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Background and Importance Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are severe developmental and epileptic encephalopathies with limited therapeutic options. Fenfluramine has shown efficacy in DS and LGS, but evidence in other epileptic syndromes is limited.Aim and Objectives To evaluate the real-world effectiveness and safety of fenfluramine in paediatric patients with refractory epileptic syndromes.Material and Methods A retrospective observational study was conducted including all paediatric patients treated with fenfluramine between January 2021 and July 2025 at a tertiary children’s hospital. Demographic, clinical, and treatment variables were collected. Effectiveness was assessed according to seizure frequency and duration at 14-week follow-up. Safety outcomes included adverse drug reactions (ADRs). A multivariable logistic regression was performed to explore predictors of response.Results A total of 45 patients were included (62.2% male), with a median age of 8 years (IQR 5–11). Diagnoses were DS (26.7%), LGS (31.1%), and other epileptic syndromes (42.2%). Before fenfluramine initiation, 23 patients (51.1%) presented more than 10 daily seizures. Concomitant cannabidiol was used in 29% of cases.The median fenfluramine dose was 0.44 mg/kg/day at initiation, increasing to 0.56 mg/kg/day at 14 weeks. Overall, 25 patients (55.6%) achieved a clinical response. Among responders, 40% had epileptic syndromes different from DS or LGS, and 40% had previously received cannabidiol. Treatment discontinuation occurred in 24.4% of patients, due to inefficacy (8/11,72.7%) and adverse drug reactions (1/11,9.1%). Logistic regression including age, sex, diagnosis, and cannabidiol co-treatment did not identify significant predictors of response. Reported ADRs were mainly somnolence (28.9%), anorexia (24.4%), diarrhoea (8.9%), and abdominal pain (4.4%), which were generally mild and resolved after dose adjustment.Conclusion and Relevance Fenfluramine appears effective and safe in the treatment of Dravet and Lennox–Gastaut syndrome and shows promising results in other difficult-to-treat epileptic syndromes. No predictors of response were identified, highlighting the need for larger multicentre studies to better define patient profiles and optimise therapy.Conflict of Interest No conflict of interest