Medical treatment in infants and young children with epilepsy: Off‐label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children

Sourbron, Jo; Auvin, Stéphane; Arzimanoglou, Alexis; Cross, J. Helen; Hartmann, Hans; Pressler, Ronit; Riney, Kate; Sugai, Kenji; Wilmshurst, Jo M.; Yozawitz, Elissa; Lagae, Lieven

doi:10.1002/epi4.12666

Cited by 11 publications

(11 citation statements)

References 52 publications

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“…There is a relative paucity of high-quality data guiding neonatal seizure management despite the high incidence of seizures in this age group, 3 yielding fewer ASMs approved for neonates and frequent off-label use of newer medications. 4 This study presents novel data that suggest tolerability of IV LCM in neonates. Keene and colleagues 25 recently reported substantial heterogeneity in institutional practice regarding neonatal seizure management.…”

Section: Discussionmentioning

confidence: 92%

“…This study demonstrates safety using real‐world data with doses of IV LCM administered in current clinical practice. There is a relative paucity of high‐quality data guiding neonatal seizure management despite the high incidence of seizures in this age group, 3 yielding fewer ASMs approved for neonates and frequent off‐label use of newer medications 4 . This study presents novel data that suggest tolerability of IV LCM in neonates.…”

Section: Discussionmentioning

confidence: 93%

“…1,2 Because approval of ASMs by the US Food and Drug Administration (FDA) has traditionally lagged for children compared to adults, there are fewer approved ASMs available for children, particularly neonates, 3 and newer ASMs are often administered off-label. 4 Lacosamide (LCM) is a newer generation ASM available in both oral and IV formulations. Adverse effects of oral LCM in children are considered uncommon, and the most frequently reported are drowsiness, dizziness, somnolence, nausea, and diplopia.…”

Section: Introductionmentioning

confidence: 99%

“…Status epilepticus is the most common pediatric neurologic emergency, and the incidence is highest in children younger than 2 years 1,2 . Because approval of ASMs by the US Food and Drug Administration (FDA) has traditionally lagged for children compared to adults, there are fewer approved ASMs available for children, particularly neonates, 3 and newer ASMs are often administered off‐label 4 …”

Section: Introductionmentioning

confidence: 99%

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Safety of intravenous lacosamide in hospitalized children and neonates

et al. 2023

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ObjectiveSeizures are common in critically ill children and neonates, and these patients would benefit from intravenous (IV) antiseizure medications with few adverse effects. We aimed to assess the safety profile of IV lacosamide (LCM) among children and neonates.MethodsThis retrospective multicenter cohort study examined the safety of IV LCM use in 686 children and 28 neonates who received care between January 2009 and February 2020.ResultsAdverse events (AEs) were attributed to LCM in only 1.5% (10 of 686) of children, including rash (n = 3, .4%), somnolence (n = 2, .3%), and bradycardia, prolonged QT interval, pancreatitis, vomiting, and nystagmus (n = 1, .1% each). There were no AEs attributed to LCM in the neonates. Across all 714 pediatric patients, treatment‐emergent AEs occurring in >1% of patients included rash, bradycardia, somnolence, tachycardia, vomiting, feeling agitated, cardiac arrest, tachyarrhythmia, low blood pressure, hypertension, decreased appetite, diarrhea, delirium, and gait disturbance. There were no reports of PR interval prolongation or severe cutaneous adverse reactions. When comparing children who received a recommended versus a higher than recommended initial dose of IV LCM, there was a twofold increase in the risk of rash in the higher dose cohort (adjusted incidence rate ratio = 2.11, 95% confidence interval = 1.02–4.38).SignificanceThis large observational study provides novel evidence demonstrating the tolerability of IV LCM in children and neonates.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Safety of intravenous lacosamide in hospitalized children and neonates

et al. 2023

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“…Despite the potential clinical utility of actionable findings, most interventions are typically off-label. Although this is not unusual in pediatric neurology practice 14 , it is notable that the evidence base for half (44.6) of the actionable interventions is limited, usually derived from small cohort studies, defined as class D or lower ( Table 4 ). This highlights a need for additional studies of potential precision medicine approaches in CP using rigorous and reproducible designs.…”

Section: Discussionmentioning

confidence: 99%

Clinical actionability of genetic findings in cerebral palsy

Lewis,

Chopra,

Cohen

et al. 2023

Preprint

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Background and objectivesSingle gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care.MethodsWe analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overallclinical utilitywas calculated from metrics assessingoutcome severityif left untreated,safety/practicalityof the intervention, and anticipated interventionefficacy.ResultsWe found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified asactionable, defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting theprimary disease mechanism, 16 hadspecific prevention strategies, and 26 hadspecific symptom managementrecommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class “D” or below. The potential interventions haveclinical utilitywith 97% of outcomes being moderate-highseverityif left untreated and 62% of interventions predicted to be of moderate-highefficacy. Most interventions (71%) were considered moderate-highsafety/practicality.DiscussionOur findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potentialefficacy, outcomeseverity, and interventionsafety/practicalityindicates moderate-highclinical utilityof these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.

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Medical treatment in infants and young children with epilepsy: Off‐label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children

et al. 2022

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Objective: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to the market authorization (MA). For treatment of -especially young-children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off-label" use of ASMs. Even though "off-label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on-label" ASM, in mono-or polytherapy, fail to achieve adequate seizure control. Methods:The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first-and second-line treatment preferences, but also to illustrate the use of "off-label" drugs in childhood epilepsies. Results:Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off-label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap.Significance: We report the relatively common use of "off-label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines.

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Medical treatment in infants and young children with epilepsy: Off‐label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children

Cited by 11 publications

References 52 publications

Safety of intravenous lacosamide in hospitalized children and neonates

Safety of intravenous lacosamide in hospitalized children and neonates

Clinical actionability of genetic findings in cerebral palsy

Medical treatment in infants and young children with epilepsy: Off‐label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children

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