Glatiramer acetate

Overdose

A few cases of overdose with Copaxone (up to 300 mg glatiramer acetate) have been reported. These cases were not associated with any adverse reactions other than those mentioned in section “Undesirable effects”.

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

A few cases of overdose with Glatiramer acetate (up to 300 mg glatiramer acetate) have been reported.

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

Contraindications

Copaxone is contraindicated under the following conditions:

-

Glatiramer acetate is contraindicated under the following conditions:

- Hypersensitivity to glatiramer acetate or mannitol.

Incompatibilities

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

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

Pharmaceutical form

Undesirable effects

Most Copaxone safety data were accumulated for Copaxone 20 mg/ml administered as a subcutaneous injection once daily. This section presents accumulated safety data from four placebo-controlled trials with Copaxone 20 mg/ml administered once daily, and from one placebo-controlled trial with Glatiramer acetate mg/ml administered three times a week.

A direct comparison of the safety between Copaxone 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed.

Copaxone 20 mg/ml (administered once daily)

In all clinical trials with Copaxone 20 mg/ml, 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 20 mg/ml (70%) than placebo injections (37%). The most commonly reported injection-site reactions, which were more frequently reported in Copaxone 20 mg/ml 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, has been described as the immediate post-injection reaction: vasodilatation, chest pain, dyspnoea, palpitation or tachycardia. 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 20 mg/ml compared to 13% of patients receiving placebo.

All adverse reactions, which were more frequently reported in Copaxone 20 mg/ml 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 20 mg/day 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 20 mg/day 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 20mg/day 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 localized lipoatrophy at the injection sites.

In the fourth trial noted above, an open-label treatment phase followed the placebo-controlled period. No change in the known risk profile of Copaxone 20 mg/ml was observed during the open-label follow-up period of up to 5 years.

Rare (>1/10,000 to <1/1,000) reports of anaphylactoid reactions were collected from MS patients treated with Copaxone in uncontrolled clinical trials and from post-marketing experience with Copaxone.

Glatiramer acetate mg/ml (administered three times per week)

The safety of Glatiramer acetate mg/ml was assessed based on a double-blind, placebo-controlled clinical trial in RRMS patients with a total of 943 patients treated with Glatiramer acetate mg/ml three times per week, and 461 patients treated with placebo for 12 months.

In general, the kind of adverse drug reactions seen in patients treated with Glatiramer acetate mg/ml administered three times per week were those already known and labelled for Copaxone 20 mg/ml administered daily. In particular, adverse injection site reactions (ISR) and immediate post-injection reactions (IPIR) were reported at lower frequency for Glatiramer acetate mg/ml administered three times per week than for Copaxone 20 mg/ml administered daily (35.5 % vs. 70 % for ISRs and 7.8 % vs. 31 % for IPIRs, respectively).

Injection site reactions were reported by 36% of the patients on Glatiramer acetate mg/ml compared to 5% on placebo. Immediate post-injection reaction was reported by 8% of the patients on Glatiramer acetate mg/ml compared to 2% on placebo.

A few specific adverse reactions are noted:

- Anaphylactic response was seen rarely (>1/10,000, <1/1,000) in MS patients treated with Copaxone 20 mg/ml in uncontrolled clinical trials and from post-marketing experience. It was reported by 0.3% of the patients on Glatiramer acetate mg/ml (Uncommon: > 1/1,000 to < 1/100).

- No injection site necrosis was reported.

- Skin erythema and pain in extremity, not labelled for Copaxone 20 mg/ml, were reported each by 2.1% of the patients on Glatiramer acetate mg/ml (Common: > 1/100 to < 1/10).

- Drug-induced liver injury and toxic hepatitis, also seen rarely in MS patients treated with Copaxone 20 mg/ml in post marketing surveillance, were each reported by one patient (0.1%) on Glatiramer acetate mg/ml (Uncommon: > 1/1,000 to < 1/100).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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 Glatiramer acetate. In controlled studies, the proportion of patients reporting these reactions, at least once, was higher following treatment with Glatiramer acetate (70%) than placebo injections (37%). The most commonly reported injection-site reactions, in clinical trials and in post marketing experience, were erythema, pain, mass, pruritus, oedema, inflammation and hypersensitivity, and rare occurrences of lipoatrophy and skin necrosis.

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

All adverse reactions, which were more frequently reported in Glatiramer acetate 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 Glatiramer acetate 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 Glatiramer acetate 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 Glatiramer acetate and 238 patients treated with placebo for up to 36 months.

* More than 2% (>2/100) higher incidence in the Glatiramer acetate 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 localized lipoatrophy at the injection sites.

In the fourth trial noted above, an open-label treatment phase followed the placebo-controlled period. No change in the known risk profile of Glatiramer acetate was observed during the open-label follow-up period of up to 5 years.

The following adverse reaction reports were collected from MS patients treated with Glatiramer acetate in uncontrolled clinical trials and from post-marketing experience with Glatiramer acetate: hypersensitivity reactions (including rare occurrence of anaphylaxis, >1/10000, < 1/1000.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Preclinical safety data

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 SmPC. 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.

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 can not 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.

Therapeutic indications

). Copaxone is not indicated in primary or secondary progressive MS.

Glatiramer acetate is not indicated in primary or secondary progressive MS.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, immunostimulantsATC 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.

Relapsing-Remitting Multiple Sclerosis

Evidence supporting the effectiveness of Glatiramer acetate mg/ml injection administered subcutaneously three times a week in decreasing the frequency of relapses derives from one 12-month placebo-controlled study.

In the pivotal clinical trial Relapsing-Remitting Multiple Sclerosis was characterized by either at least one documented relapse in the last 12 months, or at least two documented relapses in the last 24 months, or one documented relapse between the last 12 and 24 months with at least one documented T1-gadolinium enhancing lesion on magnetic resonance imaging performed the last 12 months.

The primary outcome measure was the total number of confirmed relapses. Secondary MRI outcomes included the cumulative number of new/enlarging T2 lesions and the cumulative number of enhancing lesions on T1-weighted images, both measured at months 6 and 12.

A total of 1404 patients were randomized in a 2:1 ratio to receive either Glatiramer acetate mg/ml (n=943) or placebo (n=461). Both treatment groups were comparable with respect to baseline demographics, MS disease characteristics and MRI parameters. Patients had a median of 2.0 relapses in the 2 years prior to screening.

Compared to placebo, patients treated with Glatiramer acetate mg/ml three times per week had meaningful and statistically significant reductions in the primary and secondary outcome measures which are consistent with the treatment effect of Copaxone 20 mg/ml administered daily.

The following table presents the values for the primary and secondary outcome measures for the intent-to-treat population:

*Absolute risk difference is defined as the difference between the adjusted mean ARR of GA 40 mg TIW and adjusted mean ARR of Placebo.

** Rate ratio is defined as the ratio between GA 40 mg TIW and Placebo adjusted mean rates.

A direct comparison of the efficacy and safety between Copaxone 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed.

There is no evidence that Copaxone treatment had an effect on progression of disability or relapse duration in this 12-month study.

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

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, Other Immunostimulants

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 Glatiramer acetate in three controlled trials. The first was a two-year study involving 50 patients (Glatiramer acetate 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 (Glatiramer acetate n=125, placebo n=126). The third study was a nine-month study involving 239 patients (Glatiramer acetate 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 Glatiramer acetate, 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 Glatiramer acetate.

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

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

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

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

Single clinical event suggestive of MS:

One placebo-controlled study involving 481 patients (Glatiramer acetate 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 MS that could better explain signs and symptoms of the patient had to be excluded. The placebo-controlled period was followed by an open label treatment: Patients who either presented with MS symptoms or were asymptomatic for three years, whichever came first, were assigned to active drug treatment in an open-label phase for an additional period of two years, not exceeding a maximal total treatment duration of 5 years. Of the 243 patients initially randomized to Glatiramer acetate, 198 continued Glatiramer acetate treatment in the open-label phase. Of the 238 patients initially randomized to placebo, 211 switched to Glatiramer acetate treatment in the open-label phase.

During the placebo-controlled period of up to three years, Glatiramer acetate 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 Glatiramer acetate group.

The favourable effect of treatment with Glatiramer acetate 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 Glatiramer acetate 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 Glatiramer acetate in 2.4 years. However, the impact of early treatment with Glatiramer acetate 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.

The effect shown in the placebo-controlled phase was sustained in the long-term follow-up period of up to 5 years. The time progression from the first clinical event to CDMS was prolonged with earlier Glatiramer acetate treatment as compared to delayed treatment, reflecting a 41% risk reduction with earlier versus later treatment (Hazard Ratio = 0.59; 95% CI [0.44; 0.80], p-value=0.0005). The proportion of subjects in the Delayed Start group who progressed was higher (49.6%) compared to those in the Early Start group (32.9%).

A consistent effect in favour of early treatment over delayed treatment across time was shown for the annualized number of lesions over the entire study period in new T1 Gd-enhancing lesions (reduced by 54%; p<0.0001), new T2 lesions (reduced by 42%; p<0.0001) and new T1 hypointense lesions (reduced by 52%; p<0.0001). An effect in reductions in favour of early versus delayed treatment was also observed for the total number of new T1 Gd-enhancing lesions (reduced by 46%; p=0.001), T1 Gd-enhancing lesion volume (a mean difference of -0.06 ml; p<0.001), as well as the total number of new T1 hypointense lesions (reduced by 46%; p<0.001) measured over the entire study period.

No appreciable differences between the Early Start and Delayed Start cohorts were observed for either hypointense T1 lesion volume or brain atrophy over 5 years. However, analysis of brain atrophy at last observed value (adjusted to treatment exposure) showed a reduction in favour of early treatment with GA (the mean difference of percent change in brain volume was 0.28%; p=0.0209).

Pharmacokinetic properties

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.

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.

Special warnings and precautions for use

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 symptoms may occur within minutes of a Copaxone injection: vasodilatation (flushing), chest pain, dyspnoea, palpitations or tachycardia. The majority of these symptoms is short-lived and resolves 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 for 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.

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

The initiation of Glatiramer acetate 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 symptoms may occur within minutes of a Glatiramer acetate injection: vasodilatation (flushing), chest pain, dyspnoea, palpitations or tachycardia. The majority of these symptoms is short-lived and resolves spontaneously without any sequelae. Should a severe adverse event occur, the patient must immediately stop Glatiramer acetate 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 Glatiramer acetate 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 Glatiramer acetate should be discontinued.

Glatiramer acetate-reactive antibodies were detected in patients' sera during daily chronic treatment with Glatiramer acetate. Maximal levels were attained after 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 Glatiramer acetate.

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

Effects on ability to drive and use machines

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

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

Dosage (Posology) and method of administration

Posology

The recommended dosage in adults is 40 mg of Copaxone (one pre-filled syringe), administered as a subcutaneous injection three times a week with at least 48 hours apart.

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 population

Children and adolescents: No clinical trials or pharmacokinetic studies have been conducted in children or adolescents for Copaxone. There is not enough information available on the use of Glatiramer acetate mg/ml TIW in children and adolescents below 18 years of age to make any recommendation for its use. Therefore, Glatiramer acetate mg/ml TIW should not be used in this population.

Elderly patients

Copaxone has not been specifically studied in the elderly.

Patients with renal impairment

Copaxone has not been specifically studied in patients with renal impairment.

Method of administration

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 should be chosen for every injection, 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.

Posology

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 population

Children and adolescents: No prospective, randomized, 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 Glatiramer acetate 20 mg subcutaneously every day is similar to that seen in adults. There is not enough information available on the use of Glatiramer acetate in children below 12 years of age to make any recommendation for its use. Therefore, Glatiramer acetate should not be used in this population.

Elderly patients

Glatiramer acetate has not been specifically studied in the elderly.

Patients with renal impairment

Glatiramer acetate has not been specifically studied in patients with renal impairment.

Method of administration

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.

Special precautions for disposal and other handling

For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

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