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 ( The antithrombotic agent, warfarin, shows large inter-and intra-individual differences in its pharmacokinetic and pharmacodynamic properties.1) Prothrombin time, expressed as the international normalized ratio (INR), is commonly used to adjust the individual maintenance dose of warfarin.1) Many drug-drug interactions also contribute to individual differences in warfarin dose. Sufficient understanding of these is therefore necessary for the safe and effective administration of warfarin.2) Details of interactions between warfarin and other drugs, such as the timing of onset or the degree of interaction, have yet to be elucidated. Therefore, it is difficult to decide whether or when INR should be measured.The warfarin package insert in Japan and some other reports suggest an increased risk of bleeding following coadministration of warfarin and azoles. [3][4][5][6] We recently encountered a patient at the Kyoto University Hospital, in whom the INR abruptly increased to >5 when a combination of warfarin and fluconazole (FLCZ) was administered. The inhibition of hepatic drug-metabolizing enzymes is described as the mechanism of this interaction between warfarin and azoles such as FLCZ, voriconazole (VRCZ), and itraconazole (ITCZ).3) However, we were unable to find specific information on the frequency of these interactions, their degree, or the time of onset of INR prolongation for each azole. To the best of our knowledge, there are no previous reports comparing the changes of INR following coadministration of azoles and warfarin in patients. Therefore, we retrospectively compared changes in the anticoagulant effects of warfarin in Japanese patients concomitantly administered with FLCZ, VRCZ, or ITCZ. PATIENTS AND METHODS Study PopulationPatients who were administered warfarin in combination with FLCZ, VRCZ, or ITCZ from April 2010 to March 2013 were analyzed. Patients were excluded under the following circumstances: (1) No INR data; (2) Altered dosage of other agents that were considered highly probable or probable to interact with warfarin 2) (e.g., miconazole oral gel, levofloxacin, and loxoprofen); (3) Increasing warfarin dosage after azole coadministration; (4) Observation of abnormal liver function. Liver function was considered abnormal if the aspartate aminotransferase or alanine aminotransferase level was≥the upper limit of normal×3, in accordance with the Common Terminology Criteria for Adverse Events v4.0.Study Protocol Patient age, sex, warfarin and azole dosing information, the reasons for administration of warfarin and azoles, and INR values were obtained from medical charts retrospectively. INR values were obtained within 2 weeks before commencing coadministration of warfarin and azol...

Comparison of initial warfarin dosing in hospitalised patients considered sensitive to warfarin: low‐dose versus standard‐dose strategy

“…Although azole antifungals are known to be potent inhibitors of cytochrome P450 2C9, the main substrate for warfarin metabolism, evidence supporting an interaction between azole antifungals and warfarin is limited to small studies and case reports. 7,9,10 The results of this study reinforce that concomitant use of fluconazole and warfarin could significantly affect the time to reach therapeutic INR (HR 2.471; p = 0.0309). Further analysis of our data showed that in patients who had never used warfarin before, the mean time to reach a therapeutic INR was longer when they were started on 2.5 mg warfarin than when patients were started on the standard dose.…”

“…Previously published risk factors, such decompensated heart failure, ESRD and coadministration of amiodarone and co‐trimoxazole, did not significantly affect the time to reach therapeutic INR in the present study. Although azole antifungals are known to be potent inhibitors of cytochrome P450 2C9, the main substrate for warfarin metabolism, evidence supporting an interaction between azole antifungals and warfarin is limited to small studies and case reports …”

Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects

“…In contrast to isavuconazole, which showed no significant effect on PT or INR, coadministration of fluconazole with warfarin significantly increases PT and INR values, which are associated with adverse bleeding events in patients. 14,16 Similarly, PT 16,17 and INR 16 are significantly increased when voriconazole and warfarin are administered together. Itraconazole does not appear to impact warfarin PD in vivo.…”

“…Itraconazole does not appear to impact warfarin PD in vivo. 16 Coadministration of posaconazole and warfarin has not been examined in humans. 14 Genetic factors affect patients' responses to warfarin and are important considerations when calculating appropriate dosages as certain genotypes are associated with increased bleeding complications.…”

“…Similarly, PT and INR are significantly increased when voriconazole and warfarin are administered together. Itraconazole does not appear to impact warfarin PD in vivo . Coadministration of posaconazole and warfarin has not been examined in humans …”