Safety of intravenous and oral midazolam in subjects receiving itraconazole or fluconazole

Abstract

Midazolam is metabolized by cyto-chrome P-450 3A enzymes (CYP3A). We have studied the possible interaction of two inhibitors of CYP3A, itraconazole and fluconazole, with intravenous and oral midazolam in twelve volunteers using a cross-over study design. The subjects were given an oral placebo, itraconazole (200 mg) or fluconazole (200 mg) for six days. The first challenge dose of 7.5 mg oral midazolam was ingested on the first day of pretreatment, the second dose 0.05 mg kg−1 was administered intravenously on the fourth day, and the third dose 7.5 mg orally on the sixth day. Plasma samples were collected and psychomotor performance measured. (Figure 7)Fig. 7: (abstract 9). Concentrations (mean±SEM) of midazolam in plasma after an oral or intravenous dose of midazolam following pretreatment with itraconazole (•), fluconazole (▴) or placebo (▸).On the first day of itraconazole or fluconazole treatments, the area under the oral midazolam concentration-time curve [AUC(0-∞)] was three to four times higher (P<0.001) and peak concentration (Cmax) two or three times higher (P<0.05) than those with the placebo. On the sixth day the effect of itraconazole on AUC(0-∞) and Cmax of oral midazolam was almost twice that on the first day (P<0.001), the effect of fluconazole was similar. The higher concentrations of oral midazolam during treatment with antimycotics were associated with an increased effect (P<0.001). Itraconazole and fluconazole reduced the clearance of intravenous midazolam by 69% and 51% respectively (P<0.001) but the volume of distribution of midazolam at steady-state remained unchanged. The psychomotor tests demonstrated only a relatively weak interaction between the antimycotics and intravenous midazolam. The interaction between itraconazole and fluconazole and midazolam administered orally is of major clinical significance. Prescription of oral midazolam for patients receiving intraconazole and fluconazole should be avoided. When small bolus doses of midazolam are given for sedation during minor surgical procedures, the effect of midazolam is probably not increased to a clinically significant degree. However care should also be exercised after intravenous midazolam; doses should be adjusted and patients monitored closely.