4.1. Therapeutic indications

Copaxone 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).

Copaxone is not indicated in primary or secondary progressive MS.

4.2. Posology and method of administration

The initiation of Copaxone 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

Copaxone has not been specifically studied in patients with renal impairment (see section 4.4).

Elderly

Copaxone 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 Copaxone 40 mg/ml TIW in children and adolescents below 18 years of age to make any recommendation for its use.

Therefore, Copaxone 40 mg/ml TIW should not be used in this population.

Method of administration

Copaxone 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 CSYNC device is available should the patients want to make their injection with an injection device. The CSYNC device is an autoinjector to be used with Copaxone pre-filled syringes and it has not been tested with other pre-filled syringes. The CSYNC device should be used as recommended in the information provided by the device manufacturer.

4.3. Contraindications

Copaxone 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

Copaxone should only be administered subcutaneously. Copaxone 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 Copaxone 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 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.

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 Copaxone 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 Copaxone must be discontinued (see section 4.3).

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.

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 Copaxone. 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 Copaxone should be considered.

4.5. Interaction with other medicinal products and other forms of interaction

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

Observations from existing clinical trials and post-marketing experience do not suggest any significant interactions of Copaxone with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days.

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1 000 exposed outcomes) indicate no malformative nor feto/neonatal toxicity.

Copaxone can be used during pregnancy, if clinically needed.

Breastfeeding

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.

Copaxone 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 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 Copaxone 40 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 (flushing), chest pain, dyspnoea, palpitation or tachycardia (see section 4.4). 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.

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 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.

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 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.

#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 Copaxone 20 mg/ml was observed during the open-label follow-up period of up to 5 years.

Copaxone 40 mg/ml (administered three times per week)

The safety of Copaxone 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 Copaxone 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 Copaxone 40 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 Copaxone 40 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 Copaxone 40 mg/ml compared to 5% on placebo. Immediate post-injection reaction was reported by 8% of the patients on Copaxone 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 Copaxone 20 mg/ml, were reported each by 2.1% of the patients on Copaxone 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 Copaxone 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 at: 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 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 4.8.

Management

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