FDA Approves DIACOMIT (Stiripentol) for Seizures Associated with Dravet syndrome in Patients 2 Years of Age and Older Taking Clobazam

On August 20, 2018, the U.S. Food and Drug Administration (FDA) approved DIACOMIT (stiripentol) for seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam. DIACOMIT is not indicated as monotherapy in Dravet syndrome. The approved recommended dosage of DIACOMIT capsules or powder for oral suspension is 50 mg/kg/day by mouth in 2 or 3 divided doses. DIACOMIT capsules should not be broken or opened, and must be swallowed whole with a glass of water during a meal. DIACOMIT powder for oral suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal. Round to the nearest possible dosage if the exact dosage is not achievable given the available 250 or 500 mg strengths. A combination of the two DIACOMIT strengths can be used to achieve the recommended dosage. The maximum recommended total dosage is 3,000 mg/day. Hematologic testing should be obtained prior to starting treatment with DIACOMIT. If treatment is discontinued, DIACOMIT should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: The mechanism by which DIACOMIT exerts its anticonvulsant effect in humans is unknown. Possible mechanisms of action include direct effects mediated through GABAA receptor and indirect effects involving inhibition of CYP450 activity.
  • General PK: Systemic exposure of stiripentol increases in a greater than dose proportional manner from 500 mg to 2000 mg.
  • Absorption: The median time to stiripentol peak plasma concentration is 2 to 3 hours.
  • Distribution: Protein binding of stiripentol is 99%.
  • Elimination: The elimination half-life ranges from 4.5 to 13 hours, increasing with doses of 500 mg, 1000 mg and 2000 mg.
  • Metabolism: In vitro studies suggest CYP1A2, CYP2C19, and CYP3A4 are involved in stiripentol metabolism.

Drug Interactions

  • Clobazam: Concomitant use of DIACOMIT increases plasma concentrations of clobazam (a substrate of CYP3A4) and norclobazam, the active metabolite of clobazam (a substrate of CYP2C19), which may increase the risk of clobazam-related adverse reactions. Consider a dosage reduction of clobazam if patient experiences adverse reactions with concomitant DIACOMIT.
  • CYP1A2, CYP2B6, CYP3A4 Substrates: Due to inhibition and induction in vitro, consider dosage adjustments of substrates of CYP1A2 (e.g., theophylline, caffeine), CYP2B6 (e.g., sertraline, thiotepa), and CYP3A4 (e.g., midazolam, triazolam, quinidine), as clinically appropriate when used concomitantly with DIACOMIT.
  • CYP2C8, CYP2C19, P-gp, BCRP Substrates: Due to inhibition in vitro, consider dosage reduction of substrates of CYP2C8, CYP2C19 (e.g., diazepam, clopidogrel), P-gp (e.g., carbamazepine), and BCRP (e.g., methotrxate, prazosin, glyburide), if patient experiences adverse reactions with concomitant DIACOMIT.
  • Strong CYP1A2, CYP3A4, CYP2C19 Inducers: Avoid use or adjust dosage of strong inducers of CYP1A2, CYP3A4, or CYP2C19, such as rifampin, phenytoin, phenobarbital, and carbamazepine, when used concomitantly with DIACOMIT.
  •  CNS Depressants and Alcohol: Concomitant use of DIACOMIT with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.

Use in Specific Populations

Sex does not have a clinically significant effect on the pharmacokinetics of stiripentol. The effect of age (≥ 65 years), race, renal or hepatic impairment on stiripentol pharmacokinetics is unknown. However, since DIACOMIT is mainly metabolized by the liver and its metabolites are eliminated mainly through the kidney, use of DIACOMIT is not recommended in patients with moderate or severe renal or hepatic impairment.

Pediatrics Patients: In a study of children (median age 7.3 years) with Dravet syndrome treated with DIACOMIT, valproate, and clobazam, the apparent clearance and volume of distribution of stiripentol were related to body weight. Elimination half-life increased from 8.5 hours (for 10 kg) to 23.5 hours (for 60 kg).

Efficacy and Safety

Efficacy of DIACOMIT was demonstrated in two multicenter, placebo-controlled, double-blind, randomized studies. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

Adverse reactions that occurred in at least 10% of DIACOMIT-treated patients and more frequently than in placebo consisted of somnolence, decreased appetite, agitation, ataxia, weight decreased, hypotonia, nausea, tremor, dysarthria, and insomnia.

Full prescribing information is available at https://go.usa.gov/xUzbr.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to [email protected].

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.