Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most frequently reported adverse reactions (>10 %) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity.
Somnolence and fatigue (8.2 %) were reported at a higher incidence with increasing dose.

The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7 % for patients randomized to placebo. The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %).


Tabulated list of adverse reactions

In the table below, adverse reactions, which were identified based on review of the three placebo- controlled, fixed-dose studies safety database in subjects ≥ 16 years of age, are listed by System Organ Class and frequency.
The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class             Frequency              Adverse reactions from clinical trials Infections and                 Common                 Influenza infestations
Blood and lymphatic            Uncommon               Neutropenia system disorders
Immune system disorders        Uncommon               Type I hypersensitivity Metabolism and nutrition       Common                 Decreased appetite disorders
Psychiatric disorders          Common                 Depression, anxiety, insomnia, irritability Uncommon               Suicidal ideation, psychotic disorder,
aggression, agitation
Nervous system disorders       Very common            Dizziness, somnolence Common                 Convulsion, vertigo

Respiratory, thoracic and      Common                 Upper respiratory tract infections, cough mediastinal disorders
Gastrointestinal               Common                 Nausea, vomiting, constipation disorders
General disorders and          Common                 Fatigue administration site conditions

Description of selected adverse reactions

Neutropenia has been reported in 0.5 % (6/1099) brivaracetam patients and 0 % (0/459) placebo patients. Four of these subjects had decreased neutrophil counts at baseline, and experienced additional decrease in neutrophil counts after initiation of brivaracetam treatment. None of the 6 cases of neutropenia were severe, required any specific treatment or led to discontinuation of brivaracetam and none had associated infections.

Suicidal ideation has been reported in 0.3 % (3/1099) brivaracetam patients and 0.7 % (3/459) placebo patients. In the short-term clinical studies of brivaracetam in epilepsy patients, there were no cases of completed suicide and suicide attempt, however both have been reported in open-label extension studies (see section 4.4).

Reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of brivaracetam patients (9/3022) during clinical development.

Paediatric population

The safety profile of brivaracetam observed in children was consistent with the safety profile observed in adults. In the open label, uncontrolled, long-term studies suicidal ideation was reported in 4.7 % of paediatric patients assessed from 6 years onwards (more common in adolescents) compared with 2.4 % of adults and behavioural disorders were reported in 24.8 % of paediatric patients compared with 15.1 % of adults. The majority of events were mild or moderate in intensity, were non-serious, and did not lead to discontinuation of study drug. An additional adverse reaction reported in children was psychomotor hyperactivity (4.7 %).


No specific pattern of adverse event (AE) was identified in children from 1 month to < 4 years of age.
Limited data are available on neurodevelopment in children <4 years of age. Limited clinical data are available in neonates.

Elderly

Of the 130 elderly subjects enrolled in the brivaracetam phase 2/3 development program (44 with epilepsy), 100 were 65-74 years of age and 30 were 75-84 years of age. The safety profile in elderly patients appears to be similar to that observed in younger adult patients.

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/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com