Low‐dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients

Abstract

Background and purposeDravet syndrome (DS) is a severe, drug‐resistant epilepsy. Fenfluramine has been reported to have a long‐term clinically meaningful anticonvulsive effect in patients with DS.MethodsThis prospective, open‐label study assessed the safety and effectiveness of low‐dose fenfluramine in a new cohort of patients with DS. Following a 3‐month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25–1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic–clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety.ResultsNine patients (aged 1.2–29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3–5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28–100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed.ConclusionsThe effectiveness and safety of low‐dose fenfluramine as an add‐on therapy for DS in this new prospective cohort supports previous findings.

Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population

“…Patients in these cohorts have now been treated with fenfluramine for periods of up to 28 years 35,36 . The original cohort began treatment before April 2010 18,19 , and has been treated with fenfluramine for a mean duration of 17.2 years (range ¼ 7-28 years) 36 .…”

“…The new cohort initiated treatment after April 2010 and has been followed prospectively with a structured protocol to assess safety and efficacy 20,35 . The new cohort study began with a 3-month observation period to establish the baseline frequency of major motor seizures, as well as to provide a baseline echocardiographic examination 20 .…”

“…The new cohort study began with a 3-month observation period to establish the baseline frequency of major motor seizures, as well as to provide a baseline echocardiographic examination 20 . Echocardiographic examinations were conducted at 3-month intervals during the first year of treatment with fenfluramine, at 6-month intervals during the second year of treatment, and annually thereafter.…”

“…The frequency of major motor seizures had declined by a median of 75% from the baseline frequency of 15.0/month. Each patient had received five to 11 ongoing echocardiographic examinations, and no heart valve abnormalities have been found in any patient 35 . At the start of Year 5 of treatment with fenfluramine, one patient demonstrated sub-normal systolic function (fractional shortening ¼ 26% [normal ¼ 25-43%] and ejection fraction ¼ 53% [normal >55%]) without any clinical significance due to mild hypokinesia of the interventricular septum.…”

“…Recently, the successful use of low-dose fenfluramine to control seizures in DS has been reported (see below) [18][19][20] . Because of the noteworthy anti-seizure effect of fenfluramine that has been observed in patients with DS, it will be important to determine if the use of lower doses in this patient population confers a different benefit-risk profile as opposed to its use to treat obesity in adults.…”