Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures.

OBJECTIVE: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures. METHODS: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union). RESULTS: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%). INTERPRETATION: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.

Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment Against Cholinergic-Induced Status Epilepticus in Rats.

Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.

Neonatal Cardiac Arrest Following Lacosamide Treatment: A Case Report.

BACKGROUND: Lacosamide is an antiepileptic drug with US Food and Drug Administration approval for the treatment of partial-onset seizures in patients older than one month. Lacosamide works by selective enhancement of proteins that induce preferential slow promotion of sodium channels to the hyperpolarized inactive state. Lacosamide is generally well-tolerated; however, clinical and nonclinical studies have linked its use with cardiac side effects including PR prolongation and atrioventricular (AV) block. RESULTS: We present the case of a three-week-old female neonatal patient born at 25 weeks' gestation who developed second-degree AV heart block and cardiac arrest after initiating lacosamide therapy. The patient was being treated for neonatal seizure complicated by intraventricular hemorrhage (grade II) and electrolyte disturbances with phenobarbital, levetiracetam, and phenytoin. Before addition of lacosamide therapy, the patient had an unremarkable electrocardiogram and no known cardiac risk factors for lacosamide. After medication discontinuation, the patient experienced no reoccurring episodes or other cardiac events. CONCLUSION: Use of lacosamide for neonatal populations is currently under evaluation. This is the first report of adverse cardiac event (AV block) in the setting of neonatal lacosamide use. Risk of future adverse cardiac events should be evaluated when determining the safety and efficacy of lacosamide in the neonatal population.

Safety, tolerability, and efficacy of adjunctive lacosamide in pediatric patients with epilepsy syndromes associated with generalized seizures: Phase 2, open-label exploratory trial.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of lacosamide (LCM) (up to 12 mg/kg/day or 600 mg/day) as adjunctive therapy in pediatric patients with epilepsy syndromes associated with generalized seizures. METHODS: Phase 2, multicenter, open-label exploratory trial (SP0966; NCT01969851; 2012-001446-18) of oral LCM for epilepsy syndromes associated with generalized seizures in pediatric patients ≥1 month to <18 years of age taking one to three concomitant antiseizure medications. The trial comprised a 6-week prospective baseline period, 6-week flexible titration period, and 12-week maintenance period. RESULTS: Fifty-five patients (mean age: 9.2 years; 56.4% male) took at least one dose of LCM and had at least one post-baseline efficacy-related assessment. The median treatment duration was 127.0 days. There were no clinically significant mean or median changes or worsening from baseline to end of the titration period in the count of generalized spike-wave discharges per interpretable hour on 24-h ambulatory electroencephalogram recordings, or from baseline to the maintenance period in mean and median days with any generalized or focal to bilateral tonic-clonic seizures per 28 days. Treatment-emergent adverse events (TEAEs) were reported by 49 patients (89.1%), and three patients (5.5%) discontinued due to TEAEs. The median change and median percentage change in days with any generalized or focal to bilateral tonic-clonic seizures per 28 days from baseline to the maintenance period were both 0. Trends toward improvement (decrease) were observed in median change and median percentage change in days with each individual seizure type (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, and focal to bilateral tonic-clonic) per 28 days. SIGNIFICANCE: Safety findings were consistent with the known safety profile of LCM and were as expected for the pediatric population. There was no worsening of generalized seizures with LCM. Limitations include the inability to correlate spike and wave data with clinical outcomes, and the lack of similar studies against which the results can be compared.

Real-world safety of Lacosamide: A pharmacovigilance study based on spontaneous reports in the FDA adverse event reporting system.

INTRODUCTION: Lacosamide is licensed for the treatment of focal seizures in both adults and children, however there is little information available on its adverse reactions. Using the FDA Adverse Event Reporting System (FAERS), we seek to assess adverse occurrences that may be related to Lacosamide. METHODS: On the basis of the FAERS database from the fourth quarter of 2008 to the second quarter of 2022, disproportionality analysis was carried out using the reporting odds ratio (ROR) method, the United Kingdom Medicines and Healthcare Products Regulatory Agency omnbius standard (MHRA) method, and the bayesian confidence propagation neural network (BCPNN) method. We extracted valuable positive signals for designated medical event (DME) screening, focused on the evaluation and comparison of safety signals appearing in DME with system organ classification (SOC) analysis. RESULTS: A total of 10,226 adverse reaction reports with Lacosamide as the primary suspect drug were obtained, with 30,960 reported cases, detecting 232 valuable positive signals, involving a total of 20 SOCs, of which the most frequently reported SOCs were nervous system disorders (6537 cases, 55.21%), psychiatric disorders (1530 cases, 12.92%), injury poisoning and procedural complications (1059 cases, 8.94%). According to 232 valuable positive signals with DME screening results, two signals of stevens-johnson syndrome and ventricular fibrillation were consistent with PT signals on the DME list, with the two SOCs focusing on skin and subcutaneous tissue disorders and cardiac disorders, respectively. CONCLUSIONS: Our research demonstrates that the clinical use of Lacosamide should be noticed and avoided in relation to ADRs since it raises the risk of cardiac arrest, ventricular fibrillation, stevens-johnson syndrome, and rhabdomyolysis.

Investigation of the efficacy and adverse effects of lacosamide over 36 months.

OBJECTIVE: To evaluate the efficacy and retention rate of lacosamide (LCM) over 36 months as a treatment for children and adolescents with focal and generalized epilepsy based on a retrospective study. METHODS: All patients prescribed LCM as monotherapy and add-on therapy between October 2016 and September 2019 at Jichi Children's Medical Center Tochigi were included in the study. The response rate, retention rate, and adverse effects were calculated. RESULTS: A total of 126 (female, n = 73) patients of 1.3 to 34.9 years old (median age: 12.8 years; mean ± SD 13.2 ± 6.6 years) received LCM as monotherapy or add-on treatment for focal, generalized, and combined focal and generalized epilepsy. The response rate was 40.5% at 3 months, 40.5% at 6 months, 38.1% at 9 months, 35.7% at 12 months, 25.9% at 24 months, and 29.4% at 36 months. For 34 patients who were observable for 36 months, the retention rate was 70.6% at 3 months, but then gradually declined to 34.8% at 36 months. According to the number of concomitant anti-seizure medications (ASMs), the retention rate was higher in patients receiving <3 ASMs than in those receiving ≥3 ASMs at all observation points. The most common adverse effects were somnolence in 21 patients (16.7%) and dizziness in 5 patients (39.7%). CONCLUSION: Our response rate was lower and our retention rate was higher in comparison to a previous study that observed patients over 36 months. Further prospective studies in children are required to confirm the response rate and retention rate in patients treated with LCM over 36 months.

Increasing use of newer antiseizure medication during pregnancy: An observational study with special focus on lacosamide.

INTRODUCTION: Epilepsy is a common neurological disease requiring long-term therapy also during pregnancy. Most studies on pregnancy outcomes in women with epilepsy are based on antiseizure medication (ASM) in monotherapy. However, about 20-30% of epilepsy patients require polytherapy and newer ASMs are an option, when seizure control is not achieved with first line ASMs. METHODS: Observational study evaluating the use of newer ASMs with marketing authorization since 2005 reported to the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy between 2004 and 2019. In addition, course and outcome of lacosamide exposed pregnancies were analysed. RESULTS: Our study confirms the increasing use of newer ASMs also in pregnant women. This is especially true for lacosamide, eslicarbazepine and brivaracetam with rising numbers of exposed pregnancies soon after marketing authorization. Analysis of 55 prospectively and 10 retrospectively ascertained lacosamide exposed pregnancies does not indicate increased risks of major birth defects or spontaneous abortion. However, bradycardia observed in 3 neonates might be related to prenatal lacosamide exposure. CONCLUSION: Available data do not support the assumption of lacosamide being a major teratogen. The increasing use of newer ASMs during pregnancy underscores the need for more studies to guide preconception counselling, especially for lacosamide, eslicarbazepine and brivaracetam.

Tolerability and Safety of Lacosamide in Neonatal Population.

Lacosamide is a newer antiepileptic medication used in refractory neonatal seizures with limited safety and efficacy data. This case series spans 4 years and includes 38 neonates cared for in the neonatal, pediatric, and cardiovascular intensive care units, who received lacosamide for refractory seizures. Because lacosamide affects atrioventricular node function in adults, among other metrics, electrocardiogram (ECG) changes were monitored closely in these neonates. Within this cohort, 2 neonates were found to have atrial bigeminy on ECG and telemetry. Otherwise, lacosamide was generally well tolerated with sleepiness being the most common symptom noted. This case series reports data on the tolerability of lacosamide and emphasizes the importance of monitoring key cardiac intervals with ECG before and after the use of lacosamide in this population.

Twelve-Month Efficacy of Lacosamide Monotherapy at Maximal Dose and Tolerability for Epilepsy Treatment in Pediatric Patients: Real-World Clinical Experience.

BACKGROUND: The efficacy and safety of lacosamide (LCM) monotherapy in Chinese pediatric patients with epilepsy have not been established. Therefore, this real-world retrospective study aimed to assess the efficacy of 12 months after achievement the maximal dose and tolerability of LCM as monotherapy for epilepsy treatment in pediatric patients. METHODS: Pediatric patients were administered LCM monotherapy in two ways: primary or conversion monotherapy. Seizure frequency was recorded as an average per month for the preceding three months at baseline and then at each follow-up period for three, six, and 12 months. RESULTS: Primary monotherapy with LCM was administered to 37 (33.0%) pediatric patients, whereas conversion to monotherapy was achieved in 75 (67.0%) pediatric patients. The responder rates of pediatric patients receiving primary monotherapy with LCM at three, six, and 12 months were 75.7% (28 of 37), 67.6% (23 of 34), and 58.6% (17 of 29), respectively. The responder rates of pediatric patients receiving conversion to monotherapy with LCM at three, six, and 12 months were 80.0% (60 of 75), 74.3% (55 of 74), and 68.1% (49 of 72), respectively. The incidence of adverse reactions with conversion to LCM monotherapy and primary monotherapy was 32.0% (24 of 75) and 40.5% (15 of 37), respectively. CONCLUSION: LCM is an effective and well-tolerated treatment option as monotherapy for the treatment of epilepsy.

Safety and Tolerability of Intravenous Push Lacosamide and Levetiracetam.

Background: Lacosamide and levetiracetam are antiseizure medications (ASMs) commonly utilized in the treatment and prevention of seizures. Historically, these agents have been administered as slow IV infusions after further dilution. Recent literature suggests that rapid administration via undiluted IV push may be safe and may increase efficiency of administration. Objective: This study aimed to evaluate the safety and tolerability of undiluted IV push lacosamide and levetiracetam over 5 min. Methods: This study was conducted as a single-centered, retrospective, observational cohort that analyzed the rapid administration of undiluted lacosamide and levetiracetam. Adult patients admitted from September 1st, 2019, to May 31st, 2020, receiving at least one administration of IV push lacosamide at any dose or levetiracetam at doses ≤ 1500 mg were evaluated. The primary safety outcomes were the incidence of hypotension and bradycardia. Results: A total of 86 subjects were evaluated; 36 patients were administered lacosamide, and 50 patients were administered levetiracetam. Hypotension or bradycardia occurred in 6 patients in the lacosamide group (16.6%) and 6 patients in the levetiracetam group (12.0%). There were no reported infusion site reactions. Among the subjects who received lacosamide and had a 12-lead electrocardiogram (EKG), there were no reported incidences of a prolonged PR interval. Conclusions: In this safety-analysis cohort, undiluted lacosamide and levetiracetam were not associated with significant adverse events when administered via IV push over 5 min. This seems to be a safe alternative method of administration to intermittent infusion. A larger, prospective cohort is needed to confirm these findings.

[Case Report on a Woman with Epilepsy Who Took Lacosamide during Pregnancy and Gave Birth to a Healthy Infant].

Lacosamide is a novel antiepileptic drug. Although many antiepileptic drugs reportedly pose a risk to fetuses, patients with epilepsy are advised to continue their medications during pregnancy. There have been few reports on lacosamide use during pregnancy, and its effects on the fetus remain unclear. Here, we report a case of lacosamide use during pregnancy. The 33-year-old patient was treated with oral lacosamide (400 mg/d) for symptomatic partial epilepsy. She was concomitantly treated with folic acid (5 mg/d) beginning 4 days before her last menstrual cycle. She was also concomitantly treated with oral perampanel (2 mg/d) at 5-7 weeks' gestation for seizure control but discontinued perampanel after the pregnancy was discovered. She progressed through her pregnancy with only mild seizures. Fetal growth was normal and ultrasonography revealed no external malformations. The patient had an elective cesarean section at 37 weeks and 2 days owing to a previous post-cesarean pregnancy. Her baby boy weighed 3025 g; his Apgar score was 8 and 9, 1 and 5 min, respectively, and his umbilical artery blood pH was 7.348. He had no congenital anomalies and no neonatal drug withdrawal symptoms. This suggests that lacosamide may have a low risk of teratogenicity and fetal toxicity. Thus, this case is valuable for clinicians who are considering the administration of antiepileptic drugs during pregnancy. In the future, more reports on the use of lacosamide during pregnancy should be collected.

The high incidence and risk factors of levetiracetam and lacosamide-related skin rashes in glioma patients.

OBJECTIVE: Antiseizure drug (ASD)-induced skin rash remains the main side effect of seizure management in patients with glioma. New generations of ASDs, such as levetiracetam (LEV) and lacosamide (LCM) are associated with less frequent skin rashes than conventional ASDs. However, there are few reports regarding the incidence of skin rashes by LEV and LCM in patients with glioma. Therefore, the aim of this study was to investigate the incidence and risk factors of LEV- and LCM-associated skin rashes in patients with glioma. METHODS: We compared the incidence of ASD-associated skin rash between 353 patients with glioma and 125 patients with meningioma, who received LEV or LCM and underwent surgery between 2017 and 2019 at our institution. Furthermore, to evaluate the association between potential risk factors and ASD-associated skin rashes, univariate and multivariate analyses were performed. RESULTS: The incidence of ASD-associated skin rash in patients with glioma was higher (11 %) than in those with meningiomas (1.6 %). The multivariate regression analysis showed that adjuvant treatment with radiotherapy (p = 0.023) and a history of drug allergy (p = 0.023) were significant risk factors for ASD-associated skin rash. The rate of ASD-related skin rashes in patients with glioma was also higher than the previously reported rates of 1-3 % in patients with epilepsy. CONCLUSION: Our results indicate that adjuvant treatment with radiotherapy and a history of drug allergy correlated with a high incidence of ASD-related skin rashes in patients with glioma who receive LEV and LCM. Patients with these two factors should be carefully checked for skin rashes.

DRESS is a Mess: A Case of Cross Reactivity Between Lacosamide and Lamotrigine.

Drug reaction with eosinophilia with systemic symptoms (DRESS) syndrome is a rare drug reaction often presenting with both cutaneous manifestations and potentially life-threatening internal organ involvement. The precise incidence of DRESS is still unclear as it is easily missed due to its highly variable clinical presentation. However, with an expected mortality rate of approximately 10 percent, it is important for clinicians to be familiar with pharmacologic etiologies commonly implicated in the pathogenesis. We present a case of DRESS syndrome attributed to cross-reactivity between two commonly used anticonvulsants- lacosamide and lamotrigine.

The effectiveness of antiepileptic drug treatment in glioma patients: lamotrigine versus lacosamide.

PURPOSE: Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide. METHODS: In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2-4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity. RESULTS: We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI 26-51%) versus 30% (95%CI 20-41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI 0.46-1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide. CONCLUSION: Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.

Interactions among Lacosamide and Second-Generation Antiepileptic Drugs in the Tonic-Clonic Seizure Model in Mice.

Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.