Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onset seizures were treated with eslicarbazepine acetate (1,983 adult patients and 451 paediatric patients) and 51% of those patients experienced adverse reactions.

Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the first weeks of treatment with eslicarbazepine acetate.

The risks that have been identified for Zebinix are mainly class-based, dose-dependent undesirable effects. The most common treatment-emergent adverse reactions reported, in placebo controlled adjunctive therapy studies with adult epileptic patients and in an active controlled monotherapy study comparing eslicarbazepine acetate with carbamazepine controlled release, were dizziness, somnolence, headache, and nausea. The majority of adverse reactions were reported in <3% of subjects in any treatment group.

Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in post-marketing experience with Zebinix treatment (see section 4.4).

Tabulated list of adverse reactions
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and post- marketing surveillance are tabulated below.

The following convention has been used for the classification of adverse reactions very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (frequency cannot be estimated from available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 1: Treatment emergent adverse reactions associated with Zebinix obtained from clinical studies and post-marketing surveillance
System Organ        Very         Common              Uncommon           Not known Class               common
Blood and                                            Anaemia            Thrombocytopenia, lymphatic                                                               leukopenia system disorders
Immune system                                        Hypersensitivity disorders
Endocrine                                            Hypothyroidism disorders


Metabolism and                Hyponatraemia,     Electrolyte          Inappropriate ADH nutrition                     decreased          imbalance,           secretion like disorders                     appetite           dehydration,         syndrome with hypochloraemia       signs and symptoms of lethargy, nausea,
dizziness, decrease in serum (blood) osmolality,
vomiting,
headache,
confusional state or other neurological signs and symptoms.

Psychiatric                   Insomnia           Psychotic disorders                                        disorder,
apathy,
depression,
nervousness,
agitation,
irritability,
attention deficit/ hyperactivity disorder,
confusional state, mood swings, crying,
psychomotor retardation,
anxiety
Nervous system   Dizziness,   Headache,          Coordination disorders        somnolence   disturbance in     abnormal,
attention,         memory tremor, ataxia,    impairment,
balance disorder   amnesia,
hypersomnia,
sedation,
aphasia,
dysaesthesia,
dystonia,
lethargy,
parosmia,
cerebellar syndrome,
convulsion,
peripheral neuropathy,
nystagmus,
speech disorder,
dysarthria,
burning sensation,
paraesthesia,
migraine

Eye disorders      Diplopia, vision   Visual blurred            impairment,
oscillopsia,
binocular eye movement disorder, ocular hyperaemia
Ear and            Vertigo            Hypoacusis,
labyrinth                             tinnitus disorders
Cardiac                               Palpitations,
disorders                             bradycardia
Vascular                              Hypertension disorders                             (including hypertensive crisis),
hypotension,
orthostatic hypotension,
flushing,
peripheral coldness
Respiratory,                          Epistaxis, chest thoracic and                          pain mediastinal disorders
Gastrointestinal   Nausea,            Constipation,       Pancreatitis disorders          vomiting,          dyspepsia,
diarrhoea          gastritis,
abdominal pain,
dry mouth,
abdominal discomfort,
abdominal distension,
gingivitis,
melaena,
toothache
Hepatobiliary                         Liver disorder disorders
Skin and           Rash               Alopecia, dry      Toxic epidermal subcutaneous                          skin,              necrolysis, Stevens- tissue disorders                      hyperhidrosis,     Johnson syndrome, erythema, skin     drug reaction with disorder,          eosinophilia and pruritus,          systemic symptoms dermatitis         (DRESS),
allergic           angioedema,
urticaria
Musculoskeletal                       Myalgia, bone and connective                        metabolism tissue disorders                      disorder,
muscular weakness, pain in extremity


Renal and                                               Urinary tract urinary                                                 infection disorders
General                            Fatigue, gait        Malaise, chills, disorders and                      disturbance,         oedema administration                     asthenia             peripheral site conditions
Investigations                     Weight               Blood pressure increased            decreased,
weight decreased, blood pressure increased, blood sodium decreased, blood chloride decreased,
osteocalcin increased,
haematocrit decreased,
haemoglobin decreased,
hepatic enzymes increased
Injury,                                                 Drug toxicity, poisoning and                                           fall, thermal procedural                                              burn complications

Description of selected adverse reactions

Eye and nervous system disorders
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo- controlled studies, the following adverse reactions were observed: diplopia (11.4% of subjects with concomitant carbamazepine, 2.4% of subjects without concomitant carbamazepine), abnormal coordination (6.7% with concomitant carbamazepine, 2.7% without concomitant carbamazepine), and dizziness (30.0% with concomitant carbamazepine, 11.5% without concomitant carbamazepine), see section 4.5.

PR interval
The use of eslicarbazepine acetate is associated with increase in the PR interval. Adverse reactions associated with PR interval prolongation (e.g. AV block, syncope, bradycardia) may occur.

Class related adverse reactions
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, systemic lupus erythematosus or serious cardiac arrhythmias did not occur during the placebo-controlled studies of the epilepsy program with eslicarbazepine acetate. However, they have been reported with oxcarbazepine. Therefore, their occurrence after treatment with eslicarbazepine acetate cannot be excluded.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with the structurally related antiepileptic drugs carbamazepine and oxcarbazepine. The mechanism by which bone metabolism is affected has not been identified.


Paediatric population

In placebo-controlled studies involving patients aged from 2 to 18 years with partial-onset seizures (238 patients treated with eslicarbazepine acetate and 189 with placebo), 35.7% of patients treated with eslicarbazepine acetate and 19% of patients treated with placebo experienced adverse reactions.
The most common adverse reaction in the group treated with eslicarbazepine acetate were diplopia (5.0%), somnolence (8.0%) and vomiting (4.6%).

The adverse reaction profile of eslicarbazepine acetate is generally similar across age goups. In the age group from 6 to 11 years of age, the most common adverse reactions observed in more than two patients treated with eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), diziness (6.3%), convulsion (6.3%) and nausea (3.2%); in the age group from 12 to 18 years were somnolence (7.4%), vomiting (4.2%), diplopia (3.2%) and fatigue (3.2%). The safety of Zebinix in children aged 6 years and below has not yet been established.

The safety profile of eslicarbazepine acetate was generally similar between adult and paediatric patients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were more common in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor; ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common in children than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatric population.

Long-term safety data in the paediatric population obtained from open label extensions of the phase III study was consistent with the known safety profile of the product with no new findings of concern.

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