Clobazam Use in Epilepsy: An Old Story with a New Twist. A Narrative Review

Clobazam (CLB), a 1,5-benzodiazepine, widely used and now available in an oral liquid formulation with a registered indication as adjunctive antiseizure medication for drug-resistant epilepsy, is characterized by a distinctive pharmacological profile. It is rapidly absorbed and extensively metabolised via CYP3A4 and CYP2C19 to its active metabolite, N-desmethylclobazam, with marked interindividual variability driven by pharmacokinetic interactions, genetic polymorphisms, and patient-specific factors. Its antiseizure effects are mediated through modulation of γ-aminobutyric acid_A receptor subunits and associated with a lower propensity for sedation compared with classical 1,4-benzodiazepines. There is solid evidence supporting the efficacy and safety of CLB, particularly in Lennox-Gastaut and Dravet syndromes, while its role in other epilepsy syndromes relies on an expanding, albeit heterogeneous, body of evidence. The drug is increasingly incorporated into combination regimens where pharmacokinetic interactions-most notably CYP2C19 inhibition by cannabidiol, stiripentol, and cenobamate-may enhance antiseizure efficacy but it needs appropriate dose individualisation to reduce the risk of sedation, especially in vulnerable populations. The recent approval of an oral solution as adjunctive therapy in epilepsy in adults or children can facilitate appropriate dosage adjustments regarding the clinical target, weight, and concomitant medications. Overall, CLB represents a versatile and clinically valuable therapeutic option, with its optimal use increasingly guided by precision medicine principles and rational polytherapy strategies.