Adverse reactions : תופעות לוואי

4.8. Undesirable effects
Summary of the safety profile

The most commonly reported adverse reactions were somnolence, dizziness, fatigue and headache.
The discontinuation rates because of adverse reactions in clinical trials were 5%, 6% and 19% for patients randomised to receive cenobamate at doses of 100 mg/day, 200 mg/day and 400 mg/day respectively, compared to 3% in patients randomised to receive placebo. The 400 mg dose was more associated with adverse reactions especially when taken concomitantly with clobazam.

The adverse reactions most commonly leading to discontinuation, in descending order of frequency, were: ataxia (1.6% vs 0.5% placebo), dizziness (1.6% vs 0.5% placebo), somnolence (1.4% vs 0.5% placebo), nystagmus (0.7% vs 0 % placebo), vertigo (0.7% vs 0 % placebo) and diplopia (0.5% vs 0 % placebo). These adverse reactions are dose dependent and the titration scheme should be strictly followed).

Tabulated list of adverse reactions
Adverse reactions reported in clinical studies are listed in table 2 per system organ class (SOC) and per frequency. Within each frequency group, undesirable effects are ranked in decreasing order of severity: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000).
Table 2: Tabulated list of adverse reactions
System organ class Frequency                Adverse reactions from clinical trials 
Immune system          Uncommon              Hypersensitivity* disorders
Psychiatric            Common                Confusional state, Irritability disorders
Uncommon              Suicidal ideation

Nervous system         Very common           Somnolence*, Coordination and Gait abnormalities*, disorders                                    Headache
Common                Dysarthria, Nystagmus, Aphasia, Memory impairment 

Eye disorders          Common                Diplopia, Vision blurred 
Gastrointestinal       Common                Constipation, Diarrhoea, Nausea, Vomiting, Dry disorders                                    mouth
Skin and               Common                Rash* subcutaneous tissue disorder               Rare                  Drug reaction with eosinophilia and systemic symptoms (DRESS)
Investigations         Common                Hepatic enzyme increased* 
*Grouped terms: Somnolence: Somnolence, Fatigue, Sedation and Hypersomnia; Coordination and Gait abnormalities: Dizziness, Vertigo, Balance disorder, Ataxia, Gait disturbance and abnormal coordination; Hypersensitivity: Hypersensitivity, Drug hypersensitivity, Eyelid oedema; Rash: Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash morbilliform, Rash papular, Rash pruritic; Hepatic enzyme increased: Alanine aminotransferase increased, Aspartate aminotransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Transaminases increased.

Description of selected adverse reactions

Drug reaction with eosinophilia and systemic symptoms (DRESS)
Three cases of DRESS were reported within 2 to 4 weeks of starting cenobamate in studies with high starting doses (50 mg or 100 mg once daily) and weekly or faster titration. When cenobamate was initiated at 12.5 mg/day and titrated every two weeks, in an open-label safety study of 1,340 epilepsy patients, no cases of DRESS were reported.

At the time of prescription, patients should be advised of the signs and symptoms of DRESS and monitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If signs and symptoms suggestive of these reactions appear, cenobamate should be withdrawn immediately and an alternative treatment considered (as appropriate). Xcopri should always be initiated at 12.5 mg once daily and titrated not faster than once every two weeks (see sections 4.2 and 4.4.).

Hypersensitivity
Four (0.9%) Cenobamate treated patients and one (0.5%) placebo patient experienced an event of hypersensitivity. Two patients in the cenobamate dose group experienced events of drug hypersensitivity. One cenobamate treated patient experienced an event of hypersensitivity and one cenobamate treated patient experienced an event on eyelid oedema. The placebo patient experienced an event of hypersensitivity. All events were classified as mild or moderate.

Elderly

Safety data from the Pooled Double-Blind and All Phase 2/3 datasets along with PK data from a Phase 1 study showed no additional safety risks in elderly subjects >65 years of age at study entry.
Additional subgrouping by age for subjects who were >65 years of age during study participation showed similar results for adverse reactions in these 87 subjects as compared with the 51 subjects who were >65 years of age at study entry (see section 4.2).

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