Rufinamideinteractions

7 D RUG INTERACTION S Patients on valproate should begin at a BANZEL dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) Hormonal contraceptives may be less effective with BANZEL; use additional non-hormonal forms of contraception

7.1 Effects of BANZEL on other AEDs

Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide C avss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population. Table 6 summarizes the drug-drug interactions of BANZEL with other AEDs.

Table 6: Summary of drug-drug interactions of BANZEL with other antiepileptic drugs AED Co-administered Influence of Rufinamide on AED concentration a) Influence of AED on Rufinamide concentration Carbamazepine Decrease by 7 to 13% b) Decrease by 19 to 26% Dependent on dose of carbamazepine Lamotrigine Decrease by 7 to 13% b) No Effect Phenobarbital Increase by 8 to 13% b) Decrease by 25 to 46% c) ’ d) Independent of dose or concentration of phenobarbital Phenytoin Increase by 7 to 21% b) Decrease by 25 to 46% c) ’ d) Independent of dose or concentration of phenytoin Topiramate No Effect No Effect Valproate No Effect Increase by <16 to 70% c) Dependent on concentration of valproate Primidone Not Investigated Decrease by 25 to 46% c) ’ d) Independent of dose or concentration of primidone Benzodiazepines e) Not Investigated No Effect a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL. b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in pediatric patients at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on BANZEL clearance.

Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (C avss 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.

7.2 Effects of

Other AEDs on BANZEL Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital, appear to increase the clearance of BANZEL (see Table 6). Given that the majority of clearance of BANZEL is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred, were likely to be more marked in the pediatric population. Valproate Patients stabilized on BANZEL before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a BANZEL dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults).

7.3 Effects of BANZEL on

Hormonal Contraceptives Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL.