Fenfluramine in Dravet syndrome

Dravet Syndrome (DS) is a rare epileptiform disorder typically presenting within the first year of life of a normally developing infant

• is characterized by several prolonged seizures that are often resistant to current anti-epileptic drug (AED) regimens

Fenfluramine (3-trifulormethyl-N-ethylamphetamine)

• is an amphetamine derivative that primarily affects serotonin neurotransmitter levels
• was initially prescribed in the 1960s as an appetite suppressant marketed as a weight loss drug
• is an amphetamine derivative that was found to have anti-epileptic effects since 1980s (2)
  • mechanism by which Fenfluramine treats seizures is believed to be through regulation of serotonin signaling
  • invertebrate animal models with SCN1A mutations demonstrate activity at 5-HT1D and 5-HT2C receptors
• was removed from the markets due to its association with cardiac valvopathies (1)
  • medication became popular in the 1990s as an appetite suppressant but was removed from the market due to cardiovascular complications at high doses (2)
• with respect to use in Dravet syndrome (1):
  • success of the randomized control trials suggests the addition of fenfluramine to current AED regimens may lead to better control of seizures in patients with Dravet syndrome
  • side effects of fenfluramine prove to be manageable and the concern for valvopathies has not been reproducible with low dose fenfluramine
  • weight loss was a mild side effect that should be well-tolerated if a patient experiences seizure reduction (2)

NICE state:

• Fenfluramine is recommended as an add-on to other antiseizure medicines for treating seizures associated with Dravet syndrome in people aged 2 years and older, only if:
  • seizures have not been controlled after trying 2 or more antiseizure medicines
  • the frequency of convulsive seizures is checked every 6 months, and fenfluramine is stopped if it has not fallen by at least 30% compared with the 6 months before starting treatment
  • the company provides fenfluramine according to the commercial arrangement
• the NICE committee state:
  • "..Treatment for Dravet syndrome often starts with a single antiseizure drug such as sodium valproate. Other treatments can then be added if seizures are not well controlled. In practice, standard care often involves a combination of 3 antiseizure medicines. Clinicians may offer add-on therapies such as cannabidiol with clobazam, or fenfluramine.."

Reference:

• Simon K, Sheckley H, Anderson CL, Liu Z, Carney PR. A review of fenfluramine for the treatment of Dravet syndrome patients. Curr Res Pharmacol Drug Discov. 2021 Dec 16;3:100078.
• Pierce JG, Mithal DS. Fenfluramine: New Treatment for Seizures in Dravet Syndrome. Pediatr Neurol Briefs. 2020 Mar 12;34:8.
• NICE (July 2022). Fenfluramine for treating seizures associated with Dravet syndrome