During premarketing clinical trials approximately 900 individuals received at least one dose of glatiramer acetate.

In controlled clinical trials the most commonly observed adverse experiences associated with the use of glatiramer acetate and not seen at an equivalent frequency among placebo-treated patients were: injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety, and hypertonia. Approximately 8% of the 893 subjects receiving glatiramer acetate discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reaction (6.5%), vasodilatation, unintended pregnancy, depression, dyspnea, urticaria, tachycardia, dizziness, and tremor.

Immediate Post-Injection Reaction

Approximately 10% of MS patients exposed to glatiramer acetate in premarketing studies experienced a constellation of symptoms immediately after injection that included flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In clinical trials, the symptoms were generally transient and self-limited and did not require specific treatment. 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. During the postmarketing period, there have been reports of patients with similar symptoms who received emergency medical care.

Whether an immunologic or non-immunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown.

Chest Pain

Approximately 21% of glatiramer acetate patients in the pre-marketing controlled studies (compared to 11% of placebo patients) experienced at least one episode of what was described as 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 of glatiramer acetate was not always known. The pain was transient (usually lasting only a few minutes), often unassociated with other symptoms, and appeared to have no important clinical sequelae. There has been only one episode of chest pain during which a full EKG was performed; that EKG showed no evidence of ischemia. 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.

Incidence in Controlled Clinical Studies: The following table lists treatment-emergent signs and symptoms that occurred in at least 2% of MS patients treated with glatiramer acetate in the pre-marketing placebo controlled trials. These signs and symptoms were numerically more common in patients treated with glatiramer acetate than in patients treated with placebo. These trials include the first two controlled trials in RR MS patients and a controlled trial in patients with Chronic-Progressive MS. Adverse reactions were usually mild in intensity.

The prescriber should be aware that these figures cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis on which to estimate the relative contribution of drug and nondrug factors to the adverse reaction incidences in the population studied.

Controlled Trials in Patients with Multiple Sclerosis:
Incidence of Glatiramer Acetate Adverse Reactions ≥2% and More Frequent than Placebo

Other events which occurred in at least 2% of glatiramer acetate patients but were present at equal or greater rates in the placebo group included:

Body as a Whole: Headache, injection site ecchymosis, accidental injury, abdominal pain, allergic rhinitis, neck rigidity, and malaise.

Digestive System: Dyspepsia, constipation, dysphagia, fecal incontinence, flatulence, nausea and vomiting, gastritis, gingivitis, periodontal abscess, and dry mouth.

Musculoskeletal: Myasthenia and myalgia.

Nervous System: Dizziness, hypesthesia, paresthesia, insomnia, depression, dysesthesia, incoordination, somnolence, abnormal gait, amnesia, emotional lability, Lhermitte's sign, abnormal thinking, twitching, euphoria, and sleep disorder.

Respiratory System: Pharyngitis, sinusitis, increased cough, and laryngitis.

Skin and Appendages: Acne, alopecia, and nail disorder.

Special Senses: Abnormal vision, diplopia, amblyopia, eye pain, conjunctivitis, tinnitus, taste perversion, and deafness.

Urogenital System: Urinary tract infection, urinary frequency, urinary incontinence, urinary retention, dysuria, cystitis, metrorrhagia, breast pain, and vaginitis.

Data on adverse reactions occurring in the controlled clinical trials were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-two percent of patients in these clinical trials were Caucasian. This percentage reflects the racial composition of the MS population. In addition, the vast 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.

Laboratory analyses were performed on all patients participating in the clinical program for glatiramer acetate.

Clinically significant laboratory values for hematology, chemistry, and urinalysis were similar for both glatiramer acetate and placebo groups in blinded clinical trials. No patient receiving glatiramer acetate withdrew from any trial because of abnormal laboratory findings.

Other Adverse Events Observed During Clinical Trials

Glatiramer acetate was administered to 979 individuals during premarketing clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators, using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into standardized categories using COSTART dictionary terminology. All reported events occurring at least twice and potentially important events occurring once are listed below, except those already listed in the previous table, those too general to be informative, trivial events, and other reactions which occurred in at least 2% of treated patients and were present at equal or greater rates in the placebo group. Additional adverse reactions reported during the post-marketing period are included.

Events are further classified within body system categories and listed in order of decreasing frequency using the following definitions: Frequent adverse events are defined as those occurring in at least 1/100 patients; Infrequent adverse events are those occurring in 1/100 to 1/1000 patients; Rare adverse events are those occurring in less than 1/1000 patients.

Body as a Whole:

• Frequent: Injection site edema, injection site atrophy, abscess, injection site hypersensitivity.
  
• Infrequent: Injection site hematoma, injection site fibrosis, moon face, cellulitis, generalized edema, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction.

Cardiovascular:

• Frequent: Hypertension.
  
• Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins.

Digestive:

• Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder, pancreatitis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer.

Endocrine:

• Infrequent: Goiter, hyperthyroidism, and hypothyroidism.

Gastrointestinal:

• Frequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.

Hemic and Lymphatic:

• Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly.

Metabolic and Nutritional:

• Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal healing, and xanthoma.

Musculoskeletal:

• Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis.

Nervous:

• Frequent: Abnormal dreams, emotional lability, and stupor.
  
• Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, decreased libido, manic reaction,
  memory impairment, myoclonus, neuralgia, paranoid reaction, paraplegia, psychotic depression, and transient stupor.

Respiratory:

• Frequent: Hyperventilation, hay-fever.
  
• Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.

Skin and Appendages:

• Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts.
  
• Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmentation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash.

Special Senses:

• Frequent: Visual field defect.
  
• Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss.

Urogenital:

• Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency and vaginal hemorrhage.
  
• 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.

Postmarketing Clinical Experience

Postmarketing experience has shown an adverse event profile similar to that presented above. Reports of adverse reactions occurring under treatment with COPAXONE® (glatiramer acetate for injection) not mentioned above that have been received since market introduction and that may have or not have causal relationship to the drug include the following:

Body as a Whole: sepsis; LE syndrome; hydrocephalus; enlarged abdomen; injection site hypersensitivity; allergic reaction; anaphylactoid reaction

Cardiovascular System: thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris

Digestive System: tongue edema; stomach ulcer; hemorrhage; liver function abnormality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis

Hemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute leukemia Metabolic and Nutritional Disorders: hypercholesterolemia Musculoskeletal System: rheumatoid arthritis; generalized spasm

Nervous System: myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgia

Respiratory System: pulmonary embolus; pleural effusion; carcinoma of lung; hay fever Special Senses: glaucoma; blindness; visual field defect

Urogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency

Adverse Reactions Associated with Subcutaneous Use

At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis have been reported during the postmarketing experience. 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 areas and sites on a daily basis. (See PATIENT INFORMATION)

DRUG ABUSE AND DEPENDENCE

No evidence or experience suggests that abuse or dependence occurs with COPAXONE® Injection therapy; however, the risk of dependence has not been systematically evaluated.

Interactions between COPAXONE® Injection and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE® Injection with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE® Injection has not been formally evaluated in combination with Interferon beta.

Drug/Laboratory Test Interactions

None are known.

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