Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy

doi:10.1016/j.yebeh.2011.02.005

Epilepsy & Behavior

Volume 20, Issue 4, April 2011, Pages 691-693

https://doi.org/10.1016/j.yebeh.2011.02.005 Get rights and content

Abstract

The results of adjunctive lacosamide treatment in 18 pediatric patients with pharmacoresistant focal epilepsy are reported. All had severe forms of focal epilepsy with or without secondary generalization and were concurrently receiving one to three other antiepileptic drugs. Lacosamide was administered orally, and final dose, after slow titration, ranged between 1.7 and 10 mg/kg. Mean treatment duration was 8 months (range = 3 weeks–17 months). Treatment efficacy was assessed at two time points with a 1-year interval. The reported greater than 50% reduction in seizure frequency was 36% in the initial short-term and 20% in the following long-term assessment. Side effects, mostly somnolence and irritability, were reported by 39% of patients in both evaluations. Our data suggest that lacosamide treatment in pediatric patients is safe at doses up to 10 mg/kg/day without any major side effects, but studies in larger series are needed to validate and extend these findings.

Research highlights

► Children with intractable focal epilepsy were prescribed lacosamide as add-on therapy. ► Efficacy and safety were demonstrated. ► Tolerability was excellent in doses up to 10 mg/kg.

Introduction

Epilepsy is a chronic neurological disorder complicated by neurobehavioral comorbidities and social consequences [1]. The primary goals of antiepileptic drug (AED) treatment are to achieve complete seizure freedom, ideally without adverse events, reduce morbidity and mortality, and improve the quality of life of the patients [2]. Approximately one-third of patients with refractory epilepsies treated with currently available newer AEDs fail to achieve these goals [3]. Concerns about cognitive development of children with refractory epilepsy as well as iatrogenic effects of medications have been well documented [4], [5]. This underlines the need for the development of new, effective, and well-tolerated AEDs to improve patient treatment and increase treatment options.

In recent years several new drugs have been introduced to treat seizures. Oral lacosamide (LCM) is a new antiepileptic drug approved for adjunctive use in adults with focal epilepsy. The potential unique mechanisms of action proposed are selective enhancement of slow inactivation of voltage-gated sodium channels (VGSCs) and interaction of LCM with the collapsing-response mediator protein 2 (CRMP-2) [6], [7]. LCM was found to significantly reduce seizure frequency in patients with uncontrolled focal seizures with favorable tolerability profiles in adults [8], [9], [10]. Unfortunately, no data exist on the efficacy and tolerability of LCM in pediatric patients, even though focal seizures are the most common seizure type in children [11].

This medication appears to be a very good choice for pediatric use for several reasons: it has a favorable dose-proportional pharmacokinetic profile [6], [8], it is available in a liquid form suitable for children, and it appears to be quite safe from the available studies and experience with use in the adult population [8], [9], [10]. Moreover, LCM has a low potential for drug–drug interactions, a feature that makes it suitable as an add-on treatment option in patients on multiple anticonvulsants. Lastly, it has been shown that LCM produces a general decrease in neuronal discharge frequency and synaptic excitability that is not mediated by actions at major excitatory (AMPA/NMDA) or inhibitory (GABAA) postsynaptic receptors. Apparently the anti-excitability effect that LCM has demonstrated in primary cortical cultures does not appear to result from a high-affinity interaction with an acknowledged recognition site on a target for existing AEDs [12]. These features make LCM a particularly attractive option for patients with difficult-to-treat epilepsy.

The goal of this study was to evaluate LCM when used as adjunctive antiepileptic therapy in pediatric patients with drug-resistant focal epilepsy in terms of its effects on seizure control and tolerability.

Section snippets

Methods

We enrolled 18 patients, children and adolescents, visiting the outpatient department who fulfilled the following criteria: partial epilepsy, pharmacoresistance, and current treatment with stable doses of other anticonvulsants. After the parents had been informed that its use was off-label in children, LCM was prescribed as add on therapy. Only patients who completed at least 3 months of LCM treatment (including titration) and kept a monthly seizure diary were included in the efficacy results.

Results

All 18 patients had severe forms of focal epilepsy, with or without secondary generalization, starting as early as the neonatal period. They were concurrently taking 1–3 other AEDs had unsuccessfully taken 3–16 in the past (mean number of failed AEDs = 7) (Table 1). One had not improved with vagus nerve stimulation, seizures in another patient regressed after epilepsy surgery, and 3 had not benefited from the ketogenic diet. All patients had undergone neuroimaging (17 MRI scans, 1 CT scan): 2

Discussion

Ideally an AED needs to combine good efficacy when given orally once or twice daily, good tolerability, minimal drug interaction, and no seizure aggravation. Although on the basis of adult clinical trials, LCM looks promising, the lack of data in children is a drawback and further studies are required.

We have described our experience with the use of LCM, a novel anticonvulsant, in pediatric patients with pharmacoresistant focal epilepsy. Our group of patients had a long history of epilepsy, had

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Cited by (46)

Retrospective Multicenter Cohort Study on Safety and Electroencephalographic Response to Lacosamide for Neonatal Seizures
2024, Pediatric Neurology
There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates.
A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days.
Among 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates.
The results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results.
Efficacy and safety of lacosamide in pediatric patients with epilepsy: A systematic review and meta-analysis
2022, Epilepsy and Behavior
Lacosamide (LCM), is a third-generation antiseizure medicine, with limited clinical evidence for use in pediatric populations. We aimed to evaluate evidence for the efficacy and safety of LCM in pediatric patients with epilepsy.
A systematic review was performed using literature published from inception to February 2022 identified in MEDLINE, Embase, Cochrane Library, and four Chinese databases. Efficacy and safety outcome data were collected, and a meta-analysis was performed.
Twenty-one studies involving 1230 pediatric patients were included. The median percent reduction in seizure frequency per 28 days from baseline to maintenance was 33.1% (95% confidence interval [CI] 22.7%, 43.5%). After 6 months of treatment, the 50%, 75%, and 100% responder rates were 53.3% (95% CI 40.7%, 65.9%), 28.3% (95% CI 20.8%, 35.8%), and 20.4% (95% CI 12.6%, 28.2%), respectively. After 12 months of treatment, the 50%, 75%, and 100% responder rates were 42.0% (95% CI 29.5%, 54.5%), 19.5% (95% CI 11.1%, 27.8%), and 15.2% (95% CI 6.6%, 23.8%), respectively. The most common adverse events (AEs) were drowsiness (15.0%), dizziness (9.9%), and somnolence (8.3%).
Lacosamide is generally effective and well tolerated to use in children with epilepsy. However, further research with high-quality data and long-term follow-up of LCM use in pediatric populations is needed.
Efficacy and tolerability of treatment with lacosamide in children: Postmarketing experience from the Middle East
2020, Seizure
The aim of this study was to evaluate the tolerability and efficacy of lacosamide (LCM) in Lebanese children with focal-onset seizures and to determine if specific variables are predictive of better effectiveness.
This is a retrospective analysis from three medical centers on consecutive children diagnosed with focal onset seizures and initiated on LCM. The seizure frequencies following the introduction of LCM were recorded and compared to the baseline monthly frequency at 3, 6, 12, 18, and 24 months. The primary efficacy variables were the 50% responder and seizure-free rates. The secondary outcome variables included the terminal 6-month seizure remission and percentages of discontinuation due to lack of efficacy or tolerability.
58 patients with a mean age of 10 years experiencing a mean of 36.2 seizures per month during baseline were included. The seizure-free rates were 32.8%, 29.7%, and 12.5% at 6, 12 and 24 months follow up, respectively. Patients concomitantly treated with a sodium channel blocker were less likely to achieve a terminal 6-month seizure remission while the early introduction of LCM resulted in a significantly higher likelihood of attaining such a remission. 74.1% of patients were still maintained on LCM at the last follow-up. The most common adverse events consisted of dizziness, somnolence, nausea, vomiting, and rarely double vision.
LCM is efficacious and overall well tolerated in children with focal-onset seizures and exhibits higher efficacy with early introduction and when added to a non-sodium channel blocker.
Safety and tolerability of adjunctive lacosamide in a pediatric population with focal seizures – An open-label trial
2019, Seizure
Citation Excerpt :
The availability of lacosamide as oral tablet, oral solution, and intravenous solution provides added therapeutic flexibility, with the oral solution potentially being useful for children who may find it difficult to swallow tablets. Several retrospective or prospective, open-label studies have evaluated the use of lacosamide in pediatric patients with epilepsy [13–24]. Findings from the prospective, open-label, fixed-titration trial reported here were used to guide lacosamide dosing in subsequent phase II/III trials further assessing safety and efficacy of adjunctive lacosamide.
To evaluate safety and tolerability of adjunctive lacosamide in children with focal seizures.
Patients were eligible for this open-label, fixed-titration trial (SP0847; NCT00938431) if aged 1 month–17 years with focal seizures taking 1–3 antiepileptic drugs. Findings from Cohort 1, aged 5–11 years, who received lacosamide ≤8 mg/kg/day, informed dosing for age-based cohorts 2–5, who then received ≤12 mg/kg/day (≤600 mg/day). Oral lacosamide was initiated at 2 mg/kg/day (1 mg/kg bid) and uptitrated by 2 mg/kg/day/week to the maximum cohort-defined dose (maximum trial duration: 13 weeks). Patients who did not achieve the maximum cohort-defined dose were discontinued.
Forty-seven patients (aged 6 months–≤17 years) enrolled (≥1 month–<4 years: n = 15; ≥4–<12 years: n = 23; ≥12–≤17 years: n = 9). 24/47 (51.1%) patients completed the trial at the maximum cohort-defined dose and 40/47 (85.1%) continued lacosamide in the extension trial. Treatment-emergent adverse events (TEAEs) were reported by 42/47 (89.4%) patients. The most common TEAEs (≥10% of patients) were vomiting (21.3%), diarrhea (14.9%), somnolence (12.8%), irritability, dizziness, and pyrexia (10.6% each). Twenty (42.6%) patients discontinued due to TEAEs, most commonly vomiting (8.5%), gait disturbance, dizziness, and somnolence (6.4% each). Six (12.8%) patients reported serious TEAEs, most commonly status epilepticus (3/47; 6.4%).
This fixed-titration trial supports the safety of adjunctive lacosamide in children (aged 6 months–≤17 years) with focal seizures. The TEAE profile was generally consistent with that observed in trials in adults, and no new safety concerns were identified.
Role of observational studies in supporting extrapolation of efficacy data from adults to children with epilepsy — A systematic review of the literature using lacosamide as an example
2019, European Journal of Paediatric Neurology
Citation Excerpt :
These were described as being tolerable and transient, and only one patient discontinued (due to walking instability). In the third prospective study, incidence of AEs was 39% and one patient discontinued due to AEs (pancytopaenia).19 Incidence of AEs ranged from 12.5% to 50% and discontinuation from 10% to 25% in three retrospective studies.21–23
Extrapolation of efficacy data from adults to children is accepted for focal epilepsy – the antiepileptic drug, lacosamide, has been approved for the treatment of children ≥4 years of age on this basis. Since many small-scale, open-label studies are reported in the literature before approval, a systematic review was conducted to ascertain whether results of these could be used to support extrapolation in epilepsy in the future. In the absence of randomised trials, a second analysis was conducted for reports on lacosamide use in adults with generalized epilepsies. Twenty-seven articles were included in the paediatric qualitative synthesis, and 14 in the adult. Paediatric studies were analysed separately based on seizure type: focal, generalised and mixed. In focal epilepsy, safety and seizure-related findings mirrored those observed in the adult Phase II/III trials, supporting the feasibility of data extrapolation. Few studies reported outcomes in children with epilepsies associated with generalised seizures, and those that included children with different seizure types, mostly did not provide results separately. Lacosamide treatment appeared beneficial for children and adults experiencing tonic-clonic and myoclonic seizures. Reports of seizure aggravation were inconsistent and, in many cases, could not be clearly attributed to lacosamide. Given the absence of sufficient data, evidence for the feasibility of extrapolation was not as clear-cut as it was in focal epilepsy. These results highlight the complexities of conducting trials in the generalised epilepsy setting, and the importance of studies in the real-life setting and of analysing efficacy data per generalized seizure type and syndrome.
Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: A systematic review
2018, Seizure
Lacosamide, is one of the newer antiepileptic drug approved for focal drug-resistant epilepsy as an add-on treatment in patients older than 16 years. However, there is growing evidence of its use, safety and efficacy in children. We aim to evaluate efficacy and tolerability of lacosamide in focal and generalized drug-resistant epilepsy and refractory status epilepticus in the pediatric population.
We conducted a systematic review on MEDLINE, EMBASE, COCHRANE, Google Scholar and Scielo from January 2008 to January 2017. The primary outcome was the efficacy of lacosamide in children with drug-resistant epilepsy and refractory status epilepticus. Efficacy and adverse events attributed to lacosamide were extracted from each publication and systematically reported. We performed no meta-analyses due to limited available data.
Of 175 abstracts identified by the search, 82 were reviewed as full-text. Twenty-six articles fulfilled eligibility criteria and described outcomes in 797 patients (57% male). The majority of studies were retrospective (69%) small series (84%). On average 51% of patients had 50% or greater seizure reduction. The mean seizure freedom rate was 24%. Adverse effects occurred in 18–59% of patients. The main events were dizziness, sedation, gastrointestinal upset, mood and behavioral changes. Half of the patients with Lennox Gastaut syndrome showed 50% or greater seizure reduction, 32% did not response to lacosamide and 17% suffered seizure aggravation.
Current evidence shows lacosamide as a good option in pediatric patients with focal drug-resistant epilepsy and refractory status epilepticus as an add-on therapy given its efficacy on seizure control and safety profile. The use of lacosamide in Lennox-Gastaut syndrome shows conflicting data. Large randomized controlled studies in the pediatric population are necessary to substantiate these findings.

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Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy

Abstract

Research highlights

Introduction

Section snippets

Methods

Results

Discussion

Lancet Neurol

Seizure

Epilepsy Behav

Neuropharmacology

The use of anti-epileptic drugs-principles and practice

Epilepsia

Early identification of refractory epilepsy

N Engl J Med

Newer antiepileptic drugs and cognitive issues

Epilepsia