Copaxone 20 mg/ml Solution for Injection, Pre-filled Syringe.

1 ml of solution for injection contains 20 mg glatiramer acetate*, equivalent to 18 mg of glatiramer base per pre-filled syringe.

* Glatiramer acetate is the acetate salt of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine and L-lysine, in molar fraction ranges of 0.129-0.153, 0.392-0.462, 0.086-0.100 and 0.300-0.374, respectively. The average molecular weight of glatiramer acetate is in the range of 5,000-9,000 daltons.

For full list of excipients, see section 6.1.

Solution for Injection, Pre-filled Syringe.

Clear solution free of visible particles.

Copaxone is indicated for the treatment of patients who have experienced a well-defined first clinical episode and are determined to be at high risk of developing clinically definite multiple sclerosis (CDMS) (see Section 5.1).

Copaxone is indicated for the reduction in frequency of relapses in ambulatory patients (i.e. who can walk unaided) with relapsing-remitting multiple sclerosis (MS). In clinical trials this was characterised by at least two attacks of neurological dysfunction over the preceding two-year period (see Section 5.1).

Copaxone is not indicated in primary or secondary progressive MS.

The recommended dosage in adults is 20 mg of glatiramer acetate (one pre-filled syringe), administered as a subcutaneous injection once daily.

At the present time, it is not known for how long the patient should be treated.

A decision concerning long term treatment should be made on an individual basis by the treating physician.

Paediatric Use: Children and adolescents: 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.

Use in the Elderly: Copaxone has not been specifically studied in the elderly.

Use in Patients with Impaired Renal Function: Copaxone has not been specifically studied in patients with renal impairment (see Section 4.4).

Patients should be instructed in self-injection techniques and should be supervised by a health-care professional the first time they self-inject and for 30 minutes after.

A different site for injection should be chosen every day, so this will reduce the chances of any irritation or pain at the site of the injection. Sites for self-injection include the abdomen, arms, hips and thighs.

Copaxone is contraindicated under the following conditions:

• Hypersensitivity to glatiramer acetate or mannitol

• Pregnant women

Copaxone should only be administered subcutaneously. Copaxone should not be administered by intravenous or intramuscular routes.

The initiation of Copaxone treatment should be supervised by a neurologist or a physician experienced in the treatment of MS.

The treating physician should explain to the patient that a reaction associated with at least one of the following: vasodilatation (flushing), chest pain, dyspnoea, palpitations or tachycardia, may occur within minutes of a Copaxone injection. The majority of these symptoms are short-lived and resolve spontaneously without any sequelae. Should a severe adverse event occur, the patient must immediately stop Copaxone treatment and contact his/her physician or any emergency doctor. Symptomatic treatment may be instituted at the discretion of the physician.

There is no evidence to suggest that any particular patient groups are at special risk from these reactions. Nevertheless, caution should be exercised when administering Copaxone to patients with pre-existing cardiac disorders. These patients should be followed up regularly during treatment.

Convulsions and/or anaphylactoid or allergic reactions have been reported rarely. Serious hypersensitivity reactions (e.g. bronchospasm, anaphylaxis or urticaria) may rarely occur. If reactions are severe, appropriate treatment should be instituted and Copaxone should be discontinued.

Glatiramer acetate-reactive antibodies were detected in patients' sera during daily chronic treatment with Copaxone. Maximal levels were attained after an average treatment duration of 3-4 months and, thereafter, declined and stabilised at a level slightly higher than baseline.

There is no evidence to suggest that these glatiramer acetate-reactive antibodies are neutralising or that their formation is likely to affect the clinical efficacy of Copaxone.

In patients with renal impairment, renal function should be monitored while they are treated with Copaxone. Whilst there is no evidence of glomerular deposition of immune complexes in patients, the possibility cannot be excluded.

Interaction between Copaxone and other medicinal products have not been formally evaluated.

There are no data on interaction with interferon beta.

An increased incidence of injection site reactions has been seen in Copaxone patients receiving concurrent administration of corticosteroids.

In vitro work suggests that glatiramer acetate in blood is highly bound to plasma proteins but that it is not displaced by, and does not itself displace, phenytoin or carbamazepine. Nevertheless, as Copaxone has, theoretically, the potential to affect the distribution of protein-bound substances, concomitant use of such medicinal products should be monitored carefully.

Pregnancy: There are no adequate data from the use of glatiramer acetate in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see Section 5.3). The potential risk for humans is unknown. Copaxone is contraindicated during pregnancy.

A contraceptive cover should be considered whilst using this medicinal product.

Lactation: Data regarding excretion of glatiramer acetate, its metabolites or antibodies in human milk are unavailable. Caution should be exercised when Copaxone is administered to a nursing mother. The relative risk and benefit to the mother and child should be taken into consideration.

No studies on the effects on the ability to drive and use machines have been performed.

In all clinical trials, injection-site reactions were seen to be the most frequent adverse reactions and were reported by the majority of patients receiving Copaxone. In controlled studies, the proportion of patients reporting these reactions, at least once, was higher following treatment with Copaxone (70%) than placebo injections (37%). The most commonly reported injection-site reactions, which were more frequently reported in Copaxone vs. placebo-treated patients, were erythema, pain, mass, pruritus, oedema, inflammation and hypersensitivity.

A reaction associated with at least one or more of the following symptoms: vasodilatation, chest pain, dyspnoea, palpitation or tachycardia has been described as the Immediate Post-Injection Reaction. This reaction may occur within minutes of a Copaxone injection. At least one component of this Immediate Post-Injection Reaction was reported at least once by 31% of patients receiving Copaxone compared to 13% of patients receiving placebo¹.

All adverse reactions, which were more frequently reported in Copaxone vs. placebo-treated patients, are presented in the table below. This data was derived from four pivotal, double-blind, placebo-controlled clinical trials with a total of 512 patients treated with Copaxone and 509 patients treated with placebo for up to 36 months. Three trials in relapsing-remitting MS (RRMS) included a total of 269 patients treated with Copaxone and 271 patients treated with placebo for up to 35 months. The fourth trial in patients who have experienced a first clinical episode and were determined to be at high risk of developing clinically definite MS included 243 patients treated with Copaxone and 238 patients treated with placebo for up to 36 months.

More than 2% (>2/100) higher incidence in the Copaxone treatment group than in the placebo group. Adverse reaction without the * symbol represents a difference of less than or equal to 2%.

§ The term 'Injection site reactions' (various kinds) comprises all adverse events occurring at the injection site excluding injection site atrophy and injection site necrosis, which are presented separately within the table.

♣Includes terms which relate to localised lipoatrophy at the injection sites.

Rare (>1/10000, <1/1000) reports of anaphylactoid reactions were collected from MS patients treated with Copaxone in uncontrolled clinical trials and from post-marketing experience with Copaxone.

¹ The individual components of the Immediate Post-Injection Reaction are listed in the table under their respective frequency.

A few cases of overdose with Copaxone (up to 80 mg glatiramer acetate) have been reported. These cases were not associated with any adverse reactions other than those mentioned in Section 4.8.

There is no clinical experience with doses higher than 80 mg glatiramer acetate.

In clinical trials, daily doses of up to 30 mg glatiramer acetate for up to 24 months were not associated with adverse reactions other than those mentioned in Section 4.8.

In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.

Pharmacotherapeutic group: Other cytokines and immunomodulators

ATC code: L03AX13

The mechanism(s) by which glatiramer acetate exerts its effects in patients with 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 immunisation against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in MS patients suggest that upon its administration, glatiramer acetate-specific suppressor T cells are induced and activated in the periphery.

RRMS :

A total of 269 patients have been treated with Copaxone in three controlled trials. The first was a two-year study involving 50 patients (Copaxone n=25, placebo n=25) who were diagnosed with relapsing-remitting MS by the then-applicable standard criteria, and who had at least two attacks of neurological dysfunction (exacerbations) during the preceding two years. The second study applied the same inclusion criteria and included 251 patients treated for up to 35 months (Copaxone n=125, placebo n=126). The third study was a nine-month study involving 239 patients (Copaxone n=119, placebo n=120) where inclusion criteria were similar to those in the first and second studies with the additional criterion that patients had to have at least one gadolinium-enhancing lesion on the screening MRI.

In clinical trials in MS patients receiving Copaxone, a significant reduction in the number of relapses, compared with placebo, was seen.

In the largest controlled study, the relapse rate was reduced by 32% from 1.98 under placebo to 1.34 under glatiramer acetate.

Exposure data are available for up to twelve years in 103 patients treated with Copaxone.

Copaxone has also demonstrated beneficial effects over placebo on MRI parameters relevant to relapsing-remitting MS.

Copaxone had, however, no beneficial effect on progression of disability in relapsing-remitting MS patients.

There is no evidence that Copaxone treatment has an effect on relapse duration or severity.

There is currently no evidence for the use of Copaxone in patients with primary or secondary progressive disease.

Single Clinical Event Suggestive of MS:

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). The proportion of patients who converted to CDMS was 43% for the placebo group and 25% in the Copaxone group.

The favourable effect of treatment with Copaxone over placebo was also demonstrated in two secondary MRI endpoints, i.e. number of new T₂ lesions and T₂ lesion volume.

Post-hoc subgroup analyses were performed in patients with various baseline characteristics to identify a population at high risk to develop the second attack. For subjects with baseline MRI with at least one T₁ Gd-enhancing lesion and 9 or more T₂ lesions, conversion to CDMS was evident for 50% of the placebo subjects vs. 28% of the Copaxone subjects in 2.4 years. For subjects with 9 or more T₂ lesions at baseline, conversion to CDMS was evident for 45% of the placebo subjects vs. 26% on Copaxone in 2.4 years. However, the impact of early treatment with Copaxone on the long term evolution of the disease is unknown even in these high-risk subgroups as the study was mainly designed to assess the time to the second event. In any case, treatment should only be considered for patients classified at high risk.

Pharmacokinetic studies in patients have not been performed. In vitro data and limited data from healthy volunteers indicate that with subcutaneous administration of glatiramer acetate, the active substance is readily absorbed and that a large part of the dose is rapidly degraded to smaller fragments already in subcutaneous tissue.

Preclinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity, beyond the information included in other sections of the SPC. Due to the lack of pharmacokinetic data in humans, margins of exposure between humans and animals cannot be established.

Immune complex deposition in the glomeruli of the kidney was reported in a small number of rats and monkeys treated for at least 6 months. In a 2 years rat study, no indication of immune complex deposition in the glomeruli of the kidney was seen. Anaphylaxis after administration to sensitised animals (guinea pigs or mice) was reported. The relevance of these data for humans is unknown.

Toxicity at the injection site was a common finding after repeated administration in animals.

Mannitol

Water for Injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years.

Keep the container in the outer carton, in order to protect from light.

Store in refrigerator (2°C to 8°C).

Do not freeze

If the pre-filled syringes cannot be stored in a refrigerator, they can be stored at room temperature (15°C to 25°C), once for up to one month.

After this one month period, if the Copaxone 20 mg/ml pre-filled syringes have not been used and are still in their original packaging, they must be returned to storage in a refrigerator (2°C to 8°C).

Copaxone solution for injection is contained in a pre-filled syringe, consisting of a Type I colourless glass barrel, a plastic plunger and a rubber stopper.

Packs containing 7 and 28 pre-filled syringes will be supplied.

Not all pack sizes may be marketed.

The volume of solution in the syringe is 1.0 ml.

For single use only. Any unused product or waste material must be discarded.

Teva Pharmaceuticals Ltd

5 Chancery Lane

Clifford's Inn

London

EC4A 1BU

United Kingdom

PL 10921/0023

Date of first authorisation: 7 April 2003

03 February 2009

11 LEGAL CATEGORY: POM