MIDAZOLAM SHOULD BE AVOIDED IN PATIENTS RECEIVING THE SYSTEMIC ANTIMYCOTICS KETOCONAZOLE OR ITRACONAZOLE

Interaction between ketoconaaole, itraconazole, and midazolam was inve stigated in a double-blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ket oconazole, 200 mg itraconazole, or matched placebo orally once daily f or 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma sa mples were collected and psychomotor performance was measured. Both ke toconazole and itraconazole increased the area under the midazolam con centration-time curve from 10 to 15 times (p < 0.001) and mean peak co ncentrations three to four times (P < 0.001) compared with the placebo phase. In psychomotor tests (e.g., the Digit Symbol Substitution Test ), the interaction was statistically significant (p < 0.05) until at l east 6 hours after drug administration. Inhibition of the cytochrome P 450IIIA by ketoconazole and itraconazole may explain the observed phar macokinetic interaction. Prescription of midazolam for patients receiv ing ketoconazole and itraconazole should be avoided.