AHFS Class:

• GABA-mediated Anticonvulsants 28:12.28

Generic Name(s):

• Stiripentol

Stiripentol, an aromatic allylic alcohol, is an anticonvulsant.1,3,5,7,8

Seizure Disorders

Seizures Associated with Dravet Syndrome

Stiripentol is used for the adjunctive treatment of seizures associated with Dravet syndrome in patients 2 years of age or older taking clobazam.1,2,15 The drug has been designated an orphan drug by FDA for use in this condition.6 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 for the treatment of Dravet syndrome has not been established.1

Dravet syndrome (also known as severe myoclonic epilepsy of infancy) is a rare and severe type of epilepsy characterized by early onset of multiple refractory seizure types, frequent episodes of status epilepticus, and developmental delay with cognitive and psychomotor impairment.9,10,15,17,18 Up to 85% of patients with Dravet syndrome have mutations in the SCN1A gene encoding the voltage-gated sodium channel.9,10 Seizures in patients with Dravet syndrome are generally refractory to current anticonvulsant drug options; certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, lamotrigine, phenobarbital, phenytoin, vigabatrin) may exacerbate the condition and should be avoided.9,10,17 Although evidence from controlled studies is limited,14,15,16,17 experts generally recommend initial treatment with either clobazam† or valproic acid†, followed by a combination of both drugs; however, adequate seizure control is rarely achieved with these drugs alone, and most patients will require additional anticonvulsant agents.10,14,17,18 Stiripentol has been recommended as a second-line anticonvulsant option in patients with Dravet syndrome.8,10,14,17,18 Because complete seizure freedom is typically not achievable, treatment is generally aimed at reducing the frequency of the most problematic seizures while minimizing adverse effects of anticonvulsant therapy.10,14,17,18 (See Dravet Syndrome under Uses: Epilepsy Syndromes, in the Anticonvulsants General Statement 28:12.)

Efficacy of stiripentol for the treatment of seizures associated with Dravet syndrome has been established in 2 randomized, placebo-controlled, double-blind, multicenter studies (STICLO-France and STICLO-Italy) in a total of 64 patients 3 to less than 18 years of age with Dravet syndrome whose seizures were inadequately controlled on clobazam and valproate (i.e., at least 4 generalized clonic or tonic-clonic seizures per month despite optimized therapy).1,2,3 Patients continued to receive their optimized anticonvulsant therapy during a 1-month baseline period and then were randomized to receive add-on therapy with stiripentol (fixed dosage of 50 mg/kg daily administered in 2 or 3 divided doses) or placebo for 2 months.1,2,3 The primary measure of efficacy in both studies was the responder rate, defined as the percentage of patients who experienced a greater than 50% decrease in the frequency of generalized clonic or tonic-clonic seizures during the double-blind treatment period compared with the baseline period.1,2,3

In both studies, the responder rate was substantially higher in patients receiving add-on therapy with stiripentol compared with those receiving placebo (71 versus 5% in STICLO-France and 67 versus 9% in STICLO-Italy).1,2,3 In addition, the mean frequency of generalized clonic or tonic-clonic seizures was substantially reduced with add-on stiripentol treatment compared with placebo.1,2,3 Across both studies, a greater proportion of stiripentol-treated patients had reductions in seizure frequency of 50% or greater compared with placebo.1 Pooled results showed that the overall seizure rate was reduced by 70% with add-on stiripentol therapy.16 Seizure freedom from generalized clonic or tonic-clonic seizures was achieved in 43 and 25% of patients receiving stiripentol in the STICLO-France and STICLO-Italy studies, respectively, compared with none of the placebo recipients.1,2,3

General

Because stiripentol may cause a decrease in neutrophil and/or platelet counts, complete blood counts (CBCs) should be assessed prior to initiating therapy and every 6 months during therapy.1 (See Hematologic Effects under Cautions: Warnings/Precautions.)

As with most anticonvulsant agents, stiripentol should be withdrawn gradually to minimize the potential for increased seizure frequency and status epilepticus.1 (See Discontinuance of Therapy under Cautions: Warnings/Precautions.)

Patients receiving therapy with an anticonvulsant, including stiripentol, for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.1 (See Suicidality Risk under Cautions: Warnings/Precautions.)

Restricted Distribution

Stiripentol can only be obtained through a designated specialty pharmacy.11 Clinicians may contact the specialty pharmacy provider at 833-248-0467 or consult [Web]/support/ for additional information.11,12

Administration

Stiripentol is administered orally (as capsules or oral suspension) in 2 or 3 divided doses with meals.1

Stiripentol capsules must be swallowed whole with a glass of water during a meal; the capsules should not be broken or opened.1

To prepare the oral suspension, the appropriate number of packets of powder should be mixed in a glass containing 100 mL of water and consumed immediately after mixing during a meal.1 To ensure that the entire dose is consumed, a small amount of water (25 mL) should be added to the glass and then swallowed.1

If a dose is missed, the missed dose should be taken as soon as possible.1 If it is almost time for the next dose, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.1 The dose should not be doubled to replace a missed dose.1

Dosage

For the adjunctive treatment of seizures associated with Dravet syndrome in adults and pediatric patients 2 years of age or older taking clobazam, the recommended dosage of stiripentol is 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).1 Dosage titration is not necessary.5 The maximum recommended daily dosage is 3 g.1

The calculated dosage should be rounded to the nearest achievable dosage strength (usually within 50-150 mg of the recommended daily dosage) using stiripentol capsules or packets of powder for oral suspension.1 A combination of the 2 commercially available strengths of stiripentol (250 and 500 mg) may be used to achieve the dosage.1

Special Populations

The manufacturer makes no specific dosage recommendations for patients with mild renal impairment.1 Use of the drug is not recommended in patients with moderate or severe renal impairment.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer makes no specific dosage recommendations for patients with mild hepatic impairment.1 Use of the drug is not recommended in patients with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

The manufacturer states that there are no known contraindications to the use of stiripentol.1

Warnings/Precautions

Somnolence

Stiripentol may cause somnolence.1 In controlled studies in patients with Dravet syndrome, somnolence was reported in 67% of stiripentol-treated patients compared with 23% of those receiving placebo.1 All of the patients in these studies were receiving concomitant clobazam, which also has sedating effects.1 Concurrent administration of stiripentol and clobazam can result in increased concentrations of clobazam and its active metabolite, further increasing the risk of sedation.1 Somnolence also may be potentiated by concomitant use of other CNS depressants, including alcohol.1

Patients receiving stiripentol should be monitored for somnolence, particularly when other CNS depressants are used concurrently.1 If somnolence occurs during coadministration with clobazam, an initial 25% reduction in the dosage of clobazam should be considered.1 If somnolence persists, an additional 25% reduction in the clobazam dosage should be considered along with adjustments to other concomitant anticonvulsants that can cause sedation.1 (See Drug Interactions and see also Advice to Patients.)

Decreased Appetite and Weight Loss

Stiripentol may cause decreases in appetite and weight loss.1 In controlled studies in patients with Dravet syndrome, decreased appetite or weight loss was reported in 46 or 27% of stiripentol-treated patients, respectively, compared with 10 or 6% of placebo recipients, respectively.1 Nausea and vomiting also occurred more frequently in patients receiving stiripentol than those receiving placebo.1

Body weight should be monitored in patients receiving stiripentol therapy.1 In addition, growth rate in pediatric patients receiving the drug should be carefully monitored.1

In patients receiving concomitant valproate, a 30% reduction in the weekly valproate dosage may reduce the effects of stiripentol on appetite and weight.1

Hematologic Effects

Stiripentol may cause substantial decreases in neutrophil and/or platelet counts.1 Among patients in whom neutrophil counts were monitored in controlled studies, a decline in absolute neutrophil count to less than 1500/mm³ was observed in 13% of stiripentol-treated patients compared with none of the placebo recipients.1 Among patients in whom platelet counts were monitored in controlled studies, a decrease in platelet count to less than 150,000/mm³ was observed in 13% of stiripentol-treated patients compared with none of the placebo recipients.1

Complete blood counts (CBCs) should be obtained prior to initiation of stiripentol therapy and every 6 months during treatment.1

Discontinuance of Therapy

As with most anticonvulsants, stiripentol should generally be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus.1 If rapid discontinuance of stiripentol is necessary (e.g., because of a serious adverse reaction), appropriate monitoring is recommended.1

Phenylketonuria

Stiripentol powder for suspension contains phenylalanine (a component of aspartame), which can be harmful to individuals with phenylketonuria (PKU).1 Each 250- or 500-mg packet of stiripentol powder for oral suspension contains 1.4 or 2.8 mg of phenylalanine, respectively.1 Before prescribing stiripentol powder for suspension to a patient with PKU, the combined daily amount of phenylalanine from all sources, including stiripentol powder for suspension, should be considered.1 Stiripentol capsules do not contain phenylalanine.1

Suicidality Risk

The risk of suicidal thoughts or behavior is increased in patients receiving anticonvulsants, including stiripentol, for any indication.1 An analysis of suicidality reports from 199 placebo-controlled studies involving 11 different anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1 This increased suicidality risk was consistent among anticonvulsants with varying mechanisms of actions and across a range of indications, and was observed as early as 1 week after beginning therapy.1 Because most of these studies did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior with anticonvulsant treatment beyond 24 weeks is not known.1 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1

Clinicians who prescribe stiripentol or any other anticonvulsant should balance the risk of suicidal thoughts or behavior with the risk of untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 All patients treated with an anticonvulsant for any indication should be closely monitored for the emergence or worsening of suicidal thoughts and behavior.1 If any such symptoms emerge during anticonvulsant therapy, the clinician should consider whether they may be related to the illness being treated.1 (See Advice to Patients.)

Specific Populations

Pregnancy

Based on animal data, stiripentol may cause fetal harm.1 There are no adequate data on the developmental risks associated with the use of stiripentol in pregnant women.1 Stiripentol produced developmental toxicity (e.g., fetal malformations, embryofetal mortality) when administered orally to pregnant animals at doses lower than those recommended in humans.1

Women who are pregnant while receiving stiripentol should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].1

Lactation

It is not known whether stiripentol is distributed into milk, affects milk production, or affects the breast-fed infant.1 The benefits of breast-feeding should be considered along with the importance of stiripentol to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of stiripentol for the treatment of seizures associated with Dravet syndrome have been established in pediatric patients 2 years of age or older receiving clobazam.1 The principal efficacy studies included pediatric patients 3 years of age or older.1 Efficacy of stiripentol in patients 2-3 years of age was extrapolated from the demonstration of effectiveness in older pediatric patients.1

Safety and efficacy of stiripentol have not been established in pediatric patients younger than 2 years of age.1

Clearance and volume of distribution of stiripentol are affected by body weight in pediatric patients.1,8 Elimination half-life increased from 8.5 hours for a 10-kg patient to 23.5 hours in a 60-kg patient.1,8 Compared with children older than 12 years of age, mean stiripentol concentrations are decreased by approximately 40% in children 6-12 years of age and by 57.5% in children younger than 6 years of age.8 Some clinicians suggest that dosage adjustments be considered in adolescents to reduce toxicity and adverse effects associated with higher plasma concentrations of the drug.8 (See Description.)

Geriatric Use

There is no experience with use of stiripentol in patients 65 years of age or older to determine whether these patients respond differently than younger adults.1 When stiripentol is used in patients 65 years of age or older, potential age-related abnormalities in hepatic and renal function should be considered.1

Hepatic Impairment

The pharmacokinetics of stiripentol have not been formally studied in patients with hepatic impairment.1 Because stiripentol is primarily metabolized by the liver, use of the drug in patients with moderate or severe hepatic impairment is not recommended.1

Renal Impairment

The pharmacokinetics of stiripentol have not been formally studied in patients with renal impairment.1 Because stiripentol metabolites are primarily eliminated renally, use of the drug in patients with moderate or severe renal impairment is not recommended.1

Common Adverse Effects

Adverse effects reported in at least 10% of patients with Dravet syndrome receiving stiripentol in addition to clobazam and valproate in controlled clinical trials and more frequently than with placebo include somnolence, decreased appetite, agitation, ataxia, decreased weight, hypotonia, nausea, tremor, dysarthria, and insomnia.1

Stiripentol is a substrate of cytochrome P-450 (CYP) isoenzymes 1A2, 2C19, and 3A4 in vitro.1 In vitro data indicate that stiripentol may inhibit and induce CYP isoenzymes 1A2, 2B6, and 3A4, and also inhibit CYP2C8 and CYP2C19.1 Stiripentol also can inhibit drug transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1

Drugs Affecting Hepatic Microsomal Enzymes

CYP1A2, CYP3A4, and CYP2C19 Inducers

Concomitant use of stiripentol with potent inducers of CYP1A2, CYP3A4, or CYP2C19 (e.g., rifampin, phenytoin, phenobarbital, carbamazepine) may result in decreased stiripentol concentrations and should be avoided.1 If concomitant use cannot be avoided, dosage increase of stiripentol should be considered.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2, CYP2B6, and CYP3A4 Substrates

Concomitant use of stiripentol with drugs metabolized by CYP1A2 (e.g., theophylline, caffeine), CYP2B6 (e.g., sertraline, thiotepa), or CYP3A4 (e.g., midazolam, triazolam, quinidine) may result in altered concentrations of the substrate drug because stiripentol can inhibit or induce these CYP isoenzymes.1 Dosage adjustment of the CYP1A2, CYP2B6, or CYP3A4 substrate should be considered as clinically appropriate during concomitant use.1

CYP2C8 and CYP2C19 Substrates

Concomitant use of stiripentol with drugs metabolized by CYP2C8 or CYP2C19 (e.g., diazepam, clopidogrel) may result in increased concentrations and adverse effects of the substrate drug.1 A reduction in dosage of the CYP2C8 or CYP2C19 substrate should be considered if adverse reactions occur during concomitant use.1

Transporter Systems

Because stiripentol may inhibit transporter activity, drug interactions may occur between stiripentol and drugs that are substrates of P-gp (e.g., carbamazepine) or BCRP (e.g., methotrexate, prazosin, glyburide).1 A reduction in dosage of the P-gp or BCRP substrate should be considered if adverse reactions occur during concomitant use.1

CNS Depressants

Concomitant use of stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.1 Alcohol consumption should be avoided during stiripentol therapy.1

Anticonvulsants

Cannabidiol

In a pharmacokinetic drug interaction study in healthy individuals, concomitant use of cannabidiol and stiripentol slightly increased peak plasma concentrations and area under the concentration-time curve (AUC) of stiripentol (by 1.3- and 1.6-fold, respectively), which is unlikely to be clinically important.13 No clinically important effects on cannabidiol pharmacokinetics were observed.13

Clobazam

Concomitant administration of stiripentol and clobazam increased plasma concentrations of clobazam (a CYP3A4 substrate) and its active metabolite norclobazam (a CYP2C19 substrate) by approximately twofold and fivefold, respectively; such increased concentrations may increase the risk of clobazam-related adverse reactions.1 If somnolence occurs during concomitant therapy with stiripentol and clobazam, an initial 25% reduction in dosage of clobazam should be considered.1 If somnolence persists, an additional 25% reduction in the clobazam dosage should be considered along with adjustments to other concomitant anticonvulsants that can also cause sedation.1 (See Drug Interactions: Anticonvulsants and see also Somnolence under Cautions: Warnings/Precautions.)

Valproate

In clinical studies in patients with Dravet syndrome receiving valproate and clobazam, the addition of stiripentol resulted in a modest increase in valproate concentrations.5,7,8 If valproate-related adverse effects occur (e.g., loss of appetite, loss of weight) during concomitant use of stiripentol, a reduction in the weekly valproate dosage by 30% may minimize these effects.1,7 (See Decreased Appetite and Weight Loss under Cautions: Warnings/Precautions.)

Description

Stiripentol, an aromatic allylic alcohol, is an anticonvulsant.1,3,5,7,8 The drug is structurally distinct from other currently available anticonvulsant agents.3,5,7

The exact mechanism of action by which stiripentol exerts its anticonvulsant effects has not been fully elucidated, but may involve multiple direct and indirect mechanisms including enhancement of γ-aminobutyric acid (GABA) neurotransmission and potentiation of the effects of concomitantly administered anticonvulsants (e.g., clobazam) through pharmacodynamic and pharmacokinetic interactions.1,3,4,7 In vitro studies indicate that the drug acts as a positive allosteric modulator of the GABA type A (GABA_A) receptor at a site distinct from benzodiazepines, thereby acting independently and additively with benzodiazepines at GABA_A receptors.3,4 Stiripentol enhances the opening duration rather than the opening frequency of GABA_A receptor-dependent chloride channels.3,4,8 Stiripentol also can increase plasma concentrations of clobazam (and its norclobazam metabolite) via inhibition of cytochrome P-450 (CYP) enzymes; because these drugs are used in combination, the pharmacokinetic interaction may contribute indirectly to the anticonvulsant activity of stiripentol.1,4 (See Clobazam under Drug Interactions: Anticonvulsants.)

Stiripentol exhibits nonlinear pharmacokinetics;3,7 systemic exposure increases in a greater than dose-proportional manner over the dose range of 500 mg to 2 g.1,3,7 Stiripentol is rapidly and extensively absorbed following oral administration.3,5,7 Peak plasma concentrations occur within 2-3 hours following oral administration.1 Peak plasma concentrations are 23% higher when the drug is administered as an oral suspension compared with administration as capsules; however, the area under the concentration-time curve (AUC) and time to peak plasma concentrations are similar between the dosage forms.5,7 Plasma protein binding of stiripentol is 99%.1 Stiripentol is extensively metabolized.3,5,7 Although the metabolic pathway of stiripentol has not been fully characterized, in vitro studies indicate that the metabolism of stiripentol is principally mediated by several CYP isoenzymes including CYP1A2, 2C19, and 3A4.1 The elimination half-life of stiripentol ranges from 4.5-13 hours.1 Stiripentol is mainly eliminated in the urine;1 following oral administration, approximately 73% of the dose was recovered in urine as metabolites and 13-24% was recovered in feces as unchanged drug.5

Advice to Patients

Importance of advising patients or caregivers to read the manufacturer's patient information (medication guide and instructions for use).1

Importance of informing patients or caregivers that stiripentol should be taken with a meal.1 Capsules should be swallowed whole with a glass of water during a meal and should not be broken or opened.1 Stiripentol powder should be mixed in a glass of water and taken immediately during a meal.1 (See Dosage and Administration: Administration.)

Risk of somnolence, which may require a decrease in the dosage of concomitant clobazam.1 Importance of advising patients to avoid alcohol consumption during stiripentol therapy.1 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.1 (See Somnolence under Cautions: Warnings and Precautions.)

Importance of advising patients or caregivers that decreased appetite is common during stiripentol therapy, and that nausea and vomiting also may occur.1 These adverse effects can lead to weight loss.1

Importance of advising patients or caregivers not to abruptly discontinue stiripentol therapy without consulting with their clinician.1 Abrupt withdrawal of anticonvulsant therapy may increase the risk of seizures or status epilepticus.1

Risk of neutropenia and thrombocytopenia.1 Importance of hematologic testing prior to initiation of stiripentol and every 6 months during therapy.1

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.1 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 if they are breast-feeding or plan to breast-feed during therapy.1 Importance of clinicians encouraging patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

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.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Biocodex, Inc. Diacomit^® (stiripentol) capsules and powder for oral suspension prescribing information. Redwood City, CA; 2018 Aug.

2. 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; 356:1638-42. [PubMed 11089822]

3. Frampton JE. Stiripentol: A Review in Dravet Syndrome. Drugs . 2019; 79:1785-1796. [PubMed 31617141]

4. Nabbout R, Chiron C. Stiripentol: an example of antiepileptic drug development in childhood epilepsies. Eur J Paediatr Neurol . 2012; 16 Suppl 1:S13-7. [PubMed 22695038]

5. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206709Orig1s000, 207223Orig1s000: Summary review. From FDA website. [Web]

6. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 Dec 3. [Web]

7. Plosker GL. Stiripentol : in severe myoclonic epilepsy of infancy (dravet syndrome). CNS Drugs . 2012; 26:993-1001. [PubMed 23018548]

8. Eschbach K, Knupp KG. Stiripentol for the treatment of seizures in Dravet syndrome. Expert Rev Clin Pharmacol . 2019; 12:379-388. [PubMed 31017478]

9. Gataullina S, Dulac O. From genotype to phenotype in Dravet disease. Seizure . 2017; 44:58-64. [PubMed 27817982]

10. 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. [PubMed 28284397]

11. Dravet Syndrome Foundation. Stiripentol Access. From Dravet Syndrome Foundation website. Accessed 2020 Jan 13. [Web]

12. Biocodex. Diacomit (stiripentol) website. Accessed 2020 Jan 13. [Web]

13. 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 Pharmacol Drug Dev . 2019; 8:1009-1031. [PubMed 30791225]

14. Wirrell EC. Treatment of Dravet Syndrome. Can J Neurol Sci . 2016; 43 Suppl 3:S13-8. [PubMed 27264138]

15. Brigo F, Igwe SC, Bragazzi NL. Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy. Cochrane Database Syst Rev . 2017; 5:CD010483. [PubMed 28521067]

16. Kassaï 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; 49:343-8. [PubMed 18028411]

17. Wirrell EC, Nabbout R. Recent Advances in the Drug Treatment of Dravet Syndrome. CNS Drugs . 2019; 33:867-881. [PubMed 31549357]

18. Ziobro J, Eschbach K, Sullivan JE et al. Current Treatment Strategies and Future Treatment Options for Dravet Syndrome. Curr Treat Options Neurol . 2018; 20:52. [PubMed 30315507]