Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis

Payam Tabaee Damavandi; Natalia Fabin; Riccardo Giossi; Sara Matricardi; Cinzia Del Giovane; Pasquale Striano; Stefano Meletti; Francesco Brigo; Eugen Trinka; Simona Lattanzi

doi:10.1007/s40120-023-00452-1

Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis

Neurol Ther. 2023 Apr;12(2):669-686. doi: 10.1007/s40120-023-00452-1. Epub 2023 Feb 28.

Authors

Payam Tabaee Damavandi¹, Natalia Fabin², Riccardo Giossi³, Sara Matricardi⁴, Cinzia Del Giovane^{5

6}, Pasquale Striano⁷, Stefano Meletti^{8

9}, Francesco Brigo¹⁰, Eugen Trinka^{11

12

13}, Simona Lattanzi¹⁴

Affiliations

¹ Department of Neurology, Fondazione IRCCS San Gerardo dei Tintori, School of Medicine and Surgery, Milan Center for Neuroscience, University of Milano, Bicocca, Monza, Italy.
² Laboratory of Epidemiological and Clinical Cardiology, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
³ Chemical-Clinical Analyses Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
⁴ Department of Pediatrics, University of Chieti, Chieti, Italy.
⁵ Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
⁶ Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
⁷ Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, "G. Gaslini" Institute, University of Genoa, Genoa, Italy.
⁸ Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.
⁹ Department of Biomedical, Metabolic and Neural Science, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
¹⁰ Division of Neurology, "Franz Tappeiner" Hospital, Merano, BZ, Italy.
¹¹ Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria.
¹² Center for Cognitive Neuroscience, Salzburg, Austria.
¹³ Public Health, Health Services Research and HTA, University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria.
¹⁴ Department of Experimental and Clinical Medicine, Neurological Clinic, Marche Polytechnic University, Via Conca 71, 60020, Ancona, Italy. alfierelattanzisimona@gmail.com.

Abstract

Introduction: Fenfluramine (FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy.

Methods: We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double- or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with ≥ 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and suffered adverse events (AEs). The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) along with the 95% confidence interval (CI) were estimated for each outcome.

Results: Three trials were identified and a total of 469 Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) subjects were randomized. All three trials were judged to be at low risk of biases. In patients with DS, the RRs for ≥ 50% and 100% reductions in convulsive seizure frequency for the FFA group compared to placebo were 5.61 (95% CI 2.73-11.54) and 4.71 (95% CI 0.57-39.30), respectively. In patients with LGS, the corresponding RRs for ≥ 50% and 100% reductions in drop seizure frequency were 2.58 (95% CI 1.33-5.02) and 0.50 (95% CI 0.031-7.81), respectively. The drug was withdrawn for any reason in 10.1% and 5.8% of patients receiving FFA and placebo, respectively (RR 1.79, 95% CI 0.89-3.59). Treatment discontinuation due to AEs occurred in 5.4% and 1.2% of FFA- and placebo-treated patients, respectively (RR 3.63, 95% CI 0.93-14.16). Decreased appetite, diarrhoea, fatigue, and weight loss were AEs associated with FFA treatment.

Conclusion: Fenfluramine reduces the frequency of seizures in patients with DS and LGS. Decreased appetite, diarrhoea, fatigue, and weight loss are non-cardiovascular AEs associated with FFA.

Keywords: Dravet syndrome; Epilepsy; Fenfluramine; Lennox–Gastaut syndrome; Seizures.