Adverse reactions : תופעות לוואי

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. 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.


System Organ Class (SOC)        Very Common                    Common                           Uncommon (≥1/10)                 (≥1/100 to <1/10)                (≥1/1,000 to <1/100) Infections and infestations   Infection, Influenza   Bronchitis, Gastroenteritis,    Abscess, Cellulitis, Furuncle, Herpes Simplex, Otitis Media,   Herpes Zoster, Pyelonephritis
Rhinitis, Tooth Abscess,
Vaginal Candidiasis*
Neoplasms benign, malignant                          Benign Neoplasm Of Skin,        Skin Cancer and unspecified (incl cysts                          Neoplasm and polyps)
Blood and lymphatic system                           Lymphadenopathy*                Leukocytosis, Leukopenia, disorders                                                                            Splenomegaly Thrombocytopenia, Lymphocyte Morphology
Abnormal
Immune system disorders                              Hypersensitivity Endocrine disorders                                                                  Goitre, Hyperthyroidism Metabolism and nutrition                             Anorexia, Weight Increased*     Alcohol Intolerance, Gout, disorders                                                                            Hyperlipidaemia, Blood Sodium Increased, Serum Ferritin
Decreased
Psychiatric disorders         Anxiety*,              Nervousness                     Abnormal Dreams, Confusional Depression                                             State, Euphoric Mood, Hallucination, Hostility, Mania,
Personality Disorder, Suicide
Attempt
Nervous system disorders      Headache,              Dysgeusia, Hypertonia,          Carpal Tunnel Syndrome, Migraine, Speech Disorder,      Cognitive Disorder, Convulsion,
Syncope, Tremor*                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     Dyspnoea*              Cough, Rhinitis Seasonal        Apnoea, Epistaxis, mediastinal disorders                                                                Hyperventilation, Laryngospasm, Lung Disorder, Choking Sensation



System Organ Class (SOC)            Very Common                    Common                            Uncommon (≥1/10)                 (≥1/100 to <1/10)                 (≥1/1,000 to <1/100) Gastrointestinal disorders       Nausea*                 Anorectal Disorder,              Colitis, Colonic Polyp, Constipation, Dental Caries,     Enterocolitis, Eructation,
Dyspepsia, Dysphagia, Faecal     Oesophageal Ulcer, Periodontitis
Incontinence, Vomiting*          Rectal Haemorrhage, Salivary
Gland Enlargement
Hepatobiliary disorders                                  Liver Function Test Abnormal     Cholelithiasis, Hepatomegaly Skin and subcutaneous tissue     Rash*                   Ecchymosis, Hyperhidrosis,       Angioedema, Dermatitis Contact, disorders                                                Pruritus, Skin Disorder*,        Erythema Nodosum, Skin Nodule Urticaria
Musculoskeletal and              Arthralgia, Back        Neck Pain                        Arthritis, Bursitis, Flank Pain, connective tissue disorders      Pain*                                                    Muscle Atrophy, Osteoarthritis Renal and urinary disorders                              Micturition Urgency,             Haematuria, Nephrolithiasis, Pollakiuria, Urinary Retention   Urinary Tract Disorder, Urine
Abnormality
Pregnancy, puerperium and                                                                 Abortion perinatal Conditions
Reproductive system and                                                                   Breast Engorgement, Erectile breast disorders                                                                          Dysfunction, Pelvic Prolapse, Priapism, Prostatic Disorder, Smear
Cervix Abnormal, Testicular
Disorder, Vaginal Haemorrhage,
Vulvovaginal Disorder
General disorders and            Asthenia, Chest         Chills*, Face Oedema*,           Cyst, Hangover, Hypothermia, administration site conditions   Pain*, Injection Site   Injection Site Atrophy#, Local   Immediate Post-Injection Reaction, Reactions*§, Pain*      Reaction*, Oedema Peripheral,    Inflammation, Injection Site Oedema, Pyrexia                  Necrosis, Mucous Membrane
Disorder
Injury, poisoning and                                                                     Post Vaccination Syndrome procedural complications
* 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.

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 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 Copaxone 40 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 Copaxone 40 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 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.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il