Fenfluramine for seizures associated with Dravet syndrome and Lennox–Gastaut syndrome

Background:
Fenfluramine was previously registered for weight loss in adults but was withdrawn from the market in 1997 due to an association with valvular heart disease and pulmonary arterial hypertension. It has now been registered, at lower doses, as an add-on therapy for Dravet syndrome and Lennox–Gastaut syndrome, to address the need for additional treatment options in this patient group.

Dravet syndrome, also known as severe myoclonic epilepsy in infancy, and Lennox–Gastaut syndrome are rare, severe developmental and epileptic encephalopathies that typically begin in early childhood. Both syndromes are characterised by seizures that are often resistant to anticonvulsant drugs, and are associated with significant neurodevelopmental, cognitive and behavioural impairments. Mortality rates, particularly in Dravet syndrome, are higher than in other forms of epilepsy.

Mechanism of action:
The exact mechanism of action by which fenfluramine reduces seizure activity is unclear. Fenfluramine increases serotonin release in the brain and acts as an agonist at multiple serotonin receptor subtypes (5-HT1D, 5-HT2A and 5-HT2C). It may also reduce seizures by acting at the sigma-1 receptor.

Clinical trials:
Fenfluramine registration was based on 4 key randomised, multicentre, placebo-controlled studies (ZX008-1501, ‑1502, ‑1504 and ‑1601).

Dravet syndrome: ZX008-1501 and ZX008-1502 were identical 3-arm trials. They compared 2 dose regimens of fenfluramine with placebo as add-on therapy in children and adolescents with Dravet syndrome (combined n=119) who were not adequately controlled on at least one anticonvulsant drug, excluding stiripentol (an anticonvulsant approved for the treatment of Dravet syndrome). Patients were randomised to receive fenfluramine 0.7 mg/kg/day, fenfluramine 0.2 mg/kg/day or placebo, in 2 divided doses, for 14 weeks (2-week titration and 12-week maintenance) in addition to current treatment. Using an analysis of covariance model to control for potential confounders, fenfluramine 0.7 mg/kg/day resulted in a 62% greater reduction in median monthly convulsive seizure frequency compared with placebo; fenfluramine 0.2 mg/kg/day resulted in a 32% greater reduction compared with placebo. Improvements were observed in seizure-free days and caregiver-reported quality of life.¹

ZX008-1504 was a 2-arm trial that evaluated fenfluramine as add-on therapy in patients with Dravet syndrome (n=87) who were inadequately controlled on at least one anticonvulsant drug including stiripentol. Patients were randomised to fenfluramine 0.4 mg/kg/day or placebo, in 2 divided doses, for 15 weeks (3-week titration and 12-week maintenance) in addition to current treatment. Fenfluramine-treated patients achieved a 54% greater reduction in mean monthly convulsive seizure compared with placebo (analysis of covariance model). The treatment group had more seizure-free days, but quality-of-life scores were not significantly different from placebo.²

Long-term open-label extension studies showed sustained seizure reduction and an acceptable safety profile.³

Lennox–Gastaut syndrome: ZX008-1601 was a randomised, double-blind, placebo-controlled study that compared fenfluramine with placebo as add-on therapy in patients aged 2 to 35 years with Lennox–Gastaut syndrome (n=263). Patients were randomised to receive fenfluramine 0.7 mg/kg/day or 0.2 mg/kg/day, or placebo, in 2 divided doses, for 14 weeks in addition to standard therapy (2-week titration and 12-week maintenance). Patients receiving fenfluramine 0.7 mg/kg/day achieved a 20% greater reduction in monthly generalised tonic-clonic, tonic or atonic drop-seizures compared with placebo (analysis of covariance model). A greater than 50% reduction was achieved by 25% of patients in the fenfluramine 0.7 mg/kg/day group compared with 10% in the placebo group (p=0.015).⁴

Adverse effects:
The most common adverse effects with fenfluramine are decreased appetite, diarrhoea, fatigue, lethargy, somnolence and weight loss. Decreased appetite and weight loss are likely dose related.

No cases of valvular heart disease or pulmonary arterial hypertension were observed in the above-mentioned trials. One probable case of pulmonary arterial hypertension was reported during postmarketing at a dose of 10.1 mg per day.⁵ The incidence of these adverse effects at doses used for the treatment of Dravet syndrome and Lennox–Gastaut syndrome is not known; however, the Therapeutic Goods Administration has mandated a boxed warning in the product information to highlight these potential adverse effects.

Precautions and monitoring:
Fenfluramine is contraindicated for patients with pre-existing valvular heart disease or pulmonary arterial hypertension. Echocardiogram monitoring is required for all patients before, during (every 6 months for 2 years and then yearly thereafter) and after treatment (6 months after stopping).

Weight monitoring is recommended in all patients. In individuals with a history of eating disorder, those who are markedly underweight, or those at risk of adverse effects from further weight loss, the appropriateness of this treatment should be carefully evaluated.

Fenfluramine has potential to cause serotonin syndrome, particularly when used with other serotonergic agents. Concomitant use of monoamine oxidase inhibitors (and use within 14 days) is contraindicated.⁶

No safety or efficacy data exist in patients younger than 2 years.

Dosage and administration:
The starting dose of fenfluramine for all patients is 0.1 mg/kg twice daily. After 7 days (or as soon as 4 days for patients not taking stiripentol) the dose can be increased to 0.2 mg/kg twice daily based on clinical response and tolerability. The maximum dose of fenfluramine differs depending on whether there is concomitant use of stiripentol, because an interaction between these drugs increases exposure to fenfluramine. For patients not taking stiripentol, the dose can be further increased after 4 to 7 days to 0.35 mg/kg twice daily (maximum 13 mg twice daily). The maximum daily dose for patients taking stiripentol is 0.2 mg/kg twice per day (maximum 8.6 mg twice daily). If stopping treatment, the dose should be decreased gradually.

Fenfluramine oral solution may be administered via an enteral feeding tube and is compatible with a ketogenic diet.

Dosage adjustments are needed for patients with hepatic or significant renal impairment. Dose modification may also be needed when fenfluramine is co-administered with strong inhibitors of cytochrome P450 (CYP) 1A2 or CYP2D6, or strong inducers of CYP1A2, CYP2B6 or CYP3A.^6,7

Use in pregnancy and breastfeeding:
Fenfluramine is classified as Therapeutic Goods Administration pregnancy category D and is not recommended for pregnant people or people of childbearing potential not using contraception. Breastfeeding is contraindicated while taking fenfluramine.

Place in therapy:
Fenfluramine provides another add-on treatment option for refractory seizures in patients with Dravet syndrome and Lennox–Gastaut syndrome. It is only available through a controlled access program, designed to prevent off-label use for weight loss and to ensure patients receive cardiac monitoring.⁶ The program requires prescriber and patient registration, and the medication is dispensed and delivered directly to the patient by a centralised dispensing pharmacy.

This new drug comment was finalised on 16 October 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was not available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2019;394:2243-54.
2. Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, Sanchez-Carpintero R, et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol 2020;77:300-8.
3. Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, et al. Fenfluramine HCl (Fintepla((R)) ) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study. Epilepsia 2020;61:2396-404.
4. Knupp KG, Scheffer IE, Ceulemans B, Sullivan J, Nickels KC, Lagae L, et al. Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia 2023;64:139-51.
5. European Medicines Agency. Fintepla, INN-fenfluramine - Scientific conclusions and grounds for the variation to the terms of the marketing authorisation. Reference Number: EMA/57721/2024. 2024. [cited 2025 Oct 21]
6. Therapeutic Goods Administration. Australian Product Information - FINTEPLA fenfluramine Oral Solution Bottle. Department of Health, Disability and Ageing; 2025. [cited 2025 Oct 21]
7. Frampton JE. Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes. Drugs 2023;83:923-34.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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