Diacomit: composition and pharmaceutical form
One capsule contains 250 mg or 500 mg of stiripentol; one sachet contains the same 250 mg or 500 mg. The forms are not interchangeable: the powder in the sachet reaches a slightly higher peak plasma concentration than the capsules, so they are not considered bioequivalent, and a switch from one form to the other is made under clinical observation in case of tolerability problems.
Capsules are swallowed whole with a glass of water, during a meal. Taking stiripentol with food is mandatory: in an acid environment the drug breaks down quickly — for example on contact with gastric juice on an empty stomach. It must not be taken with milk or with dairy products such as yoghurt and curd cheese, with carbonated drinks, fruit juices, or with food and drinks containing caffeine or theophylline.
How Diacomit works
In animal studies stiripentol stopped seizures induced by electroshock, pentetrazol and bicuculline. In studies on rodent brain it increased the concentration of gamma-aminobutyric acid, the main inhibitory neurotransmitter; this may rest on inhibition of the synaptic uptake of that acid or on inhibition of its aminotransferase. Stiripentol has been shown to enhance transmission at GABA-A receptors in the hippocampus of immature rats and to increase the mean open time — but not the frequency — of the chloride channels of those receptors, by a mechanism close to that of barbiturates.
The medicine's second effect is of a different kind: through pharmacokinetic interactions stiripentol enhances the action of other anticonvulsants — carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines. This is achieved mainly by inhibiting the metabolic activity of several isoenzymes, primarily CYP450 3A4 and 2C19, which take part in the hepatic metabolism of other antiepileptic drugs. That is why stiripentol has such a long list of drug interactions: a large part of its benefit and of its risk is its influence on the concentrations of other medicines.
Indications
The medicine is indicated in combination with clobazam and valproate as adjunctive therapy in patients with severe myoclonic epilepsy in infancy — Dravet syndrome — with generalised tonic-clonic seizures refractory to treatment with clobazam and valproate.
Two practical limits follow from the wording of the indication.
- stiripentol is not used on its own: it is always the third medicine in the regimen, added to clobazam and valproate rather than replacing them;
- what is meant is precisely seizures that have already proved refractory to those two medicines — that is, a situation in which the previous regimen has been tried and has not worked.
Method of use and dosage
The dose is calculated per kilogram of body weight, and the daily dose is given in 2–3 divided doses. Treatment starts gradually, increasing to the recommended 50 mg/kg per day in combination with clobazam and valproate: this dose was established from clinical trials and was the only one evaluated in the pivotal studies.
| Stage or situation | What is done |
| Week 1 | 20 mg/kg per day |
| Week 2 | 30 mg/kg per day |
| Children under 6 years | in the 3rd week another 20 mg/kg per day is added, reaching the recommended 50 mg/kg within 3 weeks |
| Children aged 6–12 years | 10 mg/kg per day is added each week, reaching 50 mg/kg within 4 weeks |
| Children and adolescents from 12 years | 5 mg/kg per day is added each week up to the optimal dose determined clinically |
| Clobazam in the regimen | in the pivotal studies it was given at 0.5 mg/kg per day, usually in two doses; at signs of adverse reactions or overdose — drowsiness, a fall in blood pressure and irritability in younger children — the daily dose was reduced by 25% per week |
| Valproate in the regimen | dose adjustment is usually not needed, since the likelihood of a metabolic interaction with stiripentol is considered slight; with gastrointestinal reactions such as loss of appetite and weight loss the daily dose was reduced by about 30% per week |
| Hepatic or renal impairment | stiripentol is not recommended |
In children with Dravet syndrome receiving stiripentol as part of the combination, an approximately two- to threefold rise in clobazam concentration and a fivefold rise in norclobazam in plasma have been described. The pivotal clinical trial included children from 3 years of age: there is little data on use in children under 12 months, who are given the medicine only under strict medical supervision, and children aged 6 months to 3 years are monitored especially closely. In adults from 18 years there is not enough long-term observation to confirm that the effect is maintained, so treatment is continued exactly as long as it brings benefit.
Contraindications
Hypersensitivity to the active substance or to any of the excipients. A history of psychoses that took the form of delirious states.
A direct prohibition from the warnings section sits alongside this short list: in the treatment of Dravet syndrome stiripentol should not be used together with carbamazepine, phenytoin or phenobarbital. Separately, use is not recommended in hepatic or renal impairment — there are no specific clinical data for those groups.
Special warnings and precautions
Before treatment starts, a full blood count and liver function tests are performed, and are then repeated every 6 months unless there are other clinical indications. The reason is simple: the combination of stiripentol, clobazam and valproate can cause neutropenia, and persistent marked neutropenia usually resolves on its own after the medicine is stopped.
- if adverse reactions appear during treatment with stiripentol, the daily dose of clobazam or valproate is reduced — that is, the whole regimen is adjusted, not only the third medicine;
- because of frequent gastrointestinal disturbances — lack of appetite, loss of appetite, nausea and vomiting — the child's growth rate is watched carefully when the drug is combined with valproate;
- as an inhibitor of the CYP2C19, CYP3A4 and CYP2D6 enzymes, stiripentol can markedly raise the plasma concentrations of substances metabolised by those enzymes and increase the risk of adverse reactions.
Driving is addressed in this leaflet in an unusual way. On the one hand, patients with diagnosed Dravet syndrome are not expected to drive vehicles or operate machinery, because of the course of the underlying disease and the consequences of long-term anticonvulsant treatment. On the other hand, it is expressly stated that stiripentol may cause dizziness and ataxia, and therefore during treatment with it one should not drive or work with machinery.
Interactions with other medicines
At therapeutic concentrations stiripentol markedly inhibits the activity of several CYP450 isoenzymes — in particular CYP2C19, CYP2D6 and CYP3A4 — so pharmacokinetic interactions with other medicines are to be expected. They lead to a rise in the concentration of active substances in the body and, with it, to stronger pharmacological effects and adverse reactions. The influence of other antiepileptic drugs on the pharmacokinetics of stiripentol itself has not been unambiguously established.
- combinations that are not recommended and are avoided unless absolutely necessary: ergot alkaloids — ergotamine and dihydroergotamine — because of the risk of poisoning with a threat of limb necrosis; cisapride, halofantrine, pimozide, quinidine and bepridil because of the increased risk of arrhythmias, especially torsades de pointes; the immunosuppressants tacrolimus, ciclosporin and sirolimus, whose blood concentration rises; statins, in which the risk of dose-dependent events such as rhabdomyolysis rises;
- combinations requiring caution: midazolam, triazolam and alprazolam — hepatic metabolism may be impaired, with a rise in benzodiazepine concentration and excessive sedation; chlorpromazine, whose central depressant effect stiripentol enhances;
- substances metabolised through CYP2C19 — citalopram, omeprazole — and through CYP3A4 are used with caution: HIV protease inhibitors, antihistamines, calcium channel blockers, oral contraceptives, codeine; combinations with CYP3A4 substrates that have a narrow therapeutic index are avoided;
- inhibition of CYP2C19 and CYP3A4 gives interactions with phenobarbital, primidone, phenytoin, carbamazepine, clobazam, valproate, diazepam, ethosuximide and tiagabine: their plasma concentrations rise along with the risk of overdose, so they are monitored and doses changed if necessary;
- there is little data on inhibition of CYP1A2, so interactions with theophylline and caffeine cannot be excluded: inhibition of their hepatic metabolism can raise the concentration to a toxic level and the combinations are not recommended — this applies not only to medicines but also to drinks such as cola and to chocolate, with trace amounts of theophylline.
There are opposite examples too. For topiramate, which in the French programme was added to stiripentol with clobazam and valproate in 41% of 230 patients, no need to change the dose was found. For levetiracetam no metabolic interactions are expected at all, since it largely does not undergo hepatic metabolism.
Pregnancy and breastfeeding
The frequency of malformations in the children of women with epilepsy is 2–3 times higher than in the general population, where it is about 3%. Accepted data indicate that the increase is caused by treatment and that, within the treated population, the frequency is higher with multi-drug therapy. Even so, effective antiepileptic treatment should not be interrupted in a pregnant woman: worsening of the disease is unfavourable both for the mother and for the fetus.
There are no data on the systemic effect of stiripentol in pregnancy. Studies in animals given doses that were not toxic to the females showed no direct or indirect harmful effect on the course of pregnancy, fetal development, delivery or postnatal development. Given the indication, use of the medicine in pregnant women or women of childbearing age is not expected; pregnant women are prescribed it with caution and effective contraception is recommended. No studies of excretion of the medicine in human breast milk have been carried out, but since in goats stiripentol passes from plasma into milk, breastfeeding during treatment is not recommended, and if treatment is continued the breastfed infant is closely monitored.
Adverse reactions
In more than one patient in ten, lack of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia and dystonia occurred. Many of the events listed below are a consequence of the rise in plasma concentration of other anticonvulsants and may resolve once the dose of those medicines is reduced.
- very common: lack and loss of appetite, weight loss, especially in combination with sodium valproate, insomnia, drowsiness, ataxia, hypotonia, dystonia;
- common: neutropenia, aggression, irritability, behavioural disturbances, oppositional behaviour, heightened excitability, sleep disturbances, hyperkinesia, nausea, vomiting, increased gamma-glutamyltransferase activity — especially in combination with carbamazepine and valproate;
- uncommon: double vision in combination with carbamazepine, photosensitivity, rash, skin allergy, urticaria, fatigue;
- rare: abnormal liver function test results.
Neutropenia deserves separate mention: persistent marked neutropenia usually resolves on its own after the medicine is withdrawn, and it is precisely for its early detection that blood monitoring every six months has been introduced.
Overdose
There are no clinical data on overdose of stiripentol. Supportive symptomatic treatment in an intensive care unit is used.
In practice another situation is more likely, and the leaflet describes it in detail: not an overdose of stiripentol itself, but an overdose of clobazam in its presence. Clobazam concentration rises 2–3 fold when stiripentol is added, and norclobazam 5 fold, which shows itself as drowsiness, a fall in blood pressure and irritability in younger children. In that case the daily dose of clobazam is reduced by 25% per week.
How to get a Diacomit prescription online
The medicine is available on prescription and only within a defined regimen: in Dravet syndrome, as the third medicine added to clobazam and valproate, when generalised tonic-clonic seizures have proved refractory to those two drugs. The conversation with the doctor therefore starts with the confirmed diagnosis, the child's age and the doses of clobazam and valproate the patient is currently receiving.
It is worth preparing recent full blood count and liver function test results for the consultation — they are needed before treatment starts and then every six months — along with a complete list of the medicines being taken. Carbamazepine, phenytoin and phenobarbital, which are not combined with this regimen, are mentioned separately, as are liver and kidney disease, a history of psychoses with delirious states and, in adolescents and adults, pregnancy and contraception. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
