Stiripentol Billev 250 mg: Uses, Dosage & Side Effects
Adjunctive Antiepileptic for Dravet Syndrome (Severe Myoclonic Epilepsy in Infancy)
Stiripentol Billev is a prescription antiepileptic medicine containing the active substance stiripentol, supplied as 250 mg hard capsules. It is used only in combination with clobazam and valproate to control refractory generalised tonic-clonic seizures in children and adults with Dravet syndrome, a rare and severe genetic epilepsy that usually begins in infancy. Stiripentol acts both directly on GABA-A receptors to enhance inhibitory neurotransmission and indirectly by boosting plasma levels of clobazam and its active metabolite through cytochrome P450 inhibition.
Quick Facts
Key Takeaways
- Stiripentol Billev 250 mg is an antiepileptic used exclusively as add-on therapy with clobazam and valproate in patients with Dravet syndrome whose seizures are not controlled by those two drugs alone.
- The target dose is typically 50 mg per kg per day, divided into two or three doses and taken with food; dose titration is performed gradually over several days by a specialist.
- Stiripentol strongly inhibits CYP3A4, CYP2C19 and CYP1A2, which markedly raises the plasma concentration of clobazam and norclobazam, so the dose of clobazam usually needs to be reduced when stiripentol is started.
- The most common side effects are drowsiness, loss of appetite, weight loss, tremor, ataxia and behavioural changes; regular monitoring of blood counts, liver enzymes and growth is recommended.
- Stiripentol has orphan drug designation in the European Union and United States for Dravet syndrome and has been shown in randomised controlled trials (STICLO studies) to significantly reduce seizure frequency.
What Is Stiripentol Billev and What Is It Used For?
Stiripentol Billev is a generic version of stiripentol, a structurally novel antiepileptic first developed in the 1980s. It is classified under the ATC code N03AX17 in the group of "other antiepileptics" and is marketed in several jurisdictions as a hard capsule containing 250 mg of the active substance. The reference product for stiripentol in the European Union is Diacomit, first authorised by the European Medicines Agency (EMA) in 2007 with orphan drug designation, and the product has subsequently also received orphan drug status in the United States.
Stiripentol is specifically indicated, in combination with clobazam and valproate, for the treatment of refractory generalised tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy, now most commonly referred to as Dravet syndrome. It is used when seizures are not adequately controlled by clobazam and valproate alone. It is not indicated as monotherapy and is not approved for other types of epilepsy outside of Dravet syndrome, although off-label use in other refractory epileptic encephalopathies is reported in some centres.
Dravet syndrome is a rare and severe developmental and epileptic encephalopathy that typically begins in the first year of life in a previously healthy infant. It is most often caused by de novo loss-of-function mutations in the SCN1A gene, which encodes the alpha-1 subunit of the voltage-gated sodium channel NaV1.1. The resulting dysfunction of inhibitory interneurons leads to recurrent, often prolonged seizures that may be triggered by fever and that are notoriously difficult to control with standard antiepileptic drugs. Children with Dravet syndrome commonly experience cognitive regression, motor problems and behavioural difficulties over time, and mortality is substantially higher than in other childhood epilepsies, largely due to sudden unexpected death in epilepsy (SUDEP) and status epilepticus.
Why Stiripentol Is Particularly Useful in Dravet Syndrome
Standard first- and second-line antiepileptic drugs such as valproate, clobazam, topiramate, levetiracetam and the newer agents fenfluramine and cannabidiol are often used in Dravet syndrome, but complete seizure control is rarely achieved. Sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, phenytoin and vigabatrin are generally avoided because they can worsen seizures by further reducing the function of already impaired sodium channels in inhibitory interneurons.
Stiripentol offers a distinct pharmacological profile that is particularly suited to this disease. It does not act on voltage-gated sodium channels and therefore does not worsen the underlying channelopathy. Instead, it potentiates GABAergic inhibition, which compensates to some extent for the lost function of SCN1A-expressing inhibitory interneurons. Landmark randomised, double-blind, placebo-controlled trials (the STICLO-France and STICLO-Italy studies) showed that the addition of stiripentol to clobazam and valproate produced a significant reduction in generalised tonic-clonic seizure frequency, with responder rates of around 70% compared with under 10% in the placebo group.
How Stiripentol Works
Stiripentol has a dual mechanism of action. It binds allosterically to GABA-A receptors, particularly those containing alpha-3 subunits, enhancing their response to GABA in a manner similar to barbiturates. This direct GABAergic effect is thought to contribute a modest but clinically meaningful anticonvulsant action. In addition, stiripentol increases synaptic GABA concentrations by reducing GABA reuptake and metabolism.
A clinically crucial second effect of stiripentol is its potent inhibition of several cytochrome P450 (CYP) isoenzymes, most importantly CYP3A4, CYP2C19 and CYP1A2. Clobazam is metabolised primarily by CYP3A4 to its active metabolite norclobazam, which in turn is cleared by CYP2C19. When stiripentol is added, the concentration of clobazam roughly doubles and the concentration of norclobazam may increase two- to four-fold. Because norclobazam is a long-acting and highly potent benzodiazepine-like compound, much of the clinical improvement seen with stiripentol is attributable to this pharmacokinetic boosting, in addition to its direct GABAergic effects.
Stiripentol provides a unique combination of direct GABAergic enhancement and pharmacokinetic boosting of clobazam. This dual action makes it particularly effective in Dravet syndrome, where loss of SCN1A-mediated inhibition is the central pathological mechanism. Most other antiepileptics either target sodium channels (which can be harmful in Dravet) or act on GABA pathways without the additional boosting effect.
What Should You Know Before Taking Stiripentol Billev?
Stiripentol is a specialist-only medicine and the decision to start it, to continue it or to withdraw it should always involve a pediatric neurologist or epileptologist with experience in the management of Dravet syndrome. Before the first dose, the treating team will review the complete medical history, current medications, seizure diary and baseline laboratory tests. It is important that caregivers understand both the potential benefits and the expected adverse effects of the treatment, and that a clear monitoring plan is agreed upon.
Contraindications
Stiripentol Billev must not be used in the following situations:
- Known hypersensitivity to the active substance stiripentol or to any of the excipients listed in the product information.
- History of psychosis in the form of episodes of delirium. Stiripentol can lower the threshold for psychiatric adverse effects, and patients with this history are at particular risk.
Although there is no absolute contraindication to use in pregnancy or severe liver disease, stiripentol is generally avoided in these situations unless the benefits are considered to clearly outweigh the risks.
Warnings and Precautions
Growth and nutritional status in children. Because stiripentol commonly causes loss of appetite, nausea and weight loss, and is usually used in children who may already be at risk of poor growth due to the underlying disease and other antiepileptics, growth and nutritional status must be carefully monitored. Weight and height should be measured at each visit and the treatment reviewed if weight loss becomes clinically significant. Involvement of a pediatric dietitian is often helpful.
Haematological monitoring. Neutropenia and, less frequently, thrombocytopenia have been reported with stiripentol, often in combination with valproate. A complete blood count is typically performed at baseline and every 6 months, or more often if clinically indicated. Parents and caregivers should be informed to seek medical advice in case of unexplained fever, recurrent infections, mouth ulcers or easy bruising.
Liver function. Stiripentol, particularly in combination with valproate, can affect liver enzymes. Liver function tests should be checked at baseline and then every 6 months, with additional testing if symptoms suggestive of liver disease (nausea, vomiting, abdominal pain, jaundice) appear.
Central nervous system effects. Sedation, drowsiness, tremor and ataxia are common, especially during initiation and dose escalation, and are frequently a consequence of raised clobazam and norclobazam concentrations rather than stiripentol itself. These effects can often be managed by reducing the dose of clobazam. Patients and caregivers should be cautioned about activities that require alertness, such as riding bicycles or using playground equipment, particularly in the first weeks of treatment.
Suicidal ideation. As with all antiepileptic drugs, there is a small but identified risk of suicidal ideation and behaviour. Patients and caregivers should be informed about this risk and advised to seek medical advice if any signs of mood change, depression or thoughts of self-harm appear.
Abrupt withdrawal. Stiripentol should not be stopped abruptly because of the risk of rebound seizures, including status epilepticus. If the medication needs to be discontinued, the dose should be reduced gradually under specialist supervision.
Pregnancy and Breastfeeding
There are very limited human data on the use of stiripentol during pregnancy. Animal studies have shown some evidence of reproductive toxicity at high doses, and the teratogenic potential of stiripentol in humans cannot be fully excluded. However, uncontrolled seizures during pregnancy are known to carry substantial risks for both mother and fetus, including hypoxia, injury and miscarriage. For women with Dravet syndrome who become pregnant while on stiripentol, the treatment decision must be made individually, usually in consultation with an epilepsy specialist and, where available, a pregnancy epilepsy register.
Women of childbearing potential should use effective contraception during treatment with stiripentol. However, because stiripentol inhibits CYP3A4, it can reduce the effectiveness of combined hormonal contraceptives. Non-hormonal or progestogen-only methods that are not affected by enzyme inhibition may be preferred, and specialist advice should be sought.
It is not known to what extent stiripentol is excreted in human milk, but animal data and the lipophilic nature of the drug suggest that exposure to the infant is likely. Because of the risk of sedation and other effects in the breastfed infant, breastfeeding is generally not recommended during treatment with stiripentol.
Use in the Elderly
The use of stiripentol in patients over 65 years is limited because Dravet syndrome is a disorder of early childhood onset and most affected individuals are diagnosed and treated during childhood. In older adults who have reached adulthood with Dravet syndrome, standard precautions for antiepileptic therapy apply, including evaluation of renal and hepatic function and attention to interacting comorbid medications.
Stiripentol Billev is not a rescue medication and is not effective for the acute treatment of prolonged or cluster seizures. Families caring for a child with Dravet syndrome should always have an individualised emergency plan for prolonged seizures or status epilepticus, typically including buccal midazolam or rectal diazepam, agreed in advance with the treating neurologist.
How Does Stiripentol Billev Interact with Other Drugs?
Because stiripentol is one of the most potent CYP inhibitors used as a chronic medication, an up-to-date medication list (including over-the-counter products, herbal remedies and food supplements) should be reviewed before starting treatment and whenever a new drug is added. The treating physician should be informed of all concomitant medications, and any planned course of antibiotics, antifungals, chemotherapy, immunosuppressants or psychiatric medication should be discussed with the epilepsy team in advance.
| Drug / Drug Class | Type of Interaction | Clinical Significance | Recommendation |
|---|---|---|---|
| Clobazam | CYP3A4 and CYP2C19 inhibition; plasma levels of clobazam and norclobazam increase 2–4 fold | Major — drowsiness, ataxia, hypersalivation | Consider reducing clobazam dose by 25–50% at initiation; titrate based on symptoms and blood levels |
| Valproate (sodium valproate) | Modest pharmacokinetic interaction; additive effects on appetite and liver enzymes | Moderate — weight loss, hepatotoxicity risk | Reduce valproate dose if GI side effects or weight loss occur; monitor liver function |
| Phenytoin, phenobarbital, carbamazepine | CYP3A4 inhibition raises plasma levels; these drugs may also reduce stiripentol levels by enzyme induction | Major — toxicity of older antiepileptics | Generally avoid combination; monitor drug levels if used together |
| Midazolam, triazolam, alprazolam | Strong CYP3A4 inhibition | Major — profound and prolonged sedation | Use with caution for procedural sedation; reduce doses; ensure airway monitoring |
| Ciclosporin, tacrolimus, sirolimus | CYP3A4 inhibition and effects on P-glycoprotein | Major — toxicity risk | Monitor trough levels closely; specialist management |
| Caffeine and theophylline | CYP1A2 inhibition raises plasma levels | Moderate — stimulant effects, cardiac symptoms | Limit caffeine-containing beverages; avoid theophylline unless levels are monitored |
| Hormonal contraceptives | CYP3A4 inhibition may alter contraceptive steroid levels | Moderate — potential reduction in contraceptive efficacy | Consider non-hormonal contraception; seek specialist advice |
| Warfarin and other CYP2C9 substrates | Weak interaction through multiple pathways | Minor to moderate | Monitor INR more frequently when starting or stopping stiripentol |
| Grapefruit juice | Additional CYP3A4 inhibition | Minor | Avoid large amounts of grapefruit juice during treatment |
Major Interactions
The single most important interaction is with clobazam. Because stiripentol inhibits both the CYP3A4-mediated formation of norclobazam from clobazam (reducing clearance of clobazam) and the CYP2C19-mediated clearance of norclobazam, both compounds accumulate. Norclobazam has a much longer half-life (typically 40–80 hours) than clobazam itself and is the main contributor to the prolonged benzodiazepine-like effect. When stiripentol is introduced, adults and children often experience a dose-dependent increase in sedation, hypotonia, drooling and loss of coordination. In many protocols the clobazam dose is empirically reduced by about a quarter to a half at the start of stiripentol, with subsequent adjustment guided by symptoms, seizure control and, where available, therapeutic drug monitoring.
Stiripentol also interacts with valproate, although the pharmacokinetic effect is smaller than with clobazam. The more important issue is overlapping adverse effect profiles: both drugs can cause appetite loss, weight loss, tremor, thrombocytopenia and hepatic enzyme elevations. Downward dose titration of valproate is often helpful if gastrointestinal or haematological side effects appear.
Combination with older enzyme-inducing antiepileptics (phenytoin, carbamazepine and phenobarbital) is generally avoided because these drugs reduce stiripentol exposure while stiripentol increases their plasma concentrations, creating a situation of reduced efficacy and increased toxicity. If such combinations cannot be avoided, therapeutic drug monitoring and careful dose adjustment are essential.
Minor Interactions and Food
Several commonly used supportive medications have only minor interactions but are worth reviewing. Proton pump inhibitors, paracetamol (acetaminophen), non-steroidal anti-inflammatory drugs and most antibiotics (other than macrolides and certain antifungals) can generally be used with ordinary caution. Macrolide antibiotics (erythromycin, clarithromycin) and azole antifungals (ketoconazole, itraconazole, voriconazole) are themselves CYP3A4 inhibitors, and their addition to a patient already on stiripentol can further raise concentrations of clobazam and norclobazam.
Stiripentol capsules should be taken with food to improve absorption. Grapefruit juice should be avoided in large amounts because it is an additional CYP3A4 inhibitor. Alcohol should be avoided by adolescents and adults on stiripentol because of additive sedative effects.
What Is the Correct Dosage of Stiripentol Billev?
Stiripentol Billev is supplied as 250 mg hard capsules, which are the most common formulation used for ongoing treatment. For very young children, an oral powder for suspension (sachets) is available in some jurisdictions and can be substituted at an equivalent milligram-per-kilogram dose. Capsules should be swallowed whole with a glass of water during a meal. They should not be chewed or crushed because of the bitter taste and potential for inconsistent absorption. For children who cannot swallow capsules, the sachet formulation should be considered.
Dose Titration Schedule
Stiripentol is introduced gradually to allow tolerance to develop and to facilitate dose adjustment of clobazam. A typical titration schedule is:
- Day 1–3: 20 mg/kg/day divided in 2–3 doses.
- Day 4–6: 35 mg/kg/day divided in 2–3 doses.
- From day 7: 50 mg/kg/day divided in 2–3 doses (target dose).
Some centres titrate even more slowly, especially in very young children or those with prominent sedation on clobazam, and may preemptively reduce the clobazam dose before reaching the full stiripentol target dose.
| Body weight (kg) | Total daily dose | Number of 250 mg capsules per day | Suggested split |
|---|---|---|---|
| 10 kg | 500 mg | 2 capsules | 1 capsule twice daily |
| 15 kg | 750 mg | 3 capsules | 1 capsule three times daily |
| 20 kg | 1000 mg | 4 capsules | 2 capsules twice daily |
| 30 kg | 1500 mg | 6 capsules | 2 capsules three times daily |
| 50 kg | 2500 mg | 10 capsules | 3–4 capsules three times daily |
| 70 kg | 3500 mg (max common adult dose) | 14 capsules | 4–5 capsules three times daily |
Doses higher than 50 mg/kg/day (up to about 100 mg/kg/day in clinical trial settings) have been used, but there is limited additional benefit and increased risk of adverse effects above this level. Most specialists aim to keep the total daily dose at or below 50 mg/kg/day in routine practice.
Dosing Considerations for Specific Populations
Adults
Adults with Dravet syndrome who have continued stiripentol into adulthood typically receive a total daily dose of around 50 mg/kg/day, split into two or three doses, with a usual upper limit of approximately 3000–3500 mg/day. Doses are often capped earlier than the pure weight-based calculation would suggest because adverse effects become more pronounced at higher absolute daily doses. Fixed adult regimens (for example 500 mg three times daily) are sometimes used if weight-based titration is difficult.
Children
Stiripentol is licensed for use in children from 6 months to 3 years of age weighing at least 7 kg in some jurisdictions, and is widely used from infancy through adolescence. The weight-based titration above applies to all pediatric ages. In infants and toddlers the oral suspension sachet formulation is usually preferred over capsules. Dosing should be reviewed at every growth spurt to ensure the milligram-per-kilogram target is maintained.
Elderly Patients
Specific data in elderly patients are sparse because of the pediatric nature of the condition. In the rare cases of adults over 65 years on stiripentol, standard cautions for antiepileptic drugs apply, including assessment of renal and hepatic function, careful review of concomitant medications and generally cautious dose titration.
Renal or Hepatic Impairment
Stiripentol is cleared primarily by hepatic metabolism. In patients with significant hepatic impairment, stiripentol should be used with caution and at lower doses, with close monitoring of clinical response and signs of toxicity. In patients with severe renal impairment, dose reduction may also be considered, although pharmacokinetic data in this population are limited.
Missed Dose
If a dose of stiripentol is missed, the missed dose should be taken as soon as it is remembered on the same day, unless it is almost time for the next dose, in which case the missed dose should be skipped. A double dose should not be taken to compensate for a missed dose, as this can increase the risk of sedation and other adverse effects. If multiple doses are missed, the treating team should be contacted, because a rapid interruption of antiepileptic therapy can trigger breakthrough seizures in Dravet syndrome.
Overdose
Experience with stiripentol overdose is limited. The expected features of overdose include marked sedation, respiratory depression (usually through enhancement of benzodiazepine effects if taken with clobazam), hypotonia, ataxia, nausea and vomiting. Management is supportive and includes airway protection, monitoring of vital signs and symptomatic treatment. There is no specific antidote for stiripentol. The benzodiazepine antagonist flumazenil is not routinely recommended in patients with Dravet syndrome because abrupt benzodiazepine reversal can precipitate prolonged seizures and status epilepticus. In the event of overdose, contact the local poison information centre and arrange immediate hospital assessment.
What Are the Side Effects of Stiripentol Billev?
Side effects are reported in the majority of patients starting stiripentol, but most are mild to moderate and respond to dose adjustment, usually of the co-administered clobazam. Careful counselling of caregivers before starting treatment, a slow titration schedule and proactive reduction of clobazam can substantially improve tolerability. Frequency categories below follow the Council for International Organizations of Medical Sciences (CIOMS) convention.
Very Common (more than 1 in 10 patients)
- Drowsiness and somnolence
- Loss of appetite (anorexia)
- Weight loss
- Hypotonia (low muscle tone)
- Ataxia (unsteadiness, poor coordination)
- Tremor
- Nausea and vomiting
Common (1 in 100 to 1 in 10 patients)
- Irritability and behavioural disturbance
- Aggression
- Hyperexcitability
- Sleep disturbance or insomnia
- Neutropenia (low white blood cell count)
- Elevated hepatic transaminases (ALT, AST)
- Increased gamma-glutamyltransferase (GGT)
- Hypersalivation and drooling
Uncommon (1 in 1,000 to 1 in 100 patients)
- Thrombocytopenia (low platelet count)
- Persistent neutropenia requiring treatment discontinuation
- Photosensitivity and skin rash
- Urticaria (hives)
- Pronounced fatigue
Rare (less than 1 in 1,000 patients)
- Severe hepatotoxicity
- Pancytopenia (suppression of multiple blood cell lines)
- Severe hypersensitivity reactions including angioedema
- Suicidal ideation or behaviour (class effect of antiepileptics)
- Psychotic symptoms, particularly in patients with a prior psychiatric history
Recognising Which Side Effects Are Due to Stiripentol and Which Are Due to Clobazam
Because stiripentol dramatically increases clobazam and norclobazam concentrations, many adverse effects that appear during the first weeks of treatment are in fact manifestations of benzodiazepine overexposure rather than direct toxicity of stiripentol. Typical features include excessive drowsiness, hypotonia, ataxia, hypersalivation and worsening of pre-existing behavioural issues. If these appear during the titration phase, the first step is usually to reduce the dose of clobazam, often by 25–50%, rather than to stop stiripentol.
In contrast, loss of appetite and weight loss are more likely to reflect a combined effect of stiripentol itself and concurrent valproate. Neutropenia also seems to be a stiripentol-specific effect that is independent of clobazam exposure. Distinguishing between these mechanisms is important because it determines whether dose adjustments should focus on stiripentol, clobazam or valproate.
Long-Term Safety Considerations
Long-term data on stiripentol use span more than two decades in some patients, since the original compassionate-use programmes in France in the 1990s. Overall, the drug appears to be well tolerated in chronic therapy. The main long-term concerns are growth and nutrition, cognitive and behavioural effects (which are also driven by the underlying disease and by benzodiazepine exposure) and cumulative hepatotoxicity in patients on triple therapy with clobazam and valproate. Regular clinical review is essential, and multi-disciplinary input from dietitians, physiotherapists, speech therapists and neuropsychologists is valuable.
Caregivers should contact the epilepsy team if the patient experiences any of the following: excessive or persistent drowsiness, inability to walk or stand safely, significant weight loss, persistent fever or recurrent infections, unexplained bruising or bleeding, yellowing of the skin or eyes, new skin rash, marked change in mood or behaviour, worsening seizure frequency, or prolonged seizures. In an emergency such as status epilepticus, local emergency services should be called immediately.
How Should Stiripentol Billev Be Stored?
Correct storage is important for maintaining the stability and safety of stiripentol capsules. The capsules should be kept in their original blister pack or bottle until immediately before use. The blister protects the capsules from moisture and light, both of which can accelerate the degradation of the active substance. The storage temperature should not exceed 25°C, which for most households corresponds to a cool cupboard or drawer away from direct sunlight and heat sources. The bathroom is generally not a suitable storage location because of humidity and temperature fluctuations.
As with all medicines, stiripentol must be kept out of sight and reach of children. This is particularly important because the medicine is used to treat a condition that often affects small children, and the medication is therefore present in households with young children. Even though the capsule formulation has a mild deterrent effect on accidental ingestion, the risk of serious sedation or respiratory depression following accidental overdose — especially in combination with clobazam or valproate — makes secure storage essential.
The expiry date is printed on both the outer carton and the blister strip. The term "EXP" followed by a month and year refers to the last day of that month. Do not use the medicine if the expiry date has passed, if the capsules look damaged or discoloured, or if the blister has been punctured. Unused, expired or damaged medicine should be returned to a pharmacy for safe disposal. Medicines should never be flushed down the toilet or thrown in the normal rubbish, as this can contribute to environmental pharmaceutical pollution.
When travelling, stiripentol should be carried in hand luggage together with the prescription or a letter from the treating physician. Patients travelling across time zones should agree a dosing plan with the epilepsy team in advance to avoid missed or doubled doses. Insulated travel cases can help keep the medicine below 25°C in hot climates.
What Does Stiripentol Billev Contain?
Stiripentol Billev 250 mg hard capsules are designed to deliver a consistent dose of the active substance while allowing reliable handling, dissolution and absorption. The capsules consist of two main parts: the capsule content, which is a powder containing the active substance and the excipients needed to produce a stable and well-absorbed product, and the capsule shell, which is made of pharmaceutical-grade gelatin and colourants.
Active Substance
- Stiripentol 250 mg per capsule — a structurally novel aromatic allylic alcohol derivative (chemical name: 4,4-dimethyl-1-[(3,4-methylenedioxyphenyl)]-1-penten-3-ol). Stiripentol is a chiral molecule and is used as a racemic mixture of the (R)- and (S)-enantiomers.
Typical Excipients
- Povidone (polyvinylpyrrolidone) — binder that helps form a uniform powder blend.
- Sodium starch glycolate — disintegrant that promotes dissolution of the capsule contents in the gastrointestinal tract.
- Magnesium stearate — lubricant used during capsule filling.
- Colloidal anhydrous silica — glidant to improve powder flow.
- Gelatin and titanium dioxide (E171) as the principal components of the hard capsule shell.
- Iron oxide colourants (may include E172) used to differentiate the capsule visually.
Patients and carers should consult the full patient information leaflet and the Summary of Product Characteristics for the specific batch in use, as the exact list of excipients can vary slightly between manufacturers and between the capsule and oral suspension formulations. The pack size for Stiripentol Billev 250 mg capsules is typically a 60-capsule or 90-capsule presentation in aluminium or PVC/aluminium blister packs, depending on the jurisdiction.
Physical Characteristics
| Property | Value |
|---|---|
| Active substance | Stiripentol (racemic mixture) |
| Molecular formula | C₁₄H₁₈O₃ |
| Molecular weight | 234.3 g/mol |
| Solubility | Practically insoluble in water; soluble in ethanol and organic solvents |
| Plasma protein binding | Approximately 99% |
| Elimination half-life | 4.5–13 hours (dose-dependent, non-linear kinetics) |
| Primary metabolism | Hepatic, via CYP1A2, CYP2C19 and CYP3A4 |
| Route of elimination | Predominantly renal excretion of metabolites |
| ATC code | N03AX17 (other antiepileptics) |
Stiripentol exhibits non-linear pharmacokinetics (also known as saturable kinetics), meaning that once a certain plasma concentration is reached, the metabolic pathways become saturated and further dose increases produce disproportionately large rises in plasma concentration. This property is an important reason why gradual dose titration and careful monitoring are needed, and why adding stiripentol can have a dramatic effect on the concentrations of other drugs metabolised by the same CYP enzymes.
Frequently Asked Questions About Stiripentol Billev
Stiripentol Billev is an antiepileptic medicine used in combination with clobazam and valproate for the treatment of refractory generalised tonic-clonic seizures in patients with Dravet syndrome (severe myoclonic epilepsy in infancy, SMEI). It is used when seizures are not adequately controlled by clobazam and valproate alone. Stiripentol has orphan drug designation in the European Union and the United States for this rare, severe form of childhood epilepsy. It is not approved for other forms of epilepsy and is not used as a single agent.
Stiripentol has two complementary mechanisms of action. It directly enhances the activity of GABA-A receptors, particularly those containing alpha-3 subunits, which increases inhibitory neurotransmission in the brain. In addition, stiripentol inhibits several cytochrome P450 enzymes (CYP3A4, CYP2C19 and CYP1A2). This enzyme inhibition markedly increases plasma levels of clobazam and especially its long-acting active metabolite norclobazam, enhancing the anticonvulsant effect of the combination. This dual action is particularly useful in Dravet syndrome, where the underlying SCN1A mutation causes loss of inhibitory interneuron function.
The recommended target dose of stiripentol is 50 mg per kg of body weight per day, divided into two or three doses and taken with food. Treatment is usually initiated at 20 mg/kg/day and titrated over about three days to the target dose. The dose of clobazam is typically reduced by 25 to 50 percent when stiripentol is added, because stiripentol greatly raises clobazam and norclobazam concentrations. All dosing decisions should be made by a pediatric neurologist or epileptologist, and weight-based doses should be reviewed at every growth check.
The most common side effects of stiripentol are drowsiness (somnolence), loss of appetite, weight loss, hypotonia, ataxia, tremor, nausea and behavioural changes such as irritability or aggression. Many of these effects are largely due to the increased plasma concentration of clobazam and its active metabolite norclobazam caused by stiripentol, and can often be reduced by lowering the clobazam dose. Neutropenia (low white blood cell count) and elevated liver enzymes are less common but clinically relevant, which is why regular blood tests are required during treatment.
Yes, in fact stiripentol is specifically designed to be used in combination with clobazam and valproate, not as monotherapy. It has clinically significant interactions with many other antiepileptics because it inhibits CYP3A4, CYP2C19 and CYP1A2. Enzyme-inducing antiepileptics such as phenytoin, carbamazepine and phenobarbital are generally avoided because they lower stiripentol levels, while stiripentol can dangerously increase their concentrations. Newer agents used in Dravet syndrome such as cannabidiol and fenfluramine can be combined with stiripentol under specialist supervision, usually with careful attention to clobazam dose.
Stiripentol is generally not recommended during pregnancy unless clearly necessary because human data are limited and some animal studies have suggested reproductive toxicity at high doses. However, uncontrolled seizures in pregnancy also carry serious risks, so the decision must be individualised with a specialist in epilepsy and pregnancy. Women of childbearing potential should use effective contraception while on stiripentol, but should be aware that stiripentol may reduce the effectiveness of hormonal contraceptives. Breastfeeding is not recommended during treatment because stiripentol is likely excreted in breast milk and may cause sedation in the infant.
If a single dose of Stiripentol Billev is missed, take it as soon as you remember on the same day, unless it is almost time for the next dose. In that case, skip the missed dose and continue with the normal schedule. Never take a double dose to make up for a missed one, as this can cause excessive sedation and other adverse effects. If several doses are missed, or if the medicine has been unavailable for a day or more, contact the treating epilepsy team promptly, because rapid interruption of antiepileptic therapy can trigger breakthrough seizures in patients with Dravet syndrome.
References and Medical Sources
All medical claims in this article are based on peer-reviewed research, systematic reviews, randomised controlled trials and international medical guidelines. Sources include the European Medicines Agency (EMA), International League Against Epilepsy (ILAE), World Health Organization (WHO) and the British National Formulary (BNF).
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Medical Editorial Team
This article has been developed by the iMedic Medical Editorial Team, comprising specialists in pediatric neurology, epileptology and clinical pharmacology. All content is reviewed according to international guidelines and evidence-based medicine principles, including the standards of the International League Against Epilepsy (ILAE), the European Medicines Agency (EMA) and the National Institute for Health and Care Excellence (NICE).
Reviewed by board-certified specialists in pediatric neurology and epileptology with experience in the management of Dravet syndrome and other developmental and epileptic encephalopathies.
Content is based on the GRADE evidence framework, drawing on randomised controlled trials (including the STICLO studies), systematic reviews, international consensus statements and regulatory summaries of product characteristics.
No pharmaceutical funding. All content is editorially independent, with no conflicts of interest. The article is reviewed at least annually to reflect the latest clinical evidence and regulatory updates.
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