Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction.

Administration of fluvoxamine with concomitant benzodiazepines is common in clinical situations. This study investigated the effects of the coadministration of fluvoxamine on plasma concentrations of etizolam and evaluated the effects of various fluvoxamine doses on drug interactions with etizolam. Subjects were 18 Japanese outpatients concomitantly treated with fluvoxamine before or after monotherapy with etizolam. Plasma concentrations of etizolam were measured using a column-switching high-performance liquid chromatographic method with ultraviolet detection. In 17 subjects treated concomitantly with fluvoxamine at 25 mg or 50 mg, the ranges of plasma concentrations of etizolam corrected for the dose increased from 2.0-13.3 (mean 6.3 +/- 3.6, n = 17) in monotherapy to 2.7-18.2 (mean 9.6 +/- 5.1, n = 17) ng/mL/mg in concomitant doses. Wide variations were observed in the drug interactions; however, coadministration with fluvoxamine produced significant changes in the plasma concentrations of etizolam (P < 0.0001) with a median of 42.9% (range 0.0 to 235.0%). Although the sleepiness of the subjects was evaluated using the Stanford Sleepiness Scale, no changes in sleepiness were found between the etizolam-monotherapy and the fluvoxamine-concomitant states. Of the 12 subjects treated concomitantly with fluvoxamine at 25 mg, 2 subjects received fluvoxamine at a dose increased up to 150 mg, and another received fluvoxamine at a dose increased up to 200 mg. They showed an increase in the plasma concentrations of etizolam in a fluvoxamine dose-dependent manner; more particularly, the increased dose of fluvoxamine (150 mg and 200 mg) resulted in about a twofold variation in plasma concentrations of etizolam.