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Review
. 2024 Oct;9(5):1643-1657.
doi: 10.1002/epi4.12998. Epub 2024 Jul 4.

Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox-Gastaut syndrome in clinical practice

Elaine C Wirrell  1 , Lieven Lagae  2 , Ingrid E Scheffer  3 , J Helen Cross  4   5 , Nicola Specchio  6 , Adam Strzelczyk  7
Affiliations
Review

Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox-Gastaut syndrome in clinical practice

Elaine C Wirrell et al. Epilepsia Open. 2024 Oct.

Abstract

Fenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma-1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients ≥2 years old and as add-on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early-line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4-29 years old in whom up to 14 ASMs had previously failed, to illustrate real-world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug-drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well-tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS. PLAIN LANGUAGE SUMMARY: Fenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox-Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors' everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine.

Keywords: Dravet syndrome; Lennox–Gastaut syndrome; antiseizure medications; fenfluramine; polytherapy.

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Conflict of interest statement

ECW has received consulting income from Acadia, Amicus, Neurocrine and Encoded Therapeutics. She also receives income from Epilepsy.com for serving as Co‐Editor in Chief. LL has received grants, and is a consultant and/or speaker for Zogenix (now a part of UCB), LivaNova, UCB Pharma, Shire, Eisai, Novartis, Takeda/Ovid, NEL, and Epihunter. IES has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, Cerecin; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, Stoke Therapeutics, Eisai, Akumentis; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, Stoke Therapeutics and Eisai; has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc, Epygenyx, ES‐Therapeutics, GW Pharma (now Jazz Pharmaceuticals), Marinus, Neurocrine BioSciences, Ovid Therapeutics, SK Life Science, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix (now a part of UCB), and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics and Biohaven Pharmaceuticals; and is a Non‐Executive Director of Bellberry Ltd and a Director of the Australian Academy of Health and Medical Sciences and the Royal Society (Australia). She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2 012 900 190 and PCT/AU2012/001321 (TECH ID:2012–009). JHC has received research grants from Zogenix (now a part of UCB), Marinus, GW Pharma (now Jazz Pharmaceuticals), Vitaflo, Stoke Therapeutics, Ultragenyx, National Institute of Health Research (NIHR), EPSRC, GOSH Charity, ERUK, the Waterloo Foundation, and the Great Ormond Street Hospital NIHR Biomedical Research Centre; and has served as consultant/advisor for Zogenix (now a part of UCB), GW Pharma (now Jazz Pharmaceuticals), and Biocodex for which remuneration was made to the department, outside of the submitted work; serves as Chair of the Medical Board for Dravet UK, Hope for Hypothalamic Hamartoma, and Matthews Friends and endowed chair at UCL Great Ormond Street Institute of Child Health. NS has served on scientific advisory boards for GW Pharma (now Jazz Pharmaceuticals), BioMarin, Arvelle, Marinus and Takeda; has received speaker honoraria from Eisai, Biomarin, Livanova, Sanofi; and has served as an investigator for Zogenix (now a part of UCB), Marinus, Biomarin, UCB and Roche. AS reports personal fees and grants from Angelini Pharma, Biocodex, Desitin Arzneimittel, Eisai, Jazz (GW) Pharmaceuticals, Marinus Pharmaceuticals, Medtronic, Takeda, UCB Pharma (Zogenix), and UNEEG. We confirm that we have read the Journal‘s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
Lines of therapy for treatment of DS. Adapted from Wirrell EC, et al. Epilepsia. 2022;63 (7):1761–77, with permission from John Wiley and Sons. aNo data to support monotherapy in DS; in EU, must be co‐administered with CLB and VPA. bIn EU, must be co‐administered with CLB. CLB, clobazam; DS, Dravet syndrome; VPA, valproate.
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References

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