Managing the Drug-Drug Interaction With Apixaban and Primidone: A Case Report

The management of the drug-drug interaction (DDI) between primidone, a moderate to strong cytochrome P-450 (CYP) 3A4 inducer, and apixaban, a direct oral anticoagulant (DOAC) and CYP3A4 substrate is complex and limited evidence exists to guide management. This case report describes a 65-year-old male, receiving primidone for essential tremor who developed an acute venous thromboembolism (VTE) requiring oral anticoagulation. DOACs are preferred over vitamin K antagonists for acute VTE treatment. Based on patient-specific variables, provider preference, and the avoidance of other DDIs, apixaban was selected. Apixaban's package insert recommends avoiding use with concomitant strong P-gp and CYP3A4 inducers due to the decreased exposure to apixaban; however, no recommendations are available for drugs that are moderate to strong CYP3A4 inducers and lack P-gp effects. Given that phenobarbital is an active metabolite of primidone, extrapolation of evidence from such literature is theoretical but provides insight into the management of this multi-faceted DDI. In the absence of the ability to monitor plasma apixaban levels, a management strategy of avoidance with a washout period of primidone based on pharmacokinetic parameters was used in this case. Additional evidence is needed to clearly understand the degree of impact and clinical significance of the DDI between apixaban and primidone.