Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile in clinical studies
A total of 1,486 patients treated with LEMTRADA (12 mg or 24 mg) constituted the safety population in a pooled analysis of MS clinical studies with a median follow-up of 6.1 years (maximum 12 years), resulting in 8,635 patient-years of safety follow-up.

The most important adverse reactions are autoimmunity (ITP, thyroid disorders, nephropathies, cytopenias), IARs, and infections. These are described in section 4.4.

The most common adverse reactions with LEMTRADA (in ≥20% of patients) were rash, headache, pyrexia, and respiratory tract infections.

Tabulated list of adverse reactions

The table below is based on the pooled safety data on all LEMTRADA 12 mg-treated patients during all available follow up in clinical trials. Adverse reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). Frequencies are defined according to the following convention: 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); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions have been presented in order of decreasing seriousness.



Table 1: Adverse reactions in study 1, 2, 3 and 4 observed in LEMTRADA 12 mg treated patients and post-marketing surveillance


System Organ         Very Common         Common               Uncommon             Rare               Not Class                                                                                                 known Infections and       Upper respiratory   Herpes zoster        Onychomycosis,                          Listeriosis/li infestations         tract infection,    infections2, lower   gingivitis, fungal                      steria urinary tract       respiratory tract    skin infection,                         meningitis, infection, herpes   infections,          tonsillitis, acute                      Epstein- virus infection1    gastroenteritis,     sinusitis,                              Barr virus oral candidiasis,    cellulitis,                             (EBV) vulvovaginal         tuberculosis,                           infection candidiasis,         cytomegaloviru                          (including influenza, ear       s infection                             reactivation infection,                                                   ) pneumonia,
vaginal infection,
tooth infection
Neoplasms                                Skin papilloma benign,
malignant and unspecified (incl.
cysts and polyps)
Blood and            Lymphopenia,        Lymphadenopath       Pancytopenia,         Haemophagoc lymphatic system     leukopenia,         y, immune            haemolytic            ytic disorders            including           thrombocytopeni      anaemia,              lymphohistioc neutropenia         c purpura,           acquired              ytosis (HLH), thrombocytopeni      haemophilia A thrombotic a, anaemia,
thrombocytopenic haematocrit purpura (TTP) decreased,
leukocytosis
Immune system                            Cytokine release     Sarcoidosis disorders                                syndrome*,
hypersensitivity including anaphylaxis*
Endocrine            Basedow’s           Autoimmune disorders            disease,            thyroiditis hyperthyrodism,     including hypothyroidism      thyroiditis subacute, goitre,
anti-thyroid antibody positive
Metabolism and                                                Decreased nutrition                                                     appetite disorders
Psychiatric                              Insomnia*,
disorders                                anxiety,
depression
Nervous system       Headache*           MS relapse,          Sensory                                 Haemorrhag disorders                                dizziness*,          disturbance,                            ic stroke**, 
hypoaesthesia,       hyperaesthesia,      cervicoceph paraesthesia,        tension headache,    alic arterial tremor,              autoimmune           dissection** dysgeusia*,          encephalitis migraine*
Eye disorders                            Conjunctivitis,      Diplopia endocrine ophthalmopathy,
vision blurred
Ear and labyrinth                        Vertigo              Ear pain disorders
Cardiac disorders   Tachycardia*         Bradycardia*,        Atrial               Myocardial palpitations*        fibrillation*        ischaemia**
, myocardial infarction**
Vascular            Flushing*            Hypotension*,
disorders                                hypertension*
Respiratory,                             Dyspnoea*,           Throat               Pulmonary thoracic and                             cough, epistaxis,    tightness*, throat   alveolar mediastinal                              hiccups,             irritation,          haemorrhag disorders                                oropharyngeal        pneumonitis          e** pain, asthma
Gastrointestinal    Nausea*              Abdominal pain,      Constipation, disorders                                vomiting,            gastro- diarrhoea,           oesophageal dyspepsia*,          reflux disease,
stomatitis           gingival bleeding, dry mouth,
dysphagia,
gastrointestinal disorder,
haematochezia
Hepatobiliary                            Aspartate            Cholecystitis        Autoimmun disorders                                aminotransferase     including            e hepatitis, increased,           acalculous           Hepatitis alanine              cholecystitis and    (associated aminotransferase     acute acalculous     with EBV increase             cholecystitis        infection)
Skin and            Urticaria*, rash*,   Erythema*,           Blister, night subcutaneous        pruritus*,           ecchymosis,          sweats, swelling tissue disorders    generalised rash*    alopecia,            face, eczema, hyperhidrosis,       vitiligo, alopecia acne, skin lesion,   areata dermatitis
Musculoskeletal                          Myalgia, muscle      Musculoskeletal      Adult Onset and connective                           weakness,            stiffness, limb      Still’s tissue disorders                         arthralgia, back     discomfort           Disease pain, pain in                             (AOSD) extremity,
muscle spasms,
neck pain,
musculoskeletal pain


Renal and                               Proteinuria,         Nephrolithiasis, urinary disorders                       haematuria           ketonuria, nephropathies including anti-
GBM disease
Reproductive                            Menorrhagia,         Cervical system and breast                       menstruation         dysplasia, disorders                               irregular            amenorrhoea General disorders   Pyrexia*,           Chest and                 fatigue*, chills*   discomfort*,
administration                          pain*, oedema site conditions                         peripheral,
asthenia,
influenza-like illness, malaise,
infusion site pain
Investigations                          Blood creatinine     Weight increased            decreased,
weight increased,
red blood cell count decreased,
bacterial test positive, blood glucose increased, mean cell volume increase
Injury, poisoning                       Contusion,
and procedural                          infusion related complications                           reaction

1
Herpes virus infections include PTs: Oral herpes, Herpes simplex, Genital herpes, Herpes virus infection, Genital herpes simplex, Herpes dermatitis, Ophthalmic herpes simplex, Herpes simplex serology positive.
2
Herpes zoster infections include PTs: Herpes zoster, Herpes zoster cutaneous disseminated, Ophthalmic herpes zoster, Herpes ophthalmic, Herpes zoster infection neurological, Herpes zoster meningitis.

Description of selected adverse reactions

Terms marked with asterisk (*) in Table 1 include adverse reactions reported as Infusion-Associated Reactions.

Terms marked with two asterisks (**) in Table 1 include adverse reactions observed in the post-marketing setting which have occurred in the majority of cases with time to onset within 1-3 days of LEMTRADA infusion, following any of the doses during the treatment course.

Neutropenia
Cases of severe (including fatal) neutropenia have been reported within 2 months of LEMTRADA infusion.

Safety profile in long-term follow-up
The type of adverse reactions including seriousness and severity observed in LEMTRADA treatment groups through all available follow-up including patients who received additional treatment courses were similar to those in the active-controlled studies. The incidence of IARs was higher in course 1 than in subsequent courses.


In patients continuing from controlled clinical studies and who did not receive any additional LEMTRADA after the initial 2 treatment courses, the rate (events per person-year) of most adverse reactions was comparable to or reduced in years 3-6 as compared to years 1 and 2. The rate of thyroid adverse reactions was highest in year three and declined thereafter.
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).