Interaction of miconazole oral gel with warfarin and cyclosporine in a patient with nephrotic syndrome

Abstract

It is well known that miconazole inhibits cytochrome P450 (CYP). However, this drug in oral gel form is believed not to absorb into systemic circulation, and therefore not to inhibit CYP. We experienced a case of increased oral bioavailability of warfarin and cyclosporine with this gel for treatment of oral candidiasis in a patient with nephrotic syndrome. Her prothrombin time-international normalized ratio (PT-INR) increased from 2 to 7.25, and the cyclosporine concentration at 2 h after final dosing (C2) increased from 633.8 to 1396.5 ng/ml 6 days after the coadministration. These problems were resolved by termination of the gel and switching to amphotericin B gargle. We further detected a significant amount of miconazole in her plasma, directly showing for the first time in a patient with this interaction that oral miconazole gel was actually absorbed into systemic circulation. Because warfarin and cyclosporine are often used simultaneously by nephrologists, caution should be applied with combined use of these drugs and oral miconazole gel to avoid adverse reaction.

Nystatin and miconazole: pharmacological and clinical evidence regarding interactions with warfarin

“…The bioavailability of miconazole oral gel was initially thought to be low; however, significant plasma concentrations of miconazole have previously been detected in healthy subjects following administration of miconazole oral gel (Cardot et al , ). Recently, significant amounts of miconazole have been measured in a patient's plasma during treatment with miconazole oral gel and warfarin, confirming its absorption in a patient and its direct association with an increase in INR (Tajima‐Okuba et al , ). Pharmacokinetic modelling has also been undertaken on concomitant administration of warfarin and miconazole oral gel showing the ability to lead to substantial increases in warfarin concentration, albeit with high interindividual variability (Miki et al , ).…”

Clinical analysis of the effects of azole antifungal agents on the anticoagulant activity of warfarin

“…[ 13 ] Miconazole also has a significant effect on warfarin for its inhibition on CYP2C9. [ 14 ] Therefore, in order to avoid clinical adverse events, INR values should also be closely monitored in patients receiving the combination of warfarin and azole antifungal agents.…”