Solution for injection Clear colourless to slightly yellow/brownish solution free from visible particles. The solution for injection has a pH of 5.5 - 7.0 and an osmolarity of about 300 mOsmol/L.

4.1 Therapeutic indications Glatiramer acetate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) (see section 5.1 for important information on the population for which efficacy has been established). Glatiramer acetate is not indicated in primary or secondary progressive MS.4.2 Posology and method of administration The initiation of glatiramer acetate treatment should be supervised by a neurologist or a physician experienced in the treatment of MS. *Posology* The recommended dosage in adults is 40 mg of glatiramer acetate (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. **Renal impairment** Glatiramer acetate has not been specifically studied in patients with renal impairment (see section 4.4). **Elderly** Glatiramer acetate has not been specifically studied in the elderly. *Paediatric population* The safety and efficacy of glatiramer acetate in children and adolescents has not been established. There is not enough information available on the use of glatiramer acetate 40 mg/ml TIW in children and adolescents below 18 years of age to make any recommendation for its use. Therefore, glatiramer acetate 40 mg/ml TIW should not be used in this population. *Method of administration* Brabio is for subcutaneous use. 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. The MyJECT device is available should the patients want to make their injection with an injection device. The MyJECT device is an autoinjector to be used with Brabio pre-filled syringes and it has not been tested with other pre-filled syringes. The MyJECT device should be used as recommended in the information provided by the device manufacturer.4.3 Contraindications Glatiramer acetate is contraindicated under the following conditions: • Hypersensitivity to the active substance glatiramer acetate or to any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use Glatiramer acetate should only be administered subcutaneously. Glatiramer acetate should not be administered by intravenous or intramuscular routes. Glatiramer acetate can cause post-injection reactions as well as anaphylactic reactions (see section 4.8): **Post-injection reactions** 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 (see section 4.8). 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 for 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. **Anaphylactic reactions** Anaphylactic reactions may occur shortly following administration of glatiramer acetate, even months up to years after initiation of treatment (see section 4.8). Cases with fatal outcome have been reported. Some signs and symptoms of anaphylactic reactions may overlap with post-injection reactions. All patients receiving treatment with [product name] and caregivers should be informed about the signs and symptoms specific for anaphylactic reactions and that they should seek immediate emergency medical care in case of experiencing such symptoms (see section 4.8). If an anaphylactic reaction occurs, treatment with [product name] must be discontinued (see section 4.3). 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. Rare cases of severe liver injury have been observed (including hepatitis with jaundice, liver failure, and in isolated cases liver transplantation). Liver injury occurred from days to years after initiating treatment with glatiramer acetate. Most instances of severe liver injury resolved with discontinuation of treatment. **In some cases, these reactions have occurred in the presence of** excessive alcohol consumption, existing or history of liver injury and use of other potentially hepatotoxic medication. **Patients should be regularly monitored for signs of hepatic injury and instructed to seek immediate medical attention in case of symptoms of liver injury.** In case of clinically significant liver injury, discontinuation of glatiramer acetate should be considered. 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.4.5 Interaction with other medicinal products and other forms of interaction Interaction between glatiramer acetate 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 glatiramer acetate 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 glatiramer acetate has, theoretically, the potential to affect the distribution of protein-bound substances, concomitant use of such medicinal products should be monitored carefully.4.6 Fertility, pregnancy and lactation **Pregnancy** A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of Brabio may be considered during pregnancy, if necessary. **Breast-feeding** The physico-chemical properties and low oral absorption suggest that exposure of newborns/infants to glatiramer acetate via human breast milk is negligible. A non-interventional retrospective study in 60 breastfed infants of mothers exposed to glatiramer acetate compared to 60 breastfed infants of mothers not exposed to any disease modifying therapy and limited post-marketing human data showed no negative effects of glatiramer acetate. Brabio can be used during breast-feeding.4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed.4.8 Undesirable effects Most glatiramer acetate safety data were accumulated for glatiramer acetate 20 mg/ml administered as a subcutaneous injection once daily. This section presents accumulated safety data from four placebo-controlled trials with glatiramer acetate 20 mg/ml administered once daily, and from one placebo-controlled trial with glatiramer acetate 40 mg/ml administered three times a week. A direct comparison of the safety between glatiramer acetate 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed. **Glatiramer acetate 20 mg/ml (administered once daily)** In all clinical trials with glatiramer acetate 20 mg/ml, 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 20 mg/ml (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, 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 (see section 4.4). 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 20 mg/ml compared to 13% of patients receiving placebo. **Adverse reactions identified from clinical trials and post marketing experience** are presented in the table below. Data from clinical trials was derived from four pivotal, double-blind, placebo-controlled clinical trials with a total of 512 patients treated with glatiramer acetate 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 glatiramer acetate 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 glatiramer acetate 20 mg/day and 238 patients treated with placebo for up to 36 months. | | | | | | | | --- | --- | --- | --- | --- | --- | | **System Organ Class (SOC)** | **Very Common** **(≥1/10)** | **Common** **( ≥1/100 to < 1/10)** | **Uncommon** **(≥1/1,000 to <1/100)** | **Rare** **(≥1/10,000 to <1/1,000)** | **Not known** **(**cannot be estimated from the available data**)** | | Infections and infestations | Infection, Influenza | Bronchitis, Gastroenteritis, Herpes simplex, Otitis Media, Rhinitis, Tooth abscess, Vaginal candidiasis\* | Abscess, Cellulitis, Furuncle, Herpes zoster, Pyelonephritis | | | | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | | Benign neoplasm of skin, Neoplasm | Skin cancer | | | | Blood and lymphatic system disorders | | Lymphadenopathy\* | Leukocytosis Leukopenia, Splenomegaly, Thrombocytopenia, Lymphocyte morphology abnormal | | | | Immune system disorders | | Hypersensitivity | Anaphylactic reaction | | | | Endocrine disorders | | | Goitre, Hyperthyroidism | | | | Metabolism and nutrition disorders | | Anorexia, Weight increased\* | Alcohol intolerance, Gout, Hyperlipidaemia, Blood sodium increased, Serum ferritin decreased | | | | Psychiatric disorders | Anxiety\, Depression | Nervousness | Abnormal dreams, Confusional state, Euphoric mood, Hallucination, Hostility, Mania, Personality disorder, Suicide attempt | | | | Nervous system disorders | Headache | Dysgeusia, Hypertonia, Migraine, Speech disorder, Syncope, Tremor\ | Carpal tunnel syndrome, Cognitive disorder, Convulsion, Dysgraphia, Dyslexia, Dystonia, Motor dysfunction, Myoclonus, Neuritis, Neuromuscular blockade, Nystagmus, Paralysis, Peroneal nerve Palsy, Stupor, Visual field defect | | | | Eye disorders | | Diplopia, Eye disorder\* | Cataract, Corneal lesion, Dry eye, Eye haemorrhage, Eyelid ptosis, Mydriasis, Optic atrophy | | | | Ear and labyrinth disorders | | Ear Disorder | | | | | Cardiac disorders | | Palpitations\, Tachycardia\ | Extrasystoles, Sinus bradycardia, Tachycardia paroxysmal | | | | Vascular disorders | Vasodilatation\* | | Varicose vein | | | | Respiratory, thoracic and mediastinal disorders | Dyspnoea\* | Cough, Rhinitis seasonal | Apnoea, Epistaxis, Hyperventilation, Laryngospasm, Lung disorder, Choking sensation | | | | Gastrointestinal disorders | Nausea\* | Anorectal disorder, Constipation, Dental caries, Dyspepsia, Dysphagia, Faecal incontinence, Vomiting\* | Colitis, Colonic polyp, Enterocolitis, Eructation, Oesophageal ulcer, Periodontitis, Rectal haemorrhage, Salivary gland enlargement | | | | Hepatobiliary disorders | | Liver function test abnormal | Cholelithiasis, Hepatomegaly | Toxic hepatitis, Liver injury | Hepatic failure# | | Skin and subcutaneous tissue disorders | Rash\* | Ecchymosis, Hyperhidrosis, Pruritus, Skin disorder\, Urticaria | Angioedema, Dermatitis contact, Erythema nodosum, Skin nodule | | | | Musculoskeletal and connective tissue disorders | Arthralgia, Back pain\ | Neck pain | Arthritis, Bursitis, Flank pain, Muscle atrophy, Osteoarthritis | | | | Renal and urinary disorders | | Micturition urgency, Pollakiuria, Urinary retention | Haematuria, Nephrolithiasis, Urinary tract disorder, Urine abnormality | | | | Reproductive system and breast disorders | | | Breast engorgement, Erectile dysfunction, Pelvic prolapse, Priapism, Prostatic disorder, Smear cervix abnormal, Testicular disorder, Vaginal haemorrhage, Vulvovaginal disorder | | | | General disorders and administration site conditions | Asthenia, Chest pain\, Injection site reactions\§, Pain\* | Chills\, Face oedema\, Injection site Atrophy♣ , Local Reaction\, Oedema peripheral, Oedema, Pyrexia | Cyst, Hangover, Hypothermia, Immediate post-injection reaction, Inflammation, Injection site necrosis, Mucous membrane disorder | | | | Injury, poisoning and procedural complications | | | Post vaccination syndrome | | | \ 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 localised lipoatrophy at the injection sites**.**

Few cases were reported with liver transplantation.

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 20 mg/ml was observed during the open-label follow-up period of up to 5 years. **Glatiramer acetate 40 mg/ml (administered three times per week)** The safety of glatiramer acetate 40 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 40 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 40 mg/ml administered three times per week were those already known and labeled for glatiramer acetate 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 40 mg/ml administered three times per week than for glatiramer acetate 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 40 mg/ml compared to 5% on placebo. Immediate post-injection reaction was reported by 8% of the patients on glatiramer acetate 40 mg/ml compared to 2% on placebo. A few specific adverse reactions are noted: • Anaphylactic reactions may occur shortly following administration of glatiramer acetate, even months up to years after initiation of treatment (see section 4.4). • No injection site necrosis was reported. • Skin erythema and pain in extremity, not labelled for glatiramer acetate 20 mg/ml, were reported each by 2.1% of the patients on glatiramer acetate 40 mg/ml (Common: ≥1/100 to < 1/10). • Drug-induced liver injury and toxic hepatitis were each reported by one patient (0.1%) on glatiramer acetate 40 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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose **Symptoms** A few cases of overdose with glatiramer acetate (up to 300 mg glatiramer acetate) have been reported. These cases were not associated with any adverse reactions other than those mentioned in section 4.8. **Management** In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunostimulants, other immunostimulants, ATC code: L03AX13 **Mechanism of action** The mechanism by which glatiramer acetate exerts therapeutic effects in relapsing forms of MS is not fully elucidated but is presumed to involve modulation of immune processes. Studies in animals and MS patients suggest glatiramer acetate acts on innate immune cells, including monocytes, dendritic cells and B cells, which in turn modulate adaptive functions of B and T cells inducing anti-inflammatory and regulatory cytokine secretion. Whether the therapeutic effect is mediated by the cellular effects described above is not known because the pathophysiology of MS is only partially understood. Clinical efficacy and safety *Relapsing-Remitting Multiple Sclerosis* Evidence supporting the effectiveness of glatiramer acetate 40 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 characterised 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 randomised in a 2:1 ratio to receive either glatiramer acetate 40 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 40 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 glatiramer acetate 20 mg/ml administered daily. The following table presents the values for the primary and secondary outcome measures for the intent-to-treat population: | | | | | | --- | --- | --- | --- | | **Outcome Measure** | **Adjusted Mean Estimates** | | **P-Value** | | **GA (40 mg/ml)** **(N=943)** | **Placebo** **(N=461)** | | Annualized relapse rate (ARR) | 0.331 | 0.505 | p<0.0001 | | Absolute Risk Difference\* (95% confidence intervals) | -0.174 [-0.2841 to -0.0639] | | | | Cumulative number of new/enlarging T2 lesions at months 6 and 12 | 3.650 | 5.592 | p<0.0001 | | Rate ratio\\ (95% confidence intervals) | 0.653 [0.546 to 0.780] | | | | Cumulative number of enhancing lesions on T1-weighted images at months 6 and 12 | 0.905 | 1.639 | p<0.0001 | | Rate ratio\\ (95% confidence intervals) | 0.552 [0.436 to 0.699] | | | \* 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 glatiramer acetate 20 mg/ml (administered daily) and 40 mg/ml (administered three times per week) in the same study has not been performed. Glatiramer acetate 40 mg/mL: The proportion of patients with 3-month confirmed disability progression (CDP) was an exploratory endpoint in a 12-month placebo-controlled study (GALA). Three-month CDP was experienced by 3% and 3.5% of placebo- and glatiramer-treated patients, respectively (odds ratio, OR [95% CI]: 1.182 [0.661, 2.117] (p=0.5726)). Including the open-label extension of the study (up to 7 years), time to 6-month CDP was an exploratory endpoint. The hazard ratio (HR) [95% CI] for the intent to treat cohort, comparing the early start glatiramer group to the delayed start group was 0.892 [0.688, 1.157] (p=0.3898). There is currently no evidence for the use of glatiramer acetate in patients with primary or secondary progressive disease. Brabio 40mg/mL solution for injection, pre-filled syringe is a hybrid medicinal product. Detailed information is available on the MRI product index; http://mri.medagencies.org/Human/.5.2 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.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, 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. In rats, a slight but statistically significant reduction in body weight gain of offspring born to dams treated during pregnancy and throughout lactation was observed at subcutaneous doses ≥ 6mg/kg/day (2.83-times the maximum recommended human daily dose for a 60 kg adult based on mg/m2) in comparison to control. No other significant effects on offspring growth and behavioural development were observed.

6.1 List of excipients Mannitol Water for injections6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.6.3 Shelf life 3 years.6.4 Special precautions for storage Store in the original package in order to protect from light. Store in a refrigerator (2°C to 8°C). Do not freeze. If the pre-filled syringes cannot be stored in a refrigerator, they can be stored between15°C and 25°C, once, for up to one month. After this one month period, if the glatiramer acetate 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).6.5 Nature and contents of container The container closure system consists of a single use glass syringe barrel with an integrated needle. A rubber stopper (bromobutyl, type 1) is fitted in the barrel for closure and acts as a piston during injection. A driving rod is screwed in the rubber stopper. The needle is covered with a needle shield. The volume of solution in the syringe is 1.0 ml. 3 pre-filled syringes 12 pre-filled syringes 36 (3x12) pre-filled syringes Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.