A Systematic Review of Clinically Significant Drug–Drug Interactions With Phenobarbital and Primidone

ABSTRACT Phenobarbital (PB) is historically used for management of seizure disorders but more recently has emerged as a prominent option for the management of alcohol withdrawal syndrome given data suggesting its benefit over benzodiazepines. An important consideration of PB therapy is its induction of cytochrome‐P 450 enzymes (CYP450), which may lead to underrecognized drug–drug interactions (DDIs). Knowledge of these PB DDIs, including their onset and offset, is important to better elucidate how to manage these DDIs. To identify published literature evaluating the relevance of DDIs between PB and selected medications, a systematic review was performed including literature published through January 2026, focused on the administration of both PB and a list of medications based on tertiary medication database review as well as clinical relevance, including anticoagulants, antimicrobials, and immunosuppressants. Included articles had to identify outcomes of interest, which were focused on laboratory, pharmacokinetic, and clinical outcomes, and had to be in humans. Data extraction included the onset and offset of PB DDIs and potential PB dose–response and magnitude of induction of target medication. A total of 3271 articles were identified, with 50 studies meeting inclusion criteria, which included both adult and pediatric populations. Thirteen studies evaluated onset of PB induction, which ranged from 6 h to 30 days. Eight studies evaluated offset of PB induction, which ranged from 2 to 8 weeks. Limited data demonstrated a PB dose–response relationship in terms of magnitude of CYP induction. We found that 86% of the included studies demonstrated an impact by PB on outcomes, which were often related to therapeutic drug monitoring. Data suggest that PB does lead to clinically significant DDIs in multiple classes of medications. Future areas of research include focused evaluations on clinical outcomes, as well as studies specifically evaluating single high‐dose PB and impact on DDI outcomes.