Copaxone
Copaxone is a clear, colourless solution for injection containing 20 mg of glatiramer acetate, 40 mg of mannitol and water for injection. Glatiramer acetate, the active ingredient of Copaxone, is the acetate salt of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L- tyrosine and L-lysine with an average molar fraction 0.141, 0.427, 0.095 and 0.338, respectively. The average molecular weight of glatiramer acetate is 5000 to 9000 daltons. Glatiramer acetate is a white to slightly yellowish lyophilised material which is sparingly soluble in water and insoluble in acetone. The pH of a 0.5% solution in water is in the range of 5.5 to 7.0. The structural formula of glatiramer acetate is shown below: Poly [ L-Glu13-15, L-Ala39-46, L-Tyr8.6-10, L-Lys30-37 ].n(CH3CO2H) n = 15 to 24 units per 100 amino acid residues. The superscripts in the formula above represent the molar fraction percent range of the amino acid residues comprising the various polypeptide species in glatiramer acetate where the sequence of the amino acid residues varies among the individual species. CAS Registry Number: 147245-92-9 CAS Registry Number of the free base: 28704-27-0
The precise mechanism by which glatiramer acetate exerts its effects in patients with multiple sclerosis (MS) is unknown. It is thought to act by modifying immune processes that are currently held to be responsible for the pathogenesis of MS. This view of glatiramer acetate derives from knowledge that it reduces the incidence and severity of experimental allergic encephalomyelitis (EAE) - a condition induced in several animal species through immunisation with CNS-derived material containing myelin and often used as an experimental animal model of MS.
There is no information regarding the absorption, distribution, metabolism or excretion profile of glatiramer acetate in humans as there is currently no direct and sensitive analytical method for measuring glatiramer acetate in biological fluids. Therefore all pharmacokinetic studies have been conducted in animals using radiolabelled glatiramer acetate. The methodology is limited because the radiolabel dissociates rapidly from glatiramer acetate and re-associates with other macromolecules. However the studies indicate that glatiramer acetate is readily absorbed; repetitive dosing has no effect on absorption; Cmax and AUC are linearly dependent across the administered glatiramer acetate dose range and there is no evidence of any tissue accumulation of glatiramer acetate. Results from studies with human tissues reveal rapid hydrolysis of glatiramer acetate by both subcutaneous and muscle tissues. In contrast, plasma has a "stabilising" effect on glatiramer acetate, which may be explained by the observation that it is 97.5% bound to plasma proteins in vitro. Based on results of animal studies and on the hydrolysis of glatiramer acetate by human tissues, it may be concluded that glatiramer acetate is extensively degraded at the site of subcutaneous injection. It has not been possible to determine the excretory fate of glatiramer acetate or its metabolites as they cannot be distinguished from naturally occurring amino acids or peptides. Although the concentration of glatiramer acetate in blood cannot be determined directly, three lines of evidence support it being bioavailable to the immune system, which is the site of its therapeutic activity:
Clinical efficacy in patients with relapsing-remitting multiple sclerosis.
Formation of antibodies to glatiramer acetate in treated patients.
Decline in the peripheral blood mononuclear cell proliferative response to glatiramer acetate following chronic exposure.
Evidence supporting the effectiveness of Copaxone for decreasing the frequency of relapses in patients with relapsing-remitting multiple sclerosis (RRMS) derives from two placebo controlled trials, both of which used a Copaxone dose of 20 mg/day. One trial enrolled 50 patients who were randomised to receive daily doses of Copaxone 20 mg or placebo subcutaneously. Patients were diagnosed with RRMS by standard criteria and had at least two exacerbations during the two years immediately preceding enrolment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Expanded Disability Scale Score (EDSS), 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 reviewed every 3 months for two years, as well as within several days of a presumed exacerbation. In order for an exacerbation to be confirmed, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (eg., the persistence of the lesion 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 two year trial, but two other important outcomes were also specified as endpoints: the frequency of relapses during the trial and the change in number of relapses compared to the previous two years. The following table presents the results of analyses of the three outcomes described above, as well as several other secondary measures. These analyses are based on the intent-to-treat population (i.e. all patients who received at least one dose of treatment and who had at least one on-treatment assessment).
| Outcome | Copaxone (n=25) | Placebo (n=25) |
| % relapse free | 56% | 28% |
| Mean relapse frequency in 2 years | 0.6 | 2.4 |
| Mean reduction in relapse rate compared to previous 2 years | 3.2 | 1.6 |
| Median time to first relapse (days) | > 700 | 150 |
| % of patients progression free * | 80% | 52% |
*Progression defined as an increase of at least 1 point on the EDSS that persists for at least 3
consecutive months.
The second trial was of similar design to the first study. A total of 251 patients were enrolled. The primary outcome measure was the mean 2 year relapse rate. The table below presents the results of the analysis of this outcome for the intent-to-treat population, as well as other secondary measures:
| Outcome | Copaxone (n=125) | Placebo (n=126) |
| Mean relapse rate in 2 years | 1.19 | 1.68 |
| % relapse free | 34% | 27% |
| Medium time to first relapse (days) | 287 | 198 |
| % of patients progression free | 78% | 75% |
| Mean change in EDSS * | -0.05 | +0.21 |
*
EDSS = Expanded DSS, using a 0.5 unit scale
Results also showed that glatiramer acetate reactive antibodies were present in all treated patient's sera, with maximal levels attained after a duration of 3-4 months. Thereafter antibody levels slowly declined and stabilised at a level slightly higher than baseline. The antibody profile in patients who experienced relapses was similar to that observed in all patients and the occurrence of relapses was independent of glatiramer acetate antibody production. The occurrence of systemic reactions had no correlation to glatiramer acetate antibody production. Analysis of glatiramer acetate antibody type revealed that specific IgG and not IgE antibodies were produced following chronic treatment with Copaxone. The ability of glatiramer acetate antibodies to neutralise the biological activity of glatiramer acetate was investigated in several in-vitro and in-vivo systems. No neutralising activity was exhibited by a variety of monoclonal and polyclonal glatiramer acetate antibodies, including those formed during long-term administration to MS patients. Thus antibody formation is unlikely to be associated with either short or long term safety issues and is unlikely to affect the clinical efficacy or the biological activity of Copaxone. In both studies, Copaxone exhibited a clear beneficial and statistically significant effect on relapse rate and it is on this basis that Copaxone is considered effective. Response rates were apparently better for those patients where therapy was initiated early in the course of the disease. A correlation between reduction in relapse frequency alone and a decreased risk of future disability remains to be established.
One placebo-controlled study involving 481 patients (Copaxone n=243, placebo n=238) was performed in patients with a well-defined, single, unifocal neurological manifestation and MRI features highly suggestive of MS (at least two cerebral lesions on the T2-weighted MRI above 6 mm diameter). Any disease other than multiple sclerosis that could better explain signs and symptoms of the patient had to be excluded. During the placebo-controlled period of up to three years, Copaxone delayed the progression from the first clinical event to clinically definite multiple sclerosis (CDMS) according to Poser criteria in a statistically significant and clinically meaningful manner, corresponding to a risk reduction of 45% (Hazard Ratio = 0.55; 95% CI [0.40; 0.77], p-value=0.0005). Copaxone prolonged the time to CDMS by 386 (115%) days, from 336 days in the placebo group to 722 days in the Copaxone group (based on the 25th percentile; Kaplan-Meier estimates). The robustness of the results was confirmed in the Completers and Per-Protocol cohorts. The favourable effect of treatment with Copaxone over placebo was also demonstrated in two secondary MRI endpoints. The first, number of new T2 lesions at last observed value (LOV) of the placebo-controlled phase was statistically significantly (p-value<0.0001) lower for patients on Copaxone, demonstrating a treatment effect of 58% for Copaxone over placebo. The mean (SD) number of new T2 lesions was 0.7 (1.7) in the Copaxone group and 1.8 (3.6) in the placebo group. The second MRI endpoint, baseline-adjusted T2 lesion volume at LOV of the placebo- controlled phase, showed a statistically significant (p-value=0.0002) reduction of 25% in T2 lesion volume. The mean (SD) change from baseline in total T2 lesion volume was 1.2 (2.6) mL in the Copaxone group and 2.6 (3.9) mL in the placebo group. The clinical secondary endpoint showed that the proportion of patients who converted to CDMS (43% of the placebo patients compared to 25% of the Copaxone patients) was statistically significantly (p-value<0.0001) lower for patients on Copaxone, demonstrating a treatment effect of 59% in favour of Copaxone. Subgroup analyses of the risk in three years for progression to CDMS according to baseline factors demonstrated evidence of efficacy in all subgroups evaluated. A significant risk reduction of 39% and 54% was obtained for patients with and without corticosteroid treatment for the initial attack, respectively, and 66% risk reduction was demonstrated for patients with a unifocal optic manifestation at the initial attack. A significant risk reduction of 71% for patients with baseline T1 gadolinium enhancement and 58% for patients with 9 or more T2 lesions at baseline was obtained. Copaxone was also effective in patients with no enhancement at baseline who demonstrated a significant risk reduction of 44%.
Reduction of the frequency of relapses in patients with Relapsing Remitting Multiple Sclerosis. Treatment of patients with a single clinical event suggestive of multiple sclerosis and at least two clinically silent MRI lesions characteristic of multiple sclerosis, if alternative diagnoses have been excluded.
Copaxone is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.
The only recommended route of administration of Copaxone injection is by the subcutaneous route. Copaxone should not be administered by the intravenous or intramuscular routes. Patients should be instructed in self-injection techniques to assure the safe administration of Copaxone (see Copaxone Consumer Medicine Information). Based on current data, no special caution is required for patients operating a car or using complex machinery.
Approximately 13% of Copaxone patients in the placebo-controlled studies presented in the Adverse Effects section experienced at least one episode of what was described as transient chest pain (see Adverse Effects). While some of these episodes occurred in the context of the immediate Post-Injection reaction, many did not. ECG monitoring was not performed during any of these episodes and the pathogenesis of this symptom is unknown.
As Copaxone is an antigenic material, it is possible that its use may lead to the induction of antibodies (see Clinical Trials section). As with all immunogenic medicines, hypersensitivity reactions may rarely occur. Although Copaxone is intended to minimise the autoimmune response to myelin, there is the possibility that chronic treatment with Copaxone might result in alteration of normal immune responses. Copaxone has not been studied in patients with a history of severe anaphylactoid reactions or asthma, nor in patients under treatment for asthma. Particular caution is therefore advised regarding the use of Copaxone in such patients.
No prospective, randomised, controlled clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents from 12 to 18 years of age receiving Copaxone 20 mg subcutaneously every day is similar to that seen in adults. There is not enough information available on the use of Copaxone in children below 12 years of age to make any recommendation for its use. Therefore, Copaxone should not be used in this population.#
Copaxone has not been studied specifically in elderly patients but safety data are reassuring for patients up to 65 years of age.
The pharmacokinetics of Copaxone in patients with impaired renal function have not been determined.
In a 2-year carcinogenicity study in mice, SC administration of glatiramer acetate at doses 3 mg/kg/day SC (approximately half the human therapeutic dose on a mg/m2 basis) was associated with increased mortality in the first 8 weeks of the study. The cause of these deaths was not established, but limited data suggest that they may have been associated with type 1 hypersensitivity reactions.
In a 2-year carcinogenicity study, repeated SC administration of glatiramer acetate to male mice at doses 12 times the human therapeutic dose on a mg/m2 basis was associated with the development of skin and subcutis sarcomas. This effect may have been associated with persistent tissue damage at injection sites, which tended to be more common and was of greater severity in males. The incidence of skin sarcoma was not increased in female mice at doses up to 12 times the human therapeutic dose on a mg/m2 basis. In a 2-year carcinogenicity study in rats, SC administration of glatiramer acetate at 12 times the therapeutic human dose on a mg/m2 basis was associated with an increased incidence of benign adrenal phaeochromocytomas in males only; this effect was not seen at 6 times the human dose and was within the historical control values for the testing laboratory. The possible relevance of these findings to humans is not known. Glatiramer acetate was not mutagenic in vitro, but a clastogenic effect was observed in two separate in vitro assays in human lymphocytes. There was no evidence of clastogenicity in a mouse bone marrow micronucleus assay in vivo. In a fertility and reproductive study in rats, glatiramer acetate had no adverse effects on reproductive parameters at SC doses of up to 36 mg/kg/day, which is 15 times the therapeutic dose in humans expressed in terms of mg/m2.
Pregnancy Category B1. No adverse effects on embryofoetal development occurred in reproduction studies in rats and rabbits receiving subcutaneous doses up to 37.5 mg/kg of glatiramer acetate during the period of organogenesis (15 and 28 times the human dose of 20 mg on a mg/m2 basis respectively). In a perinatal/postnatal study, in which rats received subcutaneous glatiramer acetate at doses 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, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Copaxone should be used during pregnancy only if clearly needed.
It is not known whether glatiramer acetate is excreted in animal or human milk. Because many medicines are excreted in human milk, caution should be exercised when Copaxone is administered to women who are breast feeding.
Results from clinical trials do not suggest any significant interactions of Copaxone with therapies commonly used in MS patients. This includes the concurrent use of corticosteroids. Copaxone has not been formally evaluated in combination with Interferon beta-1b. However, 10 patients who switched from therapy with Interferon beta-1b to Copaxone have not reported any serious or unexpected adverse events thought to be related to treatment.
None known.
The adverse event data in this section are derived from 5 pivotal, double-blind, placebo- controlled clinical trials which were conducted during pre-marketing and post-marketing periods in a total of 563 patients treated with Copaxone and 564 patients treated with placebo for up to 36 months. Three trials were conducted in RRMS and one trial in secondary progressive MS (SPMS). The fifth trial was in patients presenting with a first clinical event and MRI features suggestive of MS and included 243 patients treated with Copaxone and 238 patients treated with placebo. In the 5 placebo-controlled clinical trials the most commonly observed adverse events occurring at an incidence of at least 10% with the use of Copaxone and at least 1.5 times higher than among placebo-treated patients were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain. Approximately 5% of the subjects receiving Copaxone discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity.
Immediate Post-Injection Reaction
Approximately 16% of patients exposed to Copaxone in the 5 placebo-controlled trials experienced a constellation of symptoms immediately after injection that included flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. 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 post-marketing 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 13% of Copaxone patients in the 5 placebo-controlled studies 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 Copaxone was not always known. The pain was transient (usually lasting only a few minutes), often not associated with other symptoms, and appeared to have no important 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.
Controlled Clinical Trials Experience
The following table 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 events were usually mild in intensity.
Controlled Trials: Incidence of Copaxone Adverse Events 2% and More Frequent than Placebo
| MedDRA Version 10.0 | Copaxone 20 mg (N=563) | ||||
| No. of Patients | % of Patients | No. of % of Patients Patients | |||
| Blood And Lymphatic System Disorders | Lymphadenopathy | 39 | 7 | 15 | 3 |
| Cardiac Disorders | Palpitations | 53 | 9 | 23 | 4 |
| Tachycardia | 28 | 5 | 9 | 2 | |
| Eye Disorders | Eye Disorder | 17 | 3 | 6 | 1 |
| Diplopia | 15 | 3 | 10 | 2 | |
| Gastrointestinal Disorders | Nausea | 82 | 15 | 61 | 11 |
| Vomiting | 38 | 7 | 23 | 4 | |
| Dysphagia | 12 | 2 | 6 | 1 | |
| General Disorders And Administration Site Conditions | Injection Site Erythema | 242 | 43 | 55 | 10 |
| Injection Site Pain | 227 | 40 | 111 | 20 | |
| Injection Site Pruritus | 154 | 27 | 21 | 4 | |
| Injection Site Mass | 146 | 26 | 33 | 6 | |
| Asthenia | 124 | 22 | 118 | 21 | |
| Pain | 112 | 20 | 96 | 17 | |
| Injection Site Oedema | 109 | 19 | 23 | 4 | |
| Chest Pain | 74 | 13 | 34 | 6 | |
| Injection Site Inflammation | 49 | 9 | 8 | 1 | |
| Oedema | 46 | 8 | 11 | 2 | |
| Injection Site Reaction | 45 | 8 | 7 | 1 | |
| Pyrexia | 35 | 6 | 31 | 5 | |
| Injection Site Hypersensitivity | 22 | 4 | 0 | 0 | |
| Local Reaction | 19 | 3 | 7 | 1 | |
| Chills | 18 | 3 | 4 | 1 | |
| Face Oedema | 18 | 3 | 3 | 1 | |
| Oedema Peripheral | 17 | 3 | 13 | 2 | |
| Injection Site Fibrosis | 11 | 2 | 3 | 1 | |
| Injection Site Atrophy * | 10 | 2 | 0 | 0 | |
| Immune System Disorders | Hypersensitivity | 17 | 3 | 9 | 2 |
| Infections And Infestations | Infection | 167 | 30 | 158 | 28 |
| Influenza | 79 | 14 | 75 | 13 | |
| Rhinitis | 38 | 7 | 31 | 5 | |
| Bronchitis | 33 | 6 | 29 | 5 | |
| Gastroenteritis | 32 | 6 | 22 | 4 | |
| Vaginal Candidiasis | 25 | 4 | 13 | 2 | |
| Metabolism And Nutrition Disorders | Weight Increased | 15 | 3 | 4 | 1 |
| Musculoskeletal And Connective Tissue Disorders | Back Pain | 69 | 12 | 59 | 10 |
| Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps) | Benign Neoplasm of Skin | 9 | 2 | 3 | 1 |
| Copaxone 20 mg (N=563) | Placebo (N=564) | ||||
| No. of Patients | % of Patients | No. of Patients | % of Patients | ||
| Nervous System Disorders | Tremor | 22 | 4 | 9 | 2 |
| Migraine | 20 | 4 | 12 | 2 | |
| Syncope | 18 | 3 | 10 | 2 | |
| Speech Disorder | 9 | 2 | 3 | 1 | |
| Psychiatric Disorders | Anxiety | 73 | 13 | 56 | 10 |
| Nervousness | 13 | 2 | 5 | 1 | |
| Renal And Urinary Disorders | Micturition Urgency | 26 | 5 | 22 | 4 |
| Respiratory, Thoracic And Mediastinal Disorders | Dyspnea | 80 | 14 | 21 | 4 |
| Cough | 34 | 6 | 27 | 5 | |
| Laryngospasm | 14 | 2 | 7 | 1 | |
| Skin And Subcutaneous Tissue Disorders | Rash | 109 | 19 | 63 | 11 |
| Hyperhidrosis | 42 | 7 | 29 | 5 | |
| Pruritus | 29 | 5 | 25 | 4 | |
| Urticaria | 19 | 3 | 8 | 1 | |
| Skin Disorder | 18 | 3 | 5 | 1 | |
| Vascular Disorders | Vasodilatation | 110 | 20 | 31 | 5 |
MedDRA Version 10.0
*Injection site atrophy comprises terms relating to localised lipoatrophy at injection site The overall frequency of adverse events and the frequencies of individual adverse events were higher in patients treated with Copaxone for RRMS or SPMS, and lower in patients treated with Copaxone for a first clinical episode of MS. Events 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 haematology, chemistry, and urinalysis were similar for both Copaxone and placebo groups in blinded clinical trials. No patient receiving Copaxone withdrew from any placebo-controlled trial because of abnormal laboratory findings which were assessed as possibly related to Copaxone. In one of the placebo-controlled trials, a transient elevation in eosinophils was shown after three months of Copaxone treatment in up to 7% of the patients which gradually declined while on treatment. Data on adverse events occurring in the controlled clinical trials were analysed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. This percentage is indicative of the higher representation of Caucasians in the MS population, even though it does not reflect the exact world racial distribution among MS patients. 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 event incidence related to clinically relevant age subgroups.
Pre-marketing Clinical Trials Experience
During the pre-marketing period, clinical trials were conducted in RRMS and SPMS, only some of which were placebo-controlled. At that time, Copaxone was administered to approximately 900 individuals who received at least one dose. Similar types of events were grouped into standardised categories using COSTART dictionary terminology. All reported events occurring at least twice and potentially important events occurring once are listed below, except those too general to be informative, trivial events, and other events which occurred in at least 2% of treated patients and were present at equal or greater rates in the placebo group. Additional adverse events reported during the post-marketing period are also 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 oedema, injection site atrophy, abscess, injection site hypersensitivity.
Infrequent:
Injection site haematoma, injection site fibrosis, moon face, cellulitis, generalised oedema, 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 haemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder, pancreatitis, rectal haemorrhage, tenesmus, tongue discolouration, and duodenal ulcer.
Endocrine:
Infrequent:
Goiter, hyperthyroidism, and hypothyroidism.
Gastrointestinal:
Frequent:
Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.
Haemic and Lymphatic:
Infrequent:
Leukopenia, anaemia, cyanosis, eosinophilia, hematemesis, lymphoedema, 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 paraesthesia, depersonalisation, 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, haematuria, 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.
Post-marketing Experience
Post-marketing experience has shown an adverse event profile similar to that presented above. Reports of adverse events occurring under treatment with Copaxone Injection not mentioned above that have been received since market introduction and that may or may not have causal relationship to the drug are listed below. As 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; 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 oedema; stomach ulcer; haemorrhage; liver function abnormality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis
Haemic and Lymphatic System:
thrombocytopenia; lymphoma-like reaction; acute leukaemia
Metabolic and Nutritional Disorders:
hypercholesterolemia
Musculoskeletal System
: rheumatoid arthritis; generalized spasm
Nervous System:
myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain oedema; 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 Events Associated with Subcutaneous Use
At injection sites, localised lipoatrophy and, rarely, injection site skin necrosis have been reported during the post-marketing experience. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent.
The recommended dosage in adults is a once daily subcutaneous injection of 1 mL Copaxone 20 mg. This corresponds to one Copaxone pre-filled syringe. Copaxone pre-filled syringe contains no antimicrobial agent. It is for single use in one patient only. Discard any residue. Sites for self-injection include arms, abdomen, hips and thighs. A different site for injection should be used each day in order to reduce the likelihood of local irritation or pain as a result of the injection. Before injecting, the solution should be removed from refrigerated storage and left at room temperature for about 20 minutes to warm up.# Copaxone is intended for long-term treatment and its use should not be discontinued unless clearly indicated by a physician.
Daily doses of up to 30 mg/day to humans were not associated with side-effects other than those previously mentioned. There is no experience with higher doses. There is no specific antidote. Treatment of overdose consists of discontinuation of Copaxone, along with monitoring the patient for at least 10 hours and the institution of appropriate symptomatic and supportive therapy. Contact the Poisons Information Centre for advice on the management of overdosage.
Copaxone is supplied as a sterile pre-filled syringe containing 20 mg glatiramer acetate, 40 mg mannitol and water for injection. Copaxone is supplied in packs of 28 pre-filled syringes for subcutaneous injection. Store Copaxone at 2degC to 8degC. Refrigerate, do not freeze. In the event of refrigeration being unavailable, Copaxone may be stored below 25oC for up to one month. Protect from light.
Schedule 4 Prescription Only Medicine
sanofi-aventis australia pty ltd 12-24 Talavera Road Macquarie Park, NSW 2113 Date of TGA Approval: 26 February 2010
#Please note changes in Product Information.