Stiripentol is used to treat seizures associated with Dravet syndrome (DS) in patients 6 months of age and older weighing ≥7 kg taking clobazam.

Stiripentol Instructions

Product Name: LuciStir

Manufacturer: Lucius Pharmaceuticals

Chinese name: stiripentol

English Name: Stiripentol

Drug approval number: 12 L 1053/23

 

 

【Summary】

For the treatment of Dravet syndrome (DS)-related seizures in patients 6 months of age and older weighing ≥7 kg taking clobazam.

 

【Indications】

For the treatment of seizures associated with Dravet syndrome (DS) in patients 6 months of age and older who weigh ≥7 kg taking clobazam. There are no clinical data to support the use of stiripentol as a monotherapy for the treatment of Dravet syndrome.

 

【Specification】

250mg/tablet, 60 tablets/bottle

【Usage and Dosage】

1. The recommended oral dose is 50 mg/kg/day, administered in 2 or 3 doses (i.e. 16.67 mg/kg 3 times a day or 25 mg/kg 2 times a day), depending on the patient's age and weight.

2. If the exact dose is not achievable given the available strength, round it to the nearest possible dose.

3. The maximum recommended total dose is 3,000 mg/day.

 

【Adverse Reactions】

 The most common adverse reactions (occurring in at least 10% of LuciStir-treated patients and more frequently than in the placebo group) included:

1. Drowsiness (67%), decreased appetite (45%), agitation (27%),

2. Ataxia (27%), weight loss (27%), hypotonia (24%),

3. Nausea (15%), tremor (15%), dysarthria (12%) and insomnia (12%)

 

【 Notes 】

1. Sleepiness

LuciStir may cause somnolence. In a controlled study in patients with Dravet syndrome, the incidence of somnolence was 67% in LuciStir-treated patients compared to 23% in the placebo group. All patients in both groups were concomitantly taking clobazam, which is also known to cause somnolence. Coadministration of LuciStir with clobazam resulted in elevated levels of clobazam and its active metabolite [see Drug Interactions (7.1)]. Other CNS depressants, including alcohol, may potentiate the somnolence effects of LuciStir.

Prescribers should monitor patients for the development of somnolence. If somnolence occurs during concurrent administration of clobazam, consider reducing the initial clobazam dose by 25%. If somnolence persists, a further 25% reduction in clobazam should be considered, and the dose of other concomitant anticonvulsant medications with sedating properties should be adjusted.

Prescribers should caution patients not to engage in hazardous activities requiring mental alertness, such as operating hazardous machinery or a motor vehicle, until the effects of LuciStir on mental alertness are known.

2. Decreased appetite and weight loss

LuciStir can cause decreased appetite and weight. In controlled studies in patients with Dravet syndrome, decreased appetite occurred in 46% of LuciStir-treated patients compared to 10% of placebo-treated patients. Weight loss occurred in 27% of LuciStir-treated patients compared to 6% of placebo-treated patients. Nausea and vomiting also occurred more frequently in LuciStir-treated patients [see Adverse Reactions (6.1)]. Given the frequency of these adverse reactions, growth should be carefully monitored in pediatric patients receiving LuciStir. In some cases, reducing the concomitant valproate dose by 30%/week can reduce appetite and weight loss.

3. Neutropenia and thrombocytopenia

LuciStir can cause a significant decrease in neutrophil counts. In a controlled study in patients with Dravet syndrome, baseline and end-of-study neutrophil counts were available for 31 patients treated with LuciStir. A decrease in neutrophil counts from normal at baseline to less than 1500 cells/mm3 during the trial was observed in 13% of these LuciStir-treated patients but was not observed in any placebo-treated patients.

LuciStir can cause a significant decrease in platelet counts. In a controlled study in patients with Dravet syndrome, baseline and end-of-study platelet counts were available for 31 patients treated with LuciStir. A decrease in platelet counts from normal at baseline to less than 150,000/µL during the trial was observed in 13% of LuciStir-treated patients but not in any placebo-treated patients.

Hematologic testing should be performed prior to initiating LuciStir therapy and then every 6 months.

4. Withdrawal symptoms

As with most anti-epileptic drugs, LuciStir should generally be discontinued gradually to minimize the risk of increased seizure frequency and status epilepticus.

In situations where rapid discontinuation of LuciStir is necessary (e.g., in the event of a severe adverse reaction), appropriate monitoring is recommended.

5. Risks for people with phenylketonuria

Phenylalanine may be harmful to patients with phenylketonuria (PKU). LuciStir oral suspension contains phenylalanine, an ingredient in aspartame. Each 250 mg package contains 1.40 mg phenylalanine; each 500 mg package contains 2.80 mg phenylalanine. Before prescribing LuciStir oral suspension for patients with PKU, consider the total daily intake of phenylalanine from all sources, including LuciStir oral suspension.

LuciStir capsules do not contain phenylalanine.

6. Suicidal behavior and thoughts

AEDs, including LuciStir, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients receiving any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Anyone considering prescribing LuciStir or any other AED must balance the risk of suicidal thoughts or behavior against the risk of the untreated condition. Epilepsy and many other conditions for which AEDs are prescribed are inherently associated with morbidity and mortality as well as an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior occur during treatment, the prescriber needs to consider whether these symptoms in any particular patient are related to the condition being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviors and that they need to be alert for the emergence or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behaviors, or thoughts of self-harm. Behaviors of concern should be reported promptly to a healthcare provider.

 

【 Contraindications 】

none

【 Drug Interactions 】

1. LuciStir's impact on other drugs

CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C19, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) substrates

In vitro data indicate that stiripentol is an inhibitor and inducer of CYP1A2, CYP2B6, and CYP3A4. Due to potential drug interactions, dose adjustments of CYP1A2 substrates (e.g., theophylline, caffeine), CYP2B6 substrates (e.g., sertraline, thiotepa), and CYP3A4 substrates (e.g., midazolam, triazolam, quinidine) should be considered based on clinical circumstances when co-administered with LuciStir.

Due to the potential for inhibition of enzyme/transporter activity, a dose reduction of CYP2C8, CYP2C19 substrates (e.g., diazepam, clopidogrel), P-gp substrates (e.g., carbamazepine), and BCRP substrates (e.g., methotrexate, prazosin, glyburide) should be considered if adverse reactions occur with concomitant administration of LuciStir.

Clobazam

Coadministration of LuciStir (which inhibits CYP 3A4 and 2C19) with clobazam resulted in increased plasma concentrations of clobazam (a substrate of CYP 3A4) and norclobazam (the active metabolite of clobazam, a substrate of CYP2C19).

This may increase the risk of clobazam-related adverse reactions. If adverse reactions occur during co-administration with LuciStir, consider reducing the clobazam dose [see WARNINGS AND PRECAUTIONS].

2. Effects of other drugs on LuciStir

Induction-based interactions resulting in decreased LuciStir concentrations may occur when co-administered with strong inducers of CYP1A2, CYP3A4, or CYP2C19 (e.g., rifampin, phenytoin, phenobarbital, and carbamazepine) since these enzymes can metabolize stiripentol.

Concomitant use of LuciStir with strong inducers should be avoided or dose adjustments should be made.

3. CNS depressants and alcohol

Concomitant use of LuciStir with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence [see WARNINGS AND PRECAUTIONS].

 

【 Overdose 】

There are no data on overdose in humans. In mice given high doses of stiripentol (600-1800 mg/kg ip), decreased motor activity and reduced respiration were observed.

Treatment of overdose should be supportive (symptomatic measures in an intensive care unit).