Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction
Cenobamate is extensively metabolized, primarily by glucuronidation, with oxidation contributing to a lesser degree.

Cenobamate may reduce exposures of products primarily metabolized by CYP3A4 and 2B6.
Cenobamate may increase exposures of products primarily metabolized by CYP2C19. When initiating or discontinuing treatment with cenobamate or changing the dose, it may take 2 weeks to reach the new level of enzyme activity.

Pharmacodynamic interactions

CNS depressants
Concomitant use of cenobamate with other CNS depressants, including alcohol, barbiturates, and benzodiazepines may increase the risk of neurological adverse reactions. Therefore, based on individual response, doses of barbiturates and benzodiazepines may need to be reduced, as clinically appropriate, when used concomitantly with cenobamate.

Interactions with other antiepileptics
Phenytoin
In a study in healthy subjects, concomitant administration of cenobamate 200 mg/day and phenytoin 300 mg/day slightly reduced cenobamate exposures (Cmax by -27%, AUC by -28%), and increased phenytoin exposures (Cmax by 67%, AUC by 84%). No dose adjustment of cenobamate is required.
Phenytoin concentrations should be monitored during titration of cenobamate, and based on individual response, the dose of phenytoin may need to be reduced.


Phenobarbital
In a study in healthy subjects, concomitant administration of cenobamate 200 mg/day and phenobarbital 90 mg/day did not cause clinically meaningful changes in cenobamate exposure but led to increased phenobarbital exposures (Cmax by 34% and AUC by 37%). No dose adjustment of cenobamate is required. Concentrations of phenobarbital should be monitored during cenobamate titration, and based on individual response, the dose of phenobarbital may need to be reduced.

Clobazam
Pharmacometric analyses of data from healthy subjects and patients predict that clobazam slightly increases cenobamate exposures (by 24%). No dose adjustment of cenobamate is required.
Due to a possible increase in exposure of the active metabolite of clobazam (N-desmethylclobazam), related to the induction of CYP3A4 (formation) and the inhibition of CYP2C19 (elimination), the dose of clobazam may need to be reduced.

Lamotrigine
Pharmacometric analyses of data from healthy subjects and patients showed that concomitant administration of cenobamate with lamotrigine had no effect on cenobamate exposures, but resulted in dose-dependent decreases in lamotrigine concentrations (by -21%, -35%, and -52% for cenobamate 100, 200, and 400 mg/day). Based on subpopulation analyses of patients taking concomitant lamotrigine, higher doses (200 - 400 mg/day) of cenobamate may be required for efficacy when co- administered with lamotrigine. Depending on individual response, the dose of cenobamate may need to be increased.

Carbamazepine
In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily and carbamazepine 200 mg twice daily showed no significant change in exposure of cenobamate, but carbamazepine exposures were slightly reduced (Cmax reduced by 23%, AUC reduced by 24%). No clinically meaningful decreases in efficacy were observed in subpopulation analyses of patients taking concomitant carbamazepine. Therefore, no dose adjustments are required.

Valproic acid
In a study in healthy subjects, concomitant administration of cenobamate 150 mg once daily and valproic acid 1,000 mg once daily showed no significant changes in exposures of either medicinal product.
Pharmacometric analyses of data from healthy subjects and patients indicated that concomitant administration of cenobamate with valproic acid did not affect cenobamate exposures and had no clinically relevant reductions in valproic acid concentration. No dose adjustments are required.

Lacosamide, levetiracetam and oxcarbazepine
Pharmacometric analyses of data from healthy subjects and patients indicated that concomitant administration with lacosamide, levetiracetam, or oxcarbazepine did not affect the exposure of cenobamate, and cenobamate did not have a clinically relevant effect on exposures of lacosamide, levetiracetam, or oxcarbazepine. No dose adjustments are required for cenobamate, lacosamide, levetiracetam, or oxcarbazepine.

Other medicinal products

Oral contraceptives
Cenobamate showed a dose-dependent induction of CYP3A4, reducing exposures (AUC) of the CYP3A4 substrate, midazolam 2 mg by 72% with cenobamate 200 mg/day in healthy subjects. Since hormonal contraceptives may also be metabolized by CYP3A4, their efficacy may be reduced by concomitant use with cenobamate. Therefore, women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control (see section 4.6).

CYP3A4 substrates
In a study in healthy subjects, concomitant administration of cenobamate 100 and 200 mg once daily reduced exposures (AUC) of the CYP3A4 substrate, midazolam 2 mg by 27% and 72%, respectively.
An increase in the dose of medicines metabolized by CYP3A4 may be required when used concomitantly with cenobamate.

CYP2B6 substrates
In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily reduced exposures of the CYP2B6 substrate, bupropion 150 mg (Cmax reduced by 23%, AUC reduced by 39%).
An increase in the dose of medicines metabolized by CYP2B6 may be required when used concomitantly with cenobamate.

CYP2C19 substrates
In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily increased exposures of the CYP2C19 substrate, omeprazole 20 mg (Cmax increase by 83%, AUC increased by 107%). A dose reduction of medicines metabolized by CYP2C19 may be required when used concomitantly with cenobamate.

OAT3 substrates
In vitro studies have shown that cenobamate inhibits OAT3, a transporter predominantly involved in the elimination of certain medicines (e.g. baricitinib, cefaclor, empagliflozin, penicillin G, ritobegron, and sitagliptin). Therefore, concomitant administration of cenobamate and medicinal products transported by OAT3 may result in higher exposure of these medicinal products.