Special Populations

In patients who develop IgG antibodies, volume of distribution is decreased.1

Elimination

Half-life

Following IV infusion, plasma enzymatic activity rapidly declines with a half-life of 3.6–10.4 minutes.1

Special Populations

In patients who develop IgG antibodies, clearance is decreased and half-life is increased.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C.a

Following reconstitution, stable at room temperature (25°C) and 2–8°C for up to 12 hours.a

Following dilution, stable at 2–8°C for up to 24 hours.a

Compatibility

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

Actions

  • Replaces the deficient endogenous enzyme (β-glucocerebrosidase; glucosylceramidase) in patients with Gaucher’s disease.1 2 3 5 10 12

  • Increases the degradation of glucosylceramide (glucocerebroside) in macrophages1 2 4 6 10 by hydrolyzing the β-glycoside linkage of glucocerebroside to glucose and ceramide (N-acylsphingosine)1 4 7 10 with resultant reduction in liver and spleen size, amelioration of anemia and thrombocytopenia, decreased bone pain, decreased cachexia, and increased bone remineralization over a period of several years.1 2 3 8 10 12 14 15 17 19 27 28 29 33

Advice to Patients

  • Risk of hypersensitivity reactions (pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, hypotension).a

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

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a

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

Preparations

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

Imiglucerase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

200 units

Cerezyme

Genzyme

400 units

Cerezyme

Genzyme

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. 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. Genzyme Corporation. Cerezyme (imiglucerase) for injection prescribing information. Cambridge, MA; 2003 Mar.

2. Barton NW, Furbish FS, Murray GJ et al. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA. 1990; 87:1913-6. [PubMed 2308952]

3. Anon. Alglucerase for Gaucher’s disease. Med Lett Drugs Ther. 1991; 33:82. [PubMed 1865852]

4. Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides: II. Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun. 1965; 18:221-5. [PubMed 14282020]

5. Britton DE, Leinikki PO, Barranger JA et al. Gaucher’s disease: lack of antibody response to intravenous glucocerebrosidase. Life Sci. 1978; 23:2517-20. [PubMed 732537]

6. Basu A, Prence E, Garrett K et al. Comparison of N-acyl phosphatidylethanolamines with different N-acyl groups as activators of glucocerebrosidase in various forms of Gaucher’s disease. Arch Biochem Biophys. 1985; 243:28-34. [PubMed 3933429]

7. Furbish FS, Blair HE, Shiloach J et al. Enzyme replacement therapy in Gaucher’s disease: large-scale purification of glucocerebrosidase suitable for human administration. Proc Natl Acad Sci USA. 1977; 74:3560-3. [PubMed 269414]

8. Beutler E. Gaucher’s disease. N Engl J Med. 1991; 325:1354-60. [IDIS 287428] [PubMed 1922238]

9. Food and Drug Administration. Cumulative list of orphan drugs designated and/or approved. Rockville, MD; 2004, Aug 24. From FDA web site (http: / / www.fda.gov / ForIndustry / DevelopingProductsforRareDiseasesConditions / HowtoapplyforOrphanProductDesignation / default.htm).

10. Genzyme Corporation. Ceredase (alglucerase) prescribing information. Cambridge, MA; 1992 Feb.

11. Genzyme Corporation, Cambridge, MA. Personal communication on alglucerase.

12. Reviewers’ comments (personal observations) on alglucerase.

13. Stahl PD, Rodman JS, Miller MJ et al. Evidence for receptor-mediated binding of glycoproteins, glycoconjugates, and lysosomal glycosidases by alveolar macrophages. Proc Natl Acad Sci USA. 1978; 75:1399-1403. [PubMed 274729]

14. Weinreb NJ, Charrow J, Andersson HC et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Register. Am J Med. 2002; 113:112-9. [IDIS 484109] [PubMed 12133749]

15. Niederau C, Haussinger D. Gaucher’s disease: a review for the internist and hepatologist. Hepatogastroenterology. 2000; 47:984-7. [PubMed 11020862]

16. McCormack PL, Goa KL. Miglustat. Drugs. 2003;63:2427-34.

17. Charrow J, Andersson HC, Kaplan P et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: Consensus recommendations. J Pediatrics. 2003; 144:112-20.

18. Barton NW, Brady RO, Dambrosia JM et al. Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med. 1991; 324:1464-70. [IDIS 280934] [PubMed 2023606]

19. Rosenthal DI, Doppelt SH, Mankin HL et al. Enzyme therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics. 1995; 96:629-37. [IDIS 355405] [PubMed 7567322]

20. Beutler E, Kay AC, Saven A et al. Enzyme-replacement therapy for Gaucher’s disease. N Engl J Med. 1991; 325:1809-10. [IDIS 289025] [PubMed 1944489]

21. Beutler E, Kay A, Saven A et al. Enzyme replacement therapy for Gaucher disease. Blood. 1991; 78:1183-9. [IDIS 288172] [PubMed 1878585]

22. Parker RI, Barton NW, Read EJ et al. Hematologic improvement in a patient with Gaucher disease on long-term enzyme replacement therapy: evidence for decreased splenic sequestration and improved red blood cell survival. Am J Hematol. 1991; 38:130-7. [PubMed 1951303]

23. Barton NW, Brady RO, Dambrosia JM et al. Dose-dependent responses to macrophage-targeted glucocerebrosidase in a child with Gaucher disease. J Pediatr. 1992; 120:277-80. [IDIS 292694] [PubMed 1735829]

24. Genzyme Corporation. Ceredase treatment protocol: investigators’ brochure. IND No. 31,345. Boston, MA: 1990 Feb 6.

25. Zimran A, Hadas-Halpern I, Abrahamov A et al. Enzyme-replacement therapy for Gaucher’s disease. N Engl J Med. 1991; 325:1810-1.

26. Barton NW, Brady RO, Murray GJ et al. Enzyme-replacement therapy for Gaucher’s disease. N Engl J Med. 1991; 325:1811. [IDIS 289028] [PubMed 1944490]

27. Grabowski GA, Barton NW, Pastores G et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med. 1995; 122:33-9. [IDIS 339881] [PubMed 7985893]

28. Actelion Pharmaceuticals. Zavesca (miglustat) capsules prescribing information. South San Francisco, CA; 2003 Jul 31.

29. Elstein D, Abrahamov A, Hadas-Halpern I et al. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM. 1998; 91:483-8. [PubMed 9797931]

30. Elstein D, Abrahamov A, Hadas-Halpern I et al. Gaucher's disease. Lancet. 2001; 358:324-7. [IDIS 467174] [PubMed 11498237]

31. Genzyme Corporation, Cambridge, MA: Personal communication.

32. Charrow J, Andersson HC, Kaplan P et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med. 2000; 160:2835-43. [PubMed 11025794]

33. Poll LW, Maas M, Terk MR et al. Response of Gaucher bone disease to enzyme replacement therapy. Br J Radiol. 2002; 75(Suppl 1):A25-36.

a. Genzyme Corporation. Cerezyme (imiglucerase for injection) prescribing information. Cambridge, MA; 2005 Apr.

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