Use of Stiripentol in Dravet Syndrome A Guide for Clinicians

1. Use of Stiripentol in Dravet Syndrome: A Guide for Clinicians Overview: Challenges of Managing Dravet Syndrome Dravet syndrome is a rare and severe form of epilepsy that begins in infancy. Children with this condition face frequent, long-lasting, and difficult-to-control seizures. These seizures can be so intense that they may lead to life-threatening situations like status epilepticus. But seizures are only part of the picture. Children with Dravet syndrome often experience a range of other serious challenges, including developmental delays, behavioral issues, and intellectual disability. Sadly, the condition is also linked with a higher risk of early death.1 Most people with Dravet syndrome have a specific genetic mutation in a gene called SCN1A. When the gene doesn't work properly, it lowers the brain's resistance to seizures. Because of this, certain medications commonly used for epilepsy can make seizures worse in people with Dravet syndrome. Treatment often involves polytherapy, or using multiple anti-seizure medicines (ASMs) together. But these medicines can have strong side effects, interact with each other, and don’t work the same way for every patient. Finding the right balance of medications is a process of constant adjustment and monitoring, and often takes time. 1 What Is Stiripentol and How Does It Work? Stiripentol is a type of anti-seizure medicine used to help manage Dravet syndrome. It works by supporting the effects of other seizure medications, making them more effective in controlling difficult seizures. It was given special recognition as an "orphan drug" by the European Medicines Agency in 2000, and officially approved in Europe in 2007 for use in Dravet syndrome. Stiripentol is not used on its own, it’s added to other medicines like valproate and clobazam when those alone aren't enough to control seizures.2 Mechanism of Action: GABAergic Enhancement Stiripentol helps control seizures by making the brain’s main calming chemical, called GABA, work better. GABA is a natural messenger in the brain that slows down activity and helps prevent seizures. When GABA is released between brain cells, it attaches to special receptors that calm the receiving cell by letting in particles like chloride. This calming effect reduces the chance of a seizure.

2. Stiripentol boosts GABA’s power in more than one way. First, it increases the overall amount of GABA in the brain by stopping it from being broken down and reabsorbed too quickly. It does this by blocking the enzyme (GABA transaminase) that breaks GABA down, and by interfering with the transporters that recycle it. As a result, more GABA stays active in the brain for longer.3 Second, stiripentol attaches directly to GABA receptors, specifically to spots on the receptor that are different from where other medicines like benzodiazepines bind. This helps the receptors stay open longer when GABA is present, making their calming effect stronger. It acts on both the receptors found in the middle of brain cell connections (called synaptic) and those outside of them (extrasynaptic), helping calm the brain in both fast and steady ways. 3 Clinical Efficacy of Stiripentol in Seizure Control As per a study on children with Dravet syndrome (n=21), after starting stiripentol, more than half of the children (57%) had their seizures reduced by over 50%, and two of them stopped having seizures completely. Among the children who had experienced long, dangerous seizures (called status epilepticus), 8 out of 11 no longer had these episodes after starting stiripentol.4 The children had been taking stiripentol for an average of over three years. While the study included a small number of patients, the results suggest that stiripentol is effective in reducing both seizure frequency and the risk of severe seizure episodes. 4 Dosage, Administration, and Patient Suitability The usual goal is to reach a stiripentol dose of 50 mg per kg of body weight per day. However, in patients with very frequent seizures, doctors might consider higher doses, even up to 100 mg/kg/day. Stiripentol should be started at a low dose and increased gradually to help the body adjust and avoid side effects.5 In children under 3, stiripentol can be started early because it might help protect brain development. Children aged 3–12 follow a similar approach, with slow dose increases every 1–2 weeks. Teens and adults start at an even lower dose and increase slowly. Once at a stable dose, doctors check how well it’s working and decide if more is needed. 5 Stiripentol is usually taken two or three times a day, since it stays in the body for around 4.5 to 13 hours. It's best to take it with meals (even a small snack works) because this helps your stomach handle it better.5

3. Drug Interactions and Metabolic Considerations Stiripentol can interact with several other epilepsy medicines like clobazam, valproic acid, cannabidiol, fenfluramine and perampanel, causing various side effects, so it's important for doctors to carefully manage how it’s used alongside them.5 Note: Before beginning treatment, patients should have blood tests to check liver function, blood counts, and ammonia levels. These tests should be repeated at set times: a few months after starting, then at 6 months, 1 year, and then once a year.5 Side Effects and Long-Term Management Stiripentol can cause side effects, mostly because it interacts with other epilepsy medicines. Some common side effects include:5 •Loss of appetite or weight •Feeling very sleepy •Weak or floppy muscles (hypotonia) •Trouble with balance (ataxia) •Nausea or vomiting Rarely, it can affect blood cells (like lowering white cells or platelets). Most side effects don’t mean you need to stop stiripentol right away. Often, the problem is due to how it mixes with other medicines like valproic acid or clobazam. Instead of stopping stiripentol, doctors might lower the dose of those other medicines. 5 Side Effect What Can Help Lower the dose of clobazam; if it continues, check liver (GGT) and ammonia levels Sleepiness Irritability or weak muscles Loss of appetite/weight Nausea or vomiting Reduce clobazam slowly and watch for improvement Check valproic acid levels; adjust dose and consider adding a nutritional supplement Give stiripentol with food; if serious symptoms appear, check liver (GGT) and ammonia levels Comparing Stiripentol with Other Anti-Epileptics Stiripentol has good potential in children with drug-resistant epilepsy, especially when compared to other commonly used anti-seizure medications. After just three months of stiripentol use, 76.5% of patients with non-Dravet epilepsy and 61.1% of those with DS experienced an overall improvement in seizures, including

4. a decrease in their number, duration, and intensity. This suggests that stiripentol provided better seizure control than the other medications these children had been taking before. Notably, it reduced seizure frequency by at least 50% in over half the patients in both groups. Furthermore, 20% of all children in the study became seizure- free, something that many other ASMs had failed to achieve for them. It also offered added benefits not always seen with other ASMs, including better sleep, cognition, and even success in stopping status epilepticus when standard emergency treatments had failed.6 Accessing Stiripentol in India Under the Named Patient Program Stiripentol is not commercially available in India but can be accessed by patients with Dravet syndrome through the Named Patient Program (NPP). This pathway allows for the legal importation of essential medicines not otherwise approved in the country, ensuring life-saving therapies reach families facing rare diseases. The process involves the treating physician submitting a request with clinical justification, which then reviews and, upon approval, permits import on a per-patient basis. At this challenging step, rx4u specializes in making medicine access simple and reliable. With rx4u by your side, access to critical therapies like stiripentol becomes less daunting and much more achievable, even for the rarest conditions. FAQs for Healthcare Providers About Stiripentol What monitoring is necessary with stiripentol? Liver function, blood counts, and therapeutic drug levels (especially for clobazam and valproate) should be monitored.5 Is Stiripentol suitable as a first-line drug? No, it is indicated as adjunctive therapy after standard drugs (clobazam and valproate) have failed.2-5 Note: The information provided is for education purpose only and is subjected to prescribing information of the drug and the guidance of your treating physician. Always consult your health care provider before making any medical decision for starting your treatment.

5. References 1.Heger K, Lund C, Larsen Burns M, et al. A retrospective review of changes and challenges in the use of antiseizure medicines in Dravet syndrome in Norway. Epilepsia Open. 2020;5(3):432-441. Published 2020 Jul 6. doi:10.1002/epi4.12413 2.Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Apr. 1, INTRODUCTION. Available from: https://www.ncbi.nlm.nih.gov/books/NBK349345/ 3.Bacq A, Depaulis A, Castagné V, Le Guern ME, Wirrell EC, Verleye M. An Update on Stiripentol Mechanisms of Action: A Narrative Review. Adv Ther. 2024;41(4):1351-1371. doi:10.1007/s12325-024-02813-0 4.Yıldız EP, Ozkan MU, Uzunhan TA, et al. Efficacy of Stiripentol and the Clinical Outcome in Dravet Syndrome. J Child Neurol. 2019;34(1):33-37. doi:10.1177/0883073818811538 5.García-Peñas JJ, Calvo-Medina R, García-Ron A, Gil-Nagel A, Villanueva V, Sánchez-Carpintero R. Use of Stiripentol in Patients with Dravet Syndrome: Common Practice Among Experts in Spain. Neurol Ther. 2025;14(1):27-43. doi:10.1007/s40120-024-00677-8 6.Soto-Insuga V, González-Alguacil E, Ballarà-Petitbò M, et al. Efficacy of Stiripentol Beyond Dravet Syndrome: A Retrospective Medical Record Review of Patients with Drug-Resistant Epilepsies. Neurol Ther. 2025;14(3):1129-1150. doi:10.1007/s40120-025-00755-5