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Objective: This study aimed to compare and characterize the safety profiles of new antiseizure medications (ASMs) using a nationwide pharmacovigilance database from a long-term perspective in Korea., Methods: We reviewed adverse event reports from the Korea Adverse Event Reporting System database between January 2013 and December 2022 for descriptive analysis of six new ASMs (lacosamide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide). We investigated the frequency and characteristics of adverse drug reactions (ADRs) based on the MedDRA terminology, system organ classes, and modified WHO classification., Results: We identified 5,733 reported cases of ADRs. The commonly reported ADRs associated with total ASMs were rash/urticaria (1,822, 31.8 %), dizziness (409, 7.1 %), somnolence/drowsiness (311, 5.4 %), and hepatotoxic effects (273, 4.8 %). Type B (idiosyncratic) effects (2,932; 51.1 %) were more commonly reported than Type A (related to known drug mechanisms) effects (2,613; 45.6 %). Skin and subcutaneous tissue disorders and type B effects were most commonly reported for lamotrigine and oxcarbazepine, whereas nervous system disorders and type A effects were most commonly reported for lacosamide, topiramate, and zonisamide. The pediatric group (<18 years) exhibited skin and subcutaneous tissue disorders and type B effects relatively more frequently than the adult and older adult groups., Conclusion: Hypersensitivity skin reactions and type B effects remained significant ADRs in the new ASMs; however, type A effects were more commonly reported in some ASMs. The pediatric group showed a higher rate of type B effects. Overall, new ASMs should also be used with caution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: Recent studies suggest rapid administration of high-dose, undiluted levetiracetam is safe in adults; however, no information exists in pediatric patients. The purpose of this study was to evaluate the safety and tolerability of undiluted levetiracetam at a pediatric institution., Design: Retrospective, single-center, cohort study., Setting: Pediatric Academic Medical Center., Patients: All patients who received high-dose >60 mg/kg (-10%) up to 4500 mg undiluted or diluted intravenous levetiracetam were included., Intervention: Rapid intravenous administration of undiluted versus diluted levetiracetam., Measurements and Main Results: A total of 776 levetiracetam doses were included, 358 doses administered and 418 doses wasted. The doses administered (61 undiluted and 297 diluted) accounted for a total of 252 patients (39 received undiluted, and 213 received diluted levetiracetam) (median [minimum-maximum range] age, 2 years [1 day to 32.7 years]; mean (standard deviation [SD]) weight, 20.1 kg [22.1 kg]). The incidence of hemodynamic disturbances and infusion-related reactions was not statistically significant between undiluted (24.6%) and diluted (26.3%) groups (p = 0.87). The median (interquartile range [IQR]) time difference between first-line antiseizure medication and levetiracetam administration in patients with status epilepticus was 18 min (10.5-30.5) in the undiluted group versus 36.5 min (21.8-67.3) in the diluted group (p < 0.01). Additionally, there was a significant amount of drug waste from dispensed but not administered doses of the diluted bag compared to undiluted vials (57.6% diluted vs. 18.7% undiluted, p < 0.001)., Conclusion: Undiluted levetiracetam was not associated with an increased incidence of adverse effects compared to diluted levetiracetam in high-doses, up to 4500 mg given over 5 min in pediatric patients., (© 2023 Pharmacotherapy Publications, Inc.)

Purpose: Levetiracetam is an antiepileptic drug known for its high tolerability, and severe adverse drug reactions are rare. We report the case of a severe cutaneous adverse drug reaction in a patient who was switched from brand-name to generic levetiracetam., Summary: A 29-year-old woman undergoing contrast-enhanced computed tomography developed lesions over her trunk starting 6 hours after imaging. Although initially diagnosed as an allergy to the radiocontrast agent, the condition progressively worsened into toxic epidermal necrolysis-drug reaction with eosinophilia and systemic symptoms overlap syndrome, despite adequate hydration and treatment. Investigation of the patient's medications revealed that she had been switched from brand-name to generic levetiracetam a week before the onset of symptoms. Levetiracetam was immediately discontinued, with the patient recovering after 2 weeks of intensive care. Adverse drug reaction analysis identified excipients in generic levetiracetam as the likely cause of the severe reaction., Conclusion: This is the first reported case of severe cutaneous drug allergy after a brand-to-generic switch for levetiracetam. Brand-to-generic switches of medications can potentially cause severe allergic reactions due to differences in excipients., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Levetiracetam (LVT), while an effective treatment for multiple seizure types, is associated with a high incidence of neuropsychiatric adverse events (NPAEs). In predominantly retrospective studies, supplementation with pyridoxine/vitamin B 6 (PN) was associated with improvement in NPAEs in some people. A previous review highlighted a lack of double-blind, controlled trials of PN for the treatment of NPAEs in individuals treated with LVT. The current paper updates the findings from the previous review to include evidence from studies published since June 2019., Methods: An updated systematic review of the published literature was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies published between June 2019 and 2nd November 2022 in which supplementary PN was initiated for the treatment of LVT-associated NPAEs. All study types were eligible. The risk of bias in randomized trials was assessed using the Cochrane risk-of-bias tool., Results: Seven additional studies were identified: two double-blind, randomized controlled trials (RCTs), four retrospective studies, and one retrospective case series. One RCT reported significant improvements from baseline in behavioral adverse events (BAEs) in both the intervention (PN) group and the low-dose control group (both p < 0.05), with a significantly greater improvement in the intervention group (p < 0.001). In the second RCT, differences in BAE severity between PN and placebo groups at the endpoint were not statistically significant. In one retrospective study, subjective irritability was reported to have improved from baseline in 9/20 individuals (45%) treated with supplementary PN. Data for systematic assessments (PHQ-9 and GAD-7) were available for 10 individuals. Assessment by PHQ-9 showed that six individuals improved, two worsened and two had no change. Based on the GAD-7, three people improved, two worsened and five had no change. In the second retrospective study, 18/41 individuals (44%) who commenced PN following the emergence of BAEs showed "significant" improvement. In a separate group of individuals with pre-existing behavioral problems in whom PN treatment was initiated at the same time as commencing LVT, 3/18 (16.7%) developed BAEs. This compared with 79/458 people (17.2%) who were initially treated only with LVT. The third retrospective study compared treatment-related irritability in individuals who had been treated with both LVT and perampanel, either sequentially or concomitantly. Two people who developed irritability while receiving LVT monotherapy were able to continue treatment with the addition of PN. The fourth study reported a significantly lower LVT discontinuation rate in individuals taking PN and a higher rate of improved behavior in those who were able to continue LVT. The case series reported improvements in behavioral symptoms in six people within two to three weeks of commencing supplementary PN., Conclusion: Data published within the last three years add to earlier evidence suggesting that PN might be effective in the treatment of NPAEs associated with LVT. However, the quality of evidence remains poor and only a few prospective trials have been published. Data from placebo-controlled trials are still largely lacking. Currently, there is insufficient evidence to justify any firm recommendation for PN supplementation to treat NPAEs associated with LVT. Further well-designed, prospective trials are warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: This study was undertaken to compare the efficacy of modified Atkins diet (MAD) among children with non-surgical drug-resistant epilepsy (DRE) to levetiracetam, when added to on-going anti-seizure medications., Methods: An open-label, randomized controlled trial among children aged 2-12 years with non-surgical DRE was conducted. Eligible children were randomized in a 1:1 ratio to receive add-on MAD or levetiracetam. Baseline and post-intervention seizure frequency at 12 weeks was determined from seizure logs maintained by parents. The primary outcome was the proportion of responders, i.e., patients who achieved > 50% seizure reduction from baseline. Adverse events were compared. Analysis was intention-to-treat. (NCT04172311) RESULTS: One hundred and one children were enrolled (MAD-51, levetiracetam-50). The majority of the enrolled children had generalized seizures of mixed types secondary to structural brain lesions and Lennox-Gastaut syndrome was the most common electroclinical syndrome (46%). The proportion of children with >50% seizure reduction at 12 weeks was significantly higher in the MAD arm compared to the levetiracetam arm (27/51(52.9%) vs 11/50(22%); p < 0.001). At 12-weeks post-intervention, the change in mean seizure frequency compared to baseline was -47.33 ± 39.57% in the MAD arm and -31.15 ± 32.18% in the levetiracetam arm (p = 0.03). Constipation (41.1%) was the most frequent adverse effect with MAD. Sedation/lethargy (18%) and anxiety and irritability (14%) were the most frequent adverse effects in the levetiracetam group., Conclusion: Addition of MAD was found to be superior to levetiracetam among children with non-surgical DRE with predominant generalized seizures in achieving seizure reduction at 12 weeks. Both treatments were well tolerated. Adverse effects, although higher with MAD, were expected side effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors have no conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV., Methods: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122)., Results: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls., Significance: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: The ability to administer medications via rapid intravenous bolus has the potential to allow for the rapid attainment of therapeutic drug levels and to limit the amount of unnecessary fluid volumes infused. The purpose of this review was to evaluate the efficacy and safety of undiluted or minimally diluted levetiracetam bolus doses., Areas Covered: A total of six pieces of the literature were evaluated in this review. Doses of up to 4,500 mg of intravenous levetiracetam were found to be both efficacious and safe when administered undiluted or minimally diluted in either a peripheral or central line. Product concentrations of levetiracetam ranged from 50 mg/mL to 100 mg/mL, with volumes ranging from 10 to 30 mL. Maintenance doses of up to 1,500 mg twice daily were demonstrated to be both efficacious and safe when administered undiluted or minimally diluted. Injection site pain and agitation were the most commonly reported adverse drug effects., Expert Opinion: Although hospitals and clinicians must be judicious with regard to training and the safety concerns of bolus intravenous push doses, and will need to address numerous logistical concerns, this practice is supported by practice guidelines and should be readily employed.

Aggression is the most common adverse effect of antiepileptic drugs (AEDs). This study aimed to investigate the association of aggression with AED use. The reporting odds ratio (ROR) from adverse event reports, submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, was used to calculate and investigate the association between AEDs and aggression. We also analyzed the association of aggression with the combined use of AEDs and the relationship between AED-associated aggression and patient characteristics. A total of 433 patients developed aggression. Significant aggression signals were detected for perampanel (crude ROR: 325.04, 95% confidence interval (CI): 118.48-752.58, p < 0.01), levetiracetam (crude ROR: 17.14, 95% CI: 10.33-26.90, p < 0.01), lacosamide (crude ROR: 16.90, 95% CI: 2.02-62.51, p < 0.01), lamotrigine (crude ROR: 15.98, 95% CI: 9.99-24.39, p < 0.01), valproate (crude ROR: 6.68, 95% CI: 4.27-10.02, p < 0.01), and carbamazepine (crude ROR: 2.47, 95% CI: 1.17-4.59, p < 0.01). The combined therapy with perampanel and levetiracetam had a significant aggression signal (adjusted ROR: 25.90, 95% CI: 1.14-59.10, p < 0.01). In addition, we found that aggression frequently occurred in patients <60 year (adjusted ROR: 2.88, 95% CI: 1.49-5.56, p < 0.01) treated with levetiracetam. These results may be useful for minimizing the risk of aggression during the treatment of AEDs.

Introduction: Newer antiepileptic drugs (AEDs) are preferred over conventional AEDs with the perception of better safety profile and efficacy though there is a lack of confirmatory evidence. The present study assessed the adverse drug reactions' (ADRs) profile of AEDs prescribed in persons with epilepsy (PWE) as per the System Organ Class (SOC) and compared them on the basis of demographics and treatment pattern., Material and Methods: This prospective, cross-sectional, and observational study was conducted in PWE attending Neurology Outpatient-Department from February 2016 to April 2019 who were presented with any ADR. World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale was used for the causality assessment of suspected ADRs., Results: Among the 1011 PWE on AEDs, male:female ratio was 622:389, adult:pediatric ratio 736:275, and conventional:newer AEDs ratio 624:387. Among monotherapy PWE (47.1%), commonly used AEDs were levetiracetam (34.4%), valproic acid (22.9%), carbamazepine (18.3%), phenytoin (11.9%), and other AEDs (12.5%). A total of 1990 ADRs (1.96 ADRs per PWE) were reported as per SOC; among them, newer vs. conventional AEDs did not reveal any significant difference; however, monotherapy vs. polytherapy showed differences in nervous system disorders (p = 0.01) and skin and subcutaneous tissue disorders (p = 0.005). Causality assessment revealed 0.3% certain, 27.3% probable, 61.3% possible, and 11.1% unlikely association of ADRs with AEDs. Depending on the ADRs, there was either withdrawal of AED (0.9%), reduction in dose (48.4%), or continuation in the same dose as before (50.7%)., Conclusion: The ADR analysis showed that newer AEDs were associated with a similar trend of ADRs as that of conventional AEDs. Thus, the choice among newer and conventional AEDs should preferably focus on the experience of better efficacy in addition to safety data., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A 62-year-old previously healthy male was admitted with new onset generalised tonic-clonic seizures. Treatment was initiated with the antiepileptic levetiracetam and he had no further episodes of seizures. Creatine kinase (CPK) level was 1812 IU/L 12-hour postadmission. Despite good hydration, his CPK levels continued to rise dramatically and reached a level of 19 000 IU/L on day 5. This rise was unexplained as he did not have any further seizures and had a normal renal function. In the absence of other risk factors, the rare possibility of levetiracetam being responsible for the disproportionately high CPK was considered. Within 12 hours of withdrawal of levetiracetam, there was a downward trend in the CPK levels, with a 10-fold decrease in CPK levels over the next 4 days. This is only the ninth case reported in literature regarding this rare and potentially serious adverse effect of levetiracetam., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2015, 1308 pre-dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%-7% of cases in bi- or triple therapy. About 61% of plasma levels were found within the TR during 2001-2005, compared to 75% and 74% during 2006-2010 and 2011-2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3-fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001-2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Perampanel (PER) is a third generation antiepileptic drug (AED), recently approved as add-on therapy in both focal and generalized seizures. Levetiracetam (LEV) is a second generation AED, widely used in patients with epilepsy because of its favorable safety and efficacy profiles. Perampanel and LEV treatments have been associated with the occurrence of similar adverse events (AEs) (sleepiness, irritability, depression, anxiety, aggressiveness). The aim of the present retrospective single center study was to verify the efficacy and tolerability of PER and LEV used as first add-on therapy in patients with epilepsy affected by secondarily generalized seizures. We collected data from 15 patients treated with PER and 26 patients treated with LEV and followed at our site with follow-up visits at 3, 6, and 12months. This retrospective study documented the comparable efficacy of PER and LEV as first add-on treatments in patients affected by uncontrolled secondarily generalized seizures. However, more patients withdrawn LEV because of AEs compared with PER at the 3- and 12-month follow-up visits. The better tolerability of PER observed in this study could be related to the low therapeutic dose of PER prescribed when it is used as first adjunctive treatment for better controlling secondarily generalized seizures., (Copyright © 2018 Elsevier Inc. All rights reserved.)