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Background and Objective <p>Fluvoxamine, a potent CYP1A2 inhibitor, increases clozapine serum concentrations by inhibiting its <i>N</i>-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.</p> Methods <p>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 (<i>C</i>/<i>D</i>, 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 <i>U</i> tests.</p> Results <p>Sixty-seven patients were included. During fluvoxamine co-administration, median <i>C</i>/<i>D</i> clozapine increased from 0.70 to 1.72, <i>C</i>/<i>D</i> norclozapine from 0.43 to 0.80 and the clozapine/norclozapine ratio from 1.66 to 2.16 (all <i>p</i> &lt; 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 &gt; 25 mg and baseline clozapine levels &lt; 350 ng/mL, without a significant increase in clozapine/norclozapine ratio. Other factors showed no significant association.</p> Conclusion <p>Fluvoxamine significantly increases clozapine and norclozapine concentrations, and their ratio. Doses &gt; 25 mg lead to greater fold increases and more variability. Initiation at 25 mg with a 50% clozapine dose reduction is recommended.</p>

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The Impact of Fluvoxamine on Clozapine and Norclozapine Serum Concentrations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • G. van Weringh,
  • H. J. de Haas,
  • L. de Haan,
  • D. J. Touw,
  • M. B. de Koning

摘要

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.