DIACOMIT Hard capsule Ref.[7680] Active ingredients: Stiripentol

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

Stiripentol is an inhibitor of the enzymes CYP2C19, CYP3A4 and CYP2D6 and may markedly increase the plasma concentrations of substances metabolised by these enzymes and increase the risk of adverse reactions (see section 4.5). 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.

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

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 agents 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, CYP2D6 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. HIV protease inhibitors, antihistamines such as astemizole, 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 the 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 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).

As stiripentol inhibited CYP2D6 in vitro at concentrations that are achieved clinically in plasma, substances that are metabolized by this isoenzyme like: beta-blockers (propranolol, carvedilol, timolol), antidepressants (fluoxetine, paroxetine, sertraline, imipramine, clomipramine), antipsychotics (haloperidol), analgesics (codeine, dextromethorphan, tramadol) may be subject to metabolic interactions with stiripentol. A dose-adjustment may be necessary for substances metabolised by CYP2D6 and that are individually dose titrated.

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 coadministered 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.

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.

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).

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.

^* 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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.