Potential for other medicinal products to affect rufinamide: Other Anti-Epileptic Drugs:
Rufinamide concentrations may be decreased by co-administration with carbamazepine, phenobarbital, phenytoin, vigabatrin or primidone.
Rufinamide concentrations may be increased by co-administration with valproate. The most pronounced increases were observed in patients of low body weight (<30 kg). In children with high concentrations of valproate (median of 100 microgram/mL), rufinamide levels may be elevated by up to 70%. Therefore, consideration should be given to a dose reduction of rufinamide in patients <30 kg who are initiated on valproate therapy (see Dosage & Administration).
The addition or withdrawal of these drugs during rufinamide therapy may require an adjustment in dosage of rufinamide.
No significant changes in rufinamide concentration are observed following co-administration with lamotrigine, topiramate or benzodiazepines.
Potential for rufinamide to affect other medicinal products: Other Anti-Epileptic Drugs:
The pharmacokinetic interactions between rufinamide and other anti-epileptic drugs have been evaluated in patients with epilepsy using population pharmacokinetic modeling. Rufinamide had no clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate, phenytoin or valproate steady state concentrations.
Table 3 summarizes the drug-drug interactions of rufinamide with other AEDs. (See Table 3.)
Click on icon to see table/diagram/image
The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15 μg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction.
An interaction study was conducted to determine the effect of rufinamide on co-administered low-dose oral contraceptives (Ortho-Novum 1/35) in healthy female volunteers. Co-administration of rufinamide and Ortho-Novum 1/35 resulted in a mean decrease in the ethinyl estradiol AUC(0-24h)
of 22% and in norethindrone AUC(0-24)
of 14%. Studies with other oral or implant contraceptives have not been conducted. These changes in ethinyl estradiol and norethindrone are small and unlikely to result in diminished clinical efficacy. However, tests for ovulation were not used in this study.
Women of child-bearing potential using hormonal contraceptives are advised to use an additional safe and effective contraceptive method (see Precautions).
Cytochrome P450 Enzymes:
Rufinamide is hydrolyzed by carboxylesterases, and is not metabolized to any notable degree by cytochrome P450 enzymes. Furthermore, rufinamide does not inhibit the activity of cytochrome P450 enzymes (see Pharmacology: Pharmacokinetics under Actions). Thus, clinically significant interactions mediated through inhibition of cytochrome P450 system by rufinamide are unlikely to occur. Rufinamide has been shown to induce the cytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of drugs which are metabolized by this enzyme. The effect was modest to moderate. The mean CYP3A activity, assessed as clearance of triazolam, was increased by 55% after 11 days of treatment with rufinamide 400 mg b.i.d. The exposure of triazolam was reduced by 36%. Higher doses may result in a more pronounced induction. It may not be excluded that rufinamide may also decrease the exposure of substances metabolized by other enzymes, or transported by transport proteins such as P-glycoprotein.
It is recommended that patients treated with substances that are metabolized by the CYP3A4 enzyme system are to be carefully monitored for two weeks at the start of, or after the end of treatment with rufinamide, or after any marked change in the dose. A dose adjustment of the concomitantly administered medicinal product may need to be considered. These recommendations should also be considered when rufinamide is used concomitantly with substances with a narrow therapeutic window such as warfarin and digoxin.
A specific interaction study in healthy subjects revealed no influence of rufinamide at a dose of 400 mg bid on the pharmacokinetics of olanzapine, a CYP1A2 substrate.
Maximum plasma levels are reached approximately 6 hours after administration. Peak concentration (Cmax
) and plasma AUC of rufinamide increase less than proportionally with doses in both fasted and fed healthy subjects and in subjects, probably due to dose-limited absorption behavior. After a low single doses food increases the absorption of rufinamide by approximately 34%, however at high dose steady state there is no notable influence of food on rufinamide exposure.