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.
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       Very Common          Common                 Uncommon                Rare            Not known Class (SOC)          (≥1/10)       (≥1/100 to <1/10)          (≥1/1,000 to        (≥1/10,000 to        (cannot be <1/1,00)            <1/1,000)       estimated from the available data)
Infections and    Infection,     Bronchitis,                Abscess, Cellulitis, infestations      Influenza      Gastroenteritis, Herpes    Furuncle, Herpes Simplex, Otitis Media,     Zoster,
Rhinitis, Tooth Abscess,   Pyelonephritis
Vaginal Candidiasis*
Neoplasms                        Benign Neoplasm Of         Skin Cancer benign,                          Skin, Neoplasm malignant and unspecified
(incl cysts and polyps)
Blood and                        Lymphadenopathy*           Leukocytosis, lymphatic                                                   Leukopenia, system                                                      Splenomegaly disorders                                                   Thrombocytopenia, Lymphocyte
Morphology
Abnormal
Immune                           Hypersensitivity system disorders
Endocrine                                                   Goitre,
disorders                                                   Hyperthyroidism Metabolism                       Anorexia, Weight           Alcohol and nutrition                    Increased*                 Intolerance, Gout, disorders                                                   Hyperlipidaemia, Blood Sodium
Increased, Serum
Ferritin Decreased
Psychiatric       Anxiety*,      Nervousness                Abnormal Dreams, disorders         Depression                                Confusional State, Euphoric Mood,
Hallucination,
Hostility, Mania,
Personality
Disorder, Suicide
Attempt

System Organ        Very Common             Common                  Uncommon                Rare            Not known Class (SOC)           (≥1/10)          (≥1/100 to <1/10)           (≥1/1,000 to        (≥1/10,000 to        (cannot be <1/1,00)            <1/1,000)       estimated from the available data)
Nervous            Headache,         Dysgeusia, Hypertonia,      Carpal Tunnel system                               Migraine, Speech            Syndrome, disorders                            Disorder, Syncope,          Cognitive Disorder, Tremor*                     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                              Ear Disorder labyrinth disorders
Cardiac                              Palpitations*,              Extrasystoles, disorders                            Tachycardia*                Sinus Bradycardia, Tachycardia
Paroxysmal
Vascular           Vasodilatation*                               Varicose Vein disorders
Respiratory,       Dyspnoea*         Cough, Rhinitis Seasonal    Apnoea, Epistaxis, thoracic and                                                     Hyperventilation, mediastinal                                                      Laryngospasm, disorders                                                        Lung Disorder, Choking Sensation
Gastrointestina    Nausea*           Anorectal Disorder,         Colitis, Colonic l disorders                          Constipation, Dental        Polyp, Caries, Dyspepsia,          Enterocolitis,
Dysphagia, Faecal           Eructation,
Incontinence, Vomiting*     Oesophageal Ulcer,
Periodontitis Rectal
Haemorrhage,
Salivary Gland
Enlargement
Hepatobiliary                        Liver Function Test         Cholelithiasis,          Toxic disorders                            Abnormal                    Hepatomegaly             hepatitis,           Hepatic Liver                failure# injury
Skin and           Rash*             Ecchymosis,                 Angioedema, subcutaneous                         Hyperhidrosis, Pruritus,    Dermatitis Contact, tissue disorders                     Skin Disorder*, Urticaria   Erythema Nodosum, Skin
Nodule


System Organ        Very Common               Common                 Uncommon                Rare            Not known Class (SOC)           (≥1/10)            (≥1/100 to <1/10)          (≥1/1,000 to        (≥1/10,000 to        (cannot be <1/1,00)            <1/1,000)       estimated from the available data)
Musculoskeleta     Arthralgia, Back    Neck Pain                  Arthritis, Bursitis, l and              Pain*                                          Flank Pain, Muscle connective                                                        Atrophy, tissue disorders                                                  Osteoarthritis Renal and                              Micturition Urgency,       Haematuria, urinary                                Pollakiuria, Urinary       Nephrolithiasis, disorders                              Retention                  Urinary Tract Disorder, Urine
Abnormality


Reproductive                                                      Breast system and                                                        Engorgement, breast                                                            Erectile disorders                                                         Dysfunction, Pelvic Prolapse, Priapism,
Prostatic Disorder,
Smear Cervix
Abnormal,
Testicular
Disorder, Vaginal
Haemorrhage,
Vulvovaginal
Disorder
General            Asthenia, Chest     Chills*, Face Oedema*,     Cyst, Hangover, disorders and      Pain*, Injection    Injection Site Atrophy@,   Hypothermia, administration     Site Reactions*§,   Local Reaction*,           Immediate Post- site conditions    Pain*               Oedema Peripheral,         Injection Reaction, Oedema, Pyrexia            Inflammation,
Injection Site
Necrosis, Mucous
Membrane
Disorder
Injury,                                                           Post Vaccination poisoning and                                                     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.

# 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.
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, 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