Antiepileptic drug interactions. Part 1: Mutual interactions between antiepileptic drugs

Pharmacokinetic interactions between antiepileptic drugs are associated with enzymatic induction or inhibition. Felbamate, clobazam, lamotrigine,stiripentol, and sulthiame are significant inhibitors. Felbamate increases the levels of clonazepam, lamotrigine, mesuximide, valproicacid, and the active S(+)-enantiomer vigabatrin. Clobazam increases the levels of stiripentol, carbamazepine, and carbamazepine-10,11-epoxide.Stiripentol increases the levels of ethosuximide, phenobarbital, carbamazepine, clobazam and N-desmethylclobazam, primidone, andvalproate. Acetazolamide, felbamate, phenytoin, mesuximide, oxcarbazepine, rufinamide, and sulthiame increase the levels of phenobarbitaland phenytoin. The level of phenytoin is also increased by eslicarbazepine, clobazam, stiripentol, and topiramate. Phenobarbital and lamotrigineincrease the AUC of retigabine. Valproic acid increases the levels of phenobarbital, lamotrigine, and rufinamide, while reducing thelevels of felbamate and topiramate. It may decrease, increase as well as not affect the levels of ethosuximide, phenytoin, and carbamazepine.Eslicarbazepine, carbamazepine, phenytoin, phenobarbital, mesuximide, oxcarbazepine, primidone, and vigabatrin are enzymatic inductors.A reduction in levels due to induction may occur with eslicarbazepine, ethoxusimide, phenytoin, felbamate, phenobarbital, clobazam, clonazepam,lacosamide, lamotrigine, levetiracetam, oxcarbazepine including its metabolite, perampanel, pregabalin, primidone, retigabine, rufinamide,stiripentol, sulthiame, tiagabine, topiramate, valproate, and zonisamide. Pregabalin increases the clearance of tiagabine and topiramate. Retigabinereduces the AUC of phenobarbital.Interactions involving absorption, distribution, or excretion are less frequent: acetazolamide reduces the absorption of primidone. Phenobarbital increasesthe free fraction of valproate, while valproate increases that of phenytoin and oxcarbazepine. Gabapentin decreases the excretion of felbamate.Adverse pharmacodynamic interactions involve side effects: concomitant treatment with agents acting at the sodium channel increases the risk ofneurotoxicity. During the administration of lamotrigine with valproate, tremor can occur and the risk of skin rash and Stevens-Johnson syndromeincreases. The incidence of encephalopathy after valproate increases when it is combined with topiramate, levetiracetam, and in triple combinationwith oxcarbazepine and lacosamide. Concomitant administration of carbonic anhydrase inhibitors increases the risk of nephrolithiasis. When sulthiameand primidone are combined, children can develop dizziness, unsteady gait, and drowsiness. Phenobarbital delays the onset of action of vigabatrin.

Keywords: drug interactions, antiepileptic drugs, concentration