levetiracetam and eslicarbazepine-acetate

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

Topics: Anticonvulsants; Area Under Curve; Biological Variation, Individual; Dibenzazepines; Drug Substitution; Drugs, Generic; Europe; Gabapentin; Humans; Lacosamide; Lamotrigine; Levetiracetam; Oxcarbazepine; Pregabalin; Therapeutic Equivalency; Topiramate; Vigabatrin; Zonisamide

This study was proposed to compare the relative efficacy and tolerability of the second and third generation AEDs for refractory epilepsy. The 50% responder rate (RR) was selected as the efficacy outcome whereas the incidence of dizziness and somnolence were considered to evaluate the tolerability of AEDs. Odds ratio (OR) and their 95% credible interval (CrI) were obtained using a consistency model and surface under the cumulative ranking curve (SUCRA) value was calculated to rank AEDs. Topiramate appeared to be significantly more effective than placebo, eslicarbazepine acetate, perampanel, pregabalin, zonisamide, gabapentin and lamotrigine with respect to the 50% RR (all OR > 1). Patients who were managed by eslicarbazepine acetate, perampanel, oxcarbazepine, topiramate and pregabalin were more likely to suffer from dizziness compared to those who receive placebo (all OR > 1). Perampanel, topiramate and pregabalin were related to elevated risks of somnolence compared to placebo (all OR > 1). Moreover, topiramate ranked highest with respect to 50% RR (SUCRA = 0.968) whereas levetiracetam appeared to have balanced efficacy and tolerability (SUCRA = 0.769, 0.743, 0.604 and 0.659). In conclusion, topiramate was the most efficacious AED, while levetiracetam was able to provide patients with balanced efficacy and tolerability.

Topics: Anticonvulsants; Dibenzazepines; Drug Resistant Epilepsy; Humans; Levetiracetam; Network Meta-Analysis; Nitriles; Pyridones; Topiramate

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.. 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.. 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.. 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.. 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.

Topics: Adult; Anticonvulsants; Dibenzazepines; Double-Blind Method; Humans; Lamotrigine; Levetiracetam; Seizures; Treatment Outcome

We report outcomes from an open-label, non-randomized, 24-week study of eslicarbazepine acetate (ESL) in adults at earlier and later stages of their treatment history for focal seizures, conducted in a real-world clinical setting.. ESL was taken as the first adjunctive therapy to levetiracetam (LEV) or lamotrigine (LTG) monotherapy (Arm 1), or as a later adjunctive therapy in treatment-resistant patients (Arm 2). The primary objective was to evaluate the effectiveness of ESL (by retention rates). Secondary objectives were to evaluate efficacy (seizure frequency), safety, tolerability, behavioral changes, mood, and health-related quality of life (HRQoL) associated with ESL treatment.. The modified intent-to-treat population included 96 patients (Arm 1: n = 41; Arm 2: n = 55) and the safety population included 102 patients (Arm 1: n = 44; Arm 2: n = 58). Overall, 81.8 % of patients in Arm 1 and 63.8 % of patients in Arm 2 completed the 24-week maintenance period. Median reductions in standardized seizure frequency (SSF) were markedly higher in Arm 1 (72.8 %) than Arm 2 (22.8 %), as were responder rates (≥50 % reduction in SSF; Arm 1: 62.5 %; Arm 2: 38.5 %) and rates of seizure freedom (Arm 1: 25.0 %; Arm 2: 9.6 %). Efficacy outcomes were generally more favorable in patients taking ESL in combination with LEV versus other anti-seizure medications (ASMs). Treatment-emergent adverse events (TEAEs; 81 % vs 73 %) and TEAEs leading to discontinuation (16 % vs 2 %) were reported more frequently in Arm 2 than Arm 1, respectively. Serious adverse events were reported infrequently (Arm 1: 0; Arm 2: 7 %). The most common TEAEs were dizziness, nausea, headache, somnolence, fatigue, nasopharyngitis, vomiting, and anxiety. There were no notable changes in depressive symptoms, mood status, or aggression throughout the study. Health and HRQoL scores were generally high at baseline and did not change throughout the study. However, on average, both clinicians and patients perceived improvement in illness over the course of the study.. ESL was effective and well tolerated both as the first adjunctive therapy to either of the most prescribed first-line ASMs, LEV or LTG, and as a later adjunctive therapy in treatment-resistant patients.

Topics: Anticonvulsants; Dibenzazepines; Double-Blind Method; Humans; Lamotrigine; Levetiracetam; Quality of Life; Seizures; Treatment Outcome

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.. 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.. 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).. 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).. 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.

Topics: Adult; Anticonvulsants; Dibenzazepines; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Levetiracetam; Male; Mental Disorders; Middle Aged; Psychiatric Status Rating Scales; Retrospective Studies; Seizures; Substance Withdrawal Syndrome; Treatment Outcome; Voltage-Gated Sodium Channel Blockers

Modeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4-17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2-18 years of age treated with ESL 5-30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (including body weight and concomitant use of carbamazepine, levetiracetam, and phenobarbital-like antiepileptic drugs [AEDs]) on variability in PK parameters. Model evaluation performed using a simulation-based visual predictive check and a non-parametric bootstrap procedure indicated no substantial bias in the overall model and in the accuracy of estimates. The model estimated that concomitant use of carbamazepine or phenobarbital-like AEDs with ESL would decrease the exposure of eslicarbazepine, and that concomitant use of levetiracetam with ESL would increase the exposure of eslicarbazepine, although the small effect of levetiracetam may not represent a true difference. Model-based simulations were subsequently performed to apply target exposure matching of selected ESL doses for pediatric subjects (aged 4-17 years) to attain eslicarbazepine exposures associated with effective and well-tolerated ESL doses in adults. Overall, model-based exposure matching allowed for extrapolation of efficacy to support pediatric dose selection as part of the submission to obtain FDA approval for ESL (adjunctive therapy and monotherapy) in subjects aged 4-17 years, without requiring an additional clinical study.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dibenzazepines; Dose-Response Relationship, Drug; Female; Humans; Levetiracetam; Male; Phenobarbital; Seizures

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult