Vimpat Adverse Reactions

Summary of safety profile: Based on the analysis of pooled placebo-controlled clinical studies 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 clinical 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 study 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.
The safety profile of lacosamide reported in a study conducted in patients aged 4 years and older with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures (PGTCS) was consistent with the safety profile reported from the pooled placebo-controlled clinical studies in partial-onset seizures. Additional adverse reactions reported in PGTCS patients were myoclonic epilepsy (2.5% in the lacosamide group and 0% in the placebo group) and ataxia (3.3% in the lacosamide group and 0% in the placebo group). The most frequently reported adverse reactions were dizziness and somnolence. The most common adverse reactions resulting in discontinuation of lacosamide therapy were dizziness and suicidal ideation. The discontinuation rate due to adverse reactions was 9.1% in the lacosamide group and 4.1% in the placebo group.
Tabulated list of adverse reactions: Table 9 shows the frequencies of adverse reactions which have been reported in clinical studies 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. (See Table 9.)

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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 studies 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 study 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 studies 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 study 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 studies; however, both have been reported in open-label epilepsy studies and in post-marketing experience.
Laboratory abnormalities: Abnormalities in liver function tests have been observed in placebo-controlled clinical studies with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant antiepileptic medicinal products. Elevations of ALT to ≥3 x 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 Pharmacology: Pharmacodynamics under Actions) and in open-label clinical studies (n=408) in adjunctive therapy in children from 4 years of age with partial-onset seizures 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 were mainly stable during the course of the studies.
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. Healthcare professionals are asked to report any suspected adverse reactions.