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Glatiramer Acetate

Class: Immunomodulatory Agents
Chemical Name: l-Glutamic acid polymer with l-alanine, l-lysine, and l-tyrosine, acetate
Molecular Formula: C5H9NO4 • C3H7-5H9NO4 • C3H7NO2 • C6H14N2O2 • C9H11NO3)x • xC2H4O2)
CAS Number: 147245-92-9
Brands: Copaxone

Introduction

Immunomodulatory agent; synthetic polypeptide mixture containing 4 naturally occurring amino acids.1 2 3 4 5 6 7 8 23

Uses for Glatiramer Acetate

Relapsing-Remitting Multiple Sclerosis (RRMS)

Treatment to reduce the frequency of relapses in patients with RRMS, including those who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis (MS).1 2 4 6 7 8 9 16 23 25

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The National Clinical Advisory Board of the National Multiple Sclerosis Society recommends that therapy with glatiramer acetate or an interferon beta preparation be considered as soon as possible following a definite diagnosis of MS in patients with active, relapsing disease and may also be considered for selected patients with a first attack who are at high risk for MS.14

May be useful in patients who do not respond adequately to or who do not tolerate interferon beta therapy.15

Glatiramer Acetate Dosage and Administration

Administration

Administer only by sub-Q injection; do not administer IV.1

Administer initial self-administered dose under the supervision of a qualified clinician.1

Sub-Q Administration

Commercially available prefilled syringes intended for single use only; discard unused portion.1

Warm prefilled syringes to room temperature by removing from refrigerator about 20 minutes prior to use.1 18

Inject sub-Q into the arm, abdomen, hip, or thigh.1 6 18

To minimize risk of localized lipoatrophy and skin necrosis, follow proper injection technique and rotate injection areas and sites daily.1 22 (See Lipoatrophy and Skin Necrosis under Cautions.)

Dosage

Available as glatiramer acetate; dosage expressed in terms of the salt.1

Adults

Relapsing-Remitting Multiple Sclerosis (RRMS)
Sub-Q

Recommended dosage is 20 mg once daily.1 6

Therapy should be continued indefinitely except when there is a clear lack of benefit, intolerable adverse effects, or availability of better treatments.14

Special Populations

No special population dosage recommendations at this time.1 6

Cautions for Glatiramer Acetate

Contraindications

  • Known hypersensitivity to glatiramer acetate or mannitol.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Injection site hypersensitivity, allergic reactions, and anaphylactic or anaphylactoid reactions reported,1 10 18 23 27 including rare cases of anaphylaxis accompanied by anti-glatiramer IgE antibodies.10 18 Some reactions developed from one to several months or more after initiating therapy.7 27

General Precautions

Immediate Post-injection Reaction

Acute injection reactions reported in approximately 16% of patients immediately after sub-Q injection.1 Symptoms, which are generally transient and self-limited and do not require treatment,1 include flushing,1 2 6 7 chest pain1 2 6 or tightness,6 7 8 palpitations,1 2 5 6 7 8 anxiety,1 2 5 6 7 8 dyspnea,1 2 5 6 7 8 constriction of the throat,1 and urticaria.1 23

Reactions generally occur several months after initiation of therapy (although may occur earlier); individual patients may experience one or several episodes of these symptoms.1 6 7 During the postmarketing period, some patients with similar symptoms reportedly received emergency medical care.1

Not currently known whether reactions have an immunologic or nonimmunologic mechanism or whether multiple episodes in a given patient have similar mechanisms.1 6

Chest Pain

Transient chest pain reported, generally >1 month after initiation of therapy.1 Some episodes occurred as part of immediate post-injection reactions, but many did not.1 Episodes generally last only a few minutes, often are not associated with other symptoms, and do not appear to produce clinically important sequelae.1 Some patients experience >1 such episode.1

Lipoatrophy and Skin Necrosis

Localized lipoatrophy (i.e., loss of subcutaneous fat) and, rarely, skin necrosis at the injection site reported.1 21 22 23 Lipoatrophy may occur at various times after treatment initiation, sometimes after several months and is thought to be permanent.1 22 No known treatment for lipoatrophy.1 22

Advise patients to follow proper injection technique and rotate injection areas and sites daily to minimize risk of these events.1

Potential Effects on Immune Response

Possible modification of immune response and interference with useful immune function.1

Possible interference with the recognition of foreign antigens, which may undermine the body’s tumor surveillance ability and defenses against infection.1

Possibility of adverse effects resulting from continued alteration of cellular immunity associated with chronic administration of the drug.1

Antibody Formation

Development of IgG antibodies to glatiramer reported in most patients;1 10 however, data to date indicate that antibodies do not neutralize therapeutic effects.3 18 20

Animal studies suggest that immune complexes are deposited in renal glomeruli.1

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether glatiramer is distributed into milk.1 Use with caution in nursing women.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

Not studied in geriatric patients.1

Common Adverse Effects

Injection site reactions1 2 5 23 (e.g., pain,1 2 erythema,1 2 23 inflammation,1 2 pruritus,1 2 23 mass,1 2 edema,1 hypersensitivity,1 fibrosis,1 atrophy or lipoatrophy,1 22 necrosis),23 vasodilatation,1 rash,1 23 dyspnea,1 chest pain.1

Interactions for Glatiramer Acetate

Interactions with other drugs not fully evaluated to date.1

No clinically important interactions reported in clinical trials between glatiramer and drugs commonly used in multiple sclerosis, including concurrent corticosteroid therapy for up to 28 days.1 Not formally evaluated in combination with interferon beta.1 6

Glatiramer Acetate Pharmacokinetics

Distribution

Following sub-Q injection, some portion of the dose may enter the lymphatic circulation and some may enter systemic circulation.1 Does not appear to cross the blood-brain barrier.6

Elimination

Metabolism

Substantial portion of sub-Q dose appears to be hydrolyzed locally at injection site to small oligopeptides and free amino acids.1 6

Stability

Storage

Parenteral

Injection

2–8°C; protect from light.1 May be stored at room temperature (15–30°C) for up to one month; do not store at room temperature for >1 month.1 Do not freeze.1

Actions

  • Mechanism of action not fully elucidated;1 appears to modify immune processes responsible for the pathogenesis of MS.1 6 8 15

  • Induces and activates drug-specific suppressor T-cells that migrate into the CNS and down-regulate immune response (e.g., inflammation) to myelin antigens in the periphery.1 6 8 15

Advice to Patients

  • Importance of reading the manufacturer’s patient information prior to beginning glatiramer acetate therapy and rereading it each time prescription is refilled.1

  • Importance of clinicians instructing patients and/or caregivers in proper injection techniques and about avoiding reuse of syringes and needles and proper disposal of such equipment in a puncture-resistant container after use.1

  • Risk of immediate post-injection reaction.1 Importance of advising patients that glatiramer acetate may cause various symptoms after injection, including flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and urticaria.1 Importance of informing patients that these symptoms usually are transient and self-limited and do not require specific treatment.1 Patients also should be informed that such reactions may occur early or begin several months after initiation of treatment, and that they may experience one or several episodes of these symptoms.1

  • Importance of advising patients that they may experience chest pain either as part of an immediate post-injection reaction or without other symptoms.1 Patients should be informed that the pain should be transient (usually lasting only for a few minutes).1 Some patients may experience more than one such episode, usually beginning at least one month after beginning treatment.1 Advise patients to seek medical attention if they experience chest pain of unusual duration or intensity.1

  • Importance of clinicians advising patient about adverse effects, including instructions to contact clinician immediately and withhold further administration of glatiramer acetate if hives, skin rash with irritation, dizziness, sweating, chest pain, breathing difficulty, or severe pain at the injection site occurs.1 Importance of advising patients to seek emergency medical attention if symptoms become severe.1

  • Risk of lipoatrophy and skin necrosis at injection site.1 21 22 23 Advise patients to follow proper injection technique and rotate injection areas and sites on a daily basis.1

  • Importance of not changing dosage or dosage schedule or discontinuing therapy without consulting clinician.1

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

  • Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • 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.

Glatiramer Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

20 mg/1 mL

Copaxone (available as 1-mL prefilled syringe)

TEVA Neuroscience

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. TEVA Neuroscience, Inc. Copaxone (glatiramer acetate) injection prescribing information. Kansas City, MO; 2012 Aug.

2. Johnson KP, Brooks BR, Cohen JA et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 1995; 45:1268-76. [IDIS 350103] [PubMed 7617181]

3. Johnson KP, Brooks BR, Cohen JA et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology. 1998; 50:701-8. [IDIS 403141] [PubMed 9521260]

4. Bornstein MB, Miller A, Slagle S et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med. 1987; 317:408-14. [IDIS 232708] [PubMed 3302705]

5. Comi G, Filippi M, Wolinsky JS et al. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol. 2001; 49:290-7. [IDIS 461166] [PubMed 11261502]

6. Simpson D, Noble S, Perry C. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis. CNS Drugs. 2002; 16:825-50. [PubMed 12421116]

7. Calabresi PA. Considerations in the treatment of relapsing-remitting multiple sclerosis. Neurology. 2002; 58(Suppl 4):S10-S22.

8. Miller AE. Glatiramer acetate in the treatment of multiple sclerosis. Neurol Clin. 2005; 23:215-31. [PubMed 15661095]

9. Goodin DS, Frohman EM, Garmany GP Jr et al. Disease modifying therapies in multiple sclerosis: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology and the MS council for clinical practice guidelines. Neurology. 2002; 58: 169-178. [IDIS 475332] [PubMed 11805241]

10. Rauschka H, Farina C, Sator P et al. Severe anaphylactic reaction to glatiramer acetate with specific IgE. Neurology. 2005; 64:1481. [IDIS 534043] [PubMed 15851756]

11. Ge Y, Grossman RI, Udupa JK et al. Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS. Neurology. 2000; 54:813-7. [IDIS 443731] [PubMed 10690968]

12. Johnson KP, Ford CC, LIsak RP et al. Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data. Acta Neurol Scand. 2005; 111:42-7. [PubMed 15595937]

13. Rizvi SA, Agius MA. Current approved options for treating patients with multiple sclerosis. Neurology. 2004; 63(Suppl 6):S8-S14. [IDIS 528071] [PubMed 15623672]

14. Disease management consensus statement from the National Clinical Advisory Board of the National Multiple Sclerosis Society. Available at: http://www.nationalmssociety.org/download.aspx?id=8. Accessed Oct 4, 2012.

15. Mezzapesa DM, Rovaris M, Filippi M. Glatiramer acetate in multiple sclerosis. Expert Rev Neurotherapeutics. 2005; 5:451-8.

16. Boneschi FM, Rovaris M, Johnson KP et al. Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials. Multiple Sclerosis. 2003; 9:349-55. [PubMed 12926839]

17. Johnson KP, Brooks BR, Ford CC et al. Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial. Multiple Sclerosis. 2003; 9:585-91. [PubMed 14664471]

18. Teva Neuroscience, Overland Park, KS. Personal communication.

19. Johnson KP, Panitch HS, Ford CC et al. Long-term slowing of disability progression in patients receiving continuous glatiramer acetate compared with those withdrawing from therapy: 10 year results from an ongoing trial. Neurology. 2004; 62(7 Suppl 5):A180.

20. Teitelbaum D, Brenner T, Abramsky O et al. Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy. Mult Scler. 2003; 9:592-9. [PubMed 14664472]

21. Feldmann R, Schierl M, Rauschka H et al. Necrotizing skin lesions with involvement of muscle tissue after subcutaneous injection of glatiramer acetate. Eur J Dermatol. 2009 Jul-Aug; 19:385.

22. Edgar CM, Brunet DG, Fenton P et al. Lipoatrophy in patients with multiple sclerosis on glatiramer acetate. Can J Neurol Sci. 2004; 31:58-63. [PubMed 15038472]

23. Comi G, Martinelli V, Rodegher M et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 374:1503-11. [PubMed 19815268]

24. Hartung HP, Montalban X, Sorensen PS et al. Principles of a new treatment algorithm in multiple sclerosis. Expert Rev Neurother. 2011; 11:351-62. [PubMed 21375441]

25. Carter NJ, Keating GM. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. Drugs. 2010; 70:1545-77. [PubMed 20687620]

26. Roskell NS, Zimovetz EA, Rykroft CE et al. Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including direct comparisons versus fingolimod. Cur Med Res Opinion. 2012; 28:767-80.

27. Baumgartner A, Stich O, Rauer S et al. Anaphylactic reaction after injection of glatiramer acetate (Copaxone) in patients with relapsing-remitting multiple sclerosis. Eur Neurology. 2011; 66:368-70.

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