Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) are weak inducers in vitro and in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5 responsible for the metabolism of a very large number of drugs, for example, immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see as follows), and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products.
In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases. When initiating treatment with Kusapin or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.
In case of discontinuation of Kusapin therapy, a dose reduction of the concomitant medications may be necessary and should be decided upon by clinical and/or plasma level monitoring. The induction is likely to gradually decrease over 2 to 3 weeks after discontinuation.
Kusapin was shown to have an influence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52% and 32-52% respectively. Therefore, concurrent use of Kusapin with hormonal contraceptives may render these contraceptives ineffective. Another reliable contraceptive method should be used.
Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Kusapin with medicinal products that are mainly metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased up to 40% when Kusapin was given at doses above 1200 mg/day (see Table 2 summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required.
Antiepileptic medicinal products:
Potential interactions between Kusapin and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarised in Table 2:
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Preliminary results indicate that oxcarbazepine may result in lower lamotrigine concentration, possibly of importance in children but the interaction potential of oxcarbazepine appears lower than seen with concomitant enzyme inducing drugs (carbamazepine, phenobarbitone and phenytoin).
Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine phenytoin and phenobarbitone) have been shown to decrease the plasma levels of MHD (29-40%) in adults. In children 4 to 12 years of age MHD clearance increased by approximately 35 % when given one of the three enzyme inducing antiepileptic medicinal products compared to monotherapy. Concomitant therapy of Kusapin and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache).
Other medicinal product interactions:
Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.
The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural relationship of oxcarbazepine to tricyclic antidepressants.
Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically relevant interactions have been observed.
The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.