The Impact of Fluvoxamine on Clozapine and Norclozapine Serum Concentrations

Background and Objective: Fluvoxamine, a potent CYP1A2 inhibitor, increases clozapine serum concentrations by inhibiting its N-dealkylation to norclozapine, thus reducing norclozapine formation and increasing the clozapine/norclozapine ratio. Clinically, fluvoxamine may reduce clozapine tablet burden and mitigate norclozapine-related metabolic side-effects. However, clinical guidance on this co-administration is limited. The current study evaluates the effect of fluvoxamine and its dose on clozapine and norclozapine concentrations and their ratio, while exploring potential influencing factors. Methods: Patients from long-stay psychiatric wards were included if they had been or were currently receiving clozapine and fluvoxamine, with available steady-state concentrations with and without fluvoxamine coadministraton. Dose-adjusted clozapine and norclozapine concentrations (C/D, ng/mL per mg/day) and their ratios were compared among the two conditions using the Wilcoxon signed-rank test. Median fold increases and associations with clinical variables (e.g. gender, smoking, dosing frequency, baseline clozapine level, fluvoxamine dose), were analysed using Mann–Whitney U tests. Results: Sixty-seven patients were included. During fluvoxamine co-administration, median C/D clozapine increased from 0.70 to 1.72, C/D norclozapine from 0.43 to 0.80 and the clozapine/norclozapine ratio from 1.66 to 2.16 (all p < 0.001). Median fold increases were 2.51 (clozapine), 1.92 (norclozapine) and 1.27 (clozapine/norclozapine ratio). Greater increases were observed with fluvoxamine doses > 25 mg and baseline clozapine levels < 350 ng/mL, without a significant increase in clozapine/norclozapine ratio. Other factors showed no significant association. Conclusion: Fluvoxamine significantly increases clozapine and norclozapine concentrations, and their ratio. Doses > 25 mg lead to greater fold increases and more variability. Initiation at 25 mg with a 50% clozapine dose reduction is recommended.