stiripentol (Rx)

>10%

Somnolence (67%)

Decreased appetite (46%)

Decreased weight (27%)

Ataxia (27%)

Agitation (27%)

Hypotonia (18%)

Nausea (15%)

Tremor (15%)

Dysarthria (12%)

1-10%

Vomiting (9%)

Fatigue (9%)

Aggression (9%)

Pyrexia (6%)

Bronchitis (6%)

Nasopharyngitis (6%)

Salivary hypersecretion (6%)

Increased weight (6%)

Contraindications

None

Cautions

Decreased appetite and weight may occur; nausea and vomiting also occurred more frequently in treated patients; given the frequency of these adverse reactions, carefully monitor growth of pediatric patients treated with stiripentol

Significant decline in neutrophil and platelet count reported; hematologic testing should be obtained prior to starting treatment and then every 6 months

Like many AEDs, gradually withdraw drug to minimize the risk of increased seizure frequency and status epilepticus (see Dosing Considerations)

AEDs, including stiripentol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication; monitor for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior

Phenylketonuria

• Phenylalanine can be harmful to patients with phenylketonuria (PKU); oral suspension contains phenylalanine, a component of aspartame
• Each 250-mg packet contains 1.4 mg phenylalanine; each 500-mg packet contains 2.8 mg phenylalanine
• Prior to prescribing the oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including stiripentol oral suspension; capsules do not contain phenylalanine

Somnolence

• In controlled studies in patients with Dravet syndrome, the incidence of somnolence was 67% in treated patients, compared with 23% in patients on placebo; all patients in both groups were on concomitant clobazam, which is also known to cause somnolence
• Caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effects on mental alertness is known

Drug interactions overview

• Effect of stiripentol on other drugs

  • In vitro data show that stiripentol is a CYP1A2, CYP2B6, and CYP3A4 inhibitor/inducer
  • Consider dose adjustment of CYP1A2 substrates (eg, theophylline, caffeine), CYP2B6 substrates (eg, sertraline, thiotepa), and CYP3A4 substrates (eg, midazolam, triazolam, quinidine), as clinically appropriate, when coadministered with stiripentol
  • Because of potential inhibition of enzyme/transporter activity, consider a reduction in dosage of substrates of CYP2C8, CYP2C19 (eg, diazepam, clopidogrel), P-gp (eg, carbamazepine), and BCRP (eg, methotrexate, prazosin, glyburide) if adverse reactions are experienced when administered concomitantly with stiripentol
  • Coadministration with clobazam results in increased plasma concentrations of clobazam (a substrate of CYP3A4) and norclobazam, the active metabolite of clobazam (a substrate of CYP2C19); may increase the risk of clobazam-related adverse reactions; consider a reduction in dosage of clobazam if adverse reactions are experienced when coadministered with stiripentol

• Effect of other drugs on stiripentol

  • Induction-based interactions leading to decreases in concentrations are possible when coadministered with a potent CYP1A2, CYP3A4, or CYP2C19 inducer, such as rifampin, phenytoin, phenobarbital, or carbamazepine, as these enzymes all metabolize stiripentol; avoid concomitant use of strong inducers with stiripentol, or dosage adjustments should be made

• CNS depressants

  • Other CNS depressants, including alcohol, could potentiate the somnolence effect of stiripentol; monitor patients for somnolence
  • If somnolence occurs during coadministration with clobazam, consider an initial reduction of clobazam by 25%
  • If somnolence persists, consider further clobazam reduction by an additional 25% and adjust dosage of other concomitant anticonvulsant drugs with sedating properties

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs during pregnancy

Recommend pregnant patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; register by calling the toll free number 1-888-233-2334, and this must be done by patients themselves or their caregiver

Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/

There are no adequate data on the developmental risks associated with the use in pregnant women

Animal data

• Administration of stiripentol to pregnant animals produced evidence of developmental toxicity, including increased incidences of fetal malformations, increased embryofetal and pup mortality, and decreased embryofetal and pup growth, at maternal doses lower than the recommended clinical dose

Lactation

There are no data on the presence of stiripentol in human milk, the effects on the breastfed infant, or the effects on milk production

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Anticonvulsant effect in humans is unknown

Possible mechanisms of action include direct effects mediated through the gamma-aminobutyric acid (GABA) A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and its active metabolite

Absorption

Peak plasma time: 2-3 hr

Distribution

Protein binding: 99%

Metabolism

Metabolized in the liver by CYP1A2, CYP2C19, and CYP3A4

Elimination

Half-life (healthy adults): 4.5-13 hr, increasing with doses of 500 mg, 1000 mg, and 2000 mg

Half-life (children [median age 7.3 years] with Dravet syndrome): 8.5 hr (10-kg patient); 23.5 hr (60-kg patient)

Oral Administration

Capsules

• Swallow whole with a glass of water during a meal
• Capsule should not be broken or opened

Powder for oral suspension

• Mix in a glass of water (100 mL) and take immediately after mixing during a meal
• To be sure there is no medicine left in the glass, add a small amount of water (25 mL) to the drinking cup and drink all of the mixture
• Do not store mixture after it is mixed; must be administered immediately after mixing

Missed dose

• A missed dose should be taken as soon as possible
• If it is almost time for the next dose, do not take the missed dose; instead, the next scheduled dose should be taken
• Do not double-dose

Storage

Store in a dry place at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)