title: Comparison of the effects of azole antifungal agents on the anticoagulant activity of warfarin.
abstract: The package insert of the antithrombotic agent warfarin warns users of its interaction with azole antifungals. However, information on the frequency or degree of these interactions is limited. In particular, the time to onset of azole-mediated prothrombin time prolongation, expressed as the international normalized ratio (INR), is poorly characterized. Therefore, we retrospectively examined the INR in 29 patients administered warfarin with fluconazole (FLCZ), voriconazole (VRCZ), or itraconazole (ITCZ). INRs in 18 patients taking FLCZ and in 5 patients taking VRCZ significantly increased from 1.40 to 2.94 and from 1.95 to 2.89, respectively. The warfarin sensitivity index (WSI), calculated as INR/daily warfarin dose, also significantly increased from 1.06 to 1.89 with FLCZ and showed an upward trend from 1.13 to 2.23 with VRCZ. ITCZ had no influence on the INR or WSI in 6 patients. The INRs observed when warfarin was coadministered with azoles (Y) correlated significantly with those observed in the absence of azoles (X): FLCZ, Y=4.94X-3.96, r(2)=0.80; VRCZ, Y=2.13X-1.27, r(2)=0.93. Moreover, in all 8 patients with closely monitored INRs, the WSI increased within 1 week of FLCZ or VRCZ coadministration. In conclusion, FLCZ and VRCZ augmented the anticoagulant activity of warfarin. The INR should be closely monitored within 1 week of initiating FLCZ or VRCZ coadministration with warfarin, especially in patients with high INRs.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Habu
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Junko
authors.initials: J
authors.lastname: Ozaki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Eriko
authors.initials: E
authors.lastname: Sato
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shida
authors.forename: Sachio
authors.initials: S
authors.lastname: Fukatsu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004351:Drug Resistance; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics; D006801:Humans; D019934:International Normalized Ratio; D017964:Itraconazole / Q000493:pharmacokinetics; D008297:Male; D008661:Metabolism, Inborn Errors; D008875:Middle Aged; D012189:Retrospective Studies; D065819:Voriconazole / Q000493:pharmacokinetics; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D000935:Antifungal Agents; D017964:Itraconazole; D014859:Warfarin; D015725:Fluconazole; D065819:Voriconazole