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, valproic acid, 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, and valproate. Acetazolamide, felbamate, phenytoin, mesuximide, oxcarbazepine, rufinamide,
and sulthiame increase the levels of phenobarbital and phenytoin. The level of phenytoin is also increased by eslicarbazepine,
clobazam, stiripentol, and topiramate. Phenobarbital and lamotrigine increase the AUC of retigabine. Valproic acid increases the
levels of phenobarbital, lamotrigine, and rufinamide, while reducing the levels 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. Retigabine reduces the AUC of phenobarbital.
Interactions involving absorption, distribution, or excretion are less frequent: acetazolamide reduces the absorption of primidone.
Phenobarbital increases the 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 of neurotoxicity. During the administration of lamotrigine with valproate, tremor can occur and the risk of skin
rash and Stevens-Johnson syndrome increases. The incidence of encephalopathy after valproate increases when it is combined
with topiramate, levetiracetam, and in triple combination with oxcarbazepine and lacosamide. Concomitant administration of
carbonic anhydrase inhibitors increases the risk of nephrolithiasis. When sulthiame and 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