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Stiripentol

Class: Anticonvulsants, Miscellaneous
Chemical Name: 4,4-Dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-ol
Molecular Formula: C14H18O3
CAS Number: 49763-96-4
Brands: Diacomit

Medically reviewed by Drugs.com on Nov 23, 2020. Written by ASHP.

Introduction

Anticonvulsant; an aromatic allylic alcohol.

Uses for Stiripentol

Seizure Disorders

Adjunctive treatment of seizures associated with Dravet syndrome in patients ≥2 years of age taking clobazam. Designated an orphan drug by FDA for use in this condition.

Evidence of efficacy is based on studies in which stiripentol was administered as add-on therapy to clobazam and valproate; efficacy of stiripentol as monotherapy not established.

Stiripentol Dosage and Administration

General

  • Assess CBCs prior to initiating therapy and every 6 months during therapy. (See Hematologic Effects under Cautions.)

  • Avoid abrupt discontinuance; withdraw gradually to minimize potential for increased seizure frequency and status epilepticus. (See Discontinuance of Therapy under Cautions.)

  • Monitor for emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. (See Suicidality Risk under Cautions.)

Restricted Distribution

  • Obtain stiripentol through designated specialty pharmacies.

  • Contact specialty pharmacy provider at 833-248-0467 or consult https://www.diacomit.com/support/ for additional information.

Administration

Oral Administration

Administer orally (as tablets or oral suspension) in 2 or 3 divided doses with meals.

Swallow capsules whole with water during a meal; do not break or open capsules.

To prepare oral suspension, mix the appropriate number of packets with 100 mL of water and consume immediately after mixing during a meal. To ensure that the entire dose is consumed, add a small amount of water (25 mL) to the glass and swallow.

If a dose is missed, administer missed dose as soon as possible. If it is almost time for next dose, skip missed dose and take next dose at regularly scheduled time. Do not double the dose to replace a missed dose.

Dosage

Pediatric Patients

Seizure Disorders
Dravet Syndrome
Oral

Children and adolescents ≥2 years of age: 50 mg/kg daily, divided in 2 or 3 doses (i.e., 16.67 mg/kg 3 times daily or 25 mg/kg twice daily).

Round the calculated dosage to nearest achievable dosage strength (usually within 50–150 mg of the recommended daily dosage) using stiripentol capsules or packets of powder for oral suspension. May use a combination of the 2 commercially available strengths (250 and 500 mg) to achieve the dosage.

Adults

Seizure Disorders
Dravet Syndrome
Oral

50 mg/kg daily, divided in 2 or 3 doses (i.e., 16.67 mg/kg 3 times daily or 25 mg/kg twice daily).

Round the calculated dosage to nearest achievable dosage strength (usually within 50–150 mg of the recommended daily dosage) using stiripentol capsules or packets of powder for oral suspension. May use a combination of the 2 commercially available strengths (250 and 500 mg) to achieve the dosage.

Prescribing Limits

Pediatric Patients

Seizures Associated with Dravet Syndrome
Oral

Maximum 3 g daily.

Adults

Seizures Associated with Dravet Syndrome
Oral

Maximum 3 g daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment: No specific dosage recommendations.

Moderate or severe hepatic impairment: Use not recommended. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild renal impairment: No specific dosage recommendations.

Moderate or severe renal impairment: Use not recommended. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.

Cautions for Stiripentol

Contraindications

  • None.

Warnings/Precautions

Somnolence

Somnolence may occur; concomitant use with other CNS depressants may potentiate the effect. (See Specific Drugs under Interactions.)

Monitor for somnolence, particularly when used concomitantly with other CNS depressants, including alcohol. If somnolence occurs during coadministration with clobazam, consider initial 25% reduction in dosage of clobazam. If somnolence persists, consider additional 25% reduction in clobazam dosage along with dosage adjustments to other concomitant anticonvulsants that can cause sedation. (See Advice to Patients.)

Decreased Appetite and Weight Loss

May cause decreased appetite and weight loss; nausea and vomiting also may occur.

Carefully monitor patient weight and growth rate in pediatric patients.

In patients receiving concomitant valproate, reducing the weekly valproate dosage by 30% may decrease effects on appetite and weight.

Hematologic Effects

Substantial decreases in neutrophil and/or platelet counts may occur.

Monitor CBC prior to initiation of therapy and every 6 months during treatment.

Discontinuance of Therapy

Abrupt withdrawal of anticonvulsants may increase seizure frequency and risk of status epilepticus. Withdraw gradually; if more rapid withdrawal is necessary (e.g., due to serious adverse reaction), appropriate monitoring recommended.

Phenylketonuria (PKU)

Each 250- or 500-mg packet of stiripentol powder contains 1.40 or 2.80 mg of phenylalanine, respectively. Consider total daily intake of phenylalanine from all sources prior to use of the powder formulation in patients with PKU.

Stiripentol capsules do not contain phenylalanine.

Suicidality Risk

Increased risk of suicidal thoughts or behavior observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions; risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed as early as 1 week after initiation of anticonvulsant therapy; because most studies were ≤24 weeks' duration, risk of treatment beyond 24 weeks not known. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.

Monitor all patients receiving anticonvulsants for suicidal thoughts and behavior. If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself. (See Advice to Patients.)

Specific Populations

Pregnancy

Based on animal data, may cause fetal harm. No adequate data in humans. In animal studies, developmental toxicity and embryofetal mortality observed at doses lower than those recommended in humans.

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].

Lactation

Not known whether distributed into milk; effects on milk production or breast-fed infant also not known. Consider benefits of breast-feeding and importance of stiripentol to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.

Clearance of stiripentol is related to body weight; because adolescents may have higher plasma concentrations compared with younger children, some clinicians recommend that dosage adjustments be considered in this age group to minimize potential for adverse effects.

Geriatric Use

No experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Consider potential age-related abnormalities in hepatic and renal function.

Hepatic Impairment

Not studied in patients with hepatic impairment. Use not recommended in patients with moderate or severe hepatic impairment.

Renal Impairment

Not studied in patients with renal impairment. Use not recommended in patients with moderate or severe renal impairment.

Common Adverse Effects

Somnolence, decreased appetite, agitation, ataxia, decreased weight, hypotonia, nausea, tremor, dysarthria, insomnia.

Interactions for Stiripentol

Substrate of CYP1A2, CYP2C19, and CYP3A4 in vitro. Inhibits and induces CYP1A2, CYP2B6, and CYP3A4. Inhibits CYP2C8 and CYP2C19.

Inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP1A2, CYP3A4, or CYP2C19 inducers: Possible decreased stiripentol concentrations. Avoid concomitant use; if concomitant use cannot be avoided, consider dosage increase of stiripentol.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2, CYP2B6, or CYP3A4 substrates: Possible altered concentrations of the substrate drug. Adjust dosage of the substrate drug as clinically appropriate.

CYP2C8 or CYP2C19 substrates: Possible increased concentrations of the substrate drug. If adverse reactions related to the substrate drug occur, consider reducing dosage of the substrate drug.

Transporter Systems

P-gp or BCRP substrates: Possible pharmacokinetic interactions. A reduction in dosage of the P-gp or BCRP substrate may be necessary if adverse reactions occur during concomitant use.

Specific Drugs

Drug

Interaction

Comments

Alcohol

Increased risk of sedation and somnolence

Avoid alcohol consumption during stiripentol treatment

Caffeine

Possible altered concentrations of caffeine (CYP1A2 substrate)

Adjust dosage of caffeine as clinically appropriate

Cannabidiol

Slight increase in stiripentol concentrations; not likely to be clinically important

No clinically important effect on cannabidiol pharmacokinetics

Carbamazepine

Possible decreased stiripentol concentrations

Possible increased concentrations of carbamazepine (P-gp substrate)

Avoid concomitant use; if concomitant use cannot be avoided, consider increasing stiripentol dosage

If adverse reactions related to carbamazepine occur, consider reducing carbamazepine dosage

Clobazam

Increased plasma concentrations of clobazam and norclobazam by approximately twofold and fivefold, respectively; may increase risk of clobazam-related adverse reactions

If somnolence occurs, consider initial 25% reduction in dosage of clobazam

If somnolence persists, consider additional 25% reduction in dosage of clobazam and also consider dosage adjustments to other concomitant anticonvulsants that can cause sedation

Clopidogrel

Possible increased concentrations of clopidogrel (CYP2C19 substrate)

If adverse reactions related to clopidogrel occur, consider reducing clopidogrel dosage

CNS Depressants

Increased risk of sedation and somnolence

Diazepam

Possible increased concentrations of diazepam

If adverse reactions related to diazepam occur, consider reducing diazepam dosage

Glyburide

Possible increased concentrations of glyburide (BCRP substrate)

If adverse reactions related to glyburide occur, consider reducing glyburide dosage

Methotrexate

Possible increased concentrations of methotrexate (BCRP substrate)

If adverse reactions related to methotrexate occur, consider reducing methotrexate dosage

Midazolam

Possible altered concentrations of midazolam (CYP3A4 substrate)

Adjust dosage of midazolam as clinically appropriate

Phenobarbital

Possible decreased stiripentol concentrations

Avoid concomitant use; if concomitant use cannot be avoided, consider increasing stiripentol dosage

Phenytoin

Possible decreased stiripentol concentrations

Avoid concomitant use; if concomitant use cannot be avoided, consider increasing stiripentol dosage

Prazosin

Possible increased concentrations of prazosin (BCRP substrate)

If adverse reactions related to prazosin occur, consider reducing prazosin dosage

Quinidine

Possible altered concentrations of quinidine (CYP3A4 substrate)

Adjust dosage of quinidine as clinically appropriate

Rifampin

Possible decreased stiripentol concentrations

Avoid concomitant use; if concomitant use cannot be avoided, consider increasing stiripentol dosage

Sertraline

Possible altered concentrations of sertraline (CYP2B6 substrate)

Adjust dosage of sertraline as clinically appropriate

Theophylline

Possible altered concentrations of theophylline (CYP1A2 substrate)

Adjust dosage of theophylline as clinically appropriate

Thiotepa

Possible altered concentrations of thiotepa (CYP2B6 substrate)

Adjust dosage of thiotepa as clinically appropriate

Triazolam

Possible altered concentrations of triazolam (CYP3A4 substrate)

Adjust dosage of triazolam as clinically appropriate

Valproate

Moderate increase in valproate concentrations

If valproate-related adverse effects occur (e.g., loss of appetite, loss of weight), consider reducing weekly valproate dosage by 30%

Stiripentol Pharmacokinetics

Absorption

Bioavailability

Exhibits nonlinear pharmacokinetics; systemic exposure increases in a greater than dose proportional manner over dose range of 500 mg to 2 g.

Rapidly and extensively absorbed following oral administration. Absolute bioavailability not known.

Peak plasma concentrations occur approximately 2–3 hours following oral administration.

Capsules and oral suspension formulation are not bioequivalent. AUC and time to peak plasma concentrations are comparable, but peak plasma concentrations are 23% higher with oral suspension compared with capsules; however, this difference is not likely to be clinically important because of substantial interpatient variability in absorption.

Distribution

Plasma Protein Binding

99%.

Elimination

Metabolism

Extensively metabolized; metabolic pathway not fully characterized but principally metabolized by several CYP isoenzymes including CYP1A2, CYP2C19, and CYP3A4.

No known active circulating metabolites.

Elimination Route

Mainly eliminated renally as metabolites. Following oral administration, approximately 73% of the dose was eliminated in urine as metabolites and 13–24% was recovered in feces as unchanged drug.

Half-life

4.5–13 hours.

Special Populations

Clearance in pediatric patients is affected by body weight. Elimination half-life increased from 8.5 hours for a 10-kg patient to 23.5 hours for a 60-kg patient.

Stiripentol concentrations are approximately 58% lower in children <6 years of age and 40% lower in children 6–12 years of age compared with children >12 years of age.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Powder for Suspension

20–25°C (may be exposed to 15–30°C).

Actions

  • Exact mechanism of anticonvulsant action not fully elucidated; may involve multiple direct and indirect mechanisms including enhancement of GABA neurotransmission and potentiation of the effects of concomitantly administered anticonvulsants (e.g., clobazam) through pharmacodynamic and pharmacokinetic interactions.

  • Acts as a positive allosteric modulator of GABAA receptors at a site distinct from benzodiazepines, thereby acting independently and additively with benzodiazepines at GABAA receptors.

  • Increases plasma concentrations of clobazam and its active metabolite norclobazam (N-desmethylclobazam) via inhibition of CYP enzymes; because these drugs are used in combination, the pharmacokinetic interaction may contribute indirectly to the anticonvulsant activity of stiripentol. (See Specific Drugs under Interactions.)

Advice to Patients

  • Importance of advising patients or caregivers to read the manufacturer's patient information (medication guide and instructions for use).

  • Importance of informing patients or caregivers that stiripentol should be taken with a meal. Capsules should be swallowed whole with a glass of water during a meal and should not be broken or opened. Stiripentol powder for oral suspension should be mixed in a glass of water and taken immediately during a meal. (See Administration under Dosage and Administration.)

  • Risk of somnolence, which may require a decrease in the dosage of concomitant clobazam. Importance of advising patients to avoid alcohol consumption during stiripentol therapy. Importance of advising patients not to engage in hazardous activities requiring mental alertness, such as operating a motor vehicle or other dangerous machinery, until the effects of the drug are known. (See Somnolence under Cautions.)

  • Importance of advising patients or caregivers that decreased appetite is common during stiripentol therapy, and that nausea and vomiting also may occur. These adverse effects can lead to weight loss.

  • Importance of advising patients or caregivers not to abruptly discontinue stiripentol therapy without consulting with their clinician. Abrupt withdrawal of anticonvulsant therapy may increase the risk of seizures or status epilepticus.

  • Risk of neutropenia and thrombocytopenia. Importance of hematologic testing prior to initiation of stiripentol and every 6 months during therapy.

  • Importance of counseling patients, caregivers, and family members that anticonvulsants, including stiripentol, may increase the risk of suicidal thoughts and behavior and advising them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thought of self-harm. Patients, caregivers, or family members should inform clinician immediately if any behaviors of concern occur.

  • Importance of women notifying clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians encouraging patients to enroll in the NAAED Pregnancy Registry if they become pregnant. (See Pregnancy under Cautions.)

  • Importance of women notifying clinicians if they are breast-feeding or intend to breast-feed during therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of stiripentol is restricted. (See Restricted Distribution under Dosage and Administration.)

Stiripentol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

250 mg

Diacomit

Biocodex

500 mg

Diacomit

Biocodex

Powder for oral suspension

250 mg per packet

Diacomit

Biocodex

500 mg per packet

Diacomit

Biocodex

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 23, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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