Skip to main content

Stiripentol: A Review in Dravet Syndrome

Drugs volume 79, pages 1785–1796 (2019)Cite this article

Abstract

Stiripentol (Diacomit®) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central γ-aminobutyric acid transmission. In the EU, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome (DS; previously known as severe myoclonic epilepsy of infancy), whose seizures are not adequately controlled with clobazam and valproate. This approval (and similar DS indications in the USA, Canada and Japan), reflect the results of the STICLO studies, two small, randomized controlled trials in which stiripentol as adjunctive therapy was associated with a markedly superior response rate after 2 months compared with placebo in patients aged between 3 and ≈ 21 years with DS that was inadequately controlled with clobazam and valproate. These short-term results have subsequently been supported and extended by findings from longer-term, open-label, observational studies, including a retrospective longitudinal cohort study, which showed that the efficacy of combining stiripentol with clobazam and valproate when started at paediatric age was maintained in mid-adulthood with up to 24 years of exposure, and up to 40 years of age. Drowsiness, appetite loss, weight loss, ataxia and tremor are the most common adverse events associated with the addition of stiripentol to clobazam and valproate. Based on the available evidence, stiripentol, as an adjunct to clobazam and valproate, is a demonstrably beneficial and generally well-tolerated second-line treatment for patients with DS.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy: Dravet syndrome. In: Roger J, Bureau M, Dravet C, et al., editors. Epileptic syndromes in infancy, childhood and adolescence. Montrouge: John Libbey Eurotext Ltd.; 2005. p. 89–113.

    Google Scholar 

  2. Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet syndrome in a US population. Pediatrics. 2015;136(5):e1310.

    PubMed  PubMed Central  Google Scholar 

  3. Gataullina S, Dulac O. From genotype to phenotype in Dravet disease. Seizure. 2017;44:58–64.

    PubMed  Google Scholar 

  4. Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome. Epilepsia. 2011;52(Suppl 2):44–9.

    PubMed  Google Scholar 

  5. Cooper MS, McIntosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res. 2016;128:43–7.

    PubMed  Google Scholar 

  6. Knupp KG, Wirrell EC. Treatment strategies for Dravet syndrome. CNS Drugs. 2018;32(4):335–50.

    CAS  PubMed  Google Scholar 

  7. Djémié T, Weckhuysen S, Von Spiczak S, et al. Pitfalls in genetic testing: the story of missed SCN1A mutations. Mol Genet Genom Med. 2016;4(4):457–64.

    Google Scholar 

  8. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. Pediatr Neurol. 2017;68(18–34):e3.

    Google Scholar 

  9. Ziobro J, Eschbach K, Sullivan JE, et al. Current treatment strategies and future treatment options for Dravet syndrome. Curr Treat Options Neurol. 2018;20(12):52 (1–15).

    PubMed  Google Scholar 

  10. Plosker GL. Stiripentol: in severe myoclonic epilepsy of infancy (Dravet syndrome). CNS Drugs. 2012;26(11):993–1001.

    CAS  PubMed  Google Scholar 

  11. Nickels KC, Wirrell EC. Stiripentol in the management of epilepsy. CNS Drugs. 2017;31(5):405–16.

    CAS  PubMed  Google Scholar 

  12. Chiron C. Stiripentol for the treatment of seizures associated with Dravet syndrome. Expert Rev Neurother. 2019;19(4):301–10.

    CAS  PubMed  Google Scholar 

  13. European Medicines Agency. Stiripentol (Diacomit): EU summary of product characteristics. 2018. https://www.ema.europa.eu/documents/product-information/diacomit-epar-product-information_en.pdf. Accessed 26 Feb 2019.

  14. CRI. PrDiacomitTM (stiripentol capsules; powder for suspension): Canadian product monograph. 2012. https://pdf.hres.ca/dpd_pm/00022311.PDF. Accessed 26 Aug 2019.

  15. Meiji Seika Pharma Co. Ltd. Stiripentol (Diacomit): Japanese prescribing information. 2013. http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/1139011. Accessed 21 June 2019.

  16. Biocodex Inc. Stiripentol (DIACOMIT): US prescribing Information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206709s000,207223s000lbl.pdf. Accessed 26 Feb 2019.

  17. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000;356(9242):1638–42.

    CAS  PubMed  Google Scholar 

  18. Guerrini R, Tonnelier S, d’Athis P, et al. Stiripentol in severe myoclonic epilepsy in infancy (SMEI): a placebo-controlled Italian trial [abstract no. P496]. Epilepsia. 2002;43(Suppl. 8):155.

    Google Scholar 

  19. Center for Drug Evaluation and Research. Application number: 206709Orig1s000 207223Orig1s000 Clin. Rev. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/206709Orig1s000,207223Orig1s000MedR.pdf. Accessed 6 June 2019.

  20. Kassai B, Chiron C, Augier S, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49(2):343–8.

    PubMed  Google Scholar 

  21. Perez J, Chiron C, Musial C, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia. 1999;40(11):1618–26.

    CAS  PubMed  Google Scholar 

  22. Inoue Y, Ohtsuka Y. Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence. Epilepsy Res. 2014;108(4):725–31.

    CAS  PubMed  Google Scholar 

  23. Inoue Y, Ohtsuka Y. Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Epilepsy Res. 2015;113:90–7.

    CAS  PubMed  Google Scholar 

  24. Myers KA, Lightfoot P, Patil SG, et al. Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study. Dev Med Child Neurol. 2018;60(6):574–8.

    PubMed  Google Scholar 

  25. Nabbout R, Copioli C, Chipaux M, et al. Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study. Epilepsia. 2011;52(7):e54–7.

    PubMed  Google Scholar 

  26. Thanh TN, Chiron C, Dellatolas G, et al. Long-term efficacy and tolerance of stiripentaol in severe myoclonic epilepsy of infancy (Dravet’s syndrome). Arch Pediatr. 2002;9(11):1120–7.

    PubMed  Google Scholar 

  27. Chiron C, Helias M, Kaminska A, et al. Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood? Epilepsia. 2018;59(9):1705–17.

    CAS  PubMed  Google Scholar 

  28. Inoue Y, Ohtsuka Y, Oguni H, et al. Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia. 2009;50(11):2362–8.

    CAS  PubMed  Google Scholar 

  29. De Liso P, Chemaly N, Laschet J, et al. Patients with Dravet syndrome in the era of stiripentol: a French cohort cross-sectional study. Epilepsy Res. 2016;125:42–6.

    PubMed  Google Scholar 

  30. Wirrell EC, Laux L, Franz DN, et al. Stiripentol in Dravet syndrome: results of a retrospective US study. Epilepsia. 2013;54(9):1595–604.

    CAS  PubMed  Google Scholar 

  31. Cho MJ, Kwon SS, Ko A, et al. Efficacy of stiripentol in Dravet syndrome with or without SCN1A mutations. J Clin Neurol. 2018;14(1):22–8.

    PubMed  Google Scholar 

  32. Yildiz EP, Ozkan MU, Uzunhan TA, et al. Efficacy of stiripentol and the clinical outcome in Dravet syndrome. J Child Neurol. 2019;34(1):33–7.

    PubMed  Google Scholar 

  33. Dressler A, Trimmel-Schwahofer P, Reithofer E, et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome—comparison with various standard antiepileptic drug regimen. Epilepsy Res. 2015;109:81–9.

    PubMed  Google Scholar 

  34. Balestrini S, Sisodiya SM. Audit of use of stiripentol in adults with Dravet syndrome. Acta Neurol Scand. 2017;135(1):73–9.

    CAS  PubMed  Google Scholar 

  35. Chiron C. Stiripentol and vigabatrin current roles in the treatment of epilepsy. Expert Opin Pharmacother. 2016;17(8):1091–101.

    CAS  PubMed  Google Scholar 

  36. Strzelczyk A, Schubert-Bast S, Reese JP, et al. Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam. Epilepsy Behav. 2014;34:86–91.

    PubMed  Google Scholar 

  37. Rosander C, Hallbook T. Dravet syndrome in Sweden: a population-based study. Dev Med Child Neurol. 2015;57(7):628–33.

    PubMed  Google Scholar 

  38. Aras LM, Isla J, Mingorance-Le Meur A. The European patient with Dravet syndrome: results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome. Epilepsy Behav. 2015;44:104–9.

    PubMed  Google Scholar 

  39. Schubert-Bast S, Wolff M, Wiemer-Kruel A, et al. Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: a multicenter cohort study from Germany and review of literature. Epilepsy Behav. 2019;98(Pt A):88–95.

    PubMed  Google Scholar 

  40. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: task force report for the ILAE Commission of Pediatrics. Epilepsia. 2015;56(8):1185–97.

    PubMed  Google Scholar 

  41. Brunklaus A, Ellis R, Reavey E, et al. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain. 2012;135(Pt 8):2329–36.

    CAS  PubMed  Google Scholar 

  42. European Medicines Agency. Cannabidiol (Epidyolex): EU summary of product characteristics. 2019. https://ec.europa.eu/health/documents/community-register/2019/20190919145790/anx_145790_en.pdf. Accessed 3 Oct 2019.

  43. Greenwich Biosciences Inc. EPIDIOLEX® (cannabidiol): US prescribing Information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed 26 Feb 2019.

  44. Wirrell EC. Treatment of Dravet syndrome. Can J Neurol Sci. 2016;43(Suppl 3):S13–8.

    PubMed  Google Scholar 

  45. Strzelczyk A, Kalski M, Bast T, et al. Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: a prospective, multicenter study from Germany. Eur J Paediatr Neurol. 2019;23(3):392–403.

    PubMed  Google Scholar 

  46. Poisson M, Huguet F, Savattier A, et al. A new type of anticonvulsant, stiripentol—pharmacological profile and neurochemical study. Arzneimittel-Forschung/Drug Research. 1984;34(2):199–204.

    CAS  PubMed  Google Scholar 

  47. Grosenbaugh DK, Mott DD. Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Neuropharmacology. 2013;67:136–43.

    CAS  PubMed  Google Scholar 

  48. Sada N, Lee S, Katsu T, et al. Epilepsy treatment: targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015;347(6228):1362–7.

    CAS  PubMed  Google Scholar 

  49. Quilichini PP, Chiron C, Ben-Ari Y, et al. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA(A)-receptor channels. Epilepsia. 2006;47(4):704–16.

    CAS  PubMed  Google Scholar 

  50. Fisher JL. The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator. Neuropharmacology. 2009;56(1):190–7.

    CAS  PubMed  Google Scholar 

  51. Fisher JL. The effects of stiripentol on GABA(A) receptors. Epilepsia. 2011;52(Suppl. 2):76–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fisher JL. Interactions between modulators of the GABA(A) receptor: stiripentol and benzodiazepines. Eur J Pharmacol. 2011;654(2):160–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Verleye M, Buttigieg D, Steinschneider R. Neuroprotective activity of stiripentol with a possible involvement of voltage-dependent calcium and sodium channels. J Neurosci Res. 2016;94(2):179–89.

    CAS  PubMed  Google Scholar 

  54. Peigne S, Rey E, Le Guern ME, et al. Reassessment of stiripentol pharmacokinetics in healthy adult volunteers. Epilepsy Res. 2014;108(5):909–16.

    CAS  PubMed  Google Scholar 

  55. Peigne S, Chhun S, Tod M, et al. Population pharmacokinetics of stiripentol in paediatric patients with Dravet syndrome treated with stiripentol, valproate and clobazam combination therapy. Clin Pharmacokinet. 2018;57(6):739–48.

    CAS  PubMed  Google Scholar 

  56. Tran A, Rey E, Pons G, et al. Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: In vitro and in vivo comparison and calculation of in vivo inhibition constants. Clin Pharmacol Ther. 1997;62(5):490–504.

    CAS  PubMed  Google Scholar 

  57. Jogamoto T, Yamamoto Y, Fukuda M, et al. Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy. Epilepsy Res. 2017;130:7–12.

    CAS  PubMed  Google Scholar 

  58. Yamamoto Y, Takahashi Y, Imai K, et al. Effect of CYP inducers/inhibitors on topiramate concentration: clinical value of therapeutic drug monitoring. Ther Drug Monit. 2017;39:55–61.

    CAS  PubMed  Google Scholar 

  59. Ben-Menachem E, Gunning B, Cabrera CMA, et al. A phase 2 trial to explore the potential for a pharmacokinetic drug–drug interaction with stiripentol when in combination with cannabidiol (CBD) in patients with epilepsy [poster 338]. In: International epilepsy congress, 2019.

  60. Morrison G, Crockett J, Blakey G, et al. A Phase 1, open-label, pharmacokinetic trial to investigate possible drug–drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Clin Pharm Drug Dev. 2019. https://doi.org/10.1002/cpdd.665.

    Article  Google Scholar 

Download references

Acknowledgements

During the peer review process, the manufacturer of stiripentol was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Affiliations

  1. Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

    James E. Frampton

Authors
  1. James E. Frampton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James E. Frampton.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

James Frampton is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

Enhanced material for this Adis Drug Evaluation can be found at https://doi.org/10.6084/m9.figshare.9876596.

The manuscript was reviewed by:S. Balestrini, Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK; C. Chiron, INSERM U1141, Neurospin (CEA) and Neuropediatric Department, Necker Enfants-Malades Hospital, Paris, France; C. Dravet, Childhood Neuropsychiatry, Catholic University, Rome, Italy; A. Strzelczyk, Department of Neurology, Epilepsy Center Frankfurt Rhine‐Main, Goethe University, Frankfurt am Main, Germany; A. Verrotti, Department of Pediatrics, University of L’Aquila, L’Aquila, Italy.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 60 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Frampton, J.E. Stiripentol: A Review in Dravet Syndrome. Drugs 79, 1785–1796 (2019). https://doi.org/10.1007/s40265-019-01204-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01204-y