A real-world pharmacovigilance analysis of eslicarbazepine acetate using the FDA adverse events reporting system (FAERS) database from 2013 (Q4) to 2024 (Q1).

Background: The approval of eslicarbazepine acetate (ESL) by the Food and Drug Administration (FDA) in 2013 marked an advancement in the treatment of adult patients with partial-onset seizures. However, there still remains a paucity of real-world studies regarding the adverse events (AEs) associated with this compound. The principal aim of the present study was to scrutinize ESL-related AEs by leveraging data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: By extracting all available data since the FDA approval of ESL (2013Q4-2024Q1), disproportionality analysis was performed using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) algorithms. AE signals that simultaneously met the requirements of all four algorithms were identified as significant positive signals. Demographic information, time of onset and gender-specific signal detection were also examined. In addition, a special screening process for designated medical events (DME) was implemented to focus on the evaluation and comparison of safety signals within DME and System Organ Classification (SOC) level, as well as SMQ (Standardised MedDRA Queries) level. Stratified analysis by logistic regression is employed to examine the variations across different gender (male and female) and age groups (<18 years old, 18-64 years old, >65 years old). Results: A total of 5,719 AE reports and 1,907 reported cases were obtained. ESL related AEs were identified in relation to 27 SOCs, among which the significant positive SOCs were nervous system disorders, injury poisoning and procedural complications, etc. There were 86 severely disproportional preferred terms that complied with the four algorithms. Most AEs occurred within the first month after treatment. According to the 86 valuable positive signals with DME screening results, 3 signals of dermatitis exfoliative, stevens-johnson syndrome, drug reaction with eosinophilia and systemic symptoms were consistent with PT signals on the DME-list, with the 3 PTs focusing on skin and subcutaneous tissue disorders and hypersensitivity. Males are more commonly affected by seizures than females. Seizures, hyponatremia, and confusional states were more frequently observed in the elderly population, while aggression, irritability, DRESS (drug reaction with eosinophilia and systemic symptoms), and abnormal behavior were found to be more common in the pediatric population. Both the children and elderly groups exhibited a higher proportion of agitation than the adult group. Conclusion: Our research enhances the safety and tolerability profile of ESL, but the clinical use of ESL should be noticed and avoided in relation to AEs since it raises the risk of dermatitis exfoliative, stevens-johnson syndrome. Particular attention should be paid to DRESS in children and hyponatremia in the elderly.

Eslicarbazepine induces apoptosis and cell cycle arrest in C6 glioma cells in vitro and suppresses tumor growth in an intracranial rat model.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14-16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects. METHODS: To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI. RESULTS: The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01). CONCLUSIONS: Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma.

An update on pharmacotherapy for trigeminal neuralgia.

INTRODUCTION: Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and potentially treatment-limiting adverse effects. Third-generation anticonvulsants, new calcitonin gene-related peptide blockers for migraine, and older drugs such as ketamine and cannabinoids may be promising adjuvants or monotherapeutic options. AREAS COVERED: The new drugs, their presumed mechanisms of action, safety and efficacy are discussed herein. There is a paucity of robust clinical evidence in support of these drugs for trigeminal neuralgia. New migraine agents are considered as well although migraines and trigeminal neuralgia are distinct, albeit similar, conditions. No new drugs have been released to market in recent years with the specific indication of trigeminal neuralgia. EXPERT OPINION: In real-world clinical practice, about half of trigeminal neuralgia patients take more than one agent for prevention and combination therapy may be the optimal approach. Combination therapy might allow for lower doses of carbamazepine or oxcarbazepine, thus reducing the number and severity of potential adverse events but the potential for pharmacokinetic drug-drug interactions must be considered. Drug therapy for trigeminal neuralgia involves acute or abortive treatments, often administered in hospital versus long-term preventive therapy, usually involving oral agents.

Trigeminal neuralgia is a relatively rare condition that usually affects one side of the face below the eye around the cheekbone. The cause of trigeminal neuralgia is sometimes a damaged nerve or a nerve that has lost part of its outer protective sheath (myelin). However, trigeminal neuralgia may have other neurological causes as well. Pain can be triggered by touch, pressure, or chewing and it tends to occur in very painful brief attacks followed by pauses with little or no pain. There are two types of drug treatment for trigeminal neuralgia: drugs to stop an ongoing attack (which are often administered in an emergency room or hospital intravenously) and drugs that are taken orally over the long term to reduce or prevent attacks.The two most effective drugs for trigeminal neuralgia are carbamazepine and oxcarbazepine, which are actually drugs to prevent seizures. They are effective in reducing the pain intensity and number of attacks of trigeminal neuralgia but they have side effects. In fact, these side effects can be so severe that people stop taking the drugs.Many new drugs have come to market recently that may work for trigeminal neuralgia, although none was specifically developed for this use. The newest generation of anti-seizure medications including eslicarbazepine, lacosamide, levetiracetam, and retigabine, may be just as effective as the older carbamazepine and oxcarbazepine drugs with fewer side effects. Clinical studies are needed to test them in trigeminal neuralgia patients but their mechanisms of action suggest that they might work well.There are some new drugs developed for migraine headache that inhibit a substance in the body called CGRP. Migraine headaches and trigeminal neuralgia have some of the same symptoms but they are different conditions but both involve too much CGRP.Other new drugs include lasmiditan, pimozide (used for Tourette syndrome), tizanidine (muscle relaxant), lamotrigine and vixotrigine (anti-seizure drugs) may also be beneficial. It may be that people with trigeminal neuralgia will have to take combination therapy, the use of two or more drugs with different mechanisms of action. Older drugs like ketamine and cannabinoids are also being considered as possible add-on agents for therapy for trigeminal neuralgia.

Assessing the Effectiveness of Eslicarbazepine Acetate in Reducing Audiogenic Reflex Seizures in the GASH/Sal Model of Epilepsy.

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug indicated as monotherapy for adults with newly diagnosed epilepsy and as adjunctive therapy for the treatment of partial seizures. Our aim was to assess the effectiveness and safety of both acute and repeated ESL administration against reflex audiogenic seizures, as shown by the Genetic Audiogenic Seizures Hamster from Salamanca (GASH/Sal). Animals were subject to the intraperitoneal administration of ESL, applying doses of 100, 150 and 200 mg/kg for the acute study, whereas a daily dose of 100 mg/kg was selected for the subchronic study, which lasted 14 days. In both studies, the anticonvulsant effect of the therapy was evaluated using neuroethological methods. To assess the safety of the treatment, behavioral tests were performed, hematological and biochemical liver profiles were obtained, and body weight was monitored. In addition, the ESL levels in blood were measured after the acute administration of a 200 mg/kg dose. Treatment with ESL caused a reduction in seizure severity. No statistically significant differences were detected between the selected doses or between the acute or repeated administration of the drug. To summarize, the intraperitoneal administration of ESL is safe and shows an anticonvulsant effect in the GASH/Sal.

Overnight switch from carbamazepine to eslicarbazepine in a real-life clinical scenario: a retrospective study.

BACKGROUND: Carbamazepine (CBZ) is a first-choice anti-seizure medication (ASM) whose efficacy is often invalidated by adverse effects (AEs). Eslicarbazepine (ESL) is a structural derivative of CBZ with better pharmacokinetic/tolerability profiles. We describe our experience of the overnight CBZ to ESL switch in people with epilepsy (PwE) to improve seizure control, AEs, and ASMs adherence. METHODS: We retrospectively included 19 PwE (12 females, 53 ± 21 years old) who underwent CBZ to ESL overnight switch due to single/multiple issues: poor efficacy (pEff, N = 8, 42%), tolerability (pToll, N = 11, 58%), adherence (pAdh, N = 2, 10%). 9/19 (47%) had psychiatric comorbidities. Clinical variables, seizure frequency, and AEs were recorded at switch time (T0) after 3.5 ± 3 (T1) and 6.5 ± 1.5 months (T2). RESULTS: At T1, in pEff group, 1/8 (13%) was seizure free, 2/8 (25%) were responders (> 50% seizure reduction), 2/8 (25%) had no seizure changes, 3/8 (37%) had seizure worsening; the latter were those with the most severe epilepsy and encephalopathy. In pToll group, all PwE experienced AEs disappearance/amelioration. In pAdh group, all PwE reported adherence amelioration. Four dropouts. At T2, no changes were recorded within groups, while in the whole sample, 6/15 (40%) were responders, and 4/15 (27%) were seizure-free. No one complained of Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation psychiatric worsening, while 6/19 (32%) experienced mood/behavior benefits. CONCLUSIONS: CBZ to ESL overnight switch offers an opportunity to improve efficacy, tolerability, adherence, and psychiatric symptoms.

A real-world comparison among third-generation antiseizure medications: Results from the COMPARE study.

OBJECTIVE: There are few comparative data on the third-generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives. METHODS: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add-on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan-Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models. RESULTS: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)-naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.29) and PER groups (HR = 1.64, 95% CI = 1.06-2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71-16.61), as well as PER-treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05-2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] = .08, 95% CI = .01-.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV-naïve (OR = 10.32, 95% CI = 1.55-68.78) versus men. PER (OR = 6.93, 95% CI = 3.32-14.44) and BRV in LEV-naïve patients (OR = 6.80, 95% CI = 2.64-17.52) had a higher chance of AEs than LCM. SIGNIFICANCE: Comparative evidence from real-world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics.

Eslicarbazepine-induced hyponatremia: A retrospective single-center real clinical practice study.

Hyponatremia is a typical side effect of antiseizure drugs from the dibenzazepine family. The study investigated the prevalence of hyponatremia in patients with epilepsy who were treated with eslicarbazepine. We aimed to determine the prevalence of hyponatremia, reveal the factors leading to the discontinuation of treatment, and identify possible risk factors for the development of hyponatremia including the dose dependency. The medical records of 164 patients with epilepsy taking eslicarbazepine in our center were analyzed. The overall prevalence of hyponatremia was 30.5%. The prevalence of mild hyponatremia, seen in 14%-20% of patients, was not dose dependent. The prevalence of moderate and severe hyponatremia was significantly dose dependent. The severity of hyponatremia was significantly dose dependent. Severe hyponatremia was found in 6.1% of patients. Hyponatremia was asymptomatic in the majority of cases, and in 48% did not require any management. Hyponatremia was the reason for discontinuation in 6.2% of patients. The major risk factor for developing hyponatremia was older age. The study shows that eslicarbazepine-induced hyponatremia is usually mild and asymptomatic. It usually does not require any management and seldom leads to treatment discontinuation. Hyponatremia is dose dependent. Another major risk for developing hyponatremia (besides dose) is older age.

Thirteen years of experience with eslicarbazepine acetate in the United Kingdom and Republic of Ireland: A safety perspective.

OBJECTIVE: Eslicarbazepine acetate (ESL) is a once-daily oral antiseizure medication. Its safety and tolerability from clinical trials have been mostly confirmed by real-world data. The main purpose of this report is to provide an overview of the safety profile of ESL in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Safety data were obtained from the UK and ROI post-marketing sources (October 2009-April 2022) by the marketing authorization holder. All individual reports were included in the Argus Safety™ database. All adverse events (AEs) were coded using MedDRA® version 24.1. Only valid cases (meeting the minimum pharmacovigilance reporting requirements) were included. RESULTS: During 13 years of ESL marketing, with cumulative estimated exposure of 2 210 395 patients-years, 183 reports were received. A total of 402 AEs were reported for the 155 valid reports. The most common reported AEs (≥6% of total reported), per system organ class (SOC), were: nervous system disorders (23.4%), injury, poisoning, and procedural complications (18.9%), general disorders and administration site conditions (12.9%), psychiatric disorders (12.7%) and gastrointestinal disorders (6.7%). The most frequently reported (≥2% of total reported) AEs were: seizure (4.5%), hyponatremia (4.2%), dizziness (2.7%), rash, fatigue (2.5% each), and somnolence (2.0%). Twenty-six percent of events were classified as serious (including six fatal cases). SIGNIFICANCE: The current analysis supports the known safety profile of ESL, as generally well-tolerated with most AEs being non-serious. The most common AEs were considered either expected according to the disease itself or to the reference safety information. ESL continues to be a relevant medication in the treatment of partial (focal-onset) epilepsy, as also confirmed by the 2022 NICE guidelines.

Eslicarbazepine acetate for the treatment of status epilepticus.

OBJECTIVE: Due to the high mortality of patients with refractory status epilepticus (SE), new antiseizure medications (ASMs) are needed to improve long-term outcomes. In this study, we evaluated the efficacy and safety of eslicarbazepine acetate (ESL), a new sodium channel blocker, based on the data from a large epilepsy register. METHODS: Data on the efficacy and safety of ESL for the treatment of refractory SE were gathered from the Mainz Epilepsy Registry (MAINZ-EPIREG). Logistic regression was applied to identify predictors of status interruption. RESULTS: In total, 64 patients with remote symptomatic refractory SE were treated with ESL. No cases of idiopathic generalized epilepsy were included. The average age was 61.4 ± 11.0 years. The median number of administered ASMs before the start of ESL was three. On average, 2 days had elapsed since the onset of SE before the administration of ESL. The initial dose of 800 mg/day was increased up to a maximum daily dose of 1600 mg in case of nonresponse. In 29 of 64 patients (45.3%), the SE could be interrupted within 48 h of ESL therapy. In patients with poststroke epilepsy, the control of SE was achieved in 62% of patients (15/23). The earlier initiation of ESL therapy was an independent predictor of control of SE. Hyponatraemia occurred in five patients (7.8%). Other side effects were not observed. SIGNIFICANCE: Based on these data, ESL may be used as an adjunct therapy for the treatment of refractory SE. The best response was found in patients with poststroke epilepsy. In addition, early initiation of ESL therapy appears to result in better control of SE. Besides a few cases of hyponatraemia, no other adverse events were detected.

Potential efficacy and safety of eslicarbazepine acetate oral loading in patients with epilepsy.

Eslicarbazepine acetate (ESL) is a new antiseizure medication (ASM) approved as an adjunctive therapy or monotherapy for focal onset seizures. We performed this study to explore the potential efficacy and safety of ESL oral loading in selected patients with epilepsy. Thirty adult patients with status epilepticus or acute repetitive seizures were enrolled, and ESL was administered at a single loading dosage of 30 mg/kg. Plasma levels of an active metabolite of ESL, monohydroxy derivative (MHD), were measured at 2, 4, 6, 12, and 24 h after ESL oral loading. Two thirds of the patients reached a therapeutic level of MHD 2 h after ESL loading, and most of the patients achieved a therapeutic range within 12 h after loading. Plasma MHD levels did not rise above the supratherapeutic level in any patient throughout the study. The reported adverse effects included one patient with gaze-evoked nystagmus and another patient with a rash. No serious adverse events leading to drug discontinuation occurred. There was no discernible difference in sodium levels before and after ESL oral loading. Our study findings suggest that ESL oral loading could be a useful therapeutic option for patients with epilepsy who need rapid elevations in the therapeutic levels of ASMs.

Time to baseline seizure count in patients with focal seizures receiving adjunctive eslicarbazepine acetate in a phase IV clinical trial.

BACKGROUND: The efficacy and tolerability of eslicarbazepine acetate (ESL), a once-daily, orally-administered, anti-seizure medication (ASM), have primarily been established in treatment-resistant epilepsy patients, the population most often enrolled in clinical trials of anti-seizure medications. More recently, ESL was also shown to be effective and well-tolerated as first adjunctive therapy in non-treatment-resistant patients in an open-label, non-randomized, Phase IV, 24-week study of ESL using standard efficacy parameters in adults with focal seizures. OBJECTIVE: To determine the time required to reach baseline seizure count, as an alternative method of assessing the efficacy of adjunctive ESL in patients with relatively low baseline monthly seizure frequencies. This additional analysis was undertaken, as subtle changes and improvements are difficult to analyze using standard efficacy parameters, such as standardized seizure frequency reduction when the baseline frequency of seizures is particularly low. METHODS: This was a post-hoc analysis of the Phase IV study data, which investigated time to baseline seizure count in patients aged ≥ 18 years with focal seizures as an alternative measure of anti-seizure efficacy. In the Phase IV trial, patients had been enrolled into 2 groups: Arm 1: ESL as first adjunctive therapy to levetiracetam (LEV) or lamotrigine (LTG), the two most commonly-prescribed ASMs, in patients with inadequate response to treatment; Arm 2: ESL as a later adjunctive therapy, following prior use of 1-2 ASMs in patients who required an additional therapeutic option. RESULTS: The time to reach individual baseline seizure count was longer in patients with focal seizures receiving ESL as a first (Arm 1) versus later (Arm 2) adjunctive therapy (p = 0.005). Patients who received ESL as a first adjunctive therapy had a longer time to ESL discontinuation than patients who received ESL as a later adjunctive therapy (p = 0.04). In Arm 1, patients receiving concomitant LTG reported treatment-emergent adverse events (TEAEs) significantly earlier than those receiving LEV (p = 0.02). Compared to patients receiving concomitant LTG, a greater number of patients in Arm 1 who were taking concomitant LEV had a modal ESL dose > 1200 mg and completed the full maintenance period. A greater number of patients in Arm 1 who were receiving concomitant LEV and completed the 24-week maintenance period reached a maximum ESL dose of 1600 mg, compared to those taking LTG, who reached a maximum ESL dose of 1200 mg. CONCLUSIONS: This analysis of the Phase IV clinical trial data provides an alternative way of assessing efficacy beyond standardized seizure frequency reduction, in the context of relatively low monthly median seizure frequencies at baseline (SSF 2.0-2.4). These results provide further support for the use of ESL as an earlier or later adjunctive therapy to LEV or LTG.

In vitro effects of eslicarbazepine (S-licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders.

BACKGROUND AND PURPOSE: Variants in SCN8A, the NaV 1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. EXPERIMENTAL APPROACH: We investigated the therapeutic potential of eslicarbazepine (S-licarbazepine; S-lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain-of-function (G1475R and M1760I) and one variant with biophysical gain-of-function but neuronal loss-of-function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV 1.6-associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). KEY RESULTS: Similar to known effects on NaV 1.6 wildtype channels, S-lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S-lic exhibits variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant-associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S-lic. CONCLUSIONS AND IMPLICATIONS: S-lic has not only substance-specific effects but also variant-specific effects. Personalized treatment regimens optimized to achieve such variant-specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A-related disease.

Melting point depression for enhanced dissolution rate of eslicarbazepine acetate.

BACKGROUND: Eslicarbazepine acetate (ESL) is antiepileptic agent which is approved for use as single therapy or in combination with other drugs. However, it suffers from poor oral bioavailability. Modulation of drug crystallinity can be utilized as an approach for enhancing drug dissolution. OBJECTIVE: Accordingly, the aim of this study was to investigate possible eutectic system formation between eslicarbazepine with either tartaric acid or citric acid. METHODOLOGY: Eslicarbazepine acetate was subjected to wet co-grinding with tartaric acid or citric acid at different molar ratios. The prepared formulations were assessed using Fourier-transform infrared (FTIR), X-ray powder diffraction (XRPD), differential scanning calorimetry in addition to dissolution studies. RESULTS: The characterization techniques confirmed eutectic system formation with tartaric and citric acid with the optimum molar ratio for eutexia being 1:1 for both substances. Development of eutectic systems significantly enhanced the dissolution rate of ESL. Increasing the ratio of tartaric acid higher than the optimum ratio for eutexia resulted in additional increase in drug dissolution rate. This suggested the impact of pH modification on drug dissolution rate. The enhanced dissolution rate in case of the formulations containing ESL and citric acid was accredited to combined effect of eutaxia and pH modulation. These explanations were proven from investigating the dissolution rate of the physical mixtures which were inferior in their dissolution rate compared with the prepared formulations. CONCLUSION: co-processing of ESL with either citric acid or tartaric acid resulted in hastened dissolution rate which was accredited to combined effect of eutexia with pH modification.

Evaluation of the Effect of Eslicarbazepine Acetate on the Pharmacokinetics of Perampanel in Rats by Isotope-Dilution-UHPLC-MS/MS.

Purpose: The present study aimed to establish and validate an isotope-dilution-UHPLC-MS/MS method for the determination of perampanel (PER) concentration and investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of PER in rats. Methods: The rats were randomly divided into the control (0.5% CMC-Na) and experimental groups (ESL, 72 mg/kg), with six rats in each group. A single dose of PER (1 mg/kg) was administered after a week of repetitive 0.5% CMC-Na or ESL dosing (72 mg/kg); then, plasma samples were collected. Perampanel-d5 (PER-d5) was used as the internal standard (IS), liquid-liquid extraction of plasma samples was carried out using ethyl acetate, and chromatographic separation was carried out on a Titank C18 column (2.1 mm × 50 mm, 3.0 µm) using a gradient mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0.3 mL/min. Results: PER had good linearity (0.3-600 ng/mL, r >0.999), and the accuracy, precision, recovery rate, and matrix effects (ME) met the Food and Drug Administration (FDA) guidelines. Compared to the control group, the area under the curve AUC0→t, AUC0→∞, and Cmax of PER in the experimental group decreased by 30.28%, 30.34%, and 46.94%, respectively, and CL increased by 32.08%. Conclusion: ESL could induce the metabolism of PER in rats and decreases plasma exposure to PER. Thus, the concomitant treatment with ESL may require a high dose of PER to achieve the same efficacy.

Comparative economic outcomes in patients with focal seizures initiating eslicarbazepine acetate versus brivaracetam in the long-term care setting in the USA.

Aim: To compare all-cause and epilepsy-specific pharmacy and total costs associated with initiation of eslicarbazepine acetate (ESL) or brivaracetam (BRV) among patients with focal seizures in long-term care (LTC) in the US. Methods: This retrospective analysis used data from IQVIA's New Data Warehouse. Results: 298 patients initiated ESL and 282 patients initiated BRV. Initiation of ESL versus BRV was associated with 33.3% lower all-cause pharmacy costs, 34.4% lower epilepsy-specific pharmacy costs, 21.3% lower all-cause total costs and 30.9% lower epilepsy-specific total costs (all p < 0.0001). Conclusion: Among patients with focal seizures in LTC in the US, initiation of ESL versus BRV was associated with significant reductions in all-cause and epilepsy-specific pharmacy and total costs compared with initiation of BRV.

Eslicarbazepine acetate is porphyrogenic and should be used with caution in patients with the acute hepatic porphyrias.

Eslicarbazepine acetate, a third-generation antiepileptic drug (AED), has shown improved clinical response and safety in comparison to older generation AEDs for patients with partial-onset seizures. It is currently not known whether eslicarbazepine acetate is safe to use in patients with the acute hepatic porphyrias (AHPs) since a few first-generation AEDs, such as phenobarbital and carbamazepine, are known porphyrogenic agents. In this study, we used a recently published in vitro fluorescence-based screening assay to screen for porphyrogenicity in various agents. The assay confirmed that among the tested compounds used, allyl isopropyl acetamide, carbamazepine, eslicarbazepine acetate, and phenobarbital were porphyrogenic. Thus, eslicarbazepine acetate should be avoided if possible in patients with the AHPs, but if initiated, patients should be closely monitored and the drug should be discontinued if a porphyric exacerbation occurs.

Adjunctive Treatment With Eslicarbazepine Acetate for Adults and Children With Focal-Onset Epilepsy: A Meta-Analysis.

Background: The efficacy and tolerability of eslicarbazepine acetate (ESL) in adults and children with focal-onset epilepsy (FOE) according to the dose remain to be validated. A meta-analysis based on randomized controlled trials (RCTs) was therefore conducted as a summary. Methods: Relevant RCTs were collected by systematic searching the electronic databases of PubMed, Cochrane's Library, Embase, Wanfang and CNKI from inception to May 16, 2022. The random-effect model was adopted to pool the results by incorporating the possible heterogeneity. Efficacy outcomes including responsive rate and effective rate, defined as cases with 50 and ≥75% reduction in seizure frequency compared to baseline, were determined, respectively. Incidence of severe adverse events (AE) leading to drug discontinuation was also evaluated. Results: Ten studies including 2,565 people with epilepsy contributed to the meta-analysis. For adults, ESL 400 mg/d did not improve the response rate or the effective rate; ESL 800 mg/d was associated with improved response rate (odds ratio [OR] 2.16, 95% confidence interval [CI]: 1.65-2.83, p < 0.001) and effective rate (OR 2.16, 95% CI: 1.41-3.30, p < 0.001) without significantly increased severe AE (OR 1.58, 95% CI: 0.90-2.78, p = 0.11); ESL 1,200 mg/d improved response rate (OR 2.49, p < 0.001) and effective rate (OR 3.09, p = 0.04), but significantly increased severe AE (OR 3.72, p < 0.001). For children, ESL also did not significantly improve the response rate (OR 1.76, p = 0.22) or the effective rate (OR 2.17, p = 0.13). Conclusion: ESL 800 mg/d is effective and well-tolerated as adjuvants for adults with FOE. Efficacy of ESL in children with FOE should be further evaluated.

Psychiatric adverse events in three phase III trials of eslicarbazepine acetate for focal seizures.

OBJECTIVE: Eslicarbazepine acetate (ESL) is a once-daily (QD), oral anti-seizure medication for the treatment of focal (partial-onset) seizures. Here, we evaluate risk factors for the development of psychiatric treatment-emergent adverse events (TEAEs) in clinical trials of adjunctive ESL in adults with focal seizures. METHODS: This post-hoc analysis evaluated data pooled from three Phase III, randomized, double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients were randomized equally to receive placebo, ESL 400 mg (not reported here), 800 mg, or 1200 mg QD (up to 2-week titration; 12-week maintenance; optional open-label extension [OLE]). Incidences of psychiatric TEAEs were evaluated according to three separate criteria: medical history of psychiatric disorders (yes/no); baseline use of psychotropic drugs (yes/no); Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline (0-6: normal; 7-19: mild depression; 20-34: moderate depression). RESULTS: The analysis populations comprised 1251 patients for the controlled study period and 1137 patients for the 1-year OLE. Psychiatric TEAE incidence was similar between patients taking ESL and placebo in the controlled and OLE study periods and was not related to ESL dose. Psychiatric TEAEs generally occurred more frequently in patients with a medical history of psychiatric disorders, using psychotropic drugs, or with depressive symptoms than in those without a history, not using psychotropic drugs, or with no depressive symptoms. Depression and anxiety were the most frequently reported psychiatric TEAEs. SIGNIFICANCE: Overall, in clinical trials of ESL in adults with focal seizures, incidences of psychiatric events were not statistically different between patients taking ESL and placebo, were not related to ESL dose, and generally occurred more frequently in patients with baseline psychiatric symptoms or a history of psychiatric disorders. Long-term exposure to ESL was not associated with a marked increase in the incidence of psychiatric TEAEs.