Before 2018, there were no U.S. Food and Drug Administration-approved medications for managing seizures in Dravet syndrome (DS). Common agents used in the antiepileptic drug regimens of patients with DS included clobazam, valproic acid, topiramate, and levetiracetam, among others; however, these agents alone rarely provide adequate seizure control. Management of seizures in DS changed in recent years with the approval of cannabidiol and stiripentol in 2018 and fenfluramine in 2020. This continuing education article summarizes available efficacy and safety data involving cannabidiol, stiripentol, and fenfluramine and provides a practical review of dosing strategies, pharmacokinetics, and monitoring interventions relevant to their use.
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1. Recognize available medications used to manage treatment-refractory Dravet syndrome.
2. Evaluate the pharmacology of three novel antiepileptic medications and the efficacy and safety data available to support their use.
3. State practical considerations relevant to managing medications used to treat Dravet syndrome or related comorbidities in the outpatient setting.
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INTRODUCTION
Dravet syndrome (DS) is a rare and devastating epileptic encephalopathy predominately caused by genetic mutations in the voltage-gated sodium channel α1 subunit gene, SCN1A (
Cooper et al., 2016
; Wirrell et al., 2017
). Such mutations significantly affect the excitatory and inhibitory capabilities of the brain, resulting in severe seizures, persistent cognitive impairment, and an overall poor prognosis. The onset of DS-related seizures often presents around 6 months of age, and mortality is high. Specifically, following diagnosis, a 10-year mortality rate of 15% has been reported; up to 61% of deaths in patients with DS are attributed to a sudden unexpected death in epilepsy (Cooper et al., 2016
). In patients with DS, optimization of seizure control is essential to the quality of life; unfortunately, treatment-refractory DS is common (Chin et al., 2021
).At present, accepted first-line agents for the management of DS include clobazam and valproic acid, but complete seizure control is rarely attained (
Knupp and Wirrell, 2018
; Wirrell et al., 2017
). Strategies involving alternate medications, such as topiramate and levetiracetam, may benefit some patients, but the individual response is highly variable. Nonpharmacologic approaches, including ketogenic diet and vagal nerve stimulation, have also been used. Several new or repurposed medications have demonstrated efficacy and safety in patients with DS and uncontrolled seizures. The first U.S. Food and Drug Administration (FDA) approvals for the specific indication of DS were awarded to cannabidiol and stiripentol in 2018 and subsequently to fenfluramine in 2020 (Food and Drug Administration 2019
, Food and Drug Administration. (2019). Novel drug approvals for 2018. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2018
Food and Drug Administration 2021b
b). With the widespread availability and increasing use of these medications in the United States, clinicians must be aware of risks, benefits, and management considerations related to treating seizures associated with DS. This article aimed to review the efficacy and safety data related to these medications and important practical considerations for the pediatric clinician who may be involved in the outpatient care of infants and children with DS.Food and Drug Administration. (2021b). Novel drug approvals for 2020. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2020
PHARMACOLOGICAL MANAGEMENT OF TREATMENT-REFRACTORY DS
The pharmacological management of seizures related to treatment-refractory DS is often complex, involving several medications with varying properties. As of 2021, three medications have been approved for use within the United States to aid in attaining adequate seizure control in patients with DS: cannabidiol, stiripentol, and fenfluramine. A discussion of each agent is provided, including brief medication history, mechanism of action, efficacy, safety and monitoring, pharmacokinetic properties (Table), dosing and administration, and drug-drug interactions (DDIs). The optimal incorporation of these agents into an established antiepileptic regimen requires understanding these properties to ensure safe and effective use.
TABLEDosing, titration, and selected pharmacokinetic/pharmacodynamic properties of novel antiepileptic drugs (AEDs) for Dravet syndrome
| Cannabidiol (Epidiolex; Greenwich Biosciences, Inc. )Greenwich Biosciences, Inc. (2018). Epidiolex (cannabidiol): Highlights of prescribing information. Carlsbad, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. | |
|---|---|
| Dosing and titration ( Lexi-Drugs 2022a ) | Pharmacokinetics and pharmacodynamics |
| Starting dose: 5 mg/kg/day divided 2 times daily Titration: increase doses by 2.5 mg/kg/dose weekly based on patient response and tolerability Note: may titrate as quickly as every other day if rapid titration is required. Maximum dose: 20 mg/kg/day Note: doses of 25–50 mg/kg/day have shown to be effective; however, the risk for aspartate/alanine transaminase elevation and adverse effects is increased ( Laux et al., 2019 ) | Absorption and bioavailability: high-fat and high-calorie meals significantly increase absorption; consistent administration either with or without food is recommended Carbohydrate content: 100-mg/ml solution: carbohydrate neutral (no contribution; Greenwich Biosciences, Inc. 2021 )Greenwich Biosciences, Inc. (2021). Frequently asked questions. Retrieved from https://www.epidiolexhcp.com/resources/frequently-asked-questions Onset of action: 4 weeks Volume of distribution: 20,963–42,849 L Protein binding: 94% Time to maximum concentration: 2.5–5 hr Metabolism: primarily hepatic via CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7; 2 metabolites: 7-OH-cannabidiol (active) and 7-COOH-cannabidiol (inactive) Half-life: 56–61 hr Excretion: feces (major) and urine (minor) |
| Stiripentol (Diacomit; Biocodex, Inc. (20122018). )Biocodex, Inc. (2018). Diacomit (stiripentol): Highlights of prescribing information. Beauvais, France, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206709s000, 207223s000lbl.pdf | |
| Dosing and titration ( Lexi-Drugs 2022c ) | Pharmacokinetics and pharmacodynamics |
| Starting dose: 50 mg/kg/day divided 2 or 3 times daily Titration: may begin titration at 10–15 mg/kg/day and divided 2 or 3 times daily and titrate over 2–4 weeks to reach 50 mg/kg/day divided 2 or 3 times daily Maximum dose: 3,000 mg/day | Absorption: well absorbed; the powder is slightly better absorbed than capsules Carbohydrate content: 250 mg packet: 500 mg of carbohydrates; 500 mg packet: 1,000 mg of carbohydrates; 250 mg capsule: 3 mg of carbohydrates; 500 mg capsule: 6 mg of carbohydrates (personal communication, September 2020) Protein binding: ∼99% Bioavailability: 30% Time to maximum concentration: 2–3 hr Metabolism: demethylation via CYP1A2, CYP2C19, CYP3A4, and glucuronidation Half-life (adults): 4.5–13 hr (dose-dependent) Excretion: urine (primary), feces (unchanged drug) Additional notes: clearance and volume of distribution are related to body weight; adolescents may require lower doses than children |
| Fenfluramine (Fintepla; Zogenix, Inc. (2020). )Zogenix, Inc. (2020). Fintepla (fenfluramine): Highlights of prescribing information. Emeryville, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212102s000lbl.pdf. | |
| Dosing and titration ( Lexi-Drugs 2022b ) | Pharmacokinetics and pharmacodynamics |
| Starting dose: 0.2 mg/kg/day divided 2 times daily Titration: if not receiving stiripentol: may increase to 0.4 mg/kg/day divided 2 times daily after 1 week; may further increase to a max of 0.7 mg/kg/day divided 2 times daily after 1 additional week. If receiving stiripentol: may increase to 0.3 mg/kg/day divided 2 times daily after 1 week, and to a maximum of 0.4 mg/kg/day after 1 additional week Note: may titrate as quickly as every 4 days if rapid titration is required. Maximum dose without concomitant stiripentol: 26 mg/day Maximum dose with concomitant stiripentol: 17 mg/day | Absorption: well absorbed Carbohydrate content: 2.2-mg/ml solution: 1 mg of carbohydrates per 1 mL of solution ( Charlie Foundation 2021 )Charlie Foundation. (2021). KetoDietCalculator. Retrieved from https://www.ketodietcalculator.org/ketoweb/KetoStart Volume of distribution: 11.9 L/kg Protein binding: 50% Bioavailability: 68% to 74% Time to maximum concentration: 4–5 hr Metabolism: 75% metabolized by CYP1A2, CYP2B6, and CYP2D6 to norfenfluramine (active) Half-life: 20 hr Excretion: urine > 90%, feces < 5% Contraindication: because of the increased risk for serotonin syndrome, fenfluramine is contraindicated in patients currently taking or within 14 days of the last dose of monoamine oxidase inhibitors |
Cannabidiol
Cannabidiol oral solution was FDA-approved in June 2018 for use in the treatment of seizures associated with DS or Lennox-Gastaut syndrome in patients aged ≥ 2 years; subsequently, in 2020, an extension of approval was granted to patients aged ≥ 1 year, and use for the indication of tuberous sclerosis complex was also added (
Food and Drug Administration 2019
, Food and Drug Administration. (2019). Novel drug approvals for 2018. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2018
Food and Drug Administration 2021b
b) It is available as a strawberry-flavored, clear, and colorless to yellow 100-mg/mL solution (Food and Drug Administration. (2021b). Novel drug approvals for 2020. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2020
Greenwich Biosciences, Inc.
). Cannabidiol was the first medication with FDA approval for the treatment of DS and is the first nonsynthetic cannabinoid federally approved for any indication (Greenwich Biosciences, Inc. (2018). Epidiolex (cannabidiol): Highlights of prescribing information. Carlsbad, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
Food and Drug Administration 2019
). Although originally approved with a Drug Enforcement Administration (DEA) categorization as a Schedule V substance, it was de-scheduled in April 2020 and is no longer considered a DEA controlled substance (Food and Drug Administration. (2019). Novel drug approvals for 2018. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2018
Chapman, 2020
; Food and Drug Administration 2019
, Food and Drug Administration. (2019). Novel drug approvals for 2018. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2018
Food and Drug Administration 2021a
a, Food and Drug Administration. (2021a). FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). Retrieved from https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd
Food and Drug Administration 2021b
b).Food and Drug Administration. (2021b). Novel drug approvals for 2020. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2020
Mechanism of action
The exact mechanisms by which cannabidiol exerts its anticonvulsive effects are unknown. It is not believed to work through the cannabinoid receptors but is instead proposed to reduce neuronal hyperexcitability through other pathways, such as the transient receptor potential vanilloid 1, antagonism of the G-protein coupled receptor 55, and modulation of adenosine reuptake (
Chen et al., 2019
; Strzelczyk and Schubert-Bast, 2020
).Efficacy
The efficacy of cannabidiol was illustrated in two randomized, placebo-controlled, double-blind phase III studies: GWPCARE1 Part B (GWPCARE1B) and GWPCARE2 (
Devinsky et al., 2017
; Miller et al., 2020
). GWPCARE1B Randomized 120 children and young adults with DS (aged 2–18 years) with uncontrolled seizures to cannabidiol 20 mg/kg/day (divided twice daily) or placebo in conjunction with their current, stable antiepileptic drug (AED) regimens (e.g., various drug combinations including clobazam, valproate, stiripentol, levetiracetam, and topiramate and other nonpharmacologic interventions) for 14 weeks (Devinsky et al., 2017
). For those receiving cannabidiol, the median change in monthly convulsive seizure frequency was −38.9%, compared with −13.3% in the placebo group; the adjusted median difference of −22.8% was significant (95% confidence interval [CI], −41.1 to −5.4; p = .01). In GWPCARE2, a similar population of patients with DS (ages 2–18 years) and inadequate seizure control on their current AED regimens was randomized to one of three groups, each divided twice daily: cannabidiol 10 mg/kg/day, cannabidiol 20 mg/kg/day, or placebo (Miller et al., 2020
). After 14 weeks of treatment, the percentage reduction in convulsive seizures from placebo was 29.8% in the 10 mg/kg/day group (95% CI, 8.4–46.2; p = .01) and 25.7% in the 20 mg/kg/day group (95% CI, 2.9–43.2; p = .03). Total seizure frequency was also significantly reduced from placebo: 38% in the low-dose (LD) group (95% CI, 20.1–51.9; p < .001) and 25.1% in the high-dose (HD) group (95% CI, 3.5–41.9; p = .03). The proportion of patients who achieved at least a 75% reduction from baseline in convulsive seizure frequency was 30.3% in the 10 mg/kg/day group and 17.9% in the 20 mg/kg/day group, compared with only 6.2% in the placebo group. An analysis of patient outcomes while receiving cannabidiol through the open-label extension of GWPCARE1B later reported that patients receiving 20 mg/kg/day benefited from a median reduction in monthly convulsive seizure frequency of 38% to 44% from baseline at 48 weeks of treatment (Devinsky et al., 2019
). Caregiver Global Impression of Change scores also showed sustained improvement, with 85% of caregivers reporting improvement in the patient's overall condition at 48 weeks.Safety and monitoring
Cannabidiol is associated with a dose-dependent risk for elevated liver transaminase levels, particularly in combination with valproate (
Devinsky et al., 2017
; Devinsky et al., 2018b
; Miller et al., 2020
). Liver function should be monitored at baseline and 1, 3, and 6 months after initiation with subsequent monitoring occuring as clinically indicated. If dosing is increased or other hepatotoxic medications are added to a patient's regimen, additional monitoring should occur within 1 month. Early identification of potential abnormalities plays an important role in reducing serious adverse drug reactions (ADRs). Risk factors for hepatocellular injury include concomitant use of valproate and, to a lesser degree, clobazam. In GWPCARE1B, elevated aminotransferase enzymes (e.g., AST/ALT) occurred in 19.7% (n = 12) of patients in the cannabidiol group (compared with 1.6% in the placebo group). Three withdrew from the trial; the remaining patients continued treatment, and enzyme levels normalized without change in cannabidiol dosing (Devinsky et al., 2017
). In GWPCARE2, elevated AST/ALT levels occurred in 12% of the cannabidiol treatment groups (6.8% LD and 27.7% HD). All patients experiencing elevated AST/ALT levels received concomitant valproate in both studies. In each case, transaminase levels normalized following drug discontinuation, concomitant valproate and/or clobazam reduction, dose reduction of cannabidiol, or spontaneously. Cannabidiol should be discontinued if transaminase levels are independently sustained at > 5 times the upper limit of normal (ULN) or at > 3 times the ULN with concurrent hyperbilirubinemia (i.e., > 2 × ULN).Somnolence was the most common ADR, noted in 36% of patients treated with cannabidiol in GWPCARE1B (
Devinsky et al., 2017
). Of the 22 study patients reporting somnolence, 18 were also taking clobazam; the incidence of increased somnolence may be related to other AEDs common to DS management. It is important to note the increased risk when prescribing other central nervous system (CNS) depressants. Counseling related to exacerbation of somnolence resulting from nonprescription CNS depressants, such as alcohol or antihistamines, should occur as appropriate. Other common ADRs observed in > 10% of patients taking cannabidiol include decreased appetite (23% vs. 17% with placebo), pyrexia (23% vs. 17% with placebo) diarrhea (22% vs. 12% with placebo), dose-related weight loss (16% vs. 8% with placebo), and anemia (30% vs. 13% with placebo; Greenwich Biosciences, Inc.
; Greenwich Biosciences, Inc. (2018). Epidiolex (cannabidiol): Highlights of prescribing information. Carlsbad, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
Miller et al., 2020
). Some side effects may have been exacerbated by previously described interactions with concurrent AEDs. If side effects are present, a dose reduction of the suspected offending agent may be warranted, carefully considering the seizure risk associated with such changes.These ADR findings were confirmed by an open-label extension trial of the GWPCARE series (GWPCRE5) evaluating long-term cannabidiol treatment in patients with DS (
Scheffer et al., 2021
). This extension trial accepted 128 patients who participated in GWPCARE1 and 138 patients from GWPCARE2; it followed these patients for 1–3 years while patients were taking cannabidiol doses of ≤ 20 mg/kg/day, > 20–25 mg/kg/day, or > 25 mg/kg/day. Results found diarrhea, pyrexia, decreased appetite, somnolence, nasopharyngitis, convulsions, upper respiratory tract infections, and vomiting to be more common when taking higher doses.Since 2008, all AEDs available for use in the United States have also included product labeling to describe an increased risk for suicidal thoughts or consistent behavior across the medication class (
Klein et al., 2021
). The cannabidiol prescribing information also includes a warning to monitor patients for suicidal behaviors and thoughts. Pooled analyses from which this risk was derived did not include cannabidiol, stiripentol, or fenfluramine. No suicidal ideation or behavior was reported in any cannabidiol phase III studies (Devinsky et al., 2017
; Devinsky et al., 2018a
; Devinsky et al., 2018b
; Devinsky et al., 2019
; Miller et al., 2020
; Thiele et al., 2018
).Dosing and administation
Dosing and administration for DS, recommended starting dose, maximum dose, titration guidance, and pharmacokinetic and pharmacodynamic properties are provided in the Table. Cannabidiol's absorption is significantly increased with milk or food; therefore, it is recommended that the medication be administered consistently with regard to meal timing. When taken with a high-fat/high-calorie meal, plasma and area under the curve concentrations are increased by four to five fold; consistent administration in a fasted or fed state reduces total variability in absorption (
Greenwich Biosciences, Inc.
). Cannabidiol solution is carbohydrate neutral and may require little dietary modification for patients on the ketogenic diet. The onset of benefit occurs within 4 weeks of starting therapy. Of note, doses above the FDA approved a maximum of 20 mg/kg/day have been evaluated in treatment-resistant Lennox-Gastaut syndrome and DS (Greenwich Biosciences, Inc. (2018). Epidiolex (cannabidiol): Highlights of prescribing information. Carlsbad, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
Devinsky et al., 2017
; Devinsky et al., 2018b
; Devinsky et al., 2019
; Laux et al., 2019
; Miller et al., 2020
). Off-label doses of 25–50 mg/kg/day have shown to be effective and safe for patients with refractory seizure types; however, the risk for AST/ALT elevations and other ADRs are higher at increased doses, warranting closer monitoring (Laux et al., 2019
). Dose reduction is recommended for patients with moderate to severe hepatic impairment (e.g., Child-Pugh Class B or C; Greenwich Biosciences, Inc.
). For moderate hepatic impairment, the recommended starting dose is 1.25 mg/kg twice daily (2.5 mg/kg/day) with titration to a maintenance dose of 2.5–5 mg/kg twice daily (5–10 mg/kg/day). For patients with severe impairment, the recommended starting dose is 0.5 mg/kg twice daily (1 mg/kg/day), with titration to a maintenance dose of 1–2 mg/kg twice daily (2–4 mg/kg/day). If discontinuation is warranted, cannabidiol should not be stopped abruptly. Rather, doses should be reduced gradually to avoid the risk of status epilepticus or increased seizure frequency on withdrawal.Greenwich Biosciences, Inc. (2018). Epidiolex (cannabidiol): Highlights of prescribing information. Carlsbad, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
Drug-drug interaction
Considering that cannabidiol is metabolized by CYP2C19 and CYP3A4 isoenzymes, dose adjustments and monitoring may be needed when concomitantly taking strong cytochrome P450 enzymes inducers (e.g., rifampin, carbamazepine, topiramate, phenytoin) or inhibitors (e.g., valproate) of either enzyme (
Devinsky et al., 2018b
; Greenwich Biosciences, Inc.
; Greenwich Biosciences, Inc. (2018). Epidiolex (cannabidiol): Highlights of prescribing information. Carlsbad, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
Lexi-Drugs 2022a
). Concomitant administration of cannabidiol and valproate is associated with an increased risk for elevated liver function tests.Cannabidiol also inhibits UGT1A9, UCT2B7, CYP2C8, CYP2C9, and CYP2C19; therefore, dose reduction of medications metabolized by these enzymes may be required. Perhaps the most clinically relevant interaction for patients with DS is the combination of cannabidiol and clobazam. Specifically, cannabidiol increases the serum concentrations of clobazam (a CYP2C19 substrate) and its active metabolite by roughly 3-fold (
Devinsky et al., 2018b
). Patients should be monitored carefully for emergent ADRs, such as drowsiness, ataxia, irritability, restlessness, urinary retention, tremor, and loss of appetite when on this combination. Interestingly, this interaction is not observed for patients taking clobazam and stiripentol before adding cannabidiol, suggesting that stiripentol may inhibit CYP2C19 before adding to cannabidiol (Geffrey et al., 2015
).Stiripentol
Stiripentol was first discovered in 1978, but initial success in demonstrating benefit in the treatment of adult seizures was unable to be achieved. Since 2001, the medication has been available in Europe to treat severe myoclonic epilepsy in infancy, also known as DS (
Nabbout and Chiron, 2012
). Stiripentol was subsequently approved to manage epileptic DS in Canada in 2015 and later in Japan in 2017. FDA approval for use in the United States was eventually awarded in 2018. Stiripentol is currently approved only as an adjunctive treatment of seizures associated with DS in patients ≥ 2 years of age taking concomitant clobazam, as data are unavailable to support its use as monotherapy. Stiripentol is available as oral capsules (250 mg, 500 mg) or pale pink fruit-flavored powder packets (250 mg, 500 mg) for oral suspension.Mechanism of action
Although the exact mechanism by which stiripentol exerts its anticonvulsant effect is unknown, it has been suggested that stiripentol has both direct and indirect actions. Stiripentol may act directly at the γ-aminobutyric acid receptor and indirectly through an interaction with clobazam that increases concentrations of biologically active clobazam and the active norclobazam metabolite (
Nabbout and Chiron, 2012
).Efficacy
Two identically designed, randomized, placebo-controlled, double-blind studies, STICLO-France and STICLO-Italy, evaluated the efficacy and safety of stiripentol as an add-on therapy to valproate and clobazam for DS (
Chiron et al., 2000
; Nabbout and Chiron, 2012
). Both studies randomized patients with severe myoclonic epilepsy of infancy/DS (aged ≥ 3 years) on a current regimen consisting of valproate (maximum allowable dose of 30 mg/kg/day) and clobazam (maximum allowable dose of 0.5 mg/kg/day), among other preexisting AED regimens, to either stiripentol at a dose of 50 mg/kg/day (maximum dose of 3,000 mg/day) or placebo. Stiripentol doses were divided evenly at twice daily or three times daily intervals. In STICLO-France (n = 41), 71% of patients achieved a ≥ 50% reduction in the frequency of either clonic or tonic-clonic seizures during the second month of the treatment period compared with baseline (p < .001), including 43% of patients who were entirely free of clonic or tonic-clonic seizures (p = .001). This positive trend was also seen in STICLO-Italy (n = 23), with 67% achieving a ≥ 50% reduction in the frequency of clonic or tonic-clonic seizures during the second month of treatment compared with baseline in the stiripentol group (compared with 9.1% in the placebo group; p = .009). In addition, STICLO-Italy showed that 52% of patients were seizure-free after 1 month of treatment and 43% of patients retained seizure freedom at 2 months of blinded treatment, whereas 0% of patients achieved seizure freedom with placebo (Nabbout and Chiron, 2012
). During these trials, valproate levels were not affected; however, clobazam levels increased 2-fold, and norclobazam, the active metabolite of clobazam, increased 5–7-fold compared with baseline (Nabbout and Chiron, 2012
).Long-term efficacy has also been established in several open-label observational studies (
Inoue and Ohtsuka, 2015
; Myers et al., 2018
). The longest observational study looking at the efficacy and safety of stiripentol in patients with DS spanned 12 years, from 2003 to 2015 (Myers et al., 2018
). With a median treatment duration of 37 months (range, 2–141 months), 49% of patients (n = 41) maintained ≥ 50% long-term reduction in the frequency of tonic-clonic seizures. Forty percent of patients with DS with status epilepticus (n = 27) also experienced a frequency of status epilepticus decrease of ≥ 50%.Safety and monitoring
The most commonly reported ADR by patients taking stiripentol was drowsiness or somnolence, with a frequency of 34% to 71% reported across all described studies compared with 23% to 40% in placebo groups (
Chiron et al., 2000
; Food and Drug Administration & Center for Drug Evaluation and Research 2020
; Food and Drug Administration & Center for Drug Evaluation and Research. (2020). Diacomit clinical review. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/206709Orig1s000,207223Orig1s000MedR.pdf
IBM. 2021
; IBM. (2021). Watson health. Stiripentol: Adverse Effects [Electronic version]. Retrieved from https://www.micromedexsolutions.com/ [subscription required]
Inoue and Ohtsuka, 2015
; Myers et al., 2018
). Concomitant use of clobazam or other CNS depressants may increase this risk. Dose reductions for somnolence are proposed in the FDA-approved prescribing information and are described in the dosing and administration section. Patients and caregivers should be made aware of this risk and advised to avoid hazardous activities requiring mental alertness.Additional common ADRs occurring in > 10% of clinical trial participants included anorexia or weight loss (27% to 49% vs. 6% to 14% with placebo), ataxia (14% to 58% vs. 5% to 23% with placebo), behavioral changes (14% to 27% vs. 0% to 16% with placebo), neutropenia and thrombocytopenia (10% to 15%, not observed in placebo groups), and insomnia (10% to 12% vs. 5% to 7% with placebo;
Food and Drug Administration & Center for Drug Evaluation and Research 2020
; Food and Drug Administration & Center for Drug Evaluation and Research. (2020). Diacomit clinical review. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/206709Orig1s000,207223Orig1s000MedR.pdf
IBM. 2021
; IBM. (2021). Watson health. Stiripentol: Adverse Effects [Electronic version]. Retrieved from https://www.micromedexsolutions.com/ [subscription required]
Inoue and Ohtsuka, 2015
; Myers et al., 2018
). Nausea and vomiting may also occur (IBM. 2021
). Because of the risk for neutropenia and thrombocytopenia, hematologic monitoring should occur before and every 6 months after initial treatment.IBM. (2021). Watson health. Stiripentol: Adverse Effects [Electronic version]. Retrieved from https://www.micromedexsolutions.com/ [subscription required]
As with other AEDs, stiripentol labeling describes a risk for increased suicidal behaviors and ideation. However, there were no reports of such events in the clinical trials (
Chiron et al., 2000
; Inoue and Ohtsuka, 2015
; Myers et al., 2018
; Nabbout and Chiron, 2012
).Dosing and administration
Dosing, titration, and pharmacokinetic information for stiripentol are included in the Table. If exact dosing is not feasible because of dosage form limitations, doses should be rounded to the closest available full dosage form (multiple capsules or packets may be required). Stiripentol is well absorbed, with the powder suspension achieving 23% higher concentrations than the capsule dosage form; however, the area under the curve between the two forms is comparable (
Lexi-Drugs 2022c
; May et al., 2012
). Although stiripentol capsules contain very low carbohydrate content, the powder for dissolution does contain roughly 500 mg of carbohydrate content per 250 mg of stiripentol; this represents an important consideration for patients receiving the ketogenic diet (Biocodex, Inc, personal communication, 2020). If discontinuation of stiripentol is indicated, a gradual dose reduction is recommended to avoid the risk of status epilepticus or increased seizure frequency on withdrawal. If somnolence occurs, FDA-approved labeling recommends that a reduction of clobazam by 25% should be considered (Biocodex, Inc. (20122018).
). Further reduction of either agent is appropriate if somnolence persists.Biocodex, Inc. (2018). Diacomit (stiripentol): Highlights of prescribing information. Beauvais, France, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206709s000, 207223s000lbl.pdf
Data regarding the safety of stiripentol in patients with renal or liver impairment is lacking. Stiripentol is primarily hepatically metabolized and renally eliminated; therefore, use for patients with moderate to severe liver or renal impairment is not recommended (
Biocodex, Inc. (20122018).
).Biocodex, Inc. (2018). Diacomit (stiripentol): Highlights of prescribing information. Beauvais, France, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206709s000, 207223s000lbl.pdf
Drug-drug interactions
A major DDI occurs with the concomitant use of stiripentol and clobazam, commonly used together to manage DS. Indeed, the interaction is so significant that it is one of the underlying mechanisms for stiripentol's anticonvulsant efficacy. Stiripentol inhibits CYP3A4 and CYP2C19, which results in increased concentrations of clobazam and its active norclobazam metabolite. Therefore, an increased risk for ADRs is also possible. A reduced dose of clobazam may be warranted when taken with stiripentol; clinical judgment and close monitoring are required.
Stiripentol is also thought to be an inhibitor and inducer of CYP1A2 and CYP2B6, as evidenced by in vitro data (
Biocodex, Inc. (20122018).
). Concomitant use of stiripentol with any of the substrates of these enzymes must therefore be considered a potential DDI. If clinically warranted, a dose adjustment may be needed. Less frequently occurring drug substrates, including those of CYP2C8, CYP2C19, P-glycoprotein, and breast cancer resistance protein, may also warrant dose modification if related ADRs are suspected because of the medication's potential to inhibit these enzymes and transporters. Conversely, strong inducers of CYP1A2, CYP2C19, and CYP3A4 may result in decreased levels of stiripentol; if possible, concomitant use should be avoided or, if clinically warranted, dose adjustments should be made.Biocodex, Inc. (2018). Diacomit (stiripentol): Highlights of prescribing information. Beauvais, France, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206709s000, 207223s000lbl.pdf
Fenfluramine
Although approved in June 2020 for DS, fenfluramine is not a new medication on the market. It was first approved as the branded medication Pondimin in 1973 as an appetite suppressant. However, because of significant safety concerns associated with higher doses (e.g., 60 mg/day), fenfluramine was voluntarily withdrawn from the market in 1997 (
Connolly et al., 1997
). The FDA later reapproved fenfluramine in June 2020 to treat seizures associated with DS in patients aged ≥ 2 years (Food and Drug Administration 2021b
b). It is available as a 2.2 mg/mL cherry-flavored oral solution and is considered a Schedule IV Controlled substance by the DEA because of its low potential for abuse or dependence.Food and Drug Administration. (2021b). Novel drug approvals for 2020. Retrieved from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2020
Mechanism of action
Fenfluramine is a known modulator of serotonin; however, the exact mechanism of action for seizures is not entirely understood. Mechanisms related to fenfluramine's synergistic interaction with serotonin transporter proteins to increase extracellular serotonin activity, action at the serotonin receptors (5-HT1D, 5-HT2c, and 5-HT2A), and the modulation of the sigma-1 receptor have been proposed (
Martin et al., 2020
).Efficacy
Two randomized, placebo-controlled, double-blind phase III studies demonstrated the benefit of fenfluramine for treating seizures in patients with DS (
Lagae et al., 2019
; Nabbout et al., 2020
). The first study evaluated patients whose seizures were uncontrolled on current AEDs (Lagae et al., 2019
). Patients were randomized to receive concomitant LD fenfluramine at 0.2 mg/kg/day and HD fenfluramine at 0.7 mg/kg/day (both divided into two equivalents doses approximately 12 hr apart [maximum, 30 mg/day]) or placebo. Fenfluramine at either dose resulted in a significant reduction in the monthly frequency of convulsive seizures: 62.3% greater reduction in the HD group than placebo (p < .001) and 32.4% greater reduction in the LD group than placebo (p = .021). Both fenfluramine groups also saw significant benefit in key secondary endpoints such as 50% reduction in convulsive seizure frequency (HD: 68%, p < .001; LD: 38%, p = .009) and longest seizure-free interval days (HD: 27.5%, p = .0001; LD: 31.7%, p = .035). Importantly, this study excluded patients who were receiving concomitant stiripentol and cannabidiol.The second study evaluated the efficacy of fenfluramine when added to a stiripentol-containing AED regimen (
Nabbout et al., 2020
). Patients were randomized to receive fenfluramine at 0.4 mg/kg/day (maximum: 17 mg/day) or placebo. The mean monthly convulsive seizure frequency reduction was significantly greater in patients receiving fenfluramine than placebo, with a 54% greater reduction (p < .001). Patients treated with fenfluramine saw a median seizure-free interval of 22 days compared with 13 days with placebo (p = .004). With fenfluramine, patients also had significantly more monthly convulsive seizure-free days than placebo (median 24.4 vs. 20.3; p = .001).Safety and monitoring
In the first phase III study comparing HD fenfluramine (n = 40), LD fenfluramine (n = 39), and placebo (n = 40), frequent ADRs included: decreased appetite (HD: 38%; LD: 25%; placebo: 5%), diarrhea (HD: 18%; LD: 31%; placebo: 8%), fatigue (HD: 10%; LD: 10%; placebo: 2%), lethargy (HD: 18%; LD: 10%; placebo: 5%), nasopharyngitis (HD: 18%; LD: 10%; placebo: 12%), somnolence (HD: 10%; LD: 15%; placebo: 8%), and weight decrease (HD: 5%; LD: 13%; placebo: 0%;
Lagae et al., 2019
).Common ADRs reported by > 10% in the second phase III study comparing fenfluramine (n = 43) versus placebo (n = 44) in patients also taking concomitant stiripentol mirror those included in the first study. They include decreased appetite (44% vs. 11% with placebo), diarrhea (23% vs. 7% with placebo), fatigue (26% vs. 5% with placebo), lethargy (14% vs. 5% with placebo), and nasopharyngitis (16% vs. 34% with placebo). Decreased blood glucose (14% vs. 5% with placebo) and higher rates of pyrexia (26% vs. 9% with placebo) were also seen in this study (
Nabbout et al., 2020
).Risk Evaluation and Mitigation Strategy
Fenfluramine carries a risk of valvular heart disease (VHD) and pulmonary arterial hypertension (PAH) resulting from 5-HT2B receptor agonist activity (
Mark et al., 1997
). It does not directly affect this receptor, but the norfenfluramine metabolite is a potent agonist of 5-HT2B (Polster, 2019
). Prescribers must counsel patients and caregivers on this risk and how to recognize and respond to signs of both VHD and PAH. Historically, these increased risks were associated with doses approximately 2–3 times the maximum daily doses currently recommended for DS (Abenhaim et al., 1996
; Connolly et al., 1997
). No clinical or echocardiographic evidence of VHD or PAH was observed in either phase III clinical trials for fenfluramine in patients with DS; however, heightened monitoring of patients on fenfluramine is required (Lagae et al., 2019
; Nabbout et al., 2020
).To ensure the potential benefits of fenfluramine outweigh the risks, the medication is only available through enrollment in a Risk Evaluation and Mitigation Strategy program for prescribers, pharmacies, and patients (
Zogenix, Inc. 2021
). Patients or caregivers should notify providers of any following symptoms: dyspnea, tachycardia, fatigue, angina, pedal edema, or dizziness/fainting. Routine echocardiograms are required to identify signs of aortic or mitral regurgitation and elevated pulmonary artery pressures before symptomatic presentation. Patients must receive an echocardiogram at baseline, every 6 months during treatment, and once 3–6 months after the final dose of fenfluramine is administered. If findings are consistent with either VHD or PAH, the risk-benefit profile must be assessed, and therapy should only continue if the benefits of continuation outweigh potential risks.Zogenix, Inc. (2021). What is the FINTEPLA REMS (Risk Evaluation and Mitigation Strategy)? Retrieved from https://www.finteplarems.com/Public/Default/prescribers
In addition to monitoring for VHD and PAH, patients receiving fenfluramine should be routinely monitored for weight changes, growth in pediatric patients, behavioral changes, depression and suicidal ideations, blood pressure, and signs and symptoms of serotonin syndrome, especially if given in combination with other agents affecting serotonin (
Zogenix, Inc. (2020).
).Zogenix, Inc. (2020). Fintepla (fenfluramine): Highlights of prescribing information. Emeryville, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212102s000lbl.pdf.
Dosing and administration
Dosing, titration, and pharmacokinetic information for fenfluramine are included in the Table. Because of the important interactions described below, titration increments and maximum dosing are reduced in patients receiving concomitant stiripentol within their AED regimen. Use in patients with moderate or severe renal impairment or hepatic insufficiency is not recommended (
Lexi-Drugs 2022b
; Zogenix, Inc. (2020).
). Fenfluramine solution contains relatively low carbohydrate content, at a ratio of 1 mg of carbohydrates per 1 mL of the 2.2 mg/mL commercially available solution (Zogenix, Inc. (2020). Fintepla (fenfluramine): Highlights of prescribing information. Emeryville, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212102s000lbl.pdf.
Charlie Foundation 2021
). Discontinuation of fenfluramine should occur gradually because of the risk for status epilepticus or increased seizure frequency on withdrawal.Charlie Foundation. (2021). KetoDietCalculator. Retrieved from https://www.ketodietcalculator.org/ketoweb/KetoStart
Drug-drug interactions
Combining fenfluramine, stiripentol, and clobazam inhibits fenfluramine metabolism (
Zogenix, Inc. (2020).
). This interaction increases the plasma concentration of fenfluramine by 69% and maximum observed concentration by 18% but decreases cumulative exposure to the drug's active norfenfluramine metabolite by approximately 40%. Because of these interactions, as mentioned above, it is recommended to reduce incremental changes for all dosing titration steps and the maximum total daily dose. Stiripentol's inhibition of CYP1A2-mediated metabolism of fenfluramine is proposed to be the mechanism for this interaction.Zogenix, Inc. (2020). Fintepla (fenfluramine): Highlights of prescribing information. Emeryville, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212102s000lbl.pdf.
Conversely, fenfluramine is primarily metabolized by CYP1A2 and CYP2B6. Therefore, strong CYP1A2 and CYP2B6 inducers (e.g., rifampin) will decrease fenfluramine concentrations. An increased dose not exceeding the daily maximum may be considered if needed. Cyproheptadine may decrease the efficacy of fenfluramine because of its strong serotonin receptor antagonism, and efficacy should be monitored closely in those patients receiving this combination or other serotonin-modulating agents (
Zogenix, Inc. (2020).
). Concomitant use of medications that increase serotonin may also increase the risk for serotonin syndrome. Concomitant use of monoamine oxidase inhibitors with fenfluramine is contraindicated because of this risk.Zogenix, Inc. (2020). Fintepla (fenfluramine): Highlights of prescribing information. Emeryville, CA, Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212102s000lbl.pdf.
SUMMARY
DS is a severe genetic encephalopathy involving treatment-resistant seizures and high mortality. Because of recent FDA approvals, three medications are now more widely available to treat DS-related seizures in the United States. These medications come with risks and benefits, which should be considered when prescribing, modifying, or otherwise managing medications used to treat comorbidities in patients with this challenging disorder.
In addition to the agents described in this review, several additional medications are in various stages of clinical trial progression within the United States. Among these include ataluren, verapamil, and clemizole (each undergoing phase II trials), soticlestat, and lorcaserin (each undergoing phase III trials;
Devinsky et al., 2021
; Eisai Medical 2020
; Eisai Medical. (2020). A study of Lorcaserin as adjunctive treatment in participants with Dravet syndrome (MOMENTUM 1). Retrieved from https://clinicaltrials.gov/ct2/show/NCT04572243
Segal et al., 2020
; Segal, E., Wheless, J., & Keough, K. (2020). EPX-100 (clemizole hydrochloride) as add-on therapy to control convulsive seizures in patients with Dravet syndrome (ARGUS). Retrieved from https://clinicaltrials.gov/ct2/show/NCT04462770
Strzelczyk and Schubert-Bast, 2020
; Takeda Pharma 2021
; Takeda Pharma. (2021). A study of soticlestat as an add-on therapy in children and young adults with Dravet syndrome. Retrieved from https://clinicaltrials.gov/ct2/show/NCT04940624
Wical, 2012
). The future approval of any or all of these medications will likely alter the landscape of DS management; prescribing considerations should be reevaluated as the agents become available.Wical, B. (2012). Verapamil as therapy for children and young adults with Dravet syndrome. Retrieved from https://clinicaltrials.gov/ct2/show/NCT01607073
Antiepileptic medication regimens are complex and patient-specific; however, dosing considerations, potential ADRs, and DDIs associated with concomitant medication use should always be at the forefront of the clinician's mind when considering the next steps to treatment.
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Article info
Footnotes
Conflicts of interest: Alison Blackmer disclosed receipt of consulting fees from Wolters Kluwer, Pediatric and Neonatal Lexi-Drugs and the remaining authors, have no additional financial interests nor potential conflicts of interest to disclose.
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Copyright
Copyright © 2022 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
