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Goodman & Gilman's: Annual FDA Approvals


Brand Name


Pharmacological Class

GABA-A receptor agonist and lactate dehydrogenase inhibitor24

FDA Indication

Dravet syndrome


Stiripentol is indicated for the add-on treatment of seizures associated with Dravet syndrome in patients ≥2 years of age taking clobazam. Stiripentol has been used as an orphan drug for Dravet syndrome since 2008.21 Dravet syndrome (severe myoclonic epilepsy in infancy) occurs with an incidence of 1 in 20,000-40,000 and is one of the most treatment-resistant forms of epilepsy.123 Sodium channel alpha-1 subunit (SCN1A) gene mutations are associated with 70%–80% of cases.123

Structurally unrelated to other anticonvulsants marketed in the United States,124-126 stiripentol is an aromatic allylic alcohol126 (Figure P1-7), and its precise mechanism of action remains unsettled. In humans, stiripentol is categorized as a gamma-aminobutyric acid (GABA)-A receptor (anion channel) agonist and as a (novel) inhibitor of the A and B chains of L-lactate dehydrogenase (LDH).24 Stiripentol is known to elevate levels of the inhibitory neurotransmitter GABA and to prolong the open duration of GABA-A receptor chloride channels by a barbiturate-like mechanism.24,127 LDH plays important physiologic roles in the energy production that supports neuronal excitation.24 Stiripentol is known to bind to LDH at a site separate from the binding sites for lactate and pyruvate (which are involved in glucose metabolism), inhibiting their intra-conversion, and giving rise to the hint that LDH inhibitors, including stiripentol, may mimic a ketogenic diet.24 Long advocated as a therapeutic modality for seizure control in children, ketogenic diets result in the main energy source for the brain being switched from the use of glucose to the use of ketone bodies.24 Ketone bodies are known to directly regulate neuronal excitation and seizures via ATP-sensitive potassium channels and vesicular glutamate transporters.24 In addition to potentiation of GABAergic inhibitory neurotransmission and LDH inhibition,125 stiripentol has the indirect pharmacokinetic effect of increasing systemic exposures to clobazam and its active metabolite, norclobazam.51 The mechanism for the efficacy potentiation (and/or toxicity) when stiripentol is added to therapy with clobazam stems from inhibition of CYP3A4-mediated metabolism of clobazam and CYP2C19-mediated inhibition of norclobazam.51 Co-administration of stiripentol with clobazam typically results in a twofold increase in plasma clobazam concentrations and a fivefold increase in norclobazam.51 Up to a 50% reduction in the dose of clobazam is recommended to avert potential toxicity from co-therapy.51 Finally, by reducing calcium-mediated neurotoxicity, some evidence indicates that stiripentol may be neuroprotective.124 Regardless of the precise mechanism of action, the anticonvulsant activity of stiripentol is age-dependent, with greater efficacy in younger patients.127

The dosage of stiripentol is 50 mg/kg per day, administered by mouth in 2 or 3 divided doses with a meal.51 The maximum recommended dose is 3 g/day.51 Stiripentol is extensively metabolized24 with a half-life for elimination of 4.5–13 hours depending on dose.51 Phase 1 metabolism is through CYPs 1A2, 2C19, and 3A4.24 The predominant metabolic pathways involve demethylation and glucuronidation.24 Other catabolic pathways include oxidative cleavage of the methylenedioxy ring system, O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure.24 Stiripentol metabolites are mainly eliminated through the kidneys, with 13 varieties found in urine.24 Administration of stiripentol to patients with moderate or severe renal impairment is not recommended.51 Stiripentol is both an inhibitor and inducer of CYPs 1A2, 2B6, and 3A4, and it is an inhibitor of CYPs 2C8 and 2C19, as well as P-glycoprotein, and the breast cancer resistance protein (BCRP).51 Cytochrome P450 drug-drug interactions in addition to those mentioned for clobazam are to be expected, particularly in conjunction with other antiepileptic drugs (i.e., other benzodiazepines, carbamazepine, phenobarbital, phenytoin, and valproate). Co-therapy with these and other medications may necessitate dose reductions to avert toxicity. The chemical structure of stiripentol is shown in Figure P1-7.

Premarketing, stiripentol was administered to 55 healthy male volunteers and 438 patients with Dravet syndrome, including 310 patients treated for ≥12 months.51,128 The labeled side effects for stiripentol include somnolence (67%); neutropenia and thrombocytopenia (both 13%); decreased appetite (46%); weight loss, agitation, and ataxia (all 27%); hypotonia (24%); nausea and tremor (both 15%); dysarthria and insomnia (both 12%); and aggression (9%).51 Hematologic testing is recommended at least every 6 months during therapy.51 FDA approval of stiripentol was based on results from 2 double-blind, placebo-controlled, 8-week studies in patients 3–18 years of age (mean 9.2 years) with Dravet syndrome taking clobazam and valproate and experiencing ≥4 seizures/month.51 Among patients randomized to receive stiripentol, 23 of 33 experienced a ≥50% reduction in seizures compared to baseline versus 2 of 31 subjects given placebo.128 These results were highly statistically significant, and FDA allowed extrapolation from the experience in children ≥3 years to extend the approved labeling claim down to children ≥2 years of age.51

Figure P1-7

Chemical structure of stiripentol126 (PubChem CID: 5311454; IUPAC name: 4,4-dimethyl-1-[3,4-(methylendioxyphenyl)-1-pentene-3-ol).

Further Reading in Goodman & Gilman’s