Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
Based on the analysis of pooled placebo-controlled clinical trials in adjunctive therapy in 1,308 patients with partial-onset seizures, a total of 61.9 % of patients randomised to lacosamide and 35.2 % of patients randomised to placebo reported at least 1 adverse reaction. The most frequently reported adverse reactions (≥ 10 %) with lacosamide treatment were dizziness, headache, nausea and diplopia. They were usually mild to moderate in intensity. Some were dose-related and could be alleviated by reducing the dose. Incidence and severity of central nervous system (CNS) and gastrointestinal (GI) adverse reactions usually decreased over time.
In all of these controlled studies, the discontinuation rate due to adverse reactions was 12.2 % for patients randomised to lacosamide and 1.6 % for patients randomised to placebo. The most common adverse reaction resulting in discontinuation of lacosamide therapy was dizziness.
Incidence of CNS adverse reactions such as dizziness may be higher after a loading dose.

Based on the analysis of data from a non-inferiority monotherapy clinical trial comparing lacosamide to carbamazepine controlled release (CR), the most frequently reported adverse reactions (≥ 10 %) for lacosamide were headache and dizziness. The discontinuation rate due to adverse reactions was 10.6 % for patients treated with lacosamide and 15.6 % for patients treated with carbamazepine CR.

Tabulated list of adverse reactions
The table below shows the frequencies of adverse reactions which have been reported in clinical trials and post- marketing experience. The frequencies are defined as follows: 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 grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class      Very common         Common                    Uncommon             Not known Blood and                                                                                  Agranulocytosis(1) lymphatic disorders
Immune system                                                        Drug                   Drug reaction disorders                                                            hypersensitivity(1)   with eosinophilia and systemic symptoms
(DRESS)(1,2)
Psychiatric                                 Depression               Aggression disorders                                   Confusional state        Agitation(1) Insomnia(1)              Euphoric mood(1)
Psychotic disorder(1)
Suicide attempt(1)
Suicidal ideation
Hallucination(1)
Nervous system          Dizziness                                    Syncope(2)            Convulsion disorders               Headache            Ataxia                   Coordination Balance disorder         abnormal
Memory impairment        Dyskinesia
Cognitive disorder
Somnolence
Tremor
Nystagmus
Hypoesthesia
Dysarthria
Disturbance in attention
Paraesthesia
Eye disorders           Diplopia            Vision blurred
Ear and labyrinth                           Vertigo disorders                                   Tinnitus
Cardiac disorders                                                    Atrioventricular      Ventricular block(1,2)            tachyarrhythmia(1)
Bradycardia(1,2)
Atrial Fibrillation
(1,2)

Atrial Flutter(1,2)

System organ class     Very common           Common                   Uncommon              Not known Gastrointestinal       Nausea                Vomiting disorders                                    Constipation
Flatulence
Dyspepsia
Dry mouth
Diarrhoea
Hepatobiliary                                                         Liver function test disorders                                                             abnormal(2) Hepatic enzyme increased
(> 2x ULN)(1)
Skin and                                     Pruritus                 Angioedema(1)         Stevens-Johnson subcutaneous tissue                          Rash(1)                  Urticaria(1)          syndrome(1) disorders                                                                                   Toxic epidermal necrolysis(1)
Musculoskeletal                              Muscle spasms and connective tissue disorders
General disorders                             Gait disturbance       Erythema(3) and administration                            Asthenia site conditions                               Fatigue
Irritability
Feeling drunk
Injection site pain or discomfort (3) irritation(3)
Injury, poisoning                           Fall and procedural                              Skin laceration complications                               Contusion
(1)
Adverse reactions reported in post marketing experience.
(2)
See Description of selected adverse reactions.
(3)
Local adverse reactions associated with intravenous administration.

Description of selected adverse reactions

The use of lacosamide is associated with dose-related increase in the PR interval. Adverse reactions associated with PR interval prolongation (e.g. atrioventricular block, syncope, bradycardia) may occur.
In adjunctive clinical trials in epilepsy patients the incidence rate of reported first-degree AV Block is uncommon, 0.7 %, 0 %, 0.5 % and 0 % for lacosamide 200 mg, 400 mg, 600 mg or placebo, respectively. No second- or higher degree AV Block was seen in these studies. However, cases with second- and third-degree AV Block associated with lacosamide treatment have been reported in post-marketing experience. In the monotherapy clinical trial comparing lacosamide to carbamazepine CR the extent of increase in PR interval was comparable between lacosamide and carbamazepine.
The incidence rate for syncope reported in pooled adjunctive therapy clinical trials is uncommon and did not differ between lacosamide (n=944) treated epilepsy patients (0.1 %) and placebo (n=364) treated epilepsy patients (0.3 %). In the monotherapy clinical trial comparing lacosamide to carbamazepine CR, syncope was reported in 7/444 (1.6 %) lacosamide patients and in 1/442 (0.2 %) carbamazepine CR patients.
Atrial fibrillation or flutter were not reported in short term clinical trials; however, both have been reported in open-label epilepsy trials and in post-marketing experience.

Laboratory abnormalities
Abnormalities in liver function tests have been observed in placebo-controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant antiepileptic medicinal products.


Elevations of ALT to ≥ 3x ULN occurred in 0.7 % (7/935) of Vimpat patients and 0 % (0/356) of placebo patients.

Multiorgan hypersensitivity reactions
Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS) have been reported in patients treated with some antiepileptic medicinal products. These reactions are variable in expression but typically present with fever and rash and can be associated with involvement of different organ systems. If multiorgan hypersensitivity reaction is suspected, lacosamide should be discontinued.

Paediatric population

The safety profile of lacosamide in placebo-controlled (see study details in section 5.1) and in open-label studies (n=408) in adjunctive therapy in children from 4 years of age was consistent with the safety profile observed in adults although the frequency of some adverse reactions (somnolence, vomiting and convulsion) was increased and additional adverse reactions (nasopharyngitis, pyrexia, pharyngitis, decreased appetite, lethargy and abnormal behaviour) have been reported in paediatric patients: nasopharyngitis (15.7 %), vomiting (14.7 %), somnolence (14.0 %), dizziness (13.5 %), pyrexia (13.0 %), convulsion (7.8 %), decreased appetite (5.9 %), pharyngitis (4.7 %), lethargy (2.7 %) and abnormal behaviour (1.7 %).
A total of 67.8 % of patients randomised to lacosamide and 58.1 % of patients randomised to placebo reported at least 1 adverse reaction.
Behavioural, cognition and emotional functioning were measured by the questionnaires Achenbach CBCL and BRIEF that were applied at baseline and throughout the studies and where mainly stable during the course of the trials.

Elderly population

In the monotherapy study comparing lacosamide to carbamazepine CR, the types of adverse reactions related to lacosamide in elderly patients (≥ 65 years of age) appear to be similar to that observed in patients less than 65 years of age. However, a higher incidence (≥ 5 % difference) of fall, diarrhoea and tremor has been reported in elderly patients compared to younger adult patients. The most frequent cardiac-related adverse reaction reported in elderly compared to the younger adult population was first-degree AV block. This was reported with lacosamide in 4.8 % (3/62) in elderly patients versus 1.6 % (6/382) in younger adult patients. The discontinuation rate due to adverse events observed with lacosamide was 21.0 % (13/62) in elderly patients versus 9.2 % (35/382) in younger adult patients. These differences between elderly and younger adult patients were similar to those observed in the active comparator group.

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