LACOSAMIDE ACCORD

Posology The physician should prescribe the most appropriate formulation and strength according to weight and dose. Lacosamide must be taken twice a day, approximately 12 hours apart. If a dose is missed, the patient should be instructed to take the missed dose immediately, and then to take the next dose of lacosamide at the regularly scheduled time.

If the patient notices the missed dose within 6 hours of the next one, he/she should be instructed to wait to take the next dose of lacosamide at the regularly scheduled time. Patients should not take a double dose. Adolescents and children weighing 50 kg or more, and adults Monotherapy (in the treatment of partial-onset seizures) The recommended starting dose is 50 mg twice a day (100 mg/day) which should be increased to an initial therapeutic dose of 100 mg twice a day (200 mg/day) after one week.

Lacosamide can also be initiated at the dose of 100 mg twice a day (200 mg/day) based on the physician's assessment of required seizure reduction versus potential side effects. Depending on response and tolerability, the maintenance dose can be further increased at weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily dose of 300 mg twice a day (600 mg/day).

In patients having reached a dose greater than 400mg/day and who need an additional antiepileptic medicinal product, the posology that is recommended for adjunctive therapy below should be followed. Adjunctive therapy (in the treatment of partial-onset seizures or in the treatment of primary generalised tonic-clonic seizures) The recommended starting dose is 50 mg twice a day (100 mg/day) which should be increased to an initial therapeutic dose of 100 mg twice a day (200 mg/day) after one week.

Depending on response and tolerability, the maintenance dose can be further increased at weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily dose of 200 mg twice a day (400 mg/day). Lacosamide Accord treatment initiation pack contains 4 different packages (one for each tablet strength) with 14 tablets each, for the first 2 to 4 weeks of therapy depending on the patient´s response and tolerability.

The packages are marked with ‘week 1 (2, 3 or 4)’. On the first day of treatment the patient starts with Lacosamide Accord 50 mg tablets twice a day (100 mg/day). During the second week, the patient takes Lacosamide Accord 100 mg tablets twice a day (200 mg/day).

Depending on response and tolerability, Lacosamide Accord 150 mg tablets may be taken twice a day (300 mg/day) during the third week and Lacosamide Accord 200 mg tablets twice a day (400 mg/day) during the fourth week. Discontinuation If lacosamide has to be discontinued, it is recommended that the dose is reduced gradually in weekly decrements of 4 mg/kg/day (for patients with a body weight less than 50 kg) or 200 mg/day (for patients with a body weight of 50 kg or more) for patients who have achieved a dose of lacosamide ≥ 6 mg/kg/day or ≥ 300 mg/day, respectively.

In patients who develop serious cardiac arrhythmia, clinical benefit/risk assessment should be performed and if needed lacosamide should be discontinued. Special populations Elderly (over 65 years of age) No dose reduction is necessary in elderly patients.

2). 1). Renal impairment No dose adjustment is necessary in mildly and moderately renally impaired adult and paediatric patients (CLCR > 30 ml/min). A maximum dose of 250 mg/day is recommended for paediatric patients weighing 50 kg or more and for adult patients with severe renal impairment (CLCR ≤ 30 ml/min) or with end-stage renal disease.

In paediatric patients weighing less than 50 kg with severe renal impairment (CLCR ≤ 30 ml/min) and in those with end-stage renal disease, a reduction of 25 % of the maximum dose is recommended. For all patients requiring haemodialysis a supplement of up to 50 % of the divided daily dose directly after the end of haemodialysis is recommended.

Treatment of patients with end-stage renal disease should be made with caution as there is little clinical experience and accumulation of a metabolite (with no known pharmacological activity). 2). Hepatic impairment A maximum dose of 300 mg/day is recommended for paediatric patients weighing 50 kg or more and for adult patients with mild to moderate hepatic impairment.

The dose titration in these patients should be performed with caution considering co- existing renal impairment. Based on data in adults, in paediatric patients weighing less than 50 kg with mild to moderate hepatic impairment, a reduction of 25 % of the maximum dose should be applied.

2). Lacosamide should be administered to adult and paediatric patients with severe hepatic impairment only when the expected therapeutic benefits are anticipated to outweigh the possible risks. The dose may need to be adjusted while carefully observing disease activity and potential side effects in the patient.

Paediatric population Adolescents and children weighing 50 kg or more Dosage in adolescents and children weighing 50 kg or more is the same as in adults (see above). Children (from 2 years of age) and adolescents weighing below 50 kg This presentation is not suitable for this category of patients.

Children less than 2 years The safety and efficacy of lacosamide in children aged below 4 years have not yet been […]

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. 6 % for patients randomised to placebo.

The most common adverse reaction resulting in discontinuation of lacosamide therapy was dizziness. 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.

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.

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.

1 % in the placebo group. Tabulated list of adverse reactions The table below 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. System organ class Very common Common Uncommon Not known Blood and lymphatic disorders Agranulocytosis(1) Immune system disorders Drug hypersensitivity(1) Drug reaction with eosinophilia and systemic symptoms (DRESS) (1,2) Psychiatric disorders Depression Confusional state Insomnia(1) Aggression Agitation(1) Euphoric mood(1) Psychotic disorder(1) Suicide attempt (1) Suicidal ideation Hallucination (1) Nervous system disorders Dizziness Headache Myoclonic seizures(3) Ataxia Balance disorder Memory impairment Cognitive disorder Somnolence Tremor Nystagmus Hypoesthesia Dysarthria Disturbance in attention Paraesthesia Syncope(2) Coordination abnormal Dyskinesia Convulsion Eye disorders Diplopia Vision blurred Ear and labyrinth disorders Vertigo Tinnitus Cardiac disorders Atrioventricular block(1,2) Bradycardia(1,2) Atrial Fibrillation (1,2) Atrial Flutter (1,2) Ventricular tachyarrhythmia (1) Gastrointestinal disorders Nausea Vomiting Constipation Flatulence Dyspepsia Dry mouth Diarrhoea Hepatobiliary disorders Liver function test abnormal (2) Hepatic enzyme increased (> 2x ULN) (1) Skin and subcutaneous tissue disorders Pruritus Rash(1) Angioedema(1) Urticaria(1) Stevens-Johnson syndrome(1) Toxic epidermal necrolysis(1) Musculoskeletal and connective tissue disorders Muscle spasms General Gait disorders and administration site conditions disturbance Asthenia Fatigue Irritability Feeling drunk Injury, poisoning and procedural complications Fall Skin laceration Contusion (1) Adverse reactions reported in post marketing experience.

(2) See Description of selected adverse reactions. (3) Reported in PGTCS studies. Description of selected adverse reactions The use of lacosamide is associated with dose-related increase in the PR interval. g. atrioventricular block, syncope, bradycardia) may occur.

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. 3 %). 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 ≥ […]

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with antiepileptic medicinal products in several indications. A meta-analysis of randomised placebo-controlled clinical studies of antiepileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour.

The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lacosamide. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered.

8). Cardiac rhythm and conduction Dose-related prolongations in PR interval with lacosamide have been observed in clinical studies. g. 5), as well as in elderly patients. In these patients it should be considered to perform an ECG before a lacosamide dose increase above 400 mg/day and after lacosamide is titrated to steady-state.

In the placebo-controlled clinical studies of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however, both have been reported in open- label epilepsy studies and in post-marketing experience. In post-marketing experience, AV block (including second degree or higher AV block) has been reported.

In patients with proarrhythmic conditions, ventricular tachyarrhythmia has been reported. In rare cases, these events have led to asystole, cardiac arrest and death in patients with underlying proarrhythmic conditions. g. slow, rapid or irregular pulse, palpitations, shortness of breath, feeling lightheaded, fainting).

Patients should be counselled to seek immediate medical advice if these symptoms occur. Dizziness Treatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls. 8). Potential for new onset or worsening of myoclonic seizures New onset or worsening of myoclonic seizures has been reported in both adult and paediatric patients with PGTCS, in particular during titration.

In patients with more than one seizure type, the observed benefit of control for one seizure type should be weighed against any observed worsening in another seizure type. Potential for electro-clinical worsening in specific paediatric epilepsy syndromes The safety and efficacy of lacosamide in paediatric patients with epilepsy syndromes in which focal and generalised seizures may coexist have not been determined.

.

1. Known second- or third-degree atrioventricular (AV) block.