(glatiramer acetate for injection)
COPAXONE(r) is the brand name for glatiramer acetate (formerly known as copolymer-1). Glatiramer acetate, the active ingredient of COPAXONE(r), consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 4,700-11,000 daltons. Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is: (Glu, Ala, Lys, Tyr)x xCH3COOH (C5H9NO4 C3H7NO2 C6H14N2O2 C9H11NO3)x xC2H4O2 CAS - 147245-92-9 COPAXONE(r) is a white to off-white, sterile, lyophilized powder containing 20 mg of glatiramer acetate and 40 mg of mannitol. It is supplied in single-use vials for subcutaneous administration after reconstitution with the diluent supplied (Sterile Water for Injection).
The mechanism(s) by which glatiramer acetate exerts its effects in patients with Multiple Sclerosis (MS) is (are) not fully elucidated. However, it is thought to act by modifying immune processes that are currently believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental allergic encephalomyelitis (EAE), a condition induced in several animal species through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally occurring immune responses. Results of a limited battery of tests designed to evaluate this risk produced no finding of concern; nevertheless, there is no logical way to absolutely exclude this possibility (see PRECAUTIONS).
Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support the assumption that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Nevertheless, larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.
Evidence supporting the effectiveness of glatiramer acetate in decreasing the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RR MS) derives from two placebo-controlled trials, both of which used a glatiramer acetate dose of 20 mg/day. (No other dose or dosing regimen has been studied in placebo-controlled trials of RR MS.) One trial was performed at a single center. It enrolled 50 patients who were randomized to receive daily doses of either glatiramer acetate, 20 mg subcutaneously, or placebo (glatiramer acetate, n=25; placebo, n=25). Patients were diagnosed with RR MS by standard criteria, and had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging from 0-Normal to 10-Death due to MS. A score of 6 is defined as one at which a patient is still ambulatory with assistance; a score of 7 means the patient must use a wheelchair. Patients were examined every 3 months for 2 years, as well as within several days of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours). The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the 2 years of the trial, but two other important outcomes were also specified as endpoints: 1) the frequency of attacks during the trial, and 2) the change in the number of attacks compared with the number which occurred during the previous 2 years. Table 1 presents the values of the three outcomes described above, as well as several protocol specified secondary measures. These values are based on the intent-to-treat population (i.e., all patients who received at least 1 dose of treatment and who had at least 1 on-treatment assessment):
| Outcome | Glatiramer Acetate (N=25) | Placebo (N=25) | P-Value |
| % Relapse Free Patients | 14/25 (56%) | 7/25 (28%) | 0.085 |
| Mean Relapse Frequency | 0.6/2 years | 2.4/2 years | 0.005 |
| Reduction in Relapse Rate Compared to Pre- | 3.2 | 1.6 | 0.025 |
| Study | |||
| Median Time to First Relapse (days) | >700 | 150 | 0.03 |
| % of Progression- Free * Patients | 20/25 (80%) | 13/25 (52%) | 0.07 |
*Progression was defined as an increase of at least 1 point on the DSS, persisting for at least 3 consecutive months. The second trial was a multicenter trial of similar design which was performed in 11 US centers. A total of 251 patients (glatiramer acetate, 125; placebo, 126) were enrolled. The primary outcome measure was the Mean 2-year Relapse Rate. The table below presents the values of this outcome for the intent-to-treat population, as well as several secondary measures.
| Outcome | Glatiramer Acetate (N=125) | Placebo (N=126) | P-Value |
| Mean No. of Relapses | 1.19/2 years | 1.68 /2 years | 0.055 |
| % Relapse Free Patients | 42/125 (34%) | 34/126 (27%) | 0.25 |
| Median Time to First Relapse (days) | 287 | 198 | 0.23 |
| % of Patients Progression Free | 98/125 (78%) | 95/126 (75%) | 0.48 |
| Mean Change in DSS | -0.05 | +0.21 | 0.023 |
In both studies glatiramer acetate exhibited a clear beneficial effect on relapse rate, and it is based on this evidence that glatiramer acetate is considered effective. A third study was a multi-national study in which MRI parameters were used both as primary and secondary endpoints. A total of 239 patients with RR MS (119 on glatiramer acetate and 120 on placebo) were randomized. Inclusion criteria were similar to those in the second study with the additional criterion that patients had to have at least one Gd-enhancing lesion on the screening MRI. The patients were treated in a double-blind manner for nine months, during which they underwent monthly MRI scanning. The primary endpoint for the double-blind phase was the total cumulative number of T1 Gd-enhancing lesions over the nine months. Table 3 summarizes the result for the primary outcome measures monitored during the trial for the intent-to-treat cohort.
| Outcome | Glatiramer | Placebo | p-value |
| Acetate (N=119) | (N=120) | ||
| Medians of the Cumulative Number of T1 Gd- Enhancing Lesions | 11 | 17 | 0.0030 |
The following figure displays the results of the primary outcome on a monthly basis.
Cumulative Number of Enhancing Lesions (median)
Copaxone
14 Placebo
0 1 2 3 4 5 6 7 8 9
Months
p= 0.003 for the difference between the placebo-treated (n=120) and glatiramer acetate- treated (n=119) groups.
COPAXONE(r) is indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis.
COPAXONE(r) is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.
The only recommended route of administration of COPAXONE(r) injection is the subcutaneous route. COPAXONE(r) should not be administered by the intravenous route.
Patients should be instructed in self-injection techniques to assure the safe administration of COPAXONE(r) (see PRECAUTIONS: Information for Patients and the COPAXONE(r) PATIENT INFORMATION Booklet). Current data indicate that no special caution is required for patients operating an automobile or using complex machinery.
Because glatiramer acetate can modify immune response, it could possibly interfere with useful immune functions. For example, treatment with glatiramer acetate might, in theory, 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 glatiramer acetate does this, but there has as yet been no systematic evaluation of this risk. Because glatiramer acetate 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 glatiramer acetate is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with glatiramer acetate might result in untoward effects. Glatiramer acetate-reactive antibodies are formed in practically all patients exposed to daily treatment with the recommended dose. 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 RR MS patients given glatiramer acetate, 20 mg, subcutaneously every day for 2 years, serum lgG 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 lgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the lgG subtype-and predominantly of the lgG-1 subtype. No lgE 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.
To assure safe and effective use of COPAXONE(r), the following information and instructions should be given to patients:
Inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while taking this medication.
Inform your physician if you are nursing.
Do not change the dose or dosing schedule without consulting your physician.
Do not stop taking the drug without consulting your physician.
Patients should be instructed in the use of aseptic techniques when administering COPAXONE(r). Appropriate instructions for the reconstitution and self-injection of COPAXONE(r) should be given, including a careful review of the COPAXONE(r) PATIENT INFORMATION Booklet. The first injection should be performed under the supervision of an appropriately qualified health care professional. Patient understanding and use of aseptic self-injection techniques and procedures should be periodically reevaluated. Patients should be cautioned against the reuse of needles or syringes and instructed in safe disposal procedures. They should use a puncture-resistant container for disposal of used needles and syringes. Patients should be instructed on the safe disposal of full containers according to local laws. Awareness of Adverse Reactions: Physicians are advised to counsel patients about adverse reactions associated with the use of COPAXONE(r) (see ADVERSE REACTIONS section). In addition, patients should be advised to read the COPAXONE(r) PATIENT INFORMATION Booklet and resolve any questions regarding it prior to beginning COPAXONE(r) therapy.
Data collected during premarketing development do not suggest the need for routine laboratory monitoring.
Interactions between COPAXONE(r) and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of COPAXONE (r) with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. COPAXONE(r) has not been formally evaluated in combination with Interferon beta.
None are known.
Carcinogenesis In a two-year carcinogenicity study, mice were administered up to 60-mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on a mg/m2 basis). No increase in systemic neoplasms was observed. In males of the high dose group (60 mg/kg/day), but not in females, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over a limited skin area. In a two-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on a mg/m2 basis). No increase in systemic neoplasms was observed. Mutagenesis Glatiramer acetate was not mutagenic in four strains of Salmonella typhimurium and two strains of Escherichia coli (Ames test) or in the in vitro mouse lymphoma assay in L5178Y cells. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes; it was not clastogenic in an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility In a multigeneration reproduction and fertility study in rats, glatiramer acetate at subcutaneous doses of up to 36 mg/kg (18 times the human therapeutic dose on a mg/m2 basis) had no adverse effects on reproductive parameters. Pregnancy: Pregnancy Category B. No adverse effects on embryofetal development occurred in Reproduction studies in rats and rabbits receiving subcutaneous doses of up to mg/kg of glatiramer acetate during the period of organogenesis (18 and 36 times the therapeutic human dose on a mg/m2 basis respectively). In a prenatal and postnatal study in which rats received subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, glatiramer acetate should be used during pregnancy only if clearly needed.
In a prenatal and postnatal study, in which rats received subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery were observed. The relevance of these findings to humans is unknown.
It is not known whether glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when COPAXONE(r) is administered to a nursing woman.
The safety and efficacy of COPAXONE(r) have not been established in individuals under 18 years of age.
COPAXONE(r) has not been studied specifically in elderly patients.
The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined.
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
>=
Glatiramer Acetate (N = 201)
Placebo (N = 206)
Preferred Term N % N %
| Body as a Whole | ||||
| Asthenia | 83 | 41 | 78 | 38 |
| Back Pain | 33 | 16 | 30 | 15 |
| Bacterial Infection | 11 | 5 | 9 | 4 |
| Chest Pain | 43 | 21 | 22 | 11 |
| Chills | 8 | 4 | 2 | 1 |
| Cyst | 5 | 2 | 1 | 0 |
| Face Edema | 12 | 6 | 2 | 1 |
| Fever | 17 | 8 | 15 | 7 |
| Flu Syndrome | 38 | 19 | 35 | 17 |
| Infection | 101 | 50 | 99 | 48 |
| Injection Site Erythema | 132 | 66 | 40 | 19 |
| Injection Site Hemorrhage | 11 | 5 | 6 | 3 |
| Injection Site Induration | 26 | 13 | 1 | 0 |
Glatiramer Acetate (N = 201)
Placebo (N = 206) | ||||
|---|---|---|---|---|
| Preferred Term | N | % | N | % |
| Injection Site Inflammation | 98 | 49 | 22 | 11 |
| Injection Site Mass | 54 | 27 | 21 | 10 |
| Injection Site Pain | 147 | 73 | 78 | 38 |
| Injection Site Pruritus | 80 | 40 | 12 | 6 |
| Injection Site Urticaria | 10 | 5 | 0 | 0 |
| Injection Site Welt | 22 | 11 | 5 | 2 |
| Neck Pain | 16 | 8 | 9 | 4 |
| Pain | 56 | 28 | 52 | 25 |
Cardiovascular System
| Migraine | 10 | 5 | 5 | 2 |
| Palpitations | 35 | 17 | 16 | 8 |
| Syncope | 10 | 5 | 5 | 2 |
| Tachycardia | 11 | 5 | 8 | 4 |
| Vasodilatation | 55 | 27 | 21 | 10 |
| Digestive System | ||||
| Anorexia | 17 | 8 | 15 | 7 |
| Diarrhea | 25 | 12 | 23 | 11 |
| Gastroenteritis | 6 | 3 | 2 | 1 |
| Gastrointestinal Disorder | 10 | 5 | 8 | 4 |
| Nausea | 44 | 22 | 34 | 17 |
| Vomiting | 13 | 6 | 8 | 4 |
Hemic and Lymphatic System
Ecchymosis 16 8 13 6
Glatiramer Acetate (N = 201)
Placebo (N = 206) | ||||
|---|---|---|---|---|
| Preferred Term | N | % | N | % |
| Lymphadenopathy | 25 | 12 | 12 | 6 |
| Metabolic and Nutritional | ||||
| Edema | 5 | 3 | 1 | 0 |
| Peripheral Edema | 14 | 7 | 8 | 4 |
| Weight Gain | 7 | 3 | 0 | 0 |
Musculoskeletal System
Arthralgia 49 24 39 19
Nervous System
| Agitation | 8 | 4 | 4 | 2 |
| Anxiety | 46 | 23 | 40 | 19 |
| Confusion | 5 | 2 | 1 | 0 |
| Foot Drop | 6 | 3 | 4 | 2 |
| Hypertonia | 44 | 22 | 37 | 18 |
| Nervousness | 4 | 2 | 2 | 1 |
| Nystagmus | 5 | 2 | 2 | 1 |
| Speech Disorder | 5 | 2 | 3 | 1 |
| Tremor | 14 | 7 | 7 | 3 |
| Vertigo | 12 | 6 | 11 | 5 |
Respiratory System
| Bronchitis | 18 | 9 | 12 | 6 |
| Dyspnea | 38 | 19 | 15 | 7 |
| Laryngismus | 10 | 5 | 7 | 3 |
| Rhinitis | 29 | 14 | 27 | 13 |
Glatiramer Acetate (N = 201)
Placebo (N = 206) | ||||
|---|---|---|---|---|
| Erythema | 8 | 4 | 4 | 2 |
| Herpes Simplex | 8 | 4 | 6 | 3 |
| Pruritus | 36 | 18 | 26 | 13 |
| Rash | 37 | 18 | 30 | 15 |
| Skin Nodule | 4 | 2 | 1 | 0 |
| Sweating | 31 | 15 | 21 | 10 |
| Urticaria | 9 | 4 | 5 | 2 |
Preferred Term N % N % Skin and Appendages
Special Senses
| Ear Pain | 15 | 7 | 12 | 6 |
| Eye Disorder | 8 | 4 | 1 | 0 |
Urogenital System
| Dysmenorrhea | 12 | 6 | 10 | 5 |
| Urinary Urgency | 20 | 10 | 17 | 8 |
| Vaginal Moniliasis | 16 | 8 | 9 | 4 |
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(r) 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:
requent: Injection site edema, injection site atrophy, abscess, injection site hypersensitivity.
requent: 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:
requent:
Hypertension.
requent:
Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins.
Digestive:
requent:
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:
requent: Goiter, hyperthyroidism, and hypothyroidism.
Gastrointestinal:
requent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.
Hemic and Lymphatic:
requent:
Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly.
Metabolic and Nutritional:
n frequent:
Weight loss, alcohol intolerance, Cushing's syndrome, gout, abnormal healing, and xanthoma.
Musculoskeletal:
requent:
Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis.
Nervous:
requent:
Abnormal dreams, emotional lability, and stupor.
requent:
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:
requent:
Hyperventilation, hay-fever.
requent:
Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.
Skin and Appendages:
requent:
Eczema, herpes zoster, pustular rash, skin atrophy, and warts.
requent:
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:
requent:
Visual field defect.
requent:
Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss.
Urogenital:
requent:
Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency and vaginal hemorrhage.
requent: 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 (r)(glatiramer acetate) 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
No evidence or experience suggests that abuse or dependence occurs with COPAXONE(r) therapy; however, the risk of dependence has not been systematically evaluated.
The recommended dose of COPAXONE(r) for the treatment of RR MS is 20 mg/day injected subcutaneously.
To reconstitute lyophilized COPAXONE(r) for injection, use a sterile syringe and Mixject Vial Adapter to transfer the diluent supplied, Sterile Water for Injection, into the COPAXONE(r) vial. Gently swirl the vial of COPAXONE(r) and let stand at room temperature until the solid material is completely dissolved. Inspect the reconstituted product visually and discard or return the product to the pharmacist before use if it contains particulate matter. Soon after reconstitution, withdraw the solution into the syringe. Replace the Mixject Vial Adapter with a 27 gauge, 1/2" needle and inject the solution subcutaneously. Sites for self-injection include arms, abdomen, hips, and thighs. A vial is suitable for single use only; unused portions should be discarded. (See the COPAXONE(r) PATIENT INFORMATION Booklet for INSTRUCTIONS FOR INJECTING COPAXONE(r).)
COPAXONE(r) is supplied as a sterile, lyophilized material containing 20 mg of glatiramer acetate and 40 mg of mannitol, USP. The drug is packaged in a USP Type 1 amber glass, single-use 2 mL vial. A separate vial, containing 1.1 mL of diluent (Sterile Water for Injection) is included for each vial of drug. The recommended storage condition for the unreconstituted product is refrigeration (2oC to 8oC / 36oF to 46oF). However, excursions from recommended storage conditions to room temperature conditions (15o to 30oC / 59o to 86o F) for up to one week have been shown to have no adverse impact on the product. Exposure to higher temperatures or intense light should be avoided. The diluent may be stored at room temperature. COPAXONE(r) contains no preservative. It should be used immediately after reconstitution. COPAXONE(r) is available in packs of 32 amber vials of sterile, lyophilized material for subcutaneous injection (NDC 0088-1150-03). The diluent for COPAXONE(r) is supplied in packs of 32 clear vials.