Skip to main content
Erschienen in: Current Treatment Options in Neurology 12/2022

24.09.2022 | Epilepsy (E Waterhouse, Section Editor)

Fenfluramine for the Treatment of Dravet Syndrome and Lennox Gastaut Syndrome: A Review

verfasst von: Douglas R. Nordli III, MD, Fernando N. Galan, MD

Erschienen in: Current Treatment Options in Neurology | Ausgabe 12/2022

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

Treatment-resistant epilepsy comprises approximately 36.3% of neurology clinic-based populations in the USA. Despite new drug development over the past 50 years, the rates of drug-resistant epilepsy remain the same. The need for continued drug trials with novel mechanisms of action remains paramount in patients with drug-resistant epilepsy. In particular, patients with severe epilepsy syndromes such as Dravet syndrome (DS) and Lennox Gastaut syndrome (LGS) continue to be the most severely affected due to the increased rates of status epilepticus and sudden unexpected death (SUDEP).

Recent Findings

Fenfluramine has recently been FDA-approved for DS and LGS. There is substantial evidence highlighting the efficacy of fenfluramine in the treatment of seizures associated with DS and LGS. There are a growing number of studies investigating alternative uses of fenfluramine for treatment-resistant epilepsies.

Summary

The completed studies suggest that fenfluramine is both a safe and efficacious adjunctive therapy in the treatment of convulsive seizures and drop seizures associated with DS and LGS. Fenfluramine’s suggested mechanism of action and available human evidence likely support its efficacy as an add-on therapy for more seizure types and calls for further research to expand its clinical use.
Literatur
1.
Zurück zum Zitat Sultana B, et al. Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology. 2021;96(17):805–17.CrossRef Sultana B, et al. Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology. 2021;96(17):805–17.CrossRef
2.
Zurück zum Zitat Cross JH, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021;93:154–9.CrossRef Cross JH, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021;93:154–9.CrossRef
4.
Zurück zum Zitat Fuller RW, Snoddy HD, Robertson DW. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav. 1988;30(3):715–21.CrossRef Fuller RW, Snoddy HD, Robertson DW. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav. 1988;30(3):715–21.CrossRef
5.
Zurück zum Zitat Zhang Y, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PLoS ONE. 2015;10(5):e0125898.CrossRef Zhang Y, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PLoS ONE. 2015;10(5):e0125898.CrossRef
6.
Zurück zum Zitat Munro JF, Seaton DA, Duncan LJ. Treatment of refractory obesity with fenfluramine. BMJ. 1966;2(5514):624.CrossRef Munro JF, Seaton DA, Duncan LJ. Treatment of refractory obesity with fenfluramine. BMJ. 1966;2(5514):624.CrossRef
7.
Zurück zum Zitat Casaer P, Boel M. Fenfluramine as a potential antiepileptic drug. Epilepsia J Int League Against Epilepsy. 2002;43(2):205. Casaer P, Boel M. Fenfluramine as a potential antiepileptic drug. Epilepsia J Int League Against Epilepsy. 2002;43(2):205.
8.
Zurück zum Zitat Connolly HM, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med. 1997;337(9):581–8.CrossRef Connolly HM, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med. 1997;337(9):581–8.CrossRef
9.
Zurück zum Zitat Aicardi J, Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine. N Engl J Med. 1985;313(22):1419.CrossRef Aicardi J, Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine. N Engl J Med. 1985;313(22):1419.CrossRef
10.
Zurück zum Zitat Gastaut H, Zifkin B, Rufo M. Compulsive respiratory stereotypies in children with autistic features: polygraphic recording and treatment with fenfluramine. J Autism Dev Disord. 1987;17(3):391–406.CrossRef Gastaut H, Zifkin B, Rufo M. Compulsive respiratory stereotypies in children with autistic features: polygraphic recording and treatment with fenfluramine. J Autism Dev Disord. 1987;17(3):391–406.CrossRef
11.
Zurück zum Zitat Ceulemans B, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia. 2012;53(7):1131–9.CrossRef Ceulemans B, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia. 2012;53(7):1131–9.CrossRef
12.
Zurück zum Zitat Bonnycastle DD, Giarman NJ, Paasonen M. Anticonvulsant compounds and 5-hydroxy-tryptamine in rat brain. Br J Pharmacol Chemother. 1957;12(2):228–31.CrossRef Bonnycastle DD, Giarman NJ, Paasonen M. Anticonvulsant compounds and 5-hydroxy-tryptamine in rat brain. Br J Pharmacol Chemother. 1957;12(2):228–31.CrossRef
13.
Zurück zum Zitat Jobe PC, Browning RA. The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Epilepsy Behav. 2005;7(4):602–19.CrossRef Jobe PC, Browning RA. The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Epilepsy Behav. 2005;7(4):602–19.CrossRef
14.
Zurück zum Zitat Nabbout R, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300–8.CrossRef Nabbout R, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300–8.CrossRef
15.
Zurück zum Zitat Sullivan J, et al. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice. Eur J Paediatr Neurol. 2021;31:10–4.CrossRef Sullivan J, et al. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice. Eur J Paediatr Neurol. 2021;31:10–4.CrossRef
16.
Zurück zum Zitat Lagae L, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. The Lancet. 2019;394(10216):2243–54.CrossRef Lagae L, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. The Lancet. 2019;394(10216):2243–54.CrossRef
17.
Zurück zum Zitat Knupp KG, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–64.CrossRef Knupp KG, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–64.CrossRef
18.
Zurück zum Zitat Serial echocardiographic assessment of patients with Dravet syndrome treated with fenfluramine (Fintepla®) for up to 3 years: no incidence of valvular heart disease or pulmonary artery hypertension. Serial echocardiographic assessment of patients with Dravet syndrome treated with fenfluramine (Fintepla®) for up to 3 years: no incidence of valvular heart disease or pulmonary artery hypertension.
19.
Zurück zum Zitat Lai WW, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia. 2020;61(11):2386–95.CrossRef Lai WW, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia. 2020;61(11):2386–95.CrossRef
20.
Zurück zum Zitat Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, Polster T, Galer B, Lock M, Agarwal A, Gammaitoni A, Morrison G, Farfel G. Fenfluramine HCl (Fintepla®) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study. Epilepsia. 2020 Nov;61(11):2396–404. https://doi.org/10.1111/epi.16722. Epub 2020 Oct 19. PMID: 33078386; PMCID: PMC7756901. Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, Polster T, Galer B, Lock M, Agarwal A, Gammaitoni A, Morrison G, Farfel G. Fenfluramine HCl (Fintepla®) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study. Epilepsia. 2020 Nov;61(11):2396–404. https://​doi.​org/​10.​1111/​epi.​16722. Epub 2020 Oct 19. PMID: 33078386; PMCID: PMC7756901.
21.
Zurück zum Zitat Specchio N, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia. 2020;61(11):2405–14.CrossRef Specchio N, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia. 2020;61(11):2405–14.CrossRef
22.
Zurück zum Zitat Sullivan J, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: a time-to-event analysis. Epilepsia. 2022;63(1):130–8.CrossRef Sullivan J, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: a time-to-event analysis. Epilepsia. 2022;63(1):130–8.CrossRef
Metadaten
Titel
Fenfluramine for the Treatment of Dravet Syndrome and Lennox Gastaut Syndrome: A Review
verfasst von
Douglas R. Nordli III, MD
Fernando N. Galan, MD
Publikationsdatum
24.09.2022
Verlag
Springer US
Erschienen in
Current Treatment Options in Neurology / Ausgabe 12/2022
Print ISSN: 1092-8480
Elektronische ISSN: 1534-3138
DOI
https://doi.org/10.1007/s11940-022-00741-4

Weitere Artikel der Ausgabe 12/2022

Current Treatment Options in Neurology 12/2022 Zur Ausgabe

Cerebrovascular Disorders (D Jamieson, Section Editor)

Treatment of Intracerebral Vascular Malformations: When to Intervene

Epilepsy (E Waterhouse, Section Editor)

Self-care and Epilepsy

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Was nützt die Kraniektomie bei schwerer tiefer Hirnblutung?

17.05.2024 Hirnblutung Nachrichten

Eine Studie zum Nutzen der druckentlastenden Kraniektomie nach schwerer tiefer supratentorieller Hirnblutung deutet einen Nutzen der Operation an. Für überlebende Patienten ist das dennoch nur eine bedingt gute Nachricht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.