Stiripentol

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. 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.

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. 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.

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.

In the absence of specific clinical data, stiripentol is not recommended for use in patients with impaired hepatic function.

In the absence of specific clinical data in patients, stiripentol is not recommended for use in patients with impaired renal function.

Rye ergot alkaloids (ergotamine, dihydroergotamine)

Undesirable combination (to be avoided unless strictly necessary).

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

Statins (atorvastatin, simvastatin, etc.)

Undesirable combination (to be avoided unless strictly necessary).

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

Immunosuppressants (tacrolimus, cyclosporine, sirolimus)

Undesirable combination (to be avoided unless strictly necessary).

Raised blood levels of immunosuppressants (decreased hepatic metabolism).

Effects on other antiepileptic drugs (AEDs)

Combination requiring precaution.

Inhibition of CYP450 isoenzyme CYP2C19 and CYP3A4 may provoke pharmacokinetic interactions (inhibition of their hepatic metabolism) with phenobarbital, primidone, phenytoin, carbamazepine, clobazam, valproate, 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.

Combination requiring precaution.

Stiripentol enhances the central depressant effect of chlorpromazine.

Combinations requiring precautions.

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

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. 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.

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. 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.

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 and may regress when the dose of these medicinal products is reduced.