Safety considerations selecting antiseizure medications for the treatment of individuals with Dravet syndrome

ABSTRACT

Introduction: Management of individuals with Dravet Syndrome has evolved significantly over the past 10 years. Progress has been made in understanding the pathophysiology, the long-term outcome and possible consequences of inappropriate therapies, new drugs have been approved by the regulatory authorities and patients and families expressed their needs beyond seizures’ control.

Areas covered: The authors aimed at providing an overview of the main antiseizure medications used in Dravet syndrome with a particular focus on safety considerations. As the highly active phase of seizures takes place before the age of 5 years, the characteristics of antiseizure medications in infancy and childhood have also been considered due to their impact on antiseizure medication safety.

Expert opinion: Recent treatments, evaluated via randomized clinical trials, are promising in terms of efficacy and safety in individuals with DS. However, the balance between expected benefits and risks taken must be accurately assessed on an individual basis. There is a lack of data to understand the needs of patients and families, a major point particularly in this population, where the evaluation of efficacy and safety beyond seizures is difficult due to cognitive delay and behavioral disorders and where this evaluation is coming almost exclusively from caregivers.

KEYWORDS:

• Cannabidiol
• fenfluramine
• stiripentol
• adverse events
• scn1a
• manipulations
• off-labels

Article highlights

• Dravet syndrome is a channelopathy mainly due to the loss-of-function of voltage-gated sodium channel whose phenotype goes beyond seizures

• Before 2018, the efficacy of antiseizure medications used in Dravet syndrome was mainly based on retrospective studies or a few prospective open studies with a low level of evidence, except for stiripentol.

• Since 2018, three antiseizure medications (stiripentol, cannabidiol and fenfluramine) have been launched on the market following studies showing a high level of evidence of the efficacy of these treatments in Dravet syndrome

• The choice of an appropriate combination of antiseizure medications in Dravet syndrome should consider the individual phenotype and needs including age and behavioral and motor disorders.

• Except in emergencies, titration of new therapies should be slow, optimal doses should consider drug–drug interactions, and the evaluation of efficacy and side effects should be cautious and monitored.

Declaration of interest

R Nabbout has received grants and expertise fees from Eisai, Zogenix, Novartis, GW Pharma, Encoded, Supernus, and Takeda, and lecture fees from Eisai, Zogenix, GW Pharma, Takeda, Advicenne, and Biocodex. C Chiron has served as a consultant for Biocodex, Eisai, Neuren, Orphelia and Zogenix, and formation/conferences for Advicenne, Biocodex, Eisai and UCB Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.