lacosamide and perampanel

This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively.. We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses.. In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators.. Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Topics: Adult; Anticonvulsants; Cost-Benefit Analysis; Drug Resistant Epilepsy; Humans; Lacosamide; Seizures; State Medicine

Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.. We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).. We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).. Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.. Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

Topics: Adult; Anticonvulsants; Carbamates; Chlorophenols; Dibenzazepines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Middle Aged; Network Meta-Analysis; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic; Seizures; Tetrazoles

Cognitive and psychiatric problems are common in people with epilepsy. They can have multiple causes, including structural brain lesions, the active epilepsy, and the effect of anti-epileptic therapy. Since patients' treatment compliance and quality of life are affected by cognitive and emotional status, it is crucial for clinicians to understand how anti-seizure medications (ASMs) affect cognition and mood, and to choose the proper ASM.. To conduct a literature review of the impact on cognition and mood status of lacosamide (LCM) in people with epilepsy.. Wesearched PubMed, the Cochrane Database of Systematic Reviews and reference lists of articles for all types of articles with no limitations on publication date.. A total of 251 records were obtained, including 247 articles in PubMed and 4 articles from reference lists. We included 2 meta-analyses, one randomized controlled trials and 14 observational studies after the screening process. Most studies agree LCM has low risk of treatment-emergent adverse events (TEAEs) on cognition. Comparisons with other ASMs, LCM may be preferable to carbamazepine, topiramate and perampanel, and not inferior to lamotrigine. In spite of low incident rate, depression is the most common psychiatric change of LCM. There are no consistent positive or negative psychiatric effects of LCM.. Lacosamide has limited impact on cognitive and mood status in this review. Several factors including mechanism of co-administration of ASMs and personal history of psychiatric disorder should be considered as important in the development of cognitive and psychiatric side effects. However, the heterogeneity between studies make the quality of evidence weaker and further trials are needed.

Topics: Adult; Affect; Anticonvulsants; Carbamazepine; Cognition; Epilepsy; Humans; Lacosamide; Lamotrigine; Nitriles; Pyridones; Quality of Life; Topiramate

Eslicarbazepine (ESL), Lacosamide (LAC), Perampanel (PER) and Brivaracetam (BRV), have recently been marketed as third-generation antiepileptic drugs (AEDs). We conducted a meta-analysis to indirectly compare overall efficacy and tolerability between third-generation AEDs in uncontrolled focal epilepsy.. We performed an online database search using Pubmed, Embase, Cochrane Online Library, and Clinicaltrial.gov for all available randomized controlled trials (RCTs) that investigated the therapeutic effects over a range of AED doses versus placebo. We then compared clinical efficacy and tolerability between these newer AEDs using Indirect Treatment Comparison software.. Nineteen RCTs with a total of 7245 patients were included in our study. There were no significant differences in the risk difference of 50% responder rates and seizure free rates between third generation AEDs, regardless of dose. The risk of treatment emergent adverse events was significantly higher with ESL and PER treatment compared to BRV at all doses combined. Withdrawal rates due to adverse events were also significantly higher in patients treated with the highest doses of LAC and PER versus BRV, while treatment with ESL or LAC was related to higher withdrawal rates versus BRV when all doses were combined.. Our analysis suggested there were no significant differences in efficacy between third generation AEDs in uncontrolled focal epilepsy. BRV may have the best tolerability profile. The other AEDs were associated with a higher risk for intolerable adverse, especially when taken at a high doses. The results from these indirect comparisons warrant further examination and verification through future well-designed trials.

Topics: Anticonvulsants; Dibenzazepines; Epilepsies, Partial; Humans; Lacosamide; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic

Primary generalized tonic clonic seizures (pGTCS) are still linked to major concerns for the clinic and hazards for patients suffering from idiopathic generalized epilepsy (IGE), so a quick search of the most effective and appropriate therapy is needed to control them. The key criteria for proper treatment are syndromic diagnosis and distinction between newly diagnosed and refractory patients. Other criteria include age, gender and comorbidities. Areas covered: Treatment for pGTCS has expanded in the last two years, with new antiepileptic drugs like perampanel joining valproic acid, lamotrigine, levetiracetam, topiramate, while further evidence-based data are required for zonisamide and lacosamide. Expert opinion: Currently, valproic acid can be considered as a first choice in male or menopausal women, and in the absence of weight issue, both in adults and in children, and in the absence of side effects such as insomnia and headache. Today, valproic acid is not recommended in child-bearing age and in relation to possible cognitive problems, especially in children. Lamotrigine and levetiracetam can be a viable alternative as a first choice. Topiramate is also effective as a first choice, but concerns may arise from its potential cognitive and memory adverse side effects. Additionally, perampanel and lacosamide are promising treatments.

Topics: Acetamides; Anticonvulsants; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Isoxazoles; Lacosamide; Lamotrigine; Levetiracetam; Male; Nitriles; Piracetam; Pyridones; Randomized Controlled Trials as Topic; Topiramate; Treatment Outcome; Triazines; Valproic Acid; Zonisamide

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.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Double-Blind Method; Humans; Lacosamide; Nitriles; Prescription Drug Misuse; Pyridones; Pyrrolidinones

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Lacosamide; Longitudinal Studies; Medication Adherence; Nitriles; Product Surveillance, Postmarketing; Pyridones; Pyrrolidinones; Seizures

Brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) have been recently marketed as adjunctive treatments for focal onset seizures. To date, no randomized controlled trial (RCT) has directly compared BRV with ESL, LCM, or PER.. To compare BRV with the other add-on AEDs in patients with uncontrolled focal epilepsy, estimating their efficacy and tolerability through an adjusted, common-reference based indirect comparison meta-analysis.. We systematically searched RCTs in which add-on treatment with ESL or LCM in patients with focal onset seizures have been compared with placebo. Efficacy and tolerability outcomes were considered. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy of BRV, LCM, ESL, or PER versus placebo. Adjusted indirect comparisons were then made between BRV and the other three AEDs using the obtained results, comparing the minimum and the highest effective recommended daily dose of each drug.. Seventeen RCTs, with a total of 4971 patients were included. After adjusting for dose-effects, indirect comparisons showed no difference between BRV and LCM, ESL, or PER for responder rate and seizure freedom. Lower adverse events were observed with high dose BRV compared to high dose ESL or PER, but no difference was found in withdrawing because of adverse events.. Indirect comparisons do not demonstrate a significant difference in efficacy between add-on BRV and LCM, ESL, or PER in focal epilepsy, and might suggest a better tolerability of BRV than ESL, and possibly also PER, at the highest effective recommended dose.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lacosamide; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic

Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is a syndrome that is often refractory to drug treatment. The effects on specific syndromes are not currently available from the pre-marketing clinical development of new AEDs; this does not allow the prediction of whether new drugs will be more effective in the treatment of some patients.. We have reviewed all the existing literature relevant to the understanding of a potential effectiveness in MTLE-HS patients for the latest AEDs, namely brivaracetam, eslicarbazepine, lacosamide, perampanel and retigabine also including the most relevant clinical data and a brief description of their pharmacological profile. Records were identified using predefined search criteria using electronic databases (e.g., PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published up to the 15 June 2015 were included.. All the drugs considered have the potential to be effective in the treatment of MTLE-HS; in fact, they possess proven efficacy in animal models; currently considered valuable tools for predicting drug efficacy in TLE. Furthermore, for some of these (e.g., lacosamide and eslicarbazepine) data are already available from post-marketing studies while brivaracetam acting on SV2A like levetiracetam might have the same potential effectiveness with the possibility to be more efficacious considering its ability to inhibit voltage gated sodium channels; finally, perampanel and retigabine are very effective drugs in animal models of TLE.

Topics: Acetamides; Anticonvulsants; Carbamates; Clinical Trials as Topic; Dibenzazepines; Epilepsy, Temporal Lobe; Hippocampus; Humans; Lacosamide; Levetiracetam; Nitriles; Phenylenediamines; Piracetam; Pyridones; Sclerosis; Syndrome

This article lays the background for, and discusses the practical issues surrounding, the adjunctive use of the last four antiepileptic drugs (AEDs) to be licensed for the treatment of pharmacoresistant focal seizures in the UK and elsewhere. More than 30% of adolescent and adult patients will not be fully controlled on the currently available therapeutic armamentarium. After not responding to their first three AED schedules, only a handful of patients attained seizure freedom on subsequent regimens. To optimise the response to any new AED in this setting, it is often necessary to reduce the existing drug burden. The pharmacology, tolerability and safety, and everyday use of lacosamide, eslicarbazepine acetate, retigabine (ezogabine) and perampanel will be reviewed and discussed. This will be accompanied by data from prospective audits with each drug undertaken at the Western Infirmary in Glasgow, Scotland, and a report of their successful introduction in an illustrative case. Overall, there is a large variation in the course of refractory epilepsy and the effect of AED therapy on this process seems minimal. Nevertheless, a number of patients will benefit from the introduction of each new AED, with some becoming seizure-free.

Topics: Acetamides; Adult; Aged; Animals; Anticonvulsants; Carbamates; Dibenzazepines; Drug Resistant Epilepsy; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Nitriles; Phenylenediamines; Pyridones

Secondary generalized tonic-clonic seizures (SGTCS) are among the most severe forms of seizures, and the main risk factor for sudden unexpected death in epilepsy (SUDEP). Whether some antiepileptic drugs (AEDs) might be more efficacious than others on SGTCS in patients with drug-resistant focal epilepsy thus represents an important clinical issue for which no data are currently available.. We performed a meta-analysis of randomized controlled trials of adjunctive AED in which information on efficacy outcomes (i.e., responder rate and/or frequency per 28 days relative to baseline) were available both for all seizure types and for SGTCS. The primary analysis evaluated the efficacy of AEDs on all types of seizure and on SGTCS by comparing the responder rates for AED and for placebo.. Responder rate was available both for all seizure types and for SGTCS in 13 of the 72 eligible trials, evaluating 7 AEDs. Only three AEDs--lacosamide, perampanel and topiramate--showed greater efficacy than placebo. However, confidence intervals of relative risks overlapped for all AEDs but pregabalin, which demonstrated significantly lower efficacy than lacosamide, perampanel, and topiramate. Moreover, there was a nonsignificant trend toward a lower relative risk of responder rate for SGTCS than for all seizure types, which appeared related to a greater response to placebo for this outcome.. Indirect comparison of AEDs using randomized placebo-controlled add-on trials does not support robust differences between AEDs to prevent SGTCS. Alternative designs for evaluation of therapeutic interventions in patients at risk for SGTCS-related complications are required.

Topics: Acetamides; Anticonvulsants; Chronic Disease; Death, Sudden; Early Medical Intervention; Epilepsies, Partial; Fructose; Humans; Lacosamide; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Seizures; Topiramate; Treatment Outcome

Assess cognitive effects of adjunctive perampanel in adolescents.. In this double-blind study (ClinicalTrials.gov identifier: NCT01161524), patients aged 12 to <18 years with partial-onset seizures despite receiving 1-3 antiepileptic drugs were randomized (2:1) to perampanel or placebo. Perampanel was increased weekly in 2-mg increments to 8-12 mg/day (6-week titration; 13-week maintenance). Changes in neuropsychological outcomes were assessed at end of maintenance: Cognitive Drug Research (CDR) System Global Cognition Score (primary end point), five CDR System domain T-scores (secondary end points), letter fluency, category fluency, and Lafayette Grooved Pegboard Test (LGPT).. One hundred thirty-three patients were randomized. In the full analysis set, there were no differences of perampanel (n = 79) vs. placebo (n = 44) in CDR System Global Cognition Score (least squares mean change, -0.6 vs. 1.6; p = 0.145), Quality of Working Memory (1.1 vs. 2.0; p = 0.579), or Power of Attention (-6.9 vs. -2.7; p = 0.219). There were small differences with perampanel vs. placebo in other CDR System domains: improvements in Quality of Episodic Memory (3.0 vs. -1.2; p = 0.012), and worsening in Continuity of Attention (-3.3 vs. 1.6; p = 0.013) and Speed of Memory (0.3 vs. 7.0; p = 0.032). Letter fluency, category fluency, and LGPT were not significantly different between groups. The most frequent adverse events with perampanel were dizziness (30.6%) and somnolence (15.3%).. Perampanel did not differ from placebo in the global cognitive score, two of five subdomains, and four other cognitive measures. Perampanel was worse on two and better on one subdomain.

Topics: Acetamides; Adolescent; Anticonvulsants; Attention; Carbamazepine; Child; Cognition; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Fructose; Humans; Lacosamide; Lamotrigine; Levetiracetam; Male; Memory, Short-Term; Neuropsychological Tests; Nitriles; Oxcarbazepine; Piracetam; Pyridones; Topiramate; Treatment Outcome; Triazines; Valproic Acid

Antiepileptic drugs (AEDs) have been used to control epilepsy. More than 17 new AEDs, including gabapentin (GPN), lacosamide (LCM), perampanel (PER), pregabalin (PRG), rufinamide (RFM), and vigabatrin (VGB) have been approved and marketed since 1989. Accurate measurement of serum concentration of the antiepileptic drugs is crucial to achieve optimal efficacy and avoid adverse events. We describe an accurate and precise liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of GPN, LCM, PER, PRG, RFM, and VGB in serum. The method requires a small volume of sample (10 μL) and has a total chromatographic run time of 4 min for simultaneous measurement of these drugs. The method showed good accuracy with a bias of -0.2-5%. The intra- and inter-day imprecision were less than 5.0% for all the analytes. The linear assay ranges were 0.3-26 μg/mL for GPN, 0.15-24 μg/mL for LCM, 7.4-1881 ng/mL for PER, 0.03-13 μg/mL for PRG, 0.78-90 μg/mL for RFM, and 0.3-43 μg/mL for VGB.

Topics: Anticonvulsants; Chromatography, Liquid; Gabapentin; Lacosamide; Pregabalin; Tandem Mass Spectrometry; Vigabatrin

Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients' hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital. The main outcome measures were the length of hospital stay and days from the last seizure to hospital transfer.Ninety-four eligible patients were divided into those treated with perampanel or lacosamide (n = 18) and those treated with other agents (n = 76). The mean length of hospital stay and days from the last seizure to hospital transfer were 52.9 and 45.4 d in the perampanel and lacosamide group, and 32.7 and 28.6 d in the other medication group (p < 0.001). The mean antiseizure medication costs and total drug costs were U.S. $4.88 and $6.85 in the perampanel/lacosamide group and U.S. $1.94 and $4.41 in the other medication group (p < 0.001, p = 0.007), respectively. Considering antiseizure medication availability and cost in the transfer destination hospital is important when choosing medications for patients requiring hospital transfer from an acute-care hospital.

Topics: Hospitals; Humans; Japan; Lacosamide; Retrospective Studies; Seizures; Stroke

The association between antiseizure medications (ASMs) and suicidality remains controversial. Analyses of additional datasets are needed to further elucidate the complex relationship between antiseizure medications and suicidality.. The aim of this study was to compare the safety profile of newer ASMs with older ASMs through an analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, with a focus on suicidality.. We queried over 17 million reports in the FAERS database from 2012 to 2021 and identified cases involving ASMs. After removing incomplete and duplicate reports, the study cohort consisted of lacosamide (n = 7593), perampanel (n = 1813), clobazam (n = 3827), brivaracetam (n = 1166), and vigabatrin (n = 5293) compared with a control group of older ASMs (topiramate, lamotrigine, valproic acid, carbamazepine, levetiracetam; n = 71,535). Cases of suicidality (completed suicide, suicidal ideation, attempted suicide, suicidal behavior, suicidal depression) were identified in each group. Adjusted (age and sex) odds ratios (aOR) and associated 95% confidence intervals (CI) were calculated using logistic regression analysis for each new drug when compared with the control group of older ASM drugs.. A total of 6309 cases of suicidality were identified among reports with ASMs. Most reports were sourced from healthcare professionals (5516, 87.4%). The proportion of reports involving suicidality were 210/7593 (2.8%) for lacosamide, 185/1813 (10.2%) for perampanel, 108/3827 (2.8%) for clobazam, 57/1166 (4.9%) for brivaracetam, 14/5293 (0.3%) for vigabatrin, and 5735/71,535 (8.0%) for older ASMs. Compared with older ASMs, the aOR for suicidality was 0.33 (95% CI 0.28-0.38) for lacosamide, 1.34 (95% CI 1.15-1.56) for perampanel, 0.35 (95% CI 0.29-0.43) for clobazam, 0.60 (95% CI 0.45-0.77) for brivaracetam, and 0.03 (95% CI 0.02-0.05) for vigabatrin.. When compared with older ASMs, four newer ASMs (lacosamide, clobazam, brivaracetam, and vigabatrin) were found to have significantly lower odds of suicidality, while perampanel was found to significantly increase the odds of suicidality. Pronounced variability (greater than 30 fold) in the proportion of FAERS reports associated with suicidality among the drugs studied was identified. The results of this case control study of FDA adverse event reports spanning 10 years and 6309 cases of suicidality expand our understanding of the safety profile of newer ASMs.

Topics: Anticonvulsants; Case-Control Studies; Clobazam; Humans; Lacosamide; Suicidal Ideation; Suicide; United States; United States Food and Drug Administration; Vigabatrin

Perampanel (PER) and lacosamide (LCM) are the new third-generation anti-seizure medications (ASMs) that were approved for the monotherapy of focal epilepsy in children over four years of age in China, in 2021. Very few studies have analyzed the application of PER monotherapy among pediatric patients aged ≥four years, and no study compared the efficacy and tolerability of PER monotherapy with LCM monotherapy in pediatric patients with focal epilepsy. The present study aimed to investigate the efficacy, tolerability, and effect on behavior and emotion of PER and LCM as monotherapy in pediatric patients with newly diagnosed focal epilepsy, which is beneficial for clinicians to have more choices to treat pediatric patients with focal epilepsy.. This was a prospective, single-center, observational study that involved pediatric patients (disease onset age ≥four years) with newly diagnosed focal epilepsy treated with PER or LCM as primary monotherapy. Outcomes included retention, being responders, and seizure-free rates after 3, 6, and 12 months. Adverse events (AEs) were noticed throughout the follow-up period. Behavioral outcomes were evaluated with Achenbach Child Behavior Checklist (CBCL/4-16) at baseline and after three and six months.. Using randomization, 60 patients receiving PER (31 females, 29 males, median age: 7.79 [5.34, 10.16] years, median dose: 3.0 [2.0, 4.0] mg/day) and 60 patients receiving LCM (25 females, 35 males, median age: 7.72 [5.91, 10.72] years, median dose: 150.0 [100.0, 200.0] mg/day) were enrolled in the study. At the 12-month follow-up, the retention rates in the PER and LCM groups, both were 90.4%, and the responder rates were 65.4% and 71.2%, while seizure-free rates were 57.7% and 67.3%, respectively. There were no significant differences in the retention, responder and seizure-free rates between the two groups (P > 0.05). There were no significant differences in the responder rates between patients with BECTS, abnormal brain magnetic resonance imaging (MRI), or types of seizure in the two groups (P > 0.05). In the PER group, 28.8% (15/52) of patients experienced AEs, of which the most frequently reported were irritability (n = 7; 13.5%), dizziness (n = 5; 9.6%), somnolence (n = 3; 5.8%), ataxia (n = 1; 1.9%), headache (n = 1; 1.9%), and rash (n = 1; 1.9%). In the LCM group, 15.4% (8/52) of the patients had AEs, including headache (n = 4; 7.5%), dizziness (n = 4; 7.5%), nausea (n = 2; 3.8%), somnolence (n = 2; 3.8%), irritability (n = 1; 1.9%), stomach ache (n = 1; 1.9%), and vomiting (n = 1; 1.9%). The incidence of irritability was significantly higher in the PER group than in the LCM group (13.5% vs. 1.9%, P = 0.031), which occurred mainly within eight weeks after drug administration. Patients with irritability were not dangerous to surrounding people by the assessment of parental observation in the life. And the symptoms were relieved spontaneously within a few months. The outcomes of total scores, internalizing scores, and externalizing scores of the CBCL did not show statistically significant differences in the PER and LCM groups between baseline and three and six months. Characteristics of behavior and emotion did not have substantial changes in patients treated with PER and LCM monotherapy.. The present study documented similar good effectiveness and good tolerance of PER and LCM as monotherapy in pediatric patients with newly diagnosed focal epilepsy and showed no behavioral or emotional impact, as assessed by the CBCL. Though the incidence of irritability with PER monotherapy may be higher than that with LCM monotherapy soon after medication initiation, this side effect appears to resolve spontaneously within a few months. At present, this study was the first research about PER and LCM monotherapy in pediatric patients with newly diagnosed focal epilepsy evaluating efficacy, tolerability, and behavior in China.

Topics: Anticonvulsants; Child; Child, Preschool; Dizziness; Epilepsy, Rolandic; Female; Headache; Humans; Irritable Mood; Lacosamide; Male; Prospective Studies; Retrospective Studies; Sleepiness; Treatment Outcome

This retrospective, observational study used US claims data to assess retention rates on cenobamate compared with four branded antiseizure medications (ASMs) in patients with epilepsy.. Adults (≥18 years) with prevalent epilepsy (ICD-10 code G40.xx) and ≥ 1 prescription for cenobamate or any of the newer branded ASMs (brivaracetam, eslicarbazepine, lacosamide, or perampanel) between May 1, 2020 and December 31, 2021 were identified from the HealthVerity Marketplace database. At least 360 days of continuous enrollment was required before and after the index date (Day 1 of initiating cenobamate or branded ASM). Patients were followed until cessation of cenobamate or branded ASM or the end of data collection using Kaplan-Meier methods. Retention was compared between cenobamate and the branded ASMs (both as a group and individually) using Chi-square tests.. In total, 4109 patients were included (195 cenobamate; 3914 branded ASMs). A higher proportion of patients in the cenobamate group compared with the branded ASMs group had concurrent focal and generalized epilepsy (65.6% vs 40.0%) and were on ≥ 3 concomitant ASMs (48.2% vs 12.8%) at the index date. Median time to discontinuation (i.e., the time that half the patients discontinued) was not quite reached after 12 months in the cenobamate group (50.3% of patients remained on cenobamate) and was 7.7 months in the branded ASMs group. Retention was significantly higher with cenobamate vs the branded ASMs group (p = 0.04545) and vs the individual ASMs lacosamide (p = 0.03044) and perampanel (p = 0.01558). Twelve-month retention rates (95% confidence intervals) were 50.3% (43.1%-57.0%) for cenobamate, 40.5% (38.9%-42.0%) for branded ASMs overall, 42.3% (38.6%-46.0%) for brivaracetam, 44.1% (39.2%-49.0%) for eslicarbazepine, 39.9% (38.0%-41.8%) for lacosamide, and 36.8% (31.9%-41.8%) for perampanel.. In this real-world analysis, retention was significantly higher with cenobamate vs a pooled group of four branded ASMs despite a greater frequency of patients in the cenobamate group having characteristics of more difficult-to-treat epilepsy.

Topics: Adult; Anticonvulsants; Epilepsy; Humans; Lacosamide; Retrospective Studies; Treatment Outcome; United States

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).. Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.. This study was registered at ClinicalTrials.gov (NCT05267405).

Topics: Aged; Anticonvulsants; Benzodiazepines; Epilepsy; Humans; Ischemic Stroke; Lacosamide; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Topiramate; Zonisamide

We present pharmacokinetic data during pregnancy and lactation for brivaracetam, lacosamide and perampanel based on two case studies. Patient 1 used brivaracetam as monotherapy and gave birth to twins. Patient 2 used a combination of brivaracetam, lacosamide and perampanel. In both patients, serum drug concentrations were monitored throughout the pregnancies. Drug concentrations were also analysed in umbilical cord blood at birth, in serum from the offspring and in breastmilk after five days and 3-11 weeks. There were minor changes in concentration/dose-ratios for brivaracetam and lacosamide. The mean milk/serum ratios for brivaracetam and lacosamide were 0.71 and 0.83, respectively, five days and 3-5 weeks after delivery. The perampanel serum concentration increased by up to 80% in Patient 2 during the last part of gestation. The mean milk/serum-ratio for perampanel was 0.13, unchanged from five days to five weeks after delivery. Whereas serum concentrations of brivaracetam and lacosamide remained fairly stable throughout pregnancy, perampanel concentrations seemed to steadily increase towards the end. The distribution to milk was considerable for brivaracetam and lacosamide and low for perampanel. More studies on mother-infant pairs are warranted to confirm these results in larger groups.

Topics: Anticonvulsants; Female; Humans; Lacosamide; Lactation; Nitriles; Pharmaceutical Preparations; Pregnancy; Pyridones; Pyrrolidinones

Background The number of patients with epilepsy receiving perampanel or lacosamide as an add-on treatment following levetiracetam treatment has increased. Although levetiracetam causes psychiatric disorders, it is unclear whether they occur with the combined use of these antiepileptic drugs. Objective To determine the frequency of psychiatric disorders in patients received lacosamide or perampanel in combination with levetiracetam. Setting A single-center retrospective cohort study. Method Patients who received levetiracetam + lacosamide or levetiracetam + perampanel were selected. Medical records from the start of combination therapy contained characteristics of patients and the incidence of psychiatric disorders. Main outcome measure The frequency of psychiatric disorders, the time to onset, dose reduction or discontinuation following psychiatric disorders, and the clinical course following disorder onset. Results Forty-four patients used levetiracetam + lacosamide and 50 used levetiracetam + perampanel. The incidence of psychiatric disorders was significantly lower (p < 0.001) with levetiracetam + lacosamide (6.8%) than with levetiracetam + perampanel (44%). The incidence of affect lability was significantly higher with levetiracetam + perampanel than with levetiracetam + lacosamide (p = 0.018). The time to the onset of psychiatric disorders was within 1 month of dose initiation or increase in one case (33.3%) with levetiracetam + lacosamide and 16 cases (72.7%) with levetiracetam + perampanel. There was no significant difference in clinical characteristics and antiepileptic drug dosages owing to the presence or absence of psychiatric disorders. Conclusion As the frequency of psychiatric disorders was higher with levetiracetam + perampanel therapy, levetiracetam + lacosamide may be preferable. These disorders tended to develop within 1 month of therapy and were not dose-dependent. Antiepileptic drugs should be cautiously prescribed to avoid psychiatric disorders.

Topics: Anticonvulsants; Drug Therapy, Combination; Humans; Lacosamide; Levetiracetam; Mental Disorders; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

This retrospective longitudinal study aims to compare the longer-term cognitive and behavioral side effects of adjunctive antiepileptic treatment with perampanel (PER) and lacosamide (LCM), two third generation antiepileptic drugs with suggested favorable cognitive profiles. The two drugs were monitored according to a previously established routine diagnostic protocol (Helmstaedter et al. E&B 2013;26:182-7) which facilitates the retrospective comparison of antiepileptic drug tolerability in a naturalistic outpatient setting.. Records from 94 patients were evaluated who underwent neuropsychological assessment before and under adjunctive treatment with either PER (n = 57) or LCM (n = 37). Cognition was assessed using the EpiTrack screening for executive functions and a VLMT short form for verbal memory. Subjective assessments included a German QOLIE-10 adaptation (quality of life) and an extended Adverse Events Profile (AEP). The median follow-up interval was 36 weeks.. Multivariate repeated measures statistics revealed a non-significant trend towards an interaction effect "time - treatment arm" on both executive function and memory. When analyzed separately executive functions and memory scores significantly improved under LCM (t = -2.76 p < 0.01 and t = -2.44 p < 0.05 respectively). Subjectively, PER was associated with improvements in 2/18 physiological domains and in the LCM group 1/9 cognitive domains deteriorated. Seizure freedom was achieved for five patients treated with LCM (14%) and 15 treated with PER (26%, χ. In a naturalistic outpatient setting, chronic adjunctive treatment with PER and LCM did not negatively affect cognition and LCM may even improve cognition. Neither drug increased self-reported irritability or aggression. This suggests favorable longer-term tolerability.

Topics: Acetamides; Adult; Anticonvulsants; Cognition; Drug Therapy, Combination; Epilepsy; Executive Function; Female; Follow-Up Studies; Humans; Lacosamide; Longitudinal Studies; Male; Memory; Multivariate Analysis; Neuropsychological Tests; Nitriles; Outpatients; Pyridones; Quality of Life; Retrospective Studies; Treatment Outcome

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

Perampanel (PER) and lacosamide (LCM) are antiepileptic drugs (AEDs) approved for the adjunctive treatment of partial-onset seizures. At the time of market entry, information on clinical effectiveness of new AEDs is limited to results from pivotal trials, real-life or comparative data are missing. This analysis of data collected retrospectively in a German epilepsy center used unified evaluation criteria, and describes treatment outcomes with LCM and PER at 6 months.. Results of the first 70 consecutive patients who had received LCM or PER after their market entries in Germany were compared. Outcome measures comprised 50% responder rates, seizure freedom, retention, and incidence of adverse events (AEs).. The mean number of previous AEDs was 8.7 in the PER group, and 7.3 in the LCM group. At 6 months, the 50% responder rate for all seizures was 48.6% for PER, and 28.6% for LCM, with seizure freedom in 14.3% of patients with PER, and 4.3% with LCM. Thirty-two AEs were reported for LCM, and 51 for PER, most commonly dizziness (22.9% of patients) for LCM, and somnolence/tiredness for PER (41.4%). AEs were reported as primary reason for discontinuation in 3 patients of the PER group. Retention rates were similar.. This analysis describes initial comparative benefits of two newly available AEDs in two cohorts of patients with highly refractory epilepsies. Responder and seizure freedom rates were numerically higher for PER. The analysis suggests that new AEDs can provide a chance for seizure freedom in relevant subgroups of patients, despite previous failure of multiple AEDs.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Cohort Studies; Drug Resistant Epilepsy; Female; Germany; Humans; Lacosamide; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

To document reversible cognitive deterioration associated to high doses of zonisamide, using the Reliable Change Index to control practice effects derived from repetitive neuropsychological assessments.. A 11 year-old boy with tuberous sclerosis complex and left frontal refractory epilepsy, evaluated within a paediatric epilepsy surgery program. The epileptogenic zone was found to be related with a tuber situated on the left inferior frontal gyrus. The effects of high doses of zonisamide simulate a disturbance of eloquent cortex within the epileptogenic zone and the impact of uncontrolled seizures on cognitive functioning over the language-dominant hemisphere. Drug withdrawal significantly improved total intelligence index, verbal comprehension intellectual index and specific language-sustained cognitive abilities, beyond practice effects.. The differentiation between cognitive effects of drugs and functional deficits resulting from eloquent cortex involvement within the epileptogenic zone can be of crucial importance in the decision-making process for epilepsy surgery.. Deterioro neuropsicologico reversible asociado a zonisamida en un paciente pediatrico con esclerosis tuberosa.. Objetivo. Documentar el deterioro cognitivo reversible asociado a altas dosis de zonisamida, utilizando indices de cambio fiable para controlar los efectos de practica derivados de evaluaciones neuropsicologicas repetidas. Caso clinico. Niño de 11 años con complejo esclerosis tuberosa y epilepsia refractaria del lobulo frontal izquierdo, evaluado en el contexto de un programa de cirugia de la epilepsia pediatrica. La zona epileptogena se relaciono con un tuber epileptogeno localizado en el giro frontal inferior del hemisferio izquierdo. Los efectos de altas dosis de zonisamida mimetizaron una afectacion de la corteza elocuente en la zona epileptogena y un impacto de las crisis no controladas en el funcionamiento cognitivo asociado al hemisferio dominante para el lenguaje. La retirada del farmaco mejoro significativamente, mas alla de los efectos de practica, el cociente intelectual total, el indice intelectual de comprension verbal y habilidades cognitivas especificas sustentadas en el lenguaje. Conclusiones. La diferenciacion entre los efectos cognitivos de los farmacos y la existencia de un deficit funcional por afectacion de la corteza elocuente en el area epileptogena puede ser crucial para la toma de decisiones en cirugia de la epilepsia.

Topics: Acetamides; Anticonvulsants; Benzodiazepines; Child; Clobazam; Cognition Disorders; Dibenzazepines; Drug Substitution; Drug Therapy, Combination; Epilepsies, Partial; Frontal Lobe; Humans; Isoxazoles; Lacosamide; Language Disorders; Learning Disabilities; Male; Memory Disorders; Neuroimaging; Nitriles; Pyridones; Tuberous Sclerosis; Zonisamide

The ultimate treatment goal in epilepsy therapy is always freedom from seizures with as few treatment adverse effects as possible. If seizures persist with the first monotherapy, alternative monotherapy with another antiepileptic drug (AED) should be considered. Continuing seizures should lead to a reevaluation of differential diagnosis and adherence. Epilepsy surgery as an alternative therapy may be suitable in selected cases. If the diagnosis of epilepsy is established and epilepsy surgery is not appropriate, AED treatment should be optimized. Evidence for how to proceed is lacking. Concepts such as rational polytherapy have been advocated but remain speculative concerning better efficacy based on the use of AEDs with differing modes of action. A variety of new AEDs including rufinamide, lacosamide, vigabatrin, perampanel, and retigabine have been recently introduced in the United States. They are briefly characterized in this update review.

Topics: Acetamides; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Lacosamide; Nitriles; Pyridones; Receptors, AMPA; Vigabatrin