title: Warfarin Interaction With Hepatic Cytochrome P-450 Enzyme-Inducing Anticonvulsants.
abstract: Initiation of cytochrome P-450 (CYP)-inducing anticonvulsant medications during warfarin therapy may decrease anticoagulant effect and necessitate frequent warfarin dose adjustments to maintain therapeutic response measured by the international normalized ratio (INR). Clinical information regarding interactions between warfarin and these medications is limited. This study investigated warfarin dose and INR response following CYP-inducing anticonvulsant initiation among chronic warfarin users. This retrospective, pre-post study included patients ≥18 years who were receiving chronic warfarin therapy and who initiated carbamazepine, oxcarbazepine, phenobarbital, or phenytoin between January 1, 2006, and December 31, 2013. Mean weekly warfarin dose/INR ratio and mean weekly warfarin dose were compared in the 90 days pre- and days post-anticonvulsant initiation periods. Of the 57 included patients, 34 (60%), 15 (26%), 6 (11%), and 2 (3%) patients purchased a prescription for carbamazepine, phenytoin, oxcarbazepine, and phenobarbital, respectively. Mean age was 70 years, 59% were female, and the majority were receiving chronic warfarin therapy for atrial fibrillation (39%) or venous thromboembolism (26%). The ratio of mean warfarin dose and INR increased significantly between the pre- and post-anticonvulsant initiation periods (from 13 mg/INR to 18 mg/INR, respectively, P ≤ .001) as did the mean weekly warfarin dose (from 33 mg to 37 mg, P = <.001). Warfarin dose and dose/INR ratio significantly increased after carbamazepine initiation (both P < .001), while oxcarbazepine, phenobarbital, and phenytoin initiation did not significantly affect warfarin dosing. Our results support the presence of a clinically meaningful interaction between warfarin and carbamazepine. Frequent INR monitoring and warfarin dose escalation are recommended in this setting.
authors.affiliation: 1 Kaiser Permanente Colorado, Aurora, CO, USA.|2 University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Clark
authors.affiliation: 3 Evans Army Community Hospital, Fort Carson, CO, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Hoang
authors.affiliation: 1 Kaiser Permanente Colorado, Aurora, CO, USA.|2 University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Delate
authors.affiliation: 4 University of Washington School of Pharmacy, Seattle, WA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Horn
authors.affiliation: 5 University of Utah College of Pharmacy, Salt Lake City, UT, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Witt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics; D002220:Carbamazepine / Q000008:administration & dosage / Q000493:pharmacokinetics; D065693:Cytochrome P-450 Enzyme Inducers / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D005500:Follow-Up Studies; D006801:Humans; D019934:International Normalized Ratio; D008875:Middle Aged; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000927:Anticonvulsants; D065693:Cytochrome P-450 Enzyme Inducers; D002220:Carbamazepine; D014859:Warfarin
keywords: anticonvulsant; carbamazepine; cytochrome P-450; drug interaction; warfarin