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GLATIRAMER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Glatiramer (formerly known as copolymer-1), a random polymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, is a synthetic polypeptide, which has some structural similarity to myelin basic protein.

Specific Substances

    1) Glatiramer Acetate
    2) COP-1
    3) Copolymer 1
    4) CAS 28704-27-0 (glatiramer)
    5) CAS 147245-92-9 (glatiramer acetate)

Available Forms Sources

    A) FORMS
    1) Glatiramer is available in a lyophilized powder containing 20 mg of glatiramer acetate and 40 mg of mannitol in single use vials for subcutaneous administration after reconstitution with the diluent supplied. It is NOT intended for intravenous use (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).
    B) USES
    1) Glatiramer is used to reduce the frequency of relapses in the management of relapsing-remitting multiple sclerosis (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Glatiramer is indicated for the treatment of relapsing-remitting multiple sclerosis.
    B) PHARMACOLOGY: The exact mechanism of action is unknown; however, it is thought to modify immune processes through glatiramer-activated T-cells.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Adverse effects with glatiramer are usually transient and generally infrequent. COMMON: Transient chest pain unrelated to other systemic reactions has been reported in up to 26% of patients receiving glatiramer. No clinical sequelae have been documented due to this adverse event. Injection-site reactions (eg, pain, erythema, pruritus) are the most frequent adverse events reported with glatiramer therapy. LESS COMMON: A transient, self-limited systemic reaction consisting of facial flushing, chest tightness, palpitations, anxiety, and dyspnea has been reported in some patients following subcutaneous injection, and generally resolves within 30 seconds to 60 minutes without medical intervention. The pattern is unpredictable, and episodes have randomly reoccurred in some patients.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects from glatiramer have not yet been reported. Theoretically, any exposure to glatiramer (a protein) could result in an anaphylactic response.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Chest pain, palpitations, and vasodilation have been described during therapeutic use.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Dyspnea has been reported with therapy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Mild central nervous system effects have occurred with glatiramer therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Mild, infrequent gastrointestinal effects have been reported with therapeutic use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Injection-site reaction (eg, pain, erythema, pruritus, inflammation) is relatively common, but usually does not result in discontinuation of therapy.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Mild symptoms of arthralgia, myasthenia, and myalgia have been reported with glatiramer therapy.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Depression has been reported in some patients receiving glatiramer.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) Immediate postinjection systemic reactions have been reported as an infrequent event of glatiramer therapy.
    0.2.20) REPRODUCTIVE
    A) Glatiramer is classified as FDA pregnancy category B. At the time of this review, there were no well-controlled studies in pregnant women or nursing mothers. Reproductive studies in rats and rabbits indicated no impairment of fertility and no adverse effects on embryo fetal development, delivery, or offspring growth and development.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, in vitro and in vivo studies indicate no carcinogenic potential.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) Lymphadenopathy has been reported in patients treated with glatiramer.
    2) Generalized edema has occurred.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Monitor for evidence of an acute allergic reaction (eg urticaria, wheezing, angioedema).
    C) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with chest pain.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Immediate post injection reactions (i.e., flushing, anxiety, dyspnea) have been reported with therapy. Symptoms have been transient and resolved without medical intervention.
    B) TREATMENT OF SEVERE TOXICITY
    1) There is no specific treatment for glatiramer overdose other than supportive care. Treat severe allergic reactions with oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and/or epinephrine.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is generally NOT indicated, glatiramer is administered parenterally.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory compromise.
    E) ANTIDOTE
    1) None.
    F) ACUTE ALLERGIC REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine.
    2) SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value. No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.
    H) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with overdose ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.
    2) ADMISSION CRITERIA: Patients demonstrating severe allergic reactions should be admitted for observation.
    3) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected glatiramer overdose, the possibility of multi-drug involvement should be considered.
    J) PHARMACOKINETICS
    1) Pharmacokinetic studies suggest a substantial fraction of a therapeutic dose is hydrolyzed locally when administered subcutaneously. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter lymphatic circulation, enabling it to reach regional lymph nodes and to a lesser extent, systemic circulation.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that can cause hypersensitivity reactions.

Range Of Toxicity

    A) At the time of this review, there are no published reports of acute overdose exposures resulting in toxicity.

Clinical Effects

Summary Of Exposure

    A) USES: Glatiramer is indicated for the treatment of relapsing-remitting multiple sclerosis.
    B) PHARMACOLOGY: The exact mechanism of action is unknown; however, it is thought to modify immune processes through glatiramer-activated T-cells.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Adverse effects with glatiramer are usually transient and generally infrequent. COMMON: Transient chest pain unrelated to other systemic reactions has been reported in up to 26% of patients receiving glatiramer. No clinical sequelae have been documented due to this adverse event. Injection-site reactions (eg, pain, erythema, pruritus) are the most frequent adverse events reported with glatiramer therapy. LESS COMMON: A transient, self-limited systemic reaction consisting of facial flushing, chest tightness, palpitations, anxiety, and dyspnea has been reported in some patients following subcutaneous injection, and generally resolves within 30 seconds to 60 minutes without medical intervention. The pattern is unpredictable, and episodes have randomly reoccurred in some patients.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects from glatiramer have not yet been reported. Theoretically, any exposure to glatiramer (a protein) could result in an anaphylactic response.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Chest pain, palpitations, and vasodilation have been described during therapeutic use.
    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In controlled trials, approximately 26% of patients receiving glatiramer developed at least 1 episode of chest pain. Pathogenesis remains unknown. In most cases, the pain was described as transient (lasting only seconds), and not associated with other symptoms. Although ECG monitoring was not performed, clinical sequelae was not reported (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009) Ziemssen et al, 2001.
    1) Although some episodes of chest pain were associated with an immediate postinjection reaction, many cases were not related to this systemic response (Ziemssen et al, 2001).
    b) Some patients complained of more than one episode of chest pain, and episodes usually began 1 month after initiation of treatment (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).
    c) It has been suggested that glatiramer should be given with caution in patients with known cardiac disorders, and these patients should be monitored throughout therapy with glatiramer (Sweetman, 2002).
    B) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations have been described as a general systemic reaction to glatiramer. In controlled trials, 17% (n=201) of patients complained of symptoms (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).
    C) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) In controlled trials, 27% (n=201) of patients developed symptoms of vasodilation following glatiramer use; symptoms were sometimes described as a generalized systemic reaction to therapy. Flushing has also been observed in up to 24% of patients (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009; Johnson et al, 1995) Bornstein, et al, 1991; Bornstein et al, 1987.
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In premarketing trials, hypertension was reported in patients receiving glatiramer therapy (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dyspnea has been reported with therapy.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In controlled trials, dyspnea (19%, n=201) occurred after receiving glatiramer therapy (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mild central nervous system effects have occurred with glatiramer therapy.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) The following effects have been reported in at least 2% (n=201) of patients: dizziness, hypesthesia, paresthesia, sleep disorder (eg, insomnia, somnolence), dysesthesia, incoordination, abnormal gait, amnesia, emotional lability, abnormal thinking, and twitching (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mild, infrequent gastrointestinal effects have been reported with therapeutic use.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting, and dysphagia have been reported in greater than 2%(n=201) of patients during therapeutic administration of glatiramer (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Injection-site reaction (eg, pain, erythema, pruritus, inflammation) is relatively common, but usually does not result in discontinuation of therapy.
    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Pain, erythema, pruritus, burning, inflammation, localized edema and/or swelling have been reported at the injection-site during therapy (Lea & Goa, 1996) Ziemssen et al, 2001; (Sweetman, 2002). Injection site fibrosis, atrophy, and abscess are rare effects of therapy (Ziemssen et al, 2001).
    b) INCIDENCE: Injection site reactions are common (Johnson et al, 1998) Ziemssen et al, 2001).
    1) In controlled studies, localized adverse effects were reported in 82% of the glatiramer-treated patients (vs 48% of the placebo group). Of those, only 2% had effects that were considered severe (Ziemssen et al, 2001).
    c) RISK FACTORS: During clinical trials, patients receiving corticosteroids were more likely to develop injection-site reactions (Anon, 2001).
    B) LIPOATROPHY
    1) WITH THERAPEUTIC USE
    a) CHRONIC THERAPY: Lipoatrophy was reported in an adult female after being treated with glatiramer daily for 2 years (Hwang & Orengo, 2001).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mild symptoms of arthralgia, myasthenia, and myalgia have been reported with glatiramer therapy.
    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) Symptoms of arthralgia, myalgia, and myasthenia have occurred during therapy (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009; Anon, 2001). In one study, 5% of patients on glatiramer developed musculoskeletal symptoms (vs 3% receiving placebo) (Anon, 2001).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Immediate postinjection systemic reactions have been reported as an infrequent event of glatiramer therapy.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Theoretically, based on the protein nature of glatiramer, anaphylaxis is possible (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009). In postmarketing experience, a cluster of symptoms have been described immediately after injection: generalized flushing, vasodilation, chest pain, and dyspnea (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009) Ziemssen et al, 2001; (Sweetman, 2002). In general, systemic reactions lasted from 0.5 to 60 minutes after an injection and resolved without intervention (Lea & Goa, 1996; Johnson et al, 1998) Ziemssen et al, 2001. The occurrence appears to be unpredictable and random (Johnson et al, 1998).
    b) INCIDENCE: In one study, 9% to 15% of patients developed a benign systemic reaction following an injection at 20 mg/day, and 24% of patients experienced a reaction at 30 mg/day, which suggests a dose-dependent response (Lea & Goa, 1996). In some reports, up to 48% of patients experienced a systemic reaction (Anon, 2001).
    1) Of those patients experiencing an immediate postinjection reaction, nearly half will eventually develop another episode (Ziemssen et al, 2001). In one case report, histamine levels were not increased following a systemic reaction, and the authors concluded that the response was unlikely to be anaphylactic (Bornstein et al, 1988).
    2) At the time of this review, it has not been determined whether the reaction is mediated by an immunologic or nonimmunologic mechanism, or if multiple episodes that could occur in an individual are due to identical mechanisms (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).
    c) CASE REPORTS
    1) CASE SERIES: In a multicenter randomized, double-blinded study, immediate postinjection systemic reactions (IPISIR) were reported at least once in 37.8% of patients receiving glatiramer. Symptoms included facial flushing, chest tightness, dyspnea, palpitation, tachycardia, and anxiety. The onset of symptoms was unpredictable and started within seconds or minutes after an injection and lasted 10 to 30 minutes. Intervention was not required in any case (Comi et al, 2001).
    2) CASE SERIES: In several studies, up to 48% of patients receiving glatiramer (vs 29% receiving placebo) developed a self-limiting systemic reaction (symptoms included flushing, chest pain, palpitations, and dyspnea), which started within minutes of the injection and lasted up to 30 minutes (Anon, 2001).
    3) CASE REPORT: After 2 months of therapy with glatiramer (20 mg daily), a 30-year-old woman developed erythema of the head and neck, and a sensation of heat and shortness of breath 15 minutes after an injection. A second event occurred 6 weeks later after a routine daily injection, along with generalized erythema and wheals on the trunk. Symptoms resolved without intervention, with the wheals remaining for 4 hours. Skin testing with glatiramer was positive (Bayerl et al, 2001).
    B) MASS OF SKIN
    1) WITH THERAPEUTIC USE
    a) Subcutaneous masses (with a diameter of 5 cm or more) containing lymphocytic and eosinophilic infiltrates have developed in a small number of patients receiving glatiramer therapy. The reaction appears to be compatible with a delayed type hypersensitivity (type IV allergy) (Ziemssen et al, 2001).

Reproductive

    3.20.1) SUMMARY
    A) Glatiramer is classified as FDA pregnancy category B. At the time of this review, there were no well-controlled studies in pregnant women or nursing mothers. Reproductive studies in rats and rabbits indicated no impairment of fertility and no adverse effects on embryo fetal development, delivery, or offspring growth and development.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: No adverse effects on embryofetal development were reported in rats and rabbits with exposures of 18 and 36 times, respectively, the therapeutic human dose of 20 mg/day during organogenesis. No significant effects on delivery or on offspring growth and development were noted when rats received glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Glatiramer has been classified by the manufacturer as FDA pregnancy category B (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).
    2) There are no adequate and well-controlled studies of glatiramer use during pregnancy. In animal studies of glatiramer use, there were no adverse effects on embryofetal development, delivery, or on offspring growth and development. Due to the lack of human safety information, glatiramer should be used in pregnant women only if clearly needed (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).
    B) LACK OF EFFECT
    1) Further analysis from a previous, prospective study in patients with multiple sclerosis showed that exposure to glatiramer acetate (GA) during pregnancy was not associated with a significantly increased risk of spontaneous abortion or other negative pregnancy or fetal outcomes as compared to non-exposed pregnancies. Data were collected on 423 pregnancies that occurred in 415 women from the period of January 2002 to January 2008; of these 423 pregnancies, 17 were exposed to GA, 88 were exposed to interferon beta (IFNB), and 318 were non-exposed pregnancies (defined as suspension of the drug at least 4 weeks prior to conception or never-treated pregnancies). Exposure to GA did not increase the risk of spontaneous abortion as compared with non-exposure (5.9% vs 6.3%; odds ratio (OR), 0.44; 95% CI, 0.04 to 4.51; p=0.492). The frequency of premature deliveries was not significantly higher in patients exposed to GA than in those non-exposed (25% vs 20.1% of full-term deliveries, respectively). Mean birthweight and length were not significantly different in pregnancies exposed to GA (3357 +/- 616 g; 50.1 +/- 3.1 cm, respectively) than in non-exposed pregnancies (3209 +/- 488 g; 49.9 +/- 3.2 cm, respectively; p=0.751). These finding were confirmed in a multivariate analysis. Maternal complications were observed in 4 of 16 full-term deliveries (25%) in the GA-exposed group, all of which were minor, compared with 28 of 190 (15%) in the non-exposed group, some of which were major. No fetal complication was reported for GA-exposed pregnancies (Giannini et al, 2012).
    2) A cohort study of women with highly active relapsing-remitting multiple sclerosis (RRMS) treated with glatiramer acetate (GA) throughout pregnancy revealed no serious drug related adverse effects. Of the 22 women presented with the option of continuing treatment with GA through contraception and pregnancy, 14 women became pregnant resulting in 13 live births and 2 spontaneous abortions. Of the 13 live births, 9 were exposed to GA at the time of conception, throughout pregnancy, and following delivery and 11 of the births occurred at term. The mean birth weight of the babies born at term was 3318 g (range: 2331 to 4536 g) with no identified birth defects. Of the 14 pregnancies, 2 resulted in spontaneous abortion in a 33-year-old woman and 41-year-old woman at week 7 and week 13, respectively. The 33-year-old patient stopped treatment with GA at 4 weeks postconception while the 41-year-old patient was receiving treatment at the time of miscarriage. A total of 2 patients experienced relapse following discontinuation of GA (Salminen et al, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BREASTFEEDING
    a) No reports describing the use of glatiramer during human lactation are available, and the effects on the nursing infant from exposure to the drug in milk are unknown. Because many drugs are excreted in human milk, caution should be used when administering glatiramer to a nursing mother (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: There were no significant effects on reproductive or developmental parameters in rat offspring exposed to doses equivalent to 18 times the human dose before and during mating (males and females) and from day 15 of gestation throughout lactation (females) (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, in vitro and in vivo studies indicate no carcinogenic potential.
    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) At the time of this review, in vitro and in vivo studies have demonstrated no carcinogenic potential for glatiramer (Ziemssen et al, 2001).

Genotoxicity

    A) Glatiramer was not found to be mutagenic in four strains of Salmonella typhimurium and two strains Escherichia coli (Ames test), or in the in vitro mouse lymphoma assay in L5178Y cells (Prod Info Copaxone(R), glatiramer acetate, 2000).
    B) It was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes; but was not clastogenic in an in vivo mouse bone marrow micronucleus assay (Prod Info Copaxone(R), glatiramer acetate, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Monitor for evidence of an acute allergic reaction (eg urticaria, wheezing, angioedema).
    C) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with chest pain.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Laboratory abnormalities (blood and urine analyses) have not been reported during therapeutic use (Bornstein et al, 1991; Johnson et al, 1998).
    2) No specific laboratory monitoring is indicated following overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs in symptomatic patients. Monitor for evidence of an acute allergic reaction (eg urticaria, wheezing, angioedema). Monitor ECG in patients with chest pain or complaints of palpitations following a significant exposure.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients demonstrating severe allergic reactions should be admitted for observation.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients with overdose ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) Monitor vital signs.
    B) Monitor for evidence of an acute allergic reaction (eg urticaria, wheezing, angioedema).
    C) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with chest pain.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) At the time of this review, mild adverse events following glatiramer exposure have been reported. Due to the route of administration, gastrointestinal decontamination is generally NOT indicated.

Range Of Toxicity

Summary

    A) At the time of this review, there are no published reports of acute overdose exposures resulting in toxicity.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is subQ glatiramer acetate 20 mg/mL administered once daily or 40 mg/mL administered 3 times per week (at least 48 hours apart) (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of glatiramer have not been established in persons under 18 years of age (Prod Info COPAXONE(R) subcutaneous injection solution, 2014).

Minimum Lethal Exposure

    A) GENERAL
    1) At the time of this review, a minimum lethal exposure in humans has not been determined.

Maximum Tolerated Exposure

    A) GENERAL
    1) At the time of this review, a maximum tolerated exposure in humans has not been determined.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Glatiramer (formerly known as copolymer-1), a random polymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, is a synthetic polypeptide, which has some structural similarity to myelin basic protein (Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).
    B) The mechanism of action of glatiramer as it relates to multiple sclerosis has not been well understood; however, it is thought to modify immune processes through glatiramer-activated T-cells.(Prod Info COPAXONE(R) solution for subcutaneous injection, 2009). Multiple sclerosis histologically resembles an immune disease, and is characterized microscopically by perivascular cuffing and infiltration with immune-competent cells (i.e., lymphocytes and macrophages) that are dispersed into surrounding white matter (Rolak, 1987). Glatiramer was produced to suppress/modify the immune processes that are believed to be associated with multiple sclerosis (Rolak, 1987; Prod Info COPAXONE(R) solution for subcutaneous injection, 2009).
    C) Based on clinical and laboratory studies, it has been suggested that glatiramer is directly able to interfere with antigen (myelin basic protein) presentation by antigen-presenting cells to effector T lymphocytes, and, ultimately, partially blocking the putative demyelinating cascade (Ge et al, 2000).
    D) It has been speculated that glatiramer acetate-reactive T-helper 2-like cells are able to cross the blood-brain barrier, since they are activated by daily immunization. Once inside the CNS, glatiramer acetate-reactive T cells may cross-react with products of the local myelin turnover presented by local antigen-presenting cells. It is further hypothesized that some of the glatiramer acetate-reactive T-helper 2 cells may be stimulated to release anti-inflammatory cytokines and even neurotrophic factors. In an animal model, it was found that the production of postinflammatory cytokines by other inflammatory cells was reduced by a suppressive bystander effect (Ziemssen et al, 2001).

Physicochemical

Physical Characteristics

    A) Glatiramer is a white to off-white, sterile, lyophilized powder (Prod Info Copaxone(R), glatiramer acetate, 2000).

Molecular Weight

    A) The average molecular weight of glatiramer is 4,700 to 11,000 daltons (Prod Info Copaxone(R), glatiramer acetate, 2000).

References

General Bibliography

    1) Anon: Glatiramer acetate for multiple sclerosis. Drug and Therapeutics Bulletin 2001; 39:41-43.
    2) Bornstein MB, Miller A, & Slagle S: A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurol 1991; 41:533-539.
    3) Bornstein MB, Miller A, & Slagle S: Clinical experience with COP-1 in multiple sclerosis. Neurol 1988; 38(Suppl 2):66-69.
    4) Comi G, Filippi M, & Wolinsky JS: 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 Nerol 2001; 49:290-297.
    5) Ge Y, Grossman RI, & Udupa JK: Glatiramer acetate (copaxone) treatment in relapsing-remitting MS - quantitative MR assessment. Am Acad Neurol 2000; 54:813-817.
    6) Giannini M, Portaccio E, Ghezzi A, et al: Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol 2012; 12:124.
    7) Hwang L & Orengo I: Lipoatrophy associated with glatiramer acetate injections for the treatment of multiple sclerosis. Cutis 2001; 68:287-288.
    8) Johnson KP, Brooks BR, & Cohen JA: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurol 1995; 45:1268-1276.
    9) Johnson KP, Brooks BR, & Cohen JA: Extended use of glatiramer acetate (copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Am Acad Neurol 1998; 50:701-708.
    10) Lea AP & Goa KL: Copolymer-1 - A review of its pharmacological properties and therapeutic potential in multiple sclerosis. Clin Immunother 1996; 6:319-331.
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