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
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 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.
Table 1: Adverse reactions in controlled clinical trials
with an incidence ≥ 2% of patients and more frequent with COPAXONE than
with placebo
| |
|
GA 20 mg
(N=563) |
Placebo
(N=564) |
| Blood And Lymphatic System Disorders |
Lymphadenopathy |
7% |
3% |
| Cardiac Disorders |
Palpitations |
9% |
4% |
| Tachycardia |
5% |
2% |
| Eye Disorders |
Eye Disorder |
3% |
1% |
| Diplopia |
3% |
2% |
| Gastrointestinal Disorders |
Nausea |
15% |
11% |
| Vomiting |
7% |
4% |
| Dysphagia |
2% |
1% |
| General Disorders And Administration Site Conditions |
Injection Site Erythema |
43% |
10% |
| Injection Site Pain |
40% |
20% |
| Injection Site Pruritus |
27% |
4% |
| Injection Site Mass |
26% |
6% |
| Asthenia |
22% |
21% |
| Pain |
20% |
17% |
| Injection Site Edema |
19% |
4% |
| Chest Pain |
13% |
6% |
| Injection Site Inflammation |
9% |
1% |
| Edema |
8% |
2% |
| Injection Site Reaction |
8% |
1% |
| Pyrexia |
6% |
5% |
| Injection Site Hypersensitivity |
4% |
0% |
| Local Reaction |
3% |
1% |
| Chills |
3% |
1% |
| Face Edema |
3% |
1% |
| Edema Peripheral |
3% |
2% |
| Injection Site Fibrosis |
2% |
1% |
| Injection Site Atrophy* |
2% |
0% |
| Immune System Disorders |
Hypersensitivity |
3% |
2% |
| Infections And Infestations |
Infection |
30% |
28% |
| Influenza |
14% |
13% |
| Rhinitis |
7% |
5% |
| Bronchitis |
6% |
5% |
| Gastroenteritis |
6% |
4% |
| Vaginal Candidiasis |
4% |
2% |
| Metabolism And Nutrition Disorders |
Weight Increased |
3% |
1% |
| Musculoskeletal And Connective Tissue Disorders |
Back Pain |
12% |
10% |
| Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps) |
Benign Neoplasm of Skin |
2% |
1% |
| Nervous System Disorders |
Tremor |
4% |
2% |
| Migraine |
4% |
2% |
| Syncope |
3% |
2% |
| Speech Disorder |
2% |
1% |
| Psychiatric Disorders |
Anxiety |
13% |
10% |
| Nervousness |
2% |
1% |
| Renal And Urinary Disorders |
Micturition Urgency |
5% |
4% |
| Respiratory, Thoracic And Mediastinal Disorders |
Dyspnea |
14% |
4% |
| Cough |
6% |
5% |
| Laryngospasm |
2% |
1% |
| Skin And Subcutaneous Tissue Disorders |
Rash |
19% |
11% |
| Hyperhidrosis |
7% |
5% |
| Pruritus |
5% |
4% |
| Urticaria |
3% |
1% |
| Skin Disorder |
3% |
1% |
| Vascular Disorders |
Vasodilatation |
20% |
5% |
| *Injection site atrophy comprises terms relating to localized
lipoatrophy at injection site |
Adverse reactions which occurred only in 4-5 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 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, 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 and 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 Experience
Reports of adverse events occurring under treatment with COPAXONE not mentioned above that have been received since market introduction and may or may not have causal relationship to COPAXONE are listed below. 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; 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