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Medically reviewed by Fedorchenko Olga Valeryevna, PharmD. Last updated on 23.03.2022
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Entaxar is indicated as monotherapy and adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy.
Posology
Lacosamide therapy can be initiated with either oral or intravenous administration.).
Lacosamide must be taken twice a day (usually once in the morning and once in the evening).
Adolescents and children weighing 50 kg or more, and adults
The following table summarises the recommended posology for adolescents and children weighing 50 kg or more, and for adults. More details are provided in the table below.
| Monotherapy | Adjunctive therapy | |
| Starting dose | 100 mg/day or 200 mg/day | 100 mg/day |
| Single loading dose (if applicable) | 200 mg | 200 mg |
| Titration (incremental steps) | 50 mg twice a day (100 mg/day) at weekly intervals | 50 mg twice a day (100 mg/day) at weekly intervals |
| Maximum recommended dose | up to 600 mg/day | up to 400 mg/day |
Monotherapy
The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Lacosamide can also be initiated at the dose of 100 mg twice a 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 400 mg/day and who need an additional antiepileptic medicinal product, the posology that is recommended for adjunctive therapy below should be followed.
Adjunctive therapy
The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a 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 400 mg (200 mg twice a day).
Initiation of lacosamide treatment with a loading dose
Lacosamide treatment may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice a day (200 mg/day) maintenance dose regimen. Subsequent dose adjustments should be performed according to individual response and tolerability as described above. A loading dose may be initiated in patients in situations when the physician determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of central nervous system adverse reactions. Administration of a loading dose has not been studied in acute conditions such as status epilepticus.
Discontinuation
In accordance with current clinical practice, if lacosamide has to be discontinued, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).
Special populations
Elderly (over 65 years of age)
No dose reduction is necessary in elderly patients.). There is limited clinical data in the elderly patients with epilepsy, particularly at doses greater than 400 mg/day.
Renal impairment
No dose adjustment is necessary in mildly and moderately renally impaired adult and paediatric patients (CLCR > 30 ml/min). In paediatric patients weighing 50 kg or more and in adult patients with mild or moderate renal impairment a loading dose of 200 mg may be considered, but further dose titration (> 200 mg daily) should be performed with caution. In paediatric patients weighing 50 kg or more and in adult patients with severe renal impairment (CLCR ≤ 30 ml/min) or with end-stage renal disease, a maximum dose of 250 mg/day is recommended and the dose titration should be performed with caution. If a loading dose is indicated, an initial dose of 100 mg followed by a 50 mg twice daily regimen for the first week should be used. 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).
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. In adolescents and adults weighing 50 kg or more, a loading dose of 200 mg may be considered, but further dose titration (> 200 mg daily) should be performed with caution. 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. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients. 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
The physician should prescribe the most appropriate formulation and strength according to weight and dose.
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 4 years of age) and adolescents weighing less than 50 kg
Monotherapy
The recommended starting dose is 2 mg/kg/day which should be increased to an initial therapeutic dose of 4 mg/kg/day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 2 mg/kg/day every week. The dose should be gradually increased until the optimum response is obtained. In children weighing less than 40 kg, a maximum dose of up to 12 mg/kg/day is recommended. In children weighing from 40 to under 50 kg, a maximum dose of 10 mg/kg/day is recommended.
The following table below summarises the recommended posology in monotherapy for children and adolescents weighing less than 50 kg.
| Starting dose | 2 mg/kg/day |
| Single loading dose | Not recommended |
| Titration (incremental steps) | 2 mg/kg/day every week |
| Maximum recommended dose in patients < 40 kg | up to 12 mg/kg/day |
| Maximum recommended dose in patients > 40 kg to < 50 kg | up to 10 mg/kg/day |
The tables below provide examples of volumes of solution for infusion per administration depending on prescribed dose and body weight. The precise volume of solution for infusion is to be calculated according to the exact body weight of the child.
Monotherapy doses to be taken twice daily for children from 4 years of age weighing less than 40 kg(1):
| Weight | 0.1 ml/kg (1 mg/kg) Starting dose | 0.2 ml/kg (2 mg/kg) | 0.3 ml/kg (3 mg/kg) | 0.4 ml/kg (4 mg/kg) | 0.5 ml/kg (5 mg/kg) | 0.6 ml/kg (6 mg/kg) Maximum recommended dose |
| 10 kg | 1 ml (10 mg) | 2 ml (20 mg) | 3 ml (30 mg) | 4 ml (40 mg) | 5 ml (50 mg) | 6 ml (60 mg) |
| 15 kg | 1.5 ml (15 mg) | 3 ml (30 mg) | 4.5 ml (45 mg) | 6 ml (60 mg) | 7.5 ml (75 mg) | 9 ml (90 mg) |
| 20 kg | 2 ml (20 mg) | 4 ml (40 mg) | 6 ml (60 mg) | 8 ml (80 mg) | 10 ml (100 mg) | 12 ml (120 mg) |
| 25 kg | 2.5 ml (25 mg) | 5 ml (50 mg) | 7.5 ml (75 mg) | 10 ml (100 mg) | 12.5 ml (125 mg) | 15 ml (150 mg) |
| 30 kg | 3 ml (30 mg) | 6 ml (60 mg) | 9 ml (90 mg) | 12 ml (120 mg) | 15 ml (150 mg) | 18 ml (180 mg) |
| 35 kg | 3.5 ml (35 mg) | 7 ml (70 mg) | 10.5 ml (105 mg) | 14 ml (140 mg) | 17.5 ml (175 mg) | 21 ml (210 mg) |
| (1) Children and adolescents less than 50 kg should preferably start the treatment with Entaxar 10 mg/ml syrup. Entaxar 10 mg/ml solution for infusion is an alternative for patients when oral administration is temporarily not feasible. | ||||||
Monotherapy doses to be taken twice daily for children and adolescents from 4 years of age weighing 40 kg to under 50 kg(1) (2):
| Weight | 0.1 ml/kg (1 mg/kg) Starting dose | 0.2 ml/kg (2 mg/kg) | 0.3 ml/kg (3 mg/kg) | 0.4 ml/kg (4 mg/kg) | 0.5 ml/kg (5 mg/kg) Maximum recommended dose |
| 40 kg | 4 ml (40 mg) | 8 ml (80 mg) | 12 ml (120 mg) | 16 ml (160 mg) | 20 ml (200 mg) |
| 45 kg | 4.5 ml (45 mg) | 9 ml (90 mg) | 13.5 ml (135 mg) | 18 ml (180 mg) | 22.5 ml (225 mg) |
| (1) Children and adolescents less than 50 kg should preferably start the treatment with Entaxar 10 mg/ml syrup. Entaxar 10 mg/ml solution for infusion is an alternative for patients when oral administration is temporarily not feasible. (2) Dosage in adolescents 50 kg or more is the same as in adults. | |||||
Adjunctive therapy
The recommended starting dose is 2 mg/kg/day which should be increased to an initial therapeutic dose of 4 mg/kg/day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 2 mg/kg/day every week. The dose should be gradually adjusted until the optimum response is obtained. In children weighing less than 20 kg, due to an increased clearance compared to adults, a maximum dose of up to 12 mg/kg/day is recommended. In children weighing from 20 to under 30 kg, a maximum dose of 10 mg/kg/day is recommended and in children weighing from 30 to under 50 kg a maximum dose of 8 mg/kg/day is recommended, although in open-label studies , a dose up to 12 mg/kg/day has been used by a small number of these children.
The following table below summarises the recommended posology in adjunctive therapy for children and adolescents weighing less than 50 kg.
| Starting dose | 2 mg/kg/day |
| Single loading dose | Not recommended |
| Titration (incremental steps) | 2 mg/kg/day every week |
| Maximum recommended dose in patients < 20 kg | up to 12 mg/kg/day |
| Maximum recommended dose in patients > 20 kg to < 30 kg | up to 10 mg/kg/day |
| Maximum recommended dose in patients > 30 kg to < 50 kg | up to 8 mg/kg/day |
The tables below provide guidance on the volume of solution for infusion per administration depending on prescribed dose and body weight. The precise volume of solution for infusion is to be calculated according to the exact body weight of the child.
Adjunctive therapy doses to be taken twice daily for children from 4 years of age weighing less than 20 kg(1):
| Weight | 0.1 ml/kg (1 mg/kg) Starting dose | 0.2 ml/kg (2 mg/kg) | 0.3 ml/kg (3 mg/kg) | 0.4 ml/kg (4 mg/kg) | 0.5 ml/kg (5 mg/kg) | 0.6 ml/kg (6 mg/kg) Maximum recommended dose |
| 10 kg | 1 ml (10 mg) | 2 ml (20 mg) | 3 ml (30 mg) | 4 ml (40 mg) | 5 ml (50 mg) | 6 ml (60 mg) |
| 15 kg | 1.5 ml (15 mg) | 3 ml (30 mg) | 4.5 ml (45 mg) | 6 ml (60 mg) | 7.5 ml (75 mg) | 9 ml (90 mg) |
| (1) Children and adolescents less than 50 kg should preferably start the treatment with Entaxar 10 mg/ml syrup. Entaxar 10 mg/ml solution for infusion is an alternative for patients when oral administration is temporarily not feasible. | ||||||
Adjunctive therapy doses to be taken twice daily for children and adolescents from 4 years of age weighing 20 kg to under 30 kg(1):
| Weight | 0.1 ml/kg (1 mg/kg) Starting dose | 0.2 ml/kg (2 mg/kg) | 0.3 ml/kg (3 mg/kg) | 0.4 ml/kg (4 mg/kg) | 0.5 ml/kg (5 mg/kg) Maximum recommended dose |
| 20 kg | 2 ml (20 mg) | 4 ml (40 mg) | 6 ml (60 mg) | 8 ml (80 mg) | 10 ml (100 mg) |
| 25 kg | 2.5 ml (25 mg) | 5 ml (50 mg) | 7.5 ml (75 mg) | 10 ml (100 mg) | 12.5 ml (125 mg) |
| (1) Children and adolescents less than 50 kg should preferably start the treatment with Entaxar 10 mg/ml syrup. Entaxar 10 mg/ml solution for infusion is an alternative for patients when oral administration is temporarily not feasible. | |||||
Adjunctive therapy doses to be taken twice daily for children and adolescents from 4 years of age weighing 30 kg to under 50 kg(1):
| Weight | 0.1 ml/kg (1 mg/kg) Starting dose | 0.2 ml/kg (2 mg/kg) | 0.3 ml/kg (3 mg/kg) | 0.4 ml/kg (4 mg/kg) Maximum recommended dose |
| 30 kg | 3 ml (30 mg) | 6 ml (60 mg) | 9 ml (90 mg) | 12 ml (120 mg) |
| 35 kg | 3.5 ml (35 mg) | 7 ml (70 mg) | 10.5 ml (105 mg) | 14 ml (140 mg) |
| 40 kg | 4 ml (40 mg) | 8 ml (80 mg) | 12 ml (120 mg) | 16 ml (160 mg) |
| 45 kg | 4.5 ml (45 mg) | 9 ml (90 mg) | 13.5 ml (135 mg) | 18 ml (180 mg) |
| (1) Children and adolescents less than 50 kg should preferably start the treatment with Entaxar 10 mg/ml syrup. Entaxar 10 mg/ml solution for infusion is an alternative for patients when oral administration is temporarily not feasible. | ||||
Loading dose
Administration of a loading dose has not been studied in children. Use of a loading dose is not recommended in adolescents and children weighing less than 50 kg.
Children less than 4 years
The safety and efficacy of lacosamide in children aged below 4 years have not yet been established. No data are available.
Method of administration
The solution for infusion is infused over a period of 15 to 60 minutes twice a day. An infusion duration of at least 30 minutes for administration > 200 mg per infusion (i.e. > 400 mg/day) is preferred.
Entaxar solution for infusion can be administered intravenously without further dilution or can be diluted with sodium chloride 9 mg/ml (0.9 %) solution for injection, glucose 50 mg/ml (5 %) solution for injection or lactated Ringer's solution for injection.
Known second- or third-degree atrioventricular (AV) block.
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 trials 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. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Cardiac rhythm and conduction
Dose-related prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide should be used with caution in patients with known conduction problems, severe cardiac disease (e.g. history of myocardial infarction or heart failure), in elderly patients, or when lacosamide is used in combination with products known to be associated with PR prolongation.
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.
Second-degree or higher AV block has been reported in post-marketing experience. In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however, both have been reported in open-label epilepsy trials and in post-marketing experience.
Patients should be made aware of the symptoms of second-degree or higher AV block (e.g. slow or irregular pulse, feeling of lightheaded and fainting) and of the symptoms of atrial fibrillation and flutter (e.g. palpitations, rapid or irregular pulse, shortness of breath). Patients should be counselled to seek medical advice should any of these symptoms occur.
Dizziness
Treatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicine.
This medicinal product contains 2.6 mmol (or 59.8 mg) sodium per vial. To be taken into consideration for patients on a controlled sodium diet.
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.
Lacosamide has minor to moderate influence on the ability to drive and use machines. Lacosamide treatment has been associated with dizziness or blurred vision.
Accordingly, patients should be advised not to drive or to operate other potentially hazardous machinery until they are familiar with the effects of lacosamide on their ability to perform such activities.
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 randomized to lacosamide and 35.2 % of patients randomized 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 randomized to lacosamide and 1.6 % for patients randomized 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 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 | Balance disorder Coordination abnormal Memory impairment Cognitive disorder Somnolence Tremor Nystagmus Hypoesthesia Dysarthria Disturbance in attention Paraesthesia | Syncope(2) | Convulsion(3) |
| 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) | |||
| 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 disorders and administration site conditions | Gait disturbance Asthenia Fatigue Irritability Feeling drunk Injection site pain or discomfort (4) Irritation(4) | Erythema(4) | ||
| 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 open-label studies.
(4) 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 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 Entaxar 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 open-label studies in adjunctive therapy in children from 4 years to less than 16 years was consistent with the safety profile observed in adults. In the paediatric population the most frequently reported adverse reactions were vomiting (17.1 %), dizziness (16.7 %), somnolence (12.1 %), headache (11.7 %) and convulsion (10.1 %). Additional adverse reactions reported in children were decreased appetite (6.6 %), lethargy (4.3 %) and abnormal behaviour (1.9 %).
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 via:
United Kingdom
Yellow Card Scheme
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Ireland
HPRA Pharmacovigilance
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Fax: +353 1 6762517
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e-mail: [email protected]
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
Symptoms
Symptoms observed after an accidental or intentional overdose of lacosamide are primarily associated with CNS and gastrointestinal system.
- The types of adverse reactions experienced by patients exposed to doses above 400 mg up to 800 mg were not clinically different from those of patients administered recommended doses of lacosamide.
- Reactions reported after an intake of more than 800 mg are dizziness, nausea, vomiting, seizures (generalised tonic-clonic seizures, status epilepticus). Cardiac conduction disorders, shock and coma have also been observed. Fatalities have been reported in patients following an intake of acute single overdose of several grams of lacosamide.
Management
There is no specific antidote for overdose with lacosamide. Treatment of lacosamide overdose should include general supportive measures and may include haemodialysis if necessary.
Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX18
Mechanism of action
The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalised amino acid.
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes.
Pharmacodynamic effects
Lacosamide protected against seizures in a broad range of animal models of partial and primary generalised seizures and delayed kindling development.
In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.
Clinical efficacy and safety
Adult population
Monotherapy
Efficacy of lacosamide as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine CR in 886 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial-onset seizures with or without secondary generalisation. The patients were randomized to carbamazepine CR or lacosamide, provided as tablets, in a 1:1 ratio. The dose was based on dose-response and ranged from 400 to 1,200 mg/day for carbamazepine CR and from 200 to 600 mg/day for lacosamide. The duration of the treatment was up to 121 weeks depending on the response.
The estimated 6-month seizure freedom rates were 89.8 % for lacosamide-treated patients and 91.1 % for carbamazepine CR treated patients using the Kaplan-Meier survival analysis method. The adjusted absolute difference between treatments was -1.3 % (95 % CI: -5.5, 2.8). The Kaplan-Meier estimates of 12-month seizure freedom rates were 77.8 % for lacosamide-treated patients and 82.7 % for carbamazepine CR treated patients.
The 6-month seizure freedom rates in elderly patients of 65 and above (62 patients in lacosamide, 57 patients in carbamazepine CR) were similar between both treatment groups. The rates were also similar to those observed in the overall population. In the elderly population, the maintenance lacosamide dose was 200 mg/day in 55 patients (88.7 %), 400 mg/day in 6 patients (9.7 %) and the dose was escalated to over 400 mg/day in 1 patient (1.6 %).
Conversion to monotherapy
The efficacy and safety of lacosamide in conversion to monotherapy has been assessed in a historical-controlled, multicentre, double-blind, randomized trial. In this study, 425 patients aged 16 to 70 years with uncontrolled partial-onset seizures taking stable doses of 1 or 2 marketed antiepileptic medicinal products were randomized to be converted to lacosamide monotherapy (either 400 mg/day or 300 mg/day in a 3:1 ratio). In treated patients who completed titration and started withdrawing antiepileptic medicinal products (284 and 99 respectively), monotherapy was maintained in 71.5 % and 70.7 % of patients respectively for 57-105 days (median 71 days), over the targeted observation period of 70 days.
Adjunctive therapy
The efficacy of lacosamide as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was established in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. Lacosamide 600 mg/day was also shown to be effective in controlled adjunctive therapy trials, although the efficacy was similar to 400 mg/day and patients were less likely to tolerate this dose because of CNS- and gastrointestinal-related adverse reactions. Thus, the 600 mg/day dose is not recommended. The maximum recommended dose is 400 mg/day. These trials, involving 1,308 patients with a history of an average of 23 years of partial-onset seizures, were designed to evaluate the efficacy and safety of lacosamide when administered concomitantly with 1-3 antiepileptic medicinal products in patients with uncontrolled partial-onset seizures with or without secondary generalisation. Overall the proportion of subjects with a 50 % reduction in seizure frequency was 23 %, 34 %, and 40 % for placebo, lacosamide 200 mg/day and lacosamide 400 mg/day.
The pharmacokinetics and safety of a single loading dose of intravenous lacosamide were determined in a multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of lacosamide using a single intravenous loading dose (including 200 mg) followed by twice daily oral dosing (equivalent to the intravenous dose) as adjunctive therapy in adult subjects 16 to 60 years of age with partial-onset seizures.
Paediatric population
Partial-onset seizures have a similar clinical expression in children from 4 years of age and in adults. The efficacy of lacosamide in children aged 4 years and older has been extrapolated from data of adolescents and adults with partial-onset seizures, for whom a similar response was expected provided the paediatric dose adaptations are established and safety has been demonstrated.
Absorption
After intravenous administration, Cmax is reached at the end of infusion. The plasma concentration increases proportionally with dose after oral (100-800 mg) and intravenous (50-300 mg) administration.
Distribution
The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15 % bound to plasma proteins.
Biotransformation
95 % of the dose is excreted in the urine as lacosamide and metabolites. The metabolism of lacosamide has not been completely characterised.
The major compounds excreted in urine are unchanged lacosamide (approximately 40 % of the dose) and its O-desmethyl metabolite less than 30 %.
A polar fraction proposed to be serine derivatives accounted for approximately 20 % in urine, but was detected only in small amounts (0-2 %) in human plasma of some subjects. Small amounts (0.5-2 %) of additional metabolites were found in the urine.
In vitro data show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-desmethyl metabolite but the main contributing isoenzyme has not been confirmed in vivo. No clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19) and poor metabolisers (PMs, lacking a functional CYP2C19). Furthermore an interaction trial with omeprazole (CYP2C19-inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the importance of this pathway is minor. The plasma concentration of O-desmethyl-lacosamide is approximately 15 % of the concentration of lacosamide in plasma. This major metabolite has no known pharmacological activity.
Elimination
Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of radiolabeled lacosamide, approximately 95 % of radioactivity administered was recovered in the urine and less than 0.5 % in the faeces. The elimination half-life of lacosamide is approximately 13 hours. The pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day period. The plasma concentration increases with an accumulation factor of approximately 2.
A single loading dose of 200 mg approximates steady-state concentrations comparable to 100 mg twice daily oral administration.
Pharmacokinetics in special patient groups
Gender
Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.
Renal impairment
The AUC of lacosamide was increased by approximately 30 % in mildly and moderately and 60 % in severely renal impaired patients and patients with end-stage renal disease requiring haemodialysis compared to healthy subjects, whereas Cmax was unaffected.
Lacosamide is effectively removed from plasma by haemodialysis. Following a 4-hour haemodialysis treatment, AUC of lacosamide is reduced by approximately 50 %. Therefore, dosage supplementation following haemodialysis is recommended. The exposure of the O-desmethyl metabolite was several-fold increased in patients with moderate and severe renal impairment. In absence of haemodialysis in patients with end-stage renal disease, the levels were increased and continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite exposure in end-stage renal disease subjects could give rise to adverse effects but no pharmacological activity of the metabolite has been identified.
Hepatic impairment
Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50 % higher AUCnorm). The higher exposure was partly due to a reduced renal function in the studied subjects. The decrease in non-renal clearance in the patients of the study was estimated to give a 20 % increase in the AUC of lacosamide. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment.
Elderly (over 65 years of age)
In a study in elderly men and women including 4 patients > 75 years of age, AUC was about 30 and 50 % increased compared to young men, respectively. This is partly related to lower body weight. The body weight normalized difference is 26 and 23 %, respectively. An increased variability in exposure was also observed. The renal clearance of lacosamide was only slightly reduced in elderly subjects in this study.
A general dose reduction is not considered to be necessary unless indicated due to reduced renal function.
Paediatric population
The paediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in two open-label studies in 79 children with epilepsy aged 6 months to 17 years. The administered lacosamide doses ranged from 2 to 12 mg/kg/day (irrespective of the weight band of the child) in twice daily intake, with a maximum of 400 mg/day for children weighing 50 kg or more.
The typical plasma clearance was 1.08 L/h, 1.40 L/h and 1.92 L/h for children weighing 20 kg, 30 kg and 50 kg, respectively. In comparison, plasma clearance was estimated at 1.92 L/h in adult patients (70 kg body weight).
In the toxicity studies, the plasma concentrations of lacosamide obtained were similar or only marginally higher than those observed in patients, which leaves low or non-existing margins to human exposure.
A safety pharmacology study with intravenous administration of lacosamide in anesthetized dogs showed transient increases in PR interval and QRS complex duration and decreases in blood pressure most likely due to a cardiodepressant action. These transient changes started in the same concentration range as after maximum recommended clinical dosing. In anesthetized dogs and Cynomolgus monkeys, at intravenous doses of 15-60 mg/kg, slowing of atrial and ventricular conductivity, atrioventricular block and atrioventricular dissociation were seen.
In the repeated dose toxicity studies, mild reversible liver changes were observed in rats starting at about 3 times the clinical exposure. These changes included an increased organ weight, hypertrophy of hepatocytes, increases in serum concentrations of liver enzymes and increases in total cholesterol and triglycerides. Apart from the hypertrophy of hepatocytes, no other histopathologic changes were observed.
In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but an increase in numbers of stillborn pups and pup deaths in the peripartum period, and slightly reduced live litter sizes and pup body weights were observed at maternal toxic doses in rats corresponding to systemic exposure levels similar to the expected clinical exposure. Since higher exposure levels could not be tested in animals due to maternal toxicity, data are insufficient to fully characterise the embryofetotoxic and teratogenic potential of lacosamide.
Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.
In juvenile rats and dogs, the types of toxicity do not differ qualitatively from those observed in adult animals. In juvenile rats, a reduced body weight was observed at systemic exposure levels similar to the expected clinical exposure. In juvenile dogs, transient and dose-related CNS clinical signs started to be observed at systemic exposure levels below the expected clinical exposure.
Product with particulate matter or discolouration should not be used.
This medicinal product is for single use only, any unused solution should be discarded.
Entaxar solution for infusion was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored in glass or PVC bags at temperatures up to 25°C.
Diluents:
sodium chloride 9 mg/ml (0.9 %) solution for injection
glucose 50 mg/ml (5 %) solution for injection
lactated Ringer's solution for injection.
