Effect of fluconazole dose on the extent of fluconazole-triazolam interaction.

1. Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases. 2. Eight healthy volunteers received either 50 mg, 100 mg or 200 mg (400 mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25 mg oral dose of triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18 h. 3. The mean area under the triazolam concentration-time curve (AUC) was increased 1.6-, 2.1- and 4.4-fold (P < 0.001) by fluconazole 50 mg, 100 mg and 200 mg, respectively. The increase in the elimination half-life of triazolam (t1/2,z) varied from 1.3-fold (fluconazole 50 mg, P < 0.05) to 2.3-fold (fluconazole 200 mg, P < 0.001). The peak concentration of triazolam was also increased significantly during all fluconazole phases; more than twofold by fluconazole 200 mg (P < 0.001). 4. The pharmacodynamic effects of triazolam were increased significantly (P < 0.05) by fluconazole 100 mg and 200 mg. 5. Even a small 50 mg daily dose of fluconazole can interact with triazolam and the extent of the interaction increases with increasing fluconazole dose. When triazolam is used concomitantly with fluconazole 50-200 mg, the dose of triazolam should be reduced, accordingly. Simultaneous use of triazolam with higher fluconazole doses should be avoided.