Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Generics [UK] Limited t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Glatiramer acetate is contraindicated under the following conditions:
Glatiramer acetate should only be administered subcutaneously. Glatiramer acetate should not be administered by intravenous or intramuscular routes.
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.
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 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 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.
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.
Interaction between glatiramer acetate 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 glatiramer acetate 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 glatiramer acetate has, theoretically, the potential to affect the distribution of protein-bound substances, concomitant use of such medicinal products should be monitored carefully.
Studies in animals have not shown reproductive toxicity (see section 5.3). Current data on pregnant women indicate no malformative or feto/neonatal toxicity of glatiramer acetate. To date, no relevant epidemiological data are available. As a precautionary measure, it is preferable to avoid the use of glatiramer acetate during pregnancy unless the benefit to the mother outweighs the risk to the foetus.
It is unknown whether glatiramer acetate or its metabolites are excreted in human milk. In rats, no significant effects on offspring were observed except for a slight reduction in body weight gains in the offspring of mothers dosed during pregnancy and throughout lactation (see section 5.3).
A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from glatiramer acetate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
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 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, 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 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 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.
| 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 | ||||
| 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 | |||
| Pregnancy, Puerperium And Perinatal Conditions | Abortion | ||||
| 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%.
** Few cases were reported with liver transplantation
§ 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.
In the fourth trial noted above, an open-label treatment phase followed the placebo-controlled period (see section 5.1). 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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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