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.

Pharmacoepidemiologic Screening of Potential Oral Anticoagulant Drug Interactions Leading to Thromboembolic Events

“…[34][35][36][37] On the other hand, some previously documented DDIs were not associated with statistically significantly elevated RR or ratio of RRs in our study, for example, carbamazepine (RR=1.07, 95% CI: 0.88-1.30, ratio of RRs=0.82, 95% CI: 0.56-1.21), phenytoin (RR=0.90, 95% CI: 0.80-1.00, ratio of RRs=1.19, 95% CI: 0.90-1.58), and phenobarbital (RR=0.82, 95% CI: 0.63-1.08, ratio of RRs=1.37, 95% CI: 0.69-2.75). 38,39 This may be due to lack of dose adjustment as patients may be told to skip doses when they initiated these precipitant drugs, potential misclassification for days on warfarin, and/or insufficient power. Our approach was designed to screen a large number of potentially interacting precipitant drugs in a high-throughput fashion and generate new DDI hypotheses.…”

The optimal anticoagulant therapy for mechanical heart valves in a gallbladder cancer patient with hepatic metastases

“…[ 7 , 8 ] Moreover, warfarin is stereo selectively metabolized by hepatic cytochrome P-450 microsomal enzymes to inactive hydroxylated metabolites and by reductases to reduced metabolites with minimal anticoagulant activity. [ 9 ] Thus, hepatic impairment can potentiate the response to warfarin through decreased metabolism of warfarin. Several retrospective studies revealed that patients with liver disease were significantly more likely to have a high INR when taking warfarin, and worsening liver dysfunction was found to be strongly associated with bleeding episodes.…”

Simulation of febuxostat pharmacokinetics in healthy subjects and patients with impaired kidney function using physiologically based pharmacokinetic modeling

“…Gout is the most common form of inflammatory arthritis (Fields, 2019), and recently, it has been recognized as a serious disease that causes functional disability and has negative economic consequences for individuals and communities. This disease can affect joints in the body, not only the big toe, and in some cases it even mimics polyarthritis (Clark et al., 2018). Hyperuricemia has been identified as the most important risk factor for gout, and the successful management of this disease requires a sustained serum uric acid (sUA) level of <6.0 mg/dl (FitzGerald et al., 2020).…”