Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments

• Published in: European journal of paediatric neurology 2022-07, Vol.39, p.35-39
• Main Authors: Agarwal, Anupam, Farfel, Gail M., Gammaitoni, Arnold R., Wong, Pierre C., Pinto, Fausto J., Galer, Bradley S.
• Format: Article
• Language: English
• Subjects: Dravet syndrome; Echocardiography; Fenfluramine; Long-term; Safety
• ISSN: 1090-3798; 1532-2130
• DOI: 10.1016/j.ejpn.2022.05.006

To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4–6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. A total of 327 patients (median age, 9.0 years; range, 2–19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2–42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome. •327 Dravet syndrome patients were treated with fenfluramine for a median 23.9 months.•Serial echocardiograms were used to monitor cardiac valve function during treatment.•No cases of valvular heart disease were observed during the study.