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Overview
Glatiramer acetate is a immunologic adjuvant that is FDA approved for the treatment of relapsing forms of multiple sclerosis.. Common adverse reactions include injection site reactions, vasodilatation, rash, dyspnea, and chest pain.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Multiple sclerosis
COPAXONE is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
Dosing Information
COPAXONE is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are:
COPAXONE 20 mg per mL: administer once per day or
COPAXONE 40 mg per mL: administer three times per week and at least 48 hours apart
COPAXONE 20 mg per mL and COPAXONE 40 mg per mL are not interchangeable.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Glatiramer acetate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Glatiramer acetate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy have not been established in pediatric patients
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Glatiramer acetate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Glatiramer acetate in pediatric patients.
Contraindications
COPAXONE is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.
Warnings
Immediate Post-Injection Reaction
Approximately 16% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms immediately after injection that included at least two of the following: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a specific syndrome is uncertain. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown.
Chest Pain
Approximately 13% of COPAXONE 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to 1% of placebo patients, experienced at least one episode of transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least 1 month after the initiation of treatment. The pathogenesis of this symptom is unknown.
Lipoatrophy and Skin Necrosis
At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy occurred in approximately 2% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo-controlled trials compared to none on placebo, and 0.5% of patients exposed to COPAXONE 40 mg per mL in a single placebo-controlled trial and none on placebo. Skin necrosis has only been observed in the post-marketing setting. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection.
Potential Effects on Immune Response
Because COPAXONE can modify immune response, it may interfere with immune functions. For example, treatment with COPAXONE may interfere with the recognition of foreign antigens in a way that would undermine the body's tumor surveillance and its defenses against infection. There is no evidence that COPAXONE does this, but there has not been a systematic evaluation of this risk. Because COPAXONE is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken.
Although COPAXONE is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with COPAXONE may result in untoward effects.
Glatiramer acetate-reactive antibodies are formed in most patients receiving glatiramer acetate. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of 125 RRMS patients given COPAXONE 20 mg per mL, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the IgG subtype and predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Incidence in Controlled Clinical Trials
COPAXONE 20 mg per mL per day
Among 563 patients treated with COPAXONE in blinded placebo-controlled trials, approximately 5% of the subjects discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity. The most common adverse reactions were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain.
Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 20 mg per mL in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with COPAXONE than in patients treated with placebo. Adverse reactions were usually mild in intensity.
Injection site atrophy comprises terms relating to localized lipoatrophy at injection site
Adverse reactions which occurred only in 4 to 5 more subjects in the COPAXONE group than in the placebo group (less than 1% difference), but for which a relationship to COPAXONE could not be excluded, were arthralgia and herpes simplex.
Laboratory analyses were performed on all patients participating in the clinical program for COPAXONE. Clinically-significant laboratory values for hematology, chemistry, and urinalysis were similar for both COPAXONE and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 x109/L), which resolved after discontinuation of treatment.
Data on adverse reactions occurring in the controlled clinical trials of COPAXONE 20 mg per mL were analyzed to evaluate differences based on sex. No clinically-significant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. The majority of patients treated with COPAXONE were between the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age subgroups.
Other Adverse Reactions
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled premarketing studies (n= 979), the role of COPAXONE in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used COPAXONE and reported a reaction divided by the total number of patients exposed to COPAXONE. All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring in at least 1/100 patients and infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients.
Body as a Whole:
Frequent: Abscess
Infrequent: Injection site hematoma, moon face, cellulitis, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction.
Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis.
COPAXONE 40 mg per mL three times per week
Among 943 patients treated with COPAXONE 40 mg per mL three times per week in a blinded, placebo-controlled trial, approximately 3% of the subjects discontinued treatment because of an adverse reaction. The most common adverse reactions were injection site reactions, which were also the most common cause of discontinuation.
Table 2 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with COPAXONE 40 mg per mL in the blinded, placebo-controlled trial. These signs and symptoms were numerically more common in patients treated with COPAXONE 40 mg per mL than in patients treated with placebo. Adverse reactions were usually mild in intensity.
No new adverse reactions appeared in subjects treated with COPAXONE 40 mg per mL three times per week as compared to subjects treated with COPAXONE 20 mg per mL per day in clinical trials and during postmarketing experience. Data on adverse reactions occurring in the controlled clinical trial of COPAXONE 40 mg per mL were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-eight percent of patients in this clinical trial were Caucasian and the majority were between the ages of 18 and 50. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age groups.
Postmarketing Experience
The following adverse events occurring under treatment with COPAXONE 20 mg per mL since market introduction and not mentioned above have been identified during postapproval use of COPAXONE. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic reaction; anaphylactoid reaction
Respiratory System: pulmonary embolus; pleural effusion; carcinoma of lung
Special Senses: glaucoma; blindness
Urogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency
Drug Interactions
Interactions between COPAXONE and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated in combination with interferon beta.
Interactions between COPAXONE and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated in combination with interferon beta.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glatiramer acetate in women who are pregnant.
Labor and Delivery
The effects of COPAXONE on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known if glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when COPAXONE is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of COPAXONE have not been established in patients under 18 years of age.
Geriatic Use
COPAXONE has not been studied in elderly patients.
Gender
There is no FDA guidance on the use of Glatiramer acetate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Glatiramer acetate with respect to specific racial populations.
Renal Impairment
The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined.
Hepatic Impairment
There is no FDA guidance on the use of Glatiramer acetate in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Glatiramer acetate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Glatiramer acetate in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Glatiramer acetate in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Glatiramer acetate in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Glatiramer acetate in the drug label.
Pharmacology
There is limited information regarding Glatiramer acetate Pharmacology in the drug label.
