Diacomit (Stiripentol)

What Is Diacomit and What Is It Used For?

Diacomit contains the active substance stiripentol, a structurally unique anticonvulsant that was first approved in the European Union in 2007 by the European Medicines Agency (EMA) as an orphan medicinal product. It later received FDA approval in the United States in 2018 under the brand name Diacomit. The medication is manufactured by Biocodex, a French pharmaceutical company.

Dravet syndrome (previously known as severe myoclonic epilepsy of infancy, or SMEI) is a rare and severe form of epilepsy that typically begins during the first year of life. It is most commonly caused by mutations in the SCN1A gene, which encodes sodium channel proteins critical for normal brain function. Patients with Dravet syndrome experience frequent, prolonged seizures that are often triggered by fever, and the condition is associated with developmental delays, cognitive impairment, and an increased risk of sudden unexpected death in epilepsy (SUDEP).

Stiripentol works through a dual mechanism of action. Its primary pharmacological effect is direct enhancement of GABAergic inhibitory neurotransmission in the brain. Stiripentol acts as a positive allosteric modulator of GABA-A receptors, binding at a distinct site from benzodiazepines and barbiturates, which increases chloride ion influx and hyperpolarizes neurons, thereby reducing neuronal excitability and seizure propagation. This direct anticonvulsant action has been demonstrated in multiple animal models of epilepsy.

The secondary mechanism of action involves potent inhibition of cytochrome P450 (CYP450) liver enzymes, particularly CYP1A2, CYP2C19, and CYP3A4. This pharmacokinetic interaction is clinically significant because it slows the hepatic metabolism of co-administered antiepileptic drugs, most notably clobazam (and its active metabolite norclobazam) and valproic acid. By increasing the plasma concentrations of these companion drugs, stiripentol effectively enhances their therapeutic efficacy. Clinical studies have shown that the addition of stiripentol to clobazam and valproate therapy results in a 2-3 fold increase in norclobazam plasma levels.

In pivotal clinical trials, including the landmark STICLO France and STICLO Italy studies, stiripentol demonstrated a statistically significant reduction in seizure frequency when added to clobazam and valproate compared to placebo. Approximately 71% of patients achieved a 50% or greater reduction in clonic or tonic-clonic seizure frequency, compared to only 5% in the placebo group. These results provided strong evidence for the efficacy of stiripentol as adjunctive therapy in Dravet syndrome.

What Should You Know Before Taking Diacomit?

Contraindications

Diacomit is contraindicated (must not be used) in the following situations:

• Hypersensitivity: Known allergy to stiripentol or any of the excipients in the capsule formulation.
• History of psychosis: Patients with a previous history of psychotic episodes in the form of delirium should not use stiripentol.
• Severe hepatic impairment: Stiripentol is extensively metabolized by the liver, and impaired hepatic function can lead to dangerously elevated drug levels. Patients with significant liver disease should not take this medication.
• Severe renal impairment: Patients with significantly reduced kidney function require careful evaluation before use, as metabolite clearance may be compromised.

Warnings and Precautions

Several important precautions must be observed during treatment with Diacomit:

Blood monitoring: Regular blood tests are recommended during treatment, including complete blood counts (CBC) and liver function tests (LFTs). Stiripentol has been associated with cases of neutropenia (decreased white blood cell count) and thrombocytopenia (decreased platelet count), particularly during the early months of therapy. Liver enzymes should be checked before initiating treatment and periodically thereafter, as hepatotoxicity has been reported in rare cases.

Growth monitoring: Because Diacomit commonly causes decreased appetite and weight loss, regular monitoring of growth parameters (height, weight, and body mass index) is essential in pediatric patients. Nutritional support or supplementation may be required if growth velocity is impaired. In clinical trials, decreased appetite was reported in up to 30% of patients receiving stiripentol.

Drug level monitoring: Due to the significant pharmacokinetic interactions with co-administered antiepileptic drugs, therapeutic drug monitoring of clobazam, norclobazam, and valproate plasma levels is advisable. Dose reductions of clobazam (and occasionally valproate) are commonly required when stiripentol is added to the treatment regimen. Failure to adjust companion drug doses can lead to excessive sedation, ataxia, and other dose-related adverse effects.

Driving and machinery: Stiripentol can cause significant drowsiness, dizziness, and impaired coordination. Patients (or, more commonly, caregivers of affected children) should be warned about these effects and advised not to operate dangerous machinery while under the influence of this medication.

Pregnancy and Breastfeeding

Pregnancy: There are very limited data on the use of stiripentol in pregnant women. Animal studies have shown some evidence of reproductive toxicity at high doses. Diacomit should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential must use effective contraception during treatment. If pregnancy occurs, the treating physician should be consulted immediately, as abrupt discontinuation of antiepileptic therapy also carries significant risks.

Breastfeeding: It is not known whether stiripentol is excreted in human breast milk. Given the potential for serious adverse reactions in nursing infants, breastfeeding is generally not recommended during treatment with Diacomit. The decision to discontinue breastfeeding or discontinue the drug should be made in consultation with the treating physician, taking into account the importance of the medication to the mother.

How Does Diacomit Interact with Other Drugs?

Drug interactions are a critical consideration with Diacomit due to its potent inhibition of multiple cytochrome P450 enzyme isoforms. Healthcare providers must carefully review all concomitant medications before initiating stiripentol therapy. The most clinically significant interactions involve other antiepileptic drugs, but interactions with non-epilepsy medications metabolized by CYP enzymes are also important.

Major Interactions

Other Notable Interactions

Beyond antiepileptic drugs, stiripentol's CYP inhibitory properties can affect numerous other medications:

• Caffeine and theophylline (CYP1A2 substrates): Stiripentol can significantly slow caffeine metabolism, potentially leading to insomnia, restlessness, and cardiac palpitations. Dietary caffeine intake should be limited during treatment.
• Immunosuppressants (tacrolimus, ciclosporin): Plasma levels may increase due to CYP3A4 inhibition, potentially requiring dose adjustments and closer therapeutic drug monitoring.
• Certain statins (simvastatin, atorvastatin): CYP3A4 inhibition may increase statin exposure, raising the risk of myopathy. Consider alternative statins not metabolized by CYP3A4.
• Opioid analgesics (codeine, tramadol): Altered metabolism may affect both efficacy and toxicity. Use with caution under medical supervision.
• Oral contraceptives: CYP3A4 inhibition may affect the metabolism of hormonal contraceptives. Additional or alternative contraceptive methods should be considered.
• Warfarin: Anticoagulant effect may be altered through CYP enzyme interactions. INR should be closely monitored if co-administration is necessary.

What Is the Correct Dosage of Diacomit?

The dosing of Diacomit is weight-based and must be individualized by the treating specialist. The medication should always be introduced gradually alongside existing antiepileptic therapy with clobazam and valproate. When stiripentol is added, dose reductions of the companion medications, particularly clobazam, are often required due to the pharmacokinetic interactions described above.

Children (6 months and older)

Adults

The EMA has extended the indication of Diacomit to include adults with Dravet syndrome who have been stabilized on the triple combination therapy. Adult dosing follows the same weight-based principle of 50 mg/kg/day, though in practice, many adult patients are maintained on doses determined during their pediatric treatment phase. Clinical experience in adult patients is more limited than in children, and careful monitoring is advised during any dose adjustments.

Elderly

Dravet syndrome is a condition that primarily affects young patients, and data in elderly populations are extremely limited. If Diacomit is used in older adults, particular caution is warranted due to the potential for age-related decline in hepatic and renal function, increased sensitivity to CNS depressant effects, and a higher likelihood of concomitant medication use that could result in drug interactions.

Missed Dose

If a dose of Diacomit is missed, it should be taken as soon as possible, preferably with food. However, if it is close to the time for the next scheduled dose, skip the missed dose and return to the regular dosing schedule. Do not take a double dose to compensate for a missed one, as this increases the risk of adverse effects. If multiple doses are missed, contact the prescribing physician for guidance, as abrupt changes in antiepileptic drug levels can increase seizure risk.

Overdose

What Are the Side Effects of Diacomit?

Like all medicines, Diacomit can cause side effects, although not everybody experiences them. It is important to understand that many of the reported adverse effects are attributable to the pharmacokinetic interaction with co-administered antiepileptic drugs, particularly the elevated plasma levels of norclobazam (the active metabolite of clobazam). In clinical practice, dose reduction of clobazam often ameliorates these side effects.

The side effects reported in clinical trials and post-marketing surveillance are categorized below by frequency. These categories are defined according to international medical conventions:

How Should You Store Diacomit?

Proper storage of Diacomit is essential to maintain the medication's stability and effectiveness. The following guidelines should be followed:

• Temperature: Store at room temperature, below 25°C (77°F). Do not refrigerate or freeze. Avoid storing in locations subject to extreme temperatures, such as near radiators, in direct sunlight, or in cars during hot weather.
• Light protection: Keep Diacomit capsules in the original blister packaging or container until use. Stiripentol is sensitive to light, and prolonged exposure can degrade the active ingredient.
• Moisture: Keep the medication in a dry place. Avoid storing in bathrooms or other humid environments, as moisture can affect capsule integrity and drug stability.
• Child safety: Keep out of the sight and reach of children. Consider using child-resistant storage containers, especially given that Diacomit is primarily prescribed for young patients who may live in households with other children.
• Expiry date: Do not use Diacomit after the expiration date (EXP) stated on the packaging. The expiration date refers to the last day of that month. Dispose of expired or unused medication through a pharmacy or local medication take-back program. Do not flush medicines down the toilet or discard them in household waste.

For Diacomit powder for oral suspension, the same general storage conditions apply to the unopened sachets. Once reconstituted with water, the suspension should be consumed immediately during a meal and should not be stored for later use.

What Does Diacomit Contain?

Understanding the full composition of Diacomit is important, particularly for patients with known allergies or dietary restrictions. The formulation details are as follows:

Active ingredient:

• Stiripentol – 250 mg or 500 mg per hard capsule

Excipients (inactive ingredients) in the capsule contents:

• Povidone K29/32 (binder)
• Sodium starch glycolate Type A (disintegrant)
• Magnesium stearate (lubricant)

Capsule shell composition:

• Gelatin
• Titanium dioxide (E171)
• Erythrosine (E127) – used in certain capsule strengths for color identification

Printing ink:

• Shellac, black iron oxide (E172), propylene glycol

Diacomit capsules are not suitable for patients with gelatin allergies, as the capsule shell is made from animal-derived gelatin. The powder for oral suspension formulation uses different excipients (including glucose, erythrosine lake, carmellose sodium, sorbitol, and aspartame) and may be more appropriate for patients with specific excipient sensitivities. However, the powder formulation contains aspartame, a source of phenylalanine, and must be used with caution in patients with phenylketonuria (PKU). It also contains sorbitol, which may not be suitable for patients with hereditary fructose intolerance.

From a chemical perspective, stiripentol (chemical name: 4,4-dimethyl-1-[3,4-(methylenedioxy)phenyl]-1-penten-3-ol) is a unique anticonvulsant that is structurally unrelated to any other currently marketed antiepileptic drug. Its molecular formula is C₁₄H₁₈O₃ with a molecular weight of 234.29 g/mol. It is a chiral molecule, and the marketed product contains a racemic mixture of both enantiomers.