Interaction between fluconazole and midazolam in intensive care patients

Background: Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism. Methods: In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and alpha-hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter. Results: Concentrations of midazolam were significantly increased (range 0 to 4-fold, P<0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of alpha-hydroxymidazolam to midazolam decreased progressively (P<0.05). Conclusion: In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.