Initial monotherapy with eslicarbazepine acetate for the management of adult patients with focal epilepsy in clinical practice: a meta-analysis of observational studies.

AIM OF THE STUDY: To assess the effectiveness, overall tolerability of eslicarbazepine acetate (ESL) as an initial or early monotherapy treatment of adult patients with focal epilepsy under real-world practice conditions. MATERIALS AND METHODS: We focused on real-world longitudinal studies that included or separately reported the results of at least one of the efficacy outcomes of interest. A DerSimonian-Laird random effects model was used with the presentation of the 95% confidence intervals of the estimate. RESULTS: 5 studies met our selection criteria and were included in the quantitative synthesis. All studies were observational and uncontrolled studies, and all but one were retrospective studies. The pooled proportion of patients who were seizure-free for the entire study period was 64.6% (95% CI, 45.7 to 79.8) at month 6 and 56.6% (95% CI, 50.2 to 62.8) at month 12. Pooled retention rates were 95.0% (95% CI, 90.3 to 97.5) at 6 months and 83.6% (95% CI, 73.9 to 90.1) at 12 months. The pooled proportion of patients who reported at least one adverse event was 27.2% (95% CI, 21.7 to 33.6), and the pooled proportion of patients who discontinued ESL due to adverse events was 8.9% (95% CI 6.2 to 12.6). CONCLUSIONS: Our results suggest that initial or early monotherapy with ESL is effective and well-tolerated for the management of adult patients with focal epilepsy in clinical practice, with results that are at least similar to those reported in the pivotal randomized clinical trial of ESL monotherapy. No new safety signals with ESL have been identified in this systematic review.

Long-term therapeutic effect of eslicarbazepine acetate in children: An open-label extension of a cognition study in children aged 6-16 years.

OBJECTIVE: In Europe, eslicarbazepine acetate (ESL) is approved as adjunctive therapy for the treatment of focal seizures (FS) in children aged >6 years. In the US, ESL is approved as both monotherapy and adjunctive therapy for the treatment of FS in patients aged ≥4 years. In a phase II study of children aged 6-16 years with FS, ESL had no significant effects on attention or behavioral functioning and decreased seizure frequency during double-blind therapy and a 1-year open-label extension (OLE). This report presents data from an additional 2-year OLE of the phase II study. METHODS: Previous recipients of ESL or placebo were treated with open-label ESL (10-30 mg/kg/day, adjusted for clinical response and/or adverse events [AEs]). Safety was assessed by incidence of treatment-emergent AEs (TEAEs). Efficacy endpoints were treatment retention time and change from baseline in Clinical Global Impression-Severity (CGI-S) scale scores. RESULTS: Forty-two patients entered and 31 (73.8%) completed the 2-year OLE. Median treatment retention time was 735 (95% confidence interval 728-741) days. Seven patients (17% of total, 23% of completed) experienced ≥1 TEAE during the 2-year OLE, mostly of mild or moderate intensity. The incidence of serious TEAEs was low (n = 2; 5% of total, 6% of completed) and none were related to ESL. One child was withdrawn because of splenomegaly that was considered possibly related to ESL. The only change from baseline in CGI-S was a 0.5-point reduction in the severity of illness score. All findings were consistent across patient subgroups based on previous double-blind treatment (placebo or ESL) and patient age (6-11 or 12-16 years). CONCLUSIONS: The majority of patients remained on ESL during the 2-year OLE, and treatment efficacy was maintained. Adverse events were consistent with the known safety profile of ESL, and no new safety signals were identified.

Eslicarbazepine acetate add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an update of a review first published in 2011, and last updated in 2017. Most people with epilepsy have a good prognosis, but up to 30% of people continue to have seizures despite several regimens of antiepileptic drugs. In this review, we summarized the current evidence regarding eslicarbazepine acetate (ESL) when used as an add-on treatment for drug-resistant focal epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of ESL when used as an add-on treatment for people with drug-resistant focal epilepsy. SEARCH METHODS: For this update, we searched the following databases on 10 September 2020: Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid). CRS Web includes randomized or quasi-randomized, controlled trials from Specialized Registers of Cochrane Review Groups including Epilepsy, CENTRAL, PubMed, Embase, ClinicalTrials.gov and the WHO ICTRP. There were no language restrictions. We reviewed the reference lists of retrieved studies and contacted the manufacturers of ESL and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomized placebo-controlled double-blind add-on trials of ESL in people with drug-resistant focal epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, treatment withdrawal, adverse effects and drug interactions. Primary analyses were by intention to treat (ITT). The dose-response relationship was evaluated in regression models. MAIN RESULTS: We included seven trials (2185 participants, aged 2 to 77 years), which were at low or unclear risk of bias apart from a high risk of attrition bias; all studies were funded by the pharmaceutical company, BIAL. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.57 (95% confidence interval (CI) 1.34 to 1.83). For adults, the RR was 1.71 (95% CI 1.42 to 2.05; 5 studies, 1799 participants; moderate-certainty evidence); for children aged six to 18 years, the RR was 1.35 (95% CI 0.98 to 1.87; 2 studies, 322 participants; moderate-certainty evidence). Dose regression analysis showed evidence that ESL reduced seizure frequency with an increase in efficacy with increasing doses of ESL. ESL was associated with seizure freedom (RR 3.16, 95% CI 1.73 to 5.78; 6 studies, 1922 participants; moderate-certainty evidence). Participants were more likely to have ESL withdrawn for adverse effects (RR 2.72, 95% CI 1.66 to 4.46; 7 studies, 2185 participants; moderate-certainty evidence), but not for any reason (RR 1.25, 95% CI 0.93 to 1.70; 7 studies, 2185 participants; moderate-certainty evidence). The following adverse effects were associated with ESL: dizziness (RR 2.77, 99% CI 1.85 to 4.15); nausea (RR 2.55, 99% CI 1.39 to 4.67); somnolence (RR 1.75, 99% CI 1.18 to 2.61); diplopia (RR 4.07, 99% CI 1.86 to 8.89); and vomiting (RR 2.37, 99% CI 1.19 to 4.74). Overall, the certainty of the evidence was moderate due to a high discontinuation rate in studies of adults. AUTHORS' CONCLUSIONS: ESL reduces seizure frequency when used as an add-on treatment for adults with drug-resistant focal epilepsy. The trials included in this review were of short-term duration. In addition, this update found that ESL may reduce seizure frequency in children from 6 to 18 years of age; however the results are inconclusive.

The evidence for switching dibenzazepines in people with epilepsy.

The dibenzazepines particularly carbamazepine are associated with known adverse effects (AEs) and drug to drug interactions. Eslicarbazepine acetate (ESL) is structurally distinct from other members of the dibenzazepine family and has the advantage of once daily dosing. Observational and trial data report successful switching from older dibenzazepines to ESL. The evidence base for doing so is unclear and not standardized. This is a literature review following the PRISMA scoping guidelines identifying the evidence of switching dibenzazepines. Transition methods, ratios, tolerance to change, adverse effects and retention post-change were evaluated. Study quality was assessed using the Oxford Centre for Evidence Based Medicine levels of evidence. Seven studies investigated the outcome of transition between carbamazepine and or oxcarbazepine to ESL, with specific data on the transition dose ratio and scheduling. The available data suggest that the overnight transition between oxcarbazepine and ESL in a 1:1 ratio (most common) is generally well tolerated with high retention rates. The transition showed improvement in adverse events associated with oxcarbazepine across a variety of domains. Almost 60% transitioned because of adverse events experienced no further symptoms at 12 months. There is less data on the transition from carbamazepine to ESL. The evidence available suggests an overnight transition in the ratio of 1:1.3-1.5. The retention rate following transition from carbamazepine to ESL was 69% (follow-up of 4 months) with almost half of those transitioned because of adverse events experiencing no further symptoms. There is Grade C evidence available to help guide clinicians in the transition.

Eslicarbazepine acetate in post-stroke epilepsy: Clinical practice evidence from Euro-Esli.

OBJECTIVES: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients included in the Euro-Esli study who had focal seizures associated with post-stroke epilepsy (PSE). MATERIALS AND METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments (evaluated after 3, 6 and 12 months of ESL treatment and at final follow-up ["last visit"]) included rates of response (≥50% seizure frequency reduction), seizure freedom (no seizures since at least the prior visit) and retention. Safety/tolerability was assessed throughout ESL treatment by evaluating adverse events (AEs) and discontinuation due to AEs. A post hoc analysis was conducted of patients with PSE versus patients without PSE ("non-PSE"). RESULTS: Of 1656 patients included in the analysis, 76 (4.6%) had PSE and 1580 (95.4%) had non-PSE. Compared with non-PSE patients, PSE patients were significantly older, had significantly shorter epilepsy duration, significantly lower total baseline seizure frequency, and were treated with significantly fewer prior and concomitant antiepileptic drugs (P < .001 for all). At the last visit, the responder rate was significantly higher in PSE versus non-PSE patients (72.9% vs 60.6%; P = .040), as was the seizure freedom rate (48.6% vs 31.7%; P = .003). After 12 months, retention was significantly higher in PSE versus non-PSE patients (87.8% vs 77.4%; P = .035). The incidence of AEs was similar for PSE versus non-PSE patients (36.0% vs 35.8%; P = .966). CONCLUSIONS: These findings suggest that ESL may be an effective and well-tolerated treatment option for patients with focal seizures due to PSE.

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate.

OBJECTIVES: To evaluate cutaneous allergic reactions in clinical trials of adjunctive eslicarbazepine acetate (ESL) for focal seizures. MATERIALS AND METHODS: Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337). RESULTS: Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL. CONCLUSIONS: Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes.

Long-term safety and tolerability of adjunctive eslicarbazepine acetate in children with focal seizures.

OBJECTIVE: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. METHODS: Safety data from patients aged 4-17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10-30 mg/kg/day; maximum 1200 mg/day). RESULTS: The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. CONCLUSIONS: Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4-17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

Estimating the Risk of Pneumonia in Patients With Schizophrenia Newly Receiving Clozapine: A Nationwide Cohort Study.

PURPOSE/BACKGROUND: Patients with schizophrenia are vulnerable to pneumonia. Clozapine is associated with the greatest risk of pneumonia. We investigated the risk factors of pneumonia in patients with schizophrenia who use clozapine. METHODS/PROCEDURES: We used a large cohort of patients with schizophrenia (N = 22,774) who newly use clozapine (baseline). We divided the data set into a training cohort (entry between 1998 and 2008, n = 18,496) and test cohort (entry between 2009 and 2012, n = 4278), where 483 and 168 patients developed pneumonia requiring hospitalization within 1 year after baseline, respectively. For prediction, we developed a static model using Cox proportional hazards regression and a dynamic model using Cox regression with time-dependent modeling. Areas under receiver operating curves (AUCs) for the predictive model were estimated in the training cohort and then in the test cohort for validation. FINDINGS/RESULTS: Based on the baseline characteristics, the static model for predicting pneumonia in 3 periods (90, 180, and 365 days) was unsatisfactory (AUCs, 0.64, 0.64, and 0.65, respectively). The predictors were older age, male sex, history of nonpsychiatric hospitalization, dementia, asthma, and tuberculosis within 1 year before baseline. However, the results were improved (AUCs, 0.83, 0.79, and 0.77, respectively) after control for time-dependent variables, namely, duration of clozapine use and concomitant medications (ie, benzodiazepines, valproic acid, systemic corticosteroids). IMPLICATIONS/CONCLUSIONS: Several risk factors for predicting subsequent pneumonia after initial use of clozapine were explored, including older age, male, history of nonpsychiatric hospitalization, dementia, asthma, tuberculosis, benzodiazepines, valproic acid, systemic corticosteroids, and the use duration of clozapine. Clinical staff can use the risk factors to administer evidence-based treatment.

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.

OBJECTIVE: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures. METHODS: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. RESULTS: The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.

MONOZEB: Long-term observational study of eslicarbazepine acetate monotherapy.

AIM: The aim of the study was to evaluate the effectiveness and tolerability of eslicarbazepine acetate (ESL) when used as monotherapy for 1 year or more in routine clinical use in patients with focal seizures in epilepsy clinics in Spain. METHODS: This is a retrospective, observational, noninterventional study. Eligible patients were aged ≥18 years, had focal seizures, and started on ESL ≥1 year before database closure. Primary endpoint was the following: proportion seizure-free for ≥6 months at 1 and 2 years. Secondary endpoints included retention on ESL monotherapy at 1 and 2 years, seizure frequency change, seizure worsening, and side effects. Other analyses included seizure freedom from baseline to 1 and 2 years and outcomes in special populations. RESULTS: Four hundred thirty-five patients were included (127 on first-line monotherapy and 308 converting to ESL monotherapy): median daily dose was 800 mg at all time points; 63.2% were seizure-free at 1 year, 65.1% at 2 years, and 50.3% for the entire follow-up. Mean duration of ESL monotherapy was 66.7 months; retention was 88.0% at 1 year and 81.9% at 2 years. Mean reduction in seizure frequency was 75.5% at last visit. Over the entire follow-up, seizure worsening was seen in 22 patients (5.1%), side effects in 28.0%, considered severe in 1.8%, and leading to discontinuation in 5.7%. Dizziness, hyponatremia (sodium <135 mEq/l), and somnolence were the most frequent side effects. Outcomes in special populations (patients aged ≥65 years and those with psychiatric history or learning difficulty) were consistent with the overall population. CONCLUSIONS: Patients with focal seizures taking ESL monotherapy had excellent retention, high seizure-free rates, and good tolerability up to 2 years.

Comparative neuropsychological effects of carbamazepine and eslicarbazepine acetate.

People with epilepsy are at increased risk for neuropsychological dysfunction due to multiple factors, of which the most amendable are antiseizure medications (ASMs). Antiseizure medication effectiveness is frequently determined by tolerability. In this study, we compared the neuropsychological effects of eslicarbazepine acetate (ESL) and carbamazepine immediate-release (CBZ) using a randomized, double-blind, crossover design in healthy volunteers with a 2-week titration and 4-week maintenance phase in each treatment arm (CBZ = 400 mg BID and ESL = 800 mg qAM). Neuropsychological testing was performed at the initial visit, repeated at 1st baseline nondrug condition, end treatment #1, 2nd nondrug condition one month after treatment #1, end treatment #2, and 3rd nondrug condition one month after treatment #2. Neuropsychological testing was conducted 2 h after morning dose and included computer (i.e., dual task test, selective attention test, symbol digit, verbal memory, visuospatial memory, and 1- & 2-back continuous performance) and noncomputer tasks (i.e., Medical College of Georgia (MCG) paragraph memory, Stroop, Symbol Digit Modalities Test, Profile of Mood States). z-Scores calculated from nondrug conditions were used to compare ESL and CBZ for the 23 completers. Follow-up analyses included individual test scores and distribution of individual raw means. Mean blood levels on test day were CBZ = 8.9 µg/ml and ESL = 15.3 µg/ml. Omnibus z-score was significantly better for ESL (p = .0001). For individual measures, executive function and selective attention tests were statistically significantly better for ESL. Individual test raw means favored ESL over CBZ on 22 of 30 measures (p = .016, 2-tailed sign test). Eslicarbazepine acetate demonstrated less adverse neuropsychological effects than CBZ.

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.

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

OBJECTIVES: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. METHODS: Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. RESULTS: Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. CONCLUSIONS: Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

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.

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.

Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures.

OBJECTIVE: To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults. METHODS: This was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity. RESULTS: The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality-related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively. CONCLUSIONS: In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.

Eslicarbazepine acetate as adjunctive therapy in clinical practice: ESLADOBA study.

OBJECTIVE: To assess seizure control and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy to one baseline antiepileptic drug (AED), in adults with partial-onset seizures (POS) with or without secondary generalization. METHODS: Multicenter, non-interventional, prospective cohort study conducted between March 2012 and September 2014 at 12 neurology departments in Portugal. Adults with POS not controlled with one AED who had initiated ESL as adjunctive treatment were enrolled. Retention rate was defined at the final visit (Vfinal) 6-9 months of follow-up. Proportion of responders, seizure-free, changes in seizure frequency were evaluated using patients' diaries. Clinical Global Impression of Change (CGI-C) and Clinical Global Impression of Severity (CGI-S) were assessed by the neurologist. RESULTS: Fifty-two patients (48.1% male) were included with mean age 41.5±13.3 years. Mean epilepsy duration was 18.5±14.8 years; mean seizure frequency in the four previous weeks to baseline was 7.5±12.7. At Vfinal, retention rate was 73.0%; responder rate and seizure-free rates were 71.1% and 39.5%, respectively. The median relative reduction in seizure frequency between baseline and Vfinal was 82.2%. A reduction in epilepsy severity (CGI-S) was observed in 42.1%. According to CGI-C, 73.6% patients had their epilepsy "much improved" or "very much improved". Twelve patients (23.1%) had at least one adverse event (AE), two (3.9%) had one serious AE, and five (9.6%) discontinued due to AE. CONCLUSIONS: Eslicarbazepine acetate showed good retention rates, elicited a significant reduction in seizure frequency, and was well tolerated when used in the clinical practice.

EARLY-ESLI study: Long-term experience with eslicarbazepine acetate after first monotherapy failure.

PURPOSE: Evaluate real-life experience with eslicarbazepine acetate (ESL) after first monotherapy failure in a large series of patients with focal epilepsy. METHOD: Multicentre, retrospective, 1-year, observational study in patients older than 18 years, with focal epilepsy, who had failed first antiepileptic drug monotherapy and who received ESL. Data from clinical records were analysed at baseline, 3, 6 and 12 months to assess effectiveness and tolerability. RESULTS: Eslicarbazepine acetate was initiated in 253 patients. The 1-year retention rate was 92.9%, and the final median dose of ESL was 800 mg. At 12 months, 62.3% of patients had been seizure free for 6 months; 37.3% had been seizure free for 1 year. During follow-up, 31.6% of the patients reported ESL-related adverse events (AEs), most commonly somnolence (8.7%) and dizziness (5.1%), and 3.6% discontinued due to AEs. Hyponatraemia was observed in seven patients (2.8%). After starting ESL, 137 patients (54.2%) withdrew the prior monotherapy and converted to ESL monotherapy; 75.9% were seizure free, 87.6% were responders, 4.4% worsened, and 23.4% reported ESL-related AEs. CONCLUSION: Use of ESL after first monotherapy failure was associated with an optimal seizure control and tolerability profile. Over half of patients were converted to ESL monotherapy during follow-up.

Overnight switching from oxcarbazepine to eslicarbazepine acetate: an observational study.

OBJECTIVES: There are clinical situations where it might be appropriate to switch patients from immediate-release oxcarbazepine (OXC) to eslicarbazepine acetate (ESL). We investigated the effects of transitioning patients overnight from OXC to ESL. MATERIALS AND METHODS: A retrospective, single-center study was conducted in which patients with drug-resistant focal epilepsy on a stable dose of immediate-release OXC for at least 4 weeks were switched overnight to ESL. Patients were switched because they experienced persistent seizures with OXC but were unable to tolerate increased OXC dosing due to adverse events. Tolerability was assessed using the Adverse Events Profile (AEP), quality of life was assessed using the Quality of Life in Epilepsy Inventory 10 (QOLIE-10), and alertness was assessed as reaction time using a subtest of the Test Battery for Attention Performance version 2.3. Assessments were performed immediately prior to and 5 days after switching from OXC to ESL (days 0 and 5, respectively). RESULTS: The analysis included 21 patients (12 women, 9 men; mean age 36 years). After switching from OXC to ESL, there were significant improvements in mean scores for AEP (P<.001), QOLIE-10 (P=.001), and alertness (P<.05). Adverse Events Profile total scores improved for 21/21 (100.0%) patients, QOLIE-10 total scores improved for 17/21 (81.0%) patients, and alertness scores improved for 16/21 (76.2%) patients. CONCLUSIONS: In this short-term, single-center study, an overnight switch from twice-daily OXC to once-daily ESL in patients with drug-resistant focal epilepsies resulted in improvements in side effects, quality of life, and alertness.

When adverse effects are seen as desirable: Abuse potential of the newer generation antiepileptic drugs.

There has been growing recognition of the possible abuse potential of newer generation antiepileptic drugs, and several of these agents have been categorized as controlled substances in the United States. To properly schedule a new medication, the abuse potential, or the potential for a drug to be used for its nonmedical positive subjective effects, must be determined. Performing a human abuse potential study is one step in the overall abuse potential assessment. These studies analyze the abuse potential of a new drug in a very specific population of known recreational drug users. Studying the test drug in this population enables a more meaningful assessment of abuse, and likely represents the population most probable to abuse. In these double-blind, single-dose, active and placebo controlled studies subjects may report their subjective liking, estimated street value, and rate euphoric or depressive sensations of the test drug compared with placebo and scheduled active comparators with a known abuse potential. In order to provide an enhanced understanding of the abuse potential assessment and how it relates to controlled substance scheduling, this review will examine the human abuse potential studies of perampanel, eslicarbazepine, lacosamide, and brivaracetam.