4.1. Therapeutic indications

Diacomit is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet's syndrome (DS) whose seizures are not adequately controlled with clobazam and valproate.

4.2. Posology and method of administration

Diacomit should only be administered under the supervision of a paediatrician / paediatric neurologist / neurologist experienced in the diagnosis and management of epilepsy in infants, children and/or adults.

Posology

The dose of stiripentol is calculated on a mg/kg body weight basis.

The daily dosage may be administered in 2 or 3 divided doses.

The initiation of adjunctive therapy with stiripentol should be undertaken gradually using upwards dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with clobazam and valproate.

Stiripentol dosage escalation should be gradual, starting with 20mg/kg/day for 1 week, then 30mg/kg/day for 1 week. Further dosage escalation is age dependent:

- children less than 6 years should receive an additional 20 mg/kg/day in the third week, thus achieving the recommended dose of 50 mg/kg/day in three weeks;

- children from 6 to less than 12 years should receive an additional 10 mg/kg/day each week, thus achieving the recommended dose of 50 mg/kg/day in four weeks;

- patients above 12 years old should receive an additional 5 mg/kg/day each week until the optimum dose is reached based on clinical judgment.

The recommended dose of 50 mg/kg/day is based on the available clinical study findings and was the only dose of Diacomit evaluated in the pivotal studies (see section 5.1).

Stiripentol should not be taken with carbonated drinks, fruit juice or food and drinks that contain caffeine or theophylline

Children aged less than 3 years

The pivotal clinical evaluation of stiripentol was in children of 3 years of age and over with DS. The clinical decision for use of stiripentol in children with DS less than 3 years of age needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks. In this younger group of patients, adjunctive therapy with Diacomit should only be started when the diagnosis of DS has been clinically confirmed (see section 5.1). Data are limited about the use of stiripentol under 12 months of age. For these children the use of stiripentol will be done under the close supervision of the doctor.

Patients aged ≥ 18 years of age

Long-term data confirm the maintenance of the effect in this population. Treatment should be continued for as long as efficacy is observed. Adults may require a lower maximum dose compared to younger patients.

Dose adjustments of other antiepileptics used in combination with stiripentol

Despite the absence of comprehensive pharmacology data on potential drug interactions, the following advice regarding modification of the dose and dosage schedules of other anti-epileptic medicinal products administered in conjunction with stiripentol is provided based on clinical experience.

- Clobazam

In the pivotal studies, when the use of stiripentol was initiated, the daily dose of clobazam was 0.5 mg/kg/day usually administered in divided doses, twice daily. In the event of clinical signs of adverse reactions or overdose of clobazam (i.e., drowsiness, hypotonia, and irritability in young children), this daily dose was reduced by 25% every week. Approximately two to three-fold increases in clobazam and five-fold increases in norclobazam plasma levels respectively have been reported with co-administration of stiripentol in children with Dravet's syndrome.

- Valproate

The potential for metabolic interaction between stiripentol and valproate is considered modest and thus, no modification of valproate dosage should be needed when stiripentol is added, except for clinical safety reasons. In the pivotal studies in the event of gastrointestinal adverse reactions such as loss of appetite, loss of weight, the daily dose of valproate was reduced by around 30% every week.

Abnormal laboratory findings

In the event of an abnormal blood count or liver function test finding, the clinical decision for continuing use or adjusting the dose of stiripentol in conjunction with adjusting the doses of clobazam and valproate needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks (see section 4.4).

Effect of formulation

The sachet formulation has a slightly higher Cmax than the capsules and thus the formulations are not bioequivalent. It is recommended that if a switch of formulations is required this is done under clinical supervision, in case of problems with tolerability (see section 5.2).

Renal and hepatic impairment

Stiripentol is not recommended for use in patients with impaired hepatic and/or renal function (see section 4.4).

Method of administration

Oral use

The powder should be mixed in a glass of water and should be taken immediately after mixing.

For the interaction of stiripentol with food, please see section 4.5.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

A past history of psychoses in the form of episodes of delirium.

4.4. Special warnings and precautions for use

Carbamazepine, phenytoin and phenobarbital

These substances should not be used in conjunction with stiripentol in the management of Dravet's syndrome. The daily dosage of clobazam and/or valproate should be reduced according to the onset of side effects whilst on stiripentol therapy (see section 4.2).

Growth rate of children

Given the frequency of gastrointestinal adverse reactions to treatment with stiripentol and valproate (anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of treatment should be carefully monitored.

Blood count

Neutropenia may be associated with the administration of stiripentol, clobazam and valproate. Blood counts should be assessed prior to starting treatment with stiripentol. Unless otherwise clinically indicated, blood counts should be checked every 6 months.

Liver function

It should be assessed prior to starting treatment with stiripentol. Unless otherwise clinically indicated, liver function should be checked every 6 months.

Hepatic or renal impairment

In the absence of specific clinical data in patients with impaired hepatic or renal function, stiripentol is not recommended for use in patients with impaired hepatic and/or renal function (see section 4.2).

Substances interfering with CYP enzymes

In vitro studies show stiripentol is both an inhibitor and inducer of the enzymes CYP1A2, CYP2B6 and CYP3A4 and may markedly decrease or increase the plasma concentrations of substances metabolised by these enzymes. Stiripentol also inhibits CYP2C8, CYP2C19, and drug transporters, including P-gp and BCRP, at clinically relevant concentrations.

Because of potential drug-drug interactions, consider dose adjustment of substrates of CYP1A2, CYP2B6 and CYP3A4 if adverse reactions are experienced (see section 4.5). Because of potential inhibition of enzyme/transporter activity, consider a reduction in dosage of substrates of CYP2C8, CYP2C19, P-gp and BCRP if adverse reactions are experiences when administered concomitantly with stiripentol.

In vitro studies suggested that stiripentol phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other substances that inhibit or induce one or more of these enzymes.

Paediatric population

The pivotal clinical studies did not include children below 3 years old. As a consequence, it is recommended that children between 6 months and 3 years of age are carefully monitored whilst on stiripentol therapy.

Stiripentol powder for oral suspension in sachet contains aspartame, a source of phenylalanine.

Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age. Therefore it may be harmful for people with phenylketonuria. Patients with rare glucose-galactose malabsorption should not take this medicine, as the formulation contains glucose. As the flavouring component contains small amount of sorbitol, patients with hereditary problems of fructose intolerance should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Potential medicinal product interactions affecting stiripentol

The influence of other antiepileptic medicinal products on stiripentol pharmacokinetics is not well established.

The impact of macrolides and azole antifungal medicinal product on stiripentol metabolism, that are known to be inhibitors of CYP3A4 and substrates of the same enzyme, is not known. Likewise, the effect of stiripentol on their metabolism is not known.

In vitro studies suggested that stiripentol phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other substances that inhibit or induce one or more of these enzymes.

Effect of stiripentol on cytochrome P450 enzymes

Many of these interactions have been partially confirmed by in vitro studies and in clinical trials. The increase in steady state levels with the combined use of stiripentol, valproate, and clobazam is similar in adults and children, though inter-individual variability is marked.

At therapeutic concentrations, stiripentol significantly inhibits several CYP450 isoenzymes: for example, CYP2C19, CYP2B6 and CYP3A4. As a result, pharmacokinetic interactions of metabolic origin with other medicines may be expected. These interactions may result in increased systemic levels of these active substances that may lead to enhanced pharmacological effects and to an increase in adverse reactions.

Caution must be exercised if clinical circumstances require combining stiripentol with substances metabolised by CYP2C19 (e.g. citalopram, omeprazole) or CYP3A4 (e.g. several HIV protease inhibitors, antihistamines such as astemizole and chlorpheniramine, calcium channel blockers, statins, oral contraceptives, codeine) due to the increased risk of adverse reactions (see further in this section for antiepileptic medicines). Monitoring of plasma concentrations or adverse reactions is recommended. A dose adjustment may be necessary.

Co-administration with CYP3A4 substrates with a narrow therapeutic index should be avoided due to the markedly increased risk of severe adverse reactions.

Data on the potential for inhibition of CYP1A2 are limited, and therefore, interactions with theophylline and caffeine cannot be excluded because of increased plasma levels of theophylline and caffeine which may occur via inhibition of their hepatic metabolism, potentially leading to toxicity. Use in combination with stiripentol is not recommended. This warning is not only restricted to medicinal products but also to a considerable number of foods (for example: cola, chocolate, coffee, tea, and energy drinks) and nutritional products aimed at children: Patient should not drink cola drinks, which contain significant quantities of caffeine or chocolate, which contains trace amounts of theophylline (see section 4.2).

Potential for stiripentol to interact with other medicinal products

In the absence of available clinical data, caution should be taken with the following clinically relevant interactions with stiripentol:

Undesirable combinations (to be avoided unless strictly necessary)

- Rye ergot alkaloids (ergotamine, dihydroergotamine)

Ergotism with possibility of necrosis of the extremities (inhibition of hepatic elimination of rye ergot).

- Cisapride, halofantrine, pimozide, quinidine, bepridil

Increased risk of cardiac arrhythmias and torsades de pointes/wave burst arrhythmia in particular.

- Immunosuppressants (tacrolimus, cyclosporine, sirolimus)

Raised blood levels of immunosuppressants (decreased hepatic metabolism).

- Statins (atorvastatin, simvastatin, etc.)

Increased risk of dose-dependent adverse reactions such as rhabdomyolysis (decreased hepatic metabolism of cholesterol-lowering medicinal product).

Combinations requiring precautions

- Midazolam, triazolam, alprazolam

Increased plasma benzodiazepine levels may occur via decreased hepatic metabolism leading to excessive sedation.

- Chlorpromazine

Stiripentol enhances the central depressant effect of chlorpromazine.

- Effects on other antiepileptic drugs (AEDs)

Inhibition of CYP450 isoenzyme CYP2C19 and CYP3A4 may provoke pharmacokinetic interactions (inhibition of their hepatic metabolism) with phenobarbital, primidone, phenytoin, carbamazepine, clobazam (see section 4.2), valproate (see section 4.2), diazepam (enhanced myorelaxation), ethosuximide, and tiagabine. The consequences are increased plasma levels of these anticonvulsants with potential risk of overdose. Clinical monitoring of plasma levels of other anticonvulsants when combined with stiripentol with possible dose adjustments is recommended.

- Topiramate

In a French compassionate use program for stiripentol, topiramate was added to stiripentol, clobazam and valproate in 41% of 230 cases. Based on the clinical observations in this group of patients, there is no evidence to suggest that a change in topiramate dose and dosage schedules is needed if co- administered with stiripentol.

With regard to topiramate, it is considered that potential competition of inhibition on CYP2C19 should not occur because it probably requires plasma concentrations 5-15 times higher than plasma concentrations obtained with the standard recommended topiramate dose and dosage schedules.

- Levetiracetam

Levetiracetam does not undergo hepatic metabolism to a major extent. As a result, no pharmacokinetic metabolic drug interaction between stiripentol and levetiracetam is anticipated.

4.6. Fertility, pregnancy and lactation

Pregnancy

Risk related to epilepsy and antiepileptic medicinal products in general

It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population. Although other factors, e.g. the epilepsy, can contribute, available evidence suggests that this increase, to a large extent, is caused by the treatment. In the treated population, an increase in malformations has been noted with polytherapy.

However, effective anti-epileptic therapy should not be interrupted during pregnancy, since the aggravation of the illness may be detrimental to both the mother and the foetus.

Risk related to stiripentol

No data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development at non-maternotoxic doses (see section 5.3). In view of the indication, administration of stiripentol during pregnancy and in women of childbearing potential would not be expected. The clinical decision for use of stiripentol in pregnancy needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks. Caution should be exercised when prescribing to pregnant women and use of efficient methods of contraception is advisable.

Breastfeeding

In the absence of human studies on excretion in breast milk, and given that stiripentol passes freely from plasma into milk in the goat, breast-feeding is not recommended during treatment. In case stiripentol therapy is continued during breast-feeding, the breast-fed infant should be carefully observed for potential adverse effects.

Fertility

No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.

4.7. Effects on ability to drive and use machines

Stiripentol has major influence on the ability to drive and use machines because it may cause dizziness and ataxia. Patients should be advised not to drive or use machines until they have gained sufficient experience to gauge whether it adversely affects their abilities (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most common side effects with stiripentol are anorexia, weight loss, insomnia, drowsiness, ataxia, hypotonia and dystonia.

Tabulated list of adverse reactions

Adverse reactions encountered most often are as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing severity.

System Organ Class (MedDRA terminology)

Very common

Common

Uncommon

Rare

Blood and lymphatic system disorders

Neutropenia

Thrombocytopenia*

Metabolism and nutrition disorders

Anorexia, loss of appetite, weight loss

Psychiatric disorders

Insomnia

Aggressiveness, irritability, behaviour disorders, opposing behaviour, hyperexcitability, sleep disorders

Nervous system disorders

Drowsiness, ataxia, hypotonia, dystonia

Hyperkinesias

Eye disorders

Diplopia

Gastrointestinal disorders

Nausea, vomiting

Skin and subcutaneous tissue disorders

Photosensitivity, rash, cutaneous allergy, urticaria

General disorders and administration site conditions

Fatigue

Investigations

Raised γGT

Liver function test abnormal

* Thrombocytopenia data are derived from both clinical trials and post- marketing experience.

Description of selected adverse reactions

Many of the above adverse reactions are often due to an increase in plasma levels of other anticonvulsant medicinal products (see sections 4.4 and 4.5) and may regress when the dose of these medicinal products is reduced.

Reporting of suspected adverse reactions

If your child gets any side effects, talk to your child's doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

4.9. Overdose

Data on clinical overdose are not available. Treatment is supportive (symptomatic measures in intensive care units).