Long-term effects of adjunctive eslicarbazepine acetate in adult Asian patients with refractory focal seizures: Post hoc analysis of a phase III trial.

A post hoc analysis of data from Asian patients included in the study BIA-2093-304 was conducted to evaluate the long-term safety/tolerability and efficacy of adjunctive eslicarbazepine acetate (ESL) in adult Asian patients with refractory focal seizures. Part I was a randomized controlled trial, in which patients received ESL (800 or 1200 mg once daily [QD]) or placebo, assessed over a 12-week maintenance period. Patients completing Part I could enter two open-label extension periods (Part II, 1 year; Part III, ≥2 years), during which all received ESL (400-1600 mg QD). Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs). Efficacy assessments included responder and seizure freedom rates. The safety population included 125, 92, and 23 Asian patients in Parts I, II, and III, respectively. Incidence of ESL-related TEAEs was 61.3%, 45.7%, and 17.4% during Parts I, II, and III, respectively. ESL-related TEAEs (most commonly, dizziness, somnolence, and headache) were consistent with ESL's known safety profile. During Part I, responder rates were higher with ESL 800 (41.7%) and 1200 mg QD (44.4%) versus placebo (32.6%), although not statistically significant. Seizure freedom rates with ESL 800 (5.5%) and 1200 mg QD (11.1%) were also higher versus placebo (0%) (p < 0.05 for ESL 1200 mg QD versus placebo). At the end of Part II, responder and seizure freedom rates were 60.3% and 14.7%, respectively. In summary, adult Asian patients with refractory focal seizures were responsive to treatment with ESL as adjunctive therapy and generally showed treatment tolerance well for up to 3 years. No new/unexpected safety findings were observed.

Treatment-induced diabetes neuropathy: description of singular clinical signs to reach a prompt diagnosis.

A 23-year-old woman diagnosed with type 1 diabetes mellitus in 2011 came to our outpatient office because of an inability to walk correctly. She was under a basal bolus insulin regimen. In the summer of 2016, she experienced a rapid improvement in her glycaemic control. A few weeks later, she started to complain of a severe burning pain in the soles of her feet (pain score 10/10). Neither macrovascular nor microvascular complications were detected. The patient was forced to walk barefoot due to an intense pain using shoes or socks and used to soak her feet in water for several hours daily. She also developed severe intolerance to environmental heat, both indoors and outdoors. A diagnosis of treatment-induced diabetic neuropathy was made. The patient was admitted to a general ward to start pain therapy. After a 6-month course of different neuropathic pain drugs, the patient was able to walk autonomously again.

Eslicarbazepine Acetate: A Review in Focal-Onset Seizures.

Eslicarbazepine acetate (Zebinix®), a voltage-gated sodium channel blocker, is a once-daily, orally administered anti-seizure medication available in the EU for use as monotherapy in adults with newly diagnosed focal-onset seizures and as adjunctive therapy in adults, adolescents and children aged > 6 years with focal-onset seizures. In adult patients, adjunctive eslicarbazepine acetate was generally associated with a significant decrease in seizure frequency and an increase in responder rate compared with placebo. The drug was also an effective monotherapy agent in adult patients, demonstrating noninferiority to controlled-release carbamazepine, in terms of seizure freedom rates. In paediatric patients, eslicarbazepine acetate provided seizure control when administered as adjunctive therapy, with the benefits appearing to be dependent on age and dose. The antiepileptic efficacy of eslicarbazepine acetate as adjunctive therapy or as monotherapy was maintained during longer-term extension studies, with each extension study period being up to 2 years. Oral eslicarbazepine acetate was generally well tolerated when administered as adjunctive therapy or monotherapy in adult patients and when administered as adjunctive therapy in paediatric patients, with most adverse events being of mild or moderate intensity. In conclusion, with the convenience of once-daily administration, eslicarbazepine acetate is an effective and generally well-tolerated treatment option for adults, adolescents and children aged > 6 years with focal-onset seizures.

Eslicarbazepine for focal epilepsy and acute intermittent porphyria.

Porphyrias are rare genetic disorders which cause a deficiency in the enzymes involved in the biosynthesis of heme. The treatment of epilepsy in patients with acute intermittent porphyria can be difficult since many anticonvulsants can increase heme synthesis and trigger porphyric attacks. We report a patient with focal epilepsy successfully treated with eslicarbazepine without exacerbation of porphyria.

Simultaneous measurement of epinastine and its metabolite, 9,13b-dehydroepinastine, in human plasma by a newly developed ultra-performance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies.

Epinastine is an antiallergic drug with high selectivity for histamine receptors. It has been reported that 9,13b-dehydroepinastine is present as a metabolite in vivo in humans, but there was little information about their pharmacokinetics (PKs) in humans. Although several analytical methods have been reported for epinastine analysis in different matrices, none are available for its metabolite. Therefore, the purpose of this study was to develop an analytical method to simultaneously measure epinastine and its metabolite, 9,13b-dehydroepinastine, in human plasma samples using an ultra-performance liquid chromatography-tandem mass spectrometer. Analytes were separated on a C18 column. Quantification of this analysis was performed on a triple-quadrupole mass spectrometer. Chromatograms showed high sensitivity, selectivity, and resolution with no interference with plasma constituents. Calibration curves for both epinastine and 9,13b-dehydroepinastine in human plasma were 0.1-50 ng/ml and displayed excellent linearity with correlation coefficients (r2 ) >0.99. The developed analytical method satisfied the criteria of international guidance and was validated. The method could be successfully applied to pharmacokinetic studies of epinastine and, for the first time, the metabolite kinetics of epinastine to 9,13b-dehydroepinastine in humans after oral administration of 20 mg epinastine hydrochloride tablets. Our study is expected to be useful in future studies such as dosage settings and clinical pharmacotherapy.

Influence of dose and antiepileptic comedication on brivaracetam serum concentrations in patients with epilepsy.

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, -49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level-to-dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.

Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: A double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial.

PURPOSE: This was a phase-III, randomized, double-blind, placebo-controlled study aimed to evaluate efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS). METHODS: Children (2-18 years old) with FOS, receiving 1-2 antiepileptic drugs, were randomized to ESL or placebo. Treatment was started at 10 mg/kg/day, up-titrated up to 20-30 mg/kg/day, and maintained for 12 weeks, followed by one-year open-label follow-up. Primary efficacy endpoints were relative reduction in standardized seizure frequency (SSF) and proportion of responders (≥50% SSF reduction) from baseline. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). RESULTS: The intention-to-treat (ITT) set included 134 patients randomized to ESL and 129 to placebo; 89.6% and 91.5%, respectively, completed the trial. An unbalanced number of seizures at baseline were observed between groups. Least square (LS) mean relative change in SSF from baseline was higher in the ESL group (-18.1%) than in placebo (-8.6%). Proportion of responders between ESL and placebo groups was not statistically different. A post hoc analysis showed greater relative reduction in SSF in patients above 6 years old treated with ESL 20 or 30 mg/kg/day compared with placebo; this was significant in patients above 6 years old treated with ESL 30 mg/kg/day (LS mean difference: 31.9%; p = 0.0478). The observed safety profile in children was consistent with that established in adult studies. CONCLUSIONS: Adjunctive ESL treatment was well-tolerated, but this trial failed to demonstrate that ESL was more effective than placebo in the predefined efficacy endpoints; factors that may have contributed to this outcome, affecting particularly the young age group, include etiological heterogeneity, difficulty in recognizing simple partial seizures, high seizure frequency with risk of imbalance, and underestimation of the efficacious dose range.

Eslicarbazepine acetate interacts in a beneficial manner with standard and alternative analgesics to reduce trigeminal nociception.

RATIONALE: Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. OBJECTIVES: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. METHODS: The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. RESULTS: ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). CONCLUSIONS: ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.

Pharmacokinetic Comparison of Epinastine Using Developed Human Plasma Assays.

The purpose of the study was to develop two new methods, HPLC-UV and UPLC-MS/MS, for quantifying epinastine in human plasma and to compare pharmacokinetic (PK) parameters obtained using them. Even in the same sample, there may be a difference in the quantitative value of drug depending on the assay, so that minor changes in PK parameter values may affect drug dose and usage settings. Therefore, selection and establishment of analytical methods are very important in PK studies of drugs, and a comparison of PK parameters according to analytical methods will be vital. For this study of PK parameter change, we newly developed two methods, HPLC-UV and UPLC-MS/MS, which are most commonly used to quantify epinastine concentrations in human plasma. All developed methods satisfied the international guidelines and criteria for successful application to PK study of 20 mg epinastine hydrochloride tablets after oral administration to twenty-six humans. A comparison of these two methods for in vivo analysis of epinastine was performed for the first time. This comparison study confirmed that different dose and usage settings might be possible based on PK parameters calculated using other analyses. Such changes in calculated PK parameters according to analytical methods would be crucial in the clinic.

In vitro and in vivo performance of epinastine hydrochloride-releasing contact lenses.

A number of drug-releasing contact lenses are currently being studied to address issues inherent in eye drops as a drug delivery method. In this study, we developed epinastine hydrochloride-releasing daily soft contact lenses for treatment of allergic conjunctivitis and examined their in vitro and in vivo performance. Preformed soft contact lenses with/without ionic functional groups were soaked in a solution of epinastine hydrochloride in phosphate-buffered saline to prepare epinastine hydrochloride-releasing soft contact lenses. Among these contact lenses with different ionicities, anionic lenses demonstrated the maximum, relatively linear epinastine hydrochloride release, in vitro. The amount of epinastine hydrochloride release was directly proportional to the concentration of the epinastine hydrochloride solution used to prepare the contact lens. The epinastine hydrochloride-releasing anionic soft contact lens also demonstrated prolonged drug release and significantly greater efficacy compared with epinastine hydrochloride eye drops 12 h after treatment, in vivo. Further studies are required to determine the appropriate amount of epinastine hydrochloride to be contained in the anionic soft contact lenses.

Safety, Tolerability and Efficacy of Eslicarbazepine Acetate as Adjunctive Therapy in Patients Aged ≥ 65 Years with Focal Seizures.

BACKGROUND: The incidence of epilepsy is high within the first few years of life, stabilizes over the second through fifth decades, and then rises again. Treatment of elderly patients with antiepileptic drugs (AEDs) is complicated by increased sensitivity to drug effects, altered pharmacokinetics and an increased risk for drug interactions due to polytherapy. On the other hand, the safety and efficacy data of AEDs attained during clinical development programmes are relatively limited for this age group. OBJECTIVE: The aim of this study was to evaluate the safety, tolerability and efficacy of eslicarbazepine acetate (ESL) as adjunctive therapy in patients aged ≥ 65 years with focal-onset seizures (FOS). METHODS: This was an international, multicentre, open-label, non-controlled, single-arm, post-European approval commitment study with flexible doses of ESL between 400 and 1200 mg/day. Seventy-two elderly patients with at least two FOS in the prior 4 weeks, and treated with one or two AEDs, were enrolled. The study consisted of an 8-week baseline, followed by a 26-week treatment period during which the investigator was allowed to up- or down-titrate the ESL dose, and a 4-week follow-up period. Safety and tolerability were assessed as well as mental sedation, cognitive mental state and suicidal ideation. Efficacy was assessed based on patient diaries regarding the absolute and relative changes in seizure frequency, change in intellectual impairment and quality of life. RESULTS: Overall, 47 (65.3%) patients experienced 152 treatment-emergent adverse events (TEAEs). The most frequent were dizziness (12.5%), somnolence (9.7%), fatigue, convulsion and hyponatraemia (8.3% each). All patients that experienced hyponatraemia (6/72) recovered without sequelae. Three patients died during the study (due to cardiac failure, glioblastoma multiforme and ischaemic stroke, all considered unrelated to ESL). Overall, 16 (22.2%) patients discontinued prematurely due to TEAEs. The incidences of clinically significant findings were low for vital signs, ECG, physical and neurological examinations. No TEAEs of hypothyroidism were reported; however, 24 (33.3%) patients presented post-baseline shifts from normal to decreased free T4 levels (not clinically significant). ESL decreased standardized seizure frequency from a mean of 4.8 seizures at baseline to 3.6 seizures at endpoint (p > 0.05); and mean number of days with seizures significantly decreased from 4.1 (baseline) to 2.8 at endpoint (p = 0.0408). CONCLUSION: ESL taken once daily (400-1200 mg) as adjunctive therapy in patients aged ≥ 65 years was found to be safe, well tolerated and efficacious (EudraCT number: 2009-012587-14).

Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence.

Inflammatory pain is the most common type of pain that is treated clinically. The use of currently available treatments (classic analgesics - NSAIDs, paracetamol and opioids) is limited by insufficient efficacy and/or side effects/tolerance development. Antiepileptic drugs (AEDs) are widely used in neuropathic pain treatment, but there is substantial preclinical evidence on their efficacy against inflammatory pain, too. In this review we focus on gabapentinoids (gabapentin and pregabalin) and dibenzazepine AEDs (carbamazepine, oxcarbazepine, and recently introduced eslicarbazepine acetate) and their potential for relieving inflammatory pain. In models of somatic, visceral and trigeminal inflammatory pain, that have a translational value for inflammatory conditions in locomotor system, viscera and head/face, AEDs have demonstrated analgesic activity. This activity was mostly consistent, dependent on the dose and largely independent on the site of inflammation and method of its induction, nociceptive stimuli, species, specific drug used, its route of administration and dosing schedule. AEDs exerted comparable efficacy with classic analgesics. Effective doses of AEDs are lower than toxic doses in animals and, when expressed as equivalent human doses, they are largely overlapping with AEDs doses already used in humans for treating epilepsy/neuropathic pain. The main mechanism of antinociceptive/antihyperalgesic action of gabapentinoids in inflammatory pain models seems to be α2δ-dependent suppression of voltage-gated calcium channels in primary sensory neurons that leads to reduced release of neurotransmitters in the spinal/medullar dorsal horn. The suppression of NMDA receptors via co-agonist binding site primarily at spinal sites, activation of various types of K+ channels at spinal and peripheral sites, and activation of noradrenergic and serotonergic descending pain modulatory pathways may also contribute. Inhibition of voltage-gated sodium channels along the pain pathway is probably the main mechanism of antinociceptive/antihyperalgesic effects of dibenzazepines. The recruitment of peripheral adrenergic and purinergic mechanisms and central GABAergic mechanisms may also contribute. When co-administered with classic/other alternative analgesics, AEDs exerted synergistic/additive interactions. Reviewed data could serve as a basis for clinical studies on the efficacy/safety of AEDs as analgesics/adjuvants in patients with inflammatory pain, and contribute to the improvement of the treatment of various inflammatory pain states.

[Social cognition and cognitive functions in patients with epilepsy treated with eslicarbazepine acetate]. / Cognicion social y funciones cognitivas en pacientes con epilepsia tratados con acetato de eslicarbacepina.

INTRODUCTION: Epilepsy is accompanied by cognitive disorders, frequently aggravated by the use of antiepileptic drugs, which can affect social empathy. AIM: To analyse the impact of treatment with eslicarbazepine acetate (ESL) on social cognition and prefrontal cognitive functions in adults with focal epilepsy. PATIENTS AND METHODS: We conducted a prospective single-centre study with patients aged between 18 and 65 years with focal seizures treated with ESL. The patients were evaluated in their baseline visit and at six months after starting ESL treatment by means of tasks designed for theory of mind, executive and attentional functions, auditory-verbal memory, quality of life, and anxiety and depression. RESULTS: Forty-one patients were treated with ESL, and 30 completed the follow-up. A significant improvement was observed in the theory of mind tasks. In the analysis stratified by sex, the men showed greater improvement. A cognitive improvement was observed in the Wisconsin Card Sorting Test, Symbol Digit, Backward Digit Span and Stroop tests. No differences were found in the Quality of Life in Epilepsy-31 Inventory or in the Hospital Anxiety and Depression Scale. These results were independent of the reduction in the number of seizures and the ESL dosage. CONCLUSION: Treatment with ESL could improve some aspects of theory of mind in patients with epilepsy, especially in men and independently of the control of seizures, with no changes in quality of life, anxiety or depression.

TITLE: Cognicion social y funciones cognitivas en pacientes con epilepsia tratados con acetato de eslicarbacepina.Introduccion. La epilepsia se acompaña de alteraciones cognitivas, frecuentemente agravadas por el uso de farmacos antiepilepticos, que pueden afectar a la empatia social. Objetivo. Analizar el impacto del tratamiento con acetato de eslicarbacepina (ESL) en la cognicion social y las funciones cognitivas prefrontales en adultos con epilepsia focal. Pacientes y metodos. Estudio prospectivo y unicentrico realizado en pacientes de 18 a 65 años con crisis focales, tratados con ESL. Los pacientes fueron evaluados en la visita basal y a los seis meses tras iniciar ESL mediante tareas para la teoria de la mente, funciones ejecutivas y atencionales, memoria audioverbal, calidad de vida, y ansiedad y depresion. Resultados. Cuarenta y un pacientes fueron tratados con ESL y 30 completaron el seguimiento. Se observo una mejoria significativa en las tareas de teoria de la mente. En el analisis estratificado por sexo, los hombres mejoraron mas. Se observo una mejoria cognitiva en las pruebas Wisconsin Card Sorting Test, Symbol Digit, Backward Digit Span y test de Stroop. No hubo diferencias en el cuestionario Quality of Life in Epilepsy-31 Inventory ni en la escala de depresion y ansiedad hospitalaria (HADS). Estos resultados fueron independientes de la reduccion del numero de crisis y de la dosis de ESL. Conclusion. El tratamiento con ESL podria mejorar algunos aspectos de la teoria de la mente en pacientes con epilepsia, especialmente en hombres e independientemente del control de las crisis, sin cambios en la calidad de vida, ansiedad o depresion.

Population Pharmacokinetics and Exposure-Response Analyses of Eslicarbazepine Acetate Efficacy and Safety in Monotherapy of Partial-Onset Seizures.

Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). ESL pharmacokinetics (PK) and exposure-response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1-2 studies (ESL 600-1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure-response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1-compartment model with first-order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin ) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported.

Eslicarbazepine acetate as a replacement for levetiracetam in people with epilepsy developing behavioral adverse events.

BACKGROUND: Psychiatric and behavioral side effects (PBSEs) are a major cause of antiepileptic drug (AED) withdrawal. Levetiracetam (LEV) is a recognized first-line AED with good seizure outcomes but recognized with PBSEs. Eslicarbazepine (ESL) is considered to function similarly to an active metabolite of the commonly used carbamazepine (CBZ). Carbamazepine is used as psychotropic medication to assist in various psychiatric illnesses such as mood disorders, aggression, and anxiety. AIM: The aim was to evaluate the psychiatric profile of ESL in people who had LEV withdrawn due to PBSEs in routine clinical practice to see if ESL can be used as a possible alternative to LEV. METHODS: A retrospective observational review was conducted in two UK epilepsy centers looking at all cases exposed to ESL since its licensing in 2010. The ESL group was all patients with treatment-resistant epilepsy who developed intolerable PBSEs to LEV, subsequently trialed on ESL. The ESL group was matched to a group who tolerated LEV without intolerable PBSEs. Psychiatric disorders were identified from case notes. The Hamilton Depression Scale (HAM-D) was used to outcome change in mood. Clinical diagnoses of a mental disorder were compared between groups using the Fisher's exact test. Group differences in HAM-D scores were assessed using the independent samples t-test (alpha=0.05). RESULTS: The total number of people with active epilepsy in the two centers was 2142 of whom 46 had been exposed to ESL. Twenty-six had previous exposure to LEV and had intolerable PBSEs who were matched to a person tolerating LEV. There was no statistical differences in the two groups for mental disorders including mood as measured by HAM-D (Chi-square test: p=0.28). CONCLUSION: The ESL was well tolerated and did not produce significant PBSEs in those who had PBSEs with LEV leading to withdrawal of the drug. Though numbers were small, the findings suggest that ESL could be a treatment option in those who develop PBSEs with LEV and possibly other AEDs.

Efficacy and safety of eslicarbazepine acetate monotherapy in patients converting from carbamazepine.

OBJECTIVE: To evaluate the influence of prior use of carbamazepine (CBZ) and other antiepileptic drugs (AEDs) with a putatively similar mechanism of action (inhibition of voltage-gated sodium channels; VGSCs) on seizure outcomes and tolerability when converting to eslicarbazepine acetate (ESL), using data pooled from 2 controlled conversion-to-ESL monotherapy trials (studies: 093-045, 093-046). METHODS: Adults with treatment-resistant focal (partial-onset) seizures were randomized 2:1 to ESL 1600 or 1200 mg once daily. The primary efficacy endpoint was study exit (meeting predefined exit criteria related to worsening seizure control) versus an historical control group. Other endpoints included change in seizure frequency, responder rate, and tolerability. Endpoints were analyzed for subgroups of patients who received CBZ (or any VGSC inhibitor [VGSCi]) during baseline versus those who received other AEDs. RESULTS: Of 365 patients in the studies, 332 were evaluable for efficacy. The higher risk of study exit in the subgroups that received CBZ (or any VGSCi) during baseline, versus other AEDs, was not statistically significant (hazard ratios were 1.49 for +CBZ vs -CBZ [P = .10] and 1.27 for +VGSCi vs. -VGSCi [P = .33]). Reductions in seizure frequency and responder rates were lower in patients who converted from CBZ or other VGSCi compared with those who converted from other AEDs. There were no notable differences in overall tolerability between subgroups, but the incidence of some adverse events (eg, dizziness, somnolence, nausea) differed between subgroups and/or between treatment periods. SIGNIFICANCE: Baseline use of CBZ or other major putative VGSC inhibitors did not appear to significantly increase the risk of study exit due to worsening seizure control, or to increase the frequency of side effects when converting to ESL monotherapy. However, bigger improvements in efficacy may be possible in patients converting to ESL monotherapy from an AED regimen that does not include a VGSC inhibitor.

Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: A phase III double-blind, randomized, parallel-group, multicenter study.

OBJECTIVE: We assessed the efficacy and safety of once-daily eslicarbazepine acetate in comparison with twice-daily (BID) controlled-release carbamazepine (carbamazepine-CR) monotherapy in newly diagnosed focal epilepsy patients. METHODS: This randomized, double-blind, noninferiority trial (NCT01162460) utilized a stepwise design with 3 dose levels. Patients who remained seizure-free for the 26-week evaluation period (level A: eslicarbazepine acetate 800 mg/carbamazepine-CR 200 mg BID) entered a 6-month maintenance period. If a seizure occurred during the evaluation period, patients were titrated to the next target level (level B: eslicarbazepine acetate 1200 mg/carbamazepine-CR 400 mg BID, level C: eslicarbazepine acetate 1600 mg/carbamazepine-CR 600 mg BID) and the evaluation period began again. The primary endpoint was the proportion of seizure-free patients for 6 months after stabilization in the per protocol set. The predefined noninferiority criteria were -12% absolute and -20% relative difference between treatment groups. RESULTS: Eight hundred fifteen patients were randomly assigned; 785 (388 in the eslicarbazepine acetate group and 397 in the carbamazepine-CR group) were included in the per protocol set, and 813 (401 in the eslicarbazepine acetate group and 412 in the carbamazepine-CR group) were included in the full analysis set for the primary analysis. Overall, 71.1% of eslicarbazepine acetate-treated patients and 75.6% of carbamazepine-CR-treated patients were seizure-free for ≥6 months at the last evaluated dose (average risk difference = -4.28%, 95% confidence interval [CI] = -10.30 to 1.74; relative risk difference = -5.87%, 95% CI = -13.50 to 2.44) in the per protocol set. Rates of treatment-emergent adverse events were similar between groups for patients in the safety set. Noninferiority was also demonstrated in the full analysis set, as 70.8% of patients with eslicarbazepine acetate and 74.0% with carbamazepine-CR were seizure-free at the last evaluated dose (average risk difference = -3.07, 95% CI = -9.04 to 2.89). SIGNIFICANCE: Treatment with eslicarbazepine acetate was noninferior to BID carbamazepine-CR. With its once-daily formulation, eslicarbazepine acetate provides a useful option for first-line monotherapy for adults with newly diagnosed epilepsy and focal onset seizures.

Population Pharmacokinetic Evaluation and Missed-Dose Simulations for Eslicarbazepine Acetate Monotherapy in Patients With Partial-Onset Seizures.

Given the potential consequences of antiepileptic therapy nonadherence, missed-dose scenarios of 12- to 48-hour dose delays (4-hour intervals) for eslicarbazepine acetate monotherapy were evaluated using simulated plasma concentrations of a population pharmacokinetic model (representing 493 subjects). When 1600-mg doses were delayed 12 to <16 or 36 to <44 hours, simulations showed immediate administration of 1600 mg followed by the same dose at the scheduled time maintained plasma concentrations within the target concentration range. With 16- to 24- or 44- to 48-hour delays, administration of 2400 mg at the scheduled time followed by resumption of 1600 mg/day maintained plasma concentrations within the target concentration range. For exploratory purposes, the population pharmacokinetic model was refined to predict (n = 6 subjects) and also to allow for simulation of cerebrospinal fluid concentrations. Based on the plasma concentration simulations conducted herein, potential dosing recommendations were developed that suggest a missed ESL dose should be taken when remembered, and the usual dose regimen resumed. If it is remembered within 4 hours of the next dose, 1.5 times the usual dose should be taken immediately, the scheduled dose for that day should be skipped, and the usual regimen resumed the next day.

Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy.

OBJECTIVE: The aim of the study was to assess the clinical response to eslicarbazepine acetate (ESL) as add-on therapy in adult patients with partial-onset epilepsy by means of the time-to-baseline seizure count method. METHODS: We retrospectively identified consecutive patients with partial-onset seizures, with or without secondary generalization, prescribed to ESL add-on therapy. The primary endpoint was the time-to-baseline monthly seizure count. Subgroup analysis was performed according to carbamazepine (CBZ)/oxcarbazepine (OXC) status (prior vs never use). Secondary outcomes were the rate of treatment-related adverse events (AEs) and the AEs affecting ≥5% of patients. RESULTS: One-hundred and eighteen patients were included. The median time-to-baseline monthly seizure count was 46 (35-101) days in the overall study cohort. The number of concomitant anti-epileptic drugs (AEDs) was associated with the time-to-endpoint (adjusted hazard ratio [adj HR]=2.22, 95% CI 1.18-4.14, P=.013 for two AEDs vs one; adj HR=3.65, 95% CI 1.66-8.06, P=.001 for three or more AEDs vs one). Groupwise, the median times-to-baseline seizure count were 47 (35-97) and 43 (34-103) in patients with prior and never exposure to CBZ/OXC, respectively (P for log-rank test=.807). Adverse events occurred in 53.4% (63 of 118) of patients; the most frequently reported were dizziness (13.6%), somnolence (11.9%), nausea (6.8%), and fatigue (5.1%). CONCLUSIONS: Add-on ESL improved seizure control and was overall well-tolerated in adult patients with partial-onset epilepsy.

Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials.

OBJECTIVE: To examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). METHODS: Data from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2-week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. RESULTS: 1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. CONCLUSIONS: Initiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation.