Which SSRIs or SNRIs are contraindicated with fezolinetant?

Published

Prescribing Information including BOXED WARNING

Fluvoxamine (a selective serotonin reuptake inhibitor [SSRI]) and viloxazine (a serotonin and norepinephrine reuptake inhibitor [SNRI]) are examples of CYP1A2 inhibitors. Fezolinetant is contraindicated in individuals using CYP1A2 inhibitors

Several electronic resources include tables of CYP substrates, inhibitors, and inducers (e.g., FDA, UpToDate^® Lexidrug™, Indiana University).^1–3
It is important to be aware that drug-drug interactions may differ from one drug database to another, and from the fezolinetant approved product label information.

Fezolinetant is a substrate of CYP1A2 and concomitant use with drugs that are weak, moderate, or strong CYP1A2 inhibitors increases the maximum plasma concentration (C_max) and area under the concentration-time curve (AUC) of fezolinetant.⁴
The SSRI fluvoxamine is a strong CYP1A2 inhibitor.⁵ Following concomitant use with fluvoxamine, fezolinetant C_max increased by 80% and AUC increased by 840%⁴
Any treatment for VMS (prescription, over the counter or herbal), as well as strong and moderate CYP1A2 inhibitors (including fluvoxamine), were prohibited during the fezolinetant Phase 3 trials.⁶
The following SSRIs and SNRIs were used concomitantly^a by participants in the Phase 3 trails of fezolinetant (52-week study period; safety analysis set^b):⁶

	Placebo^c (n = 952)	Fezolinetant 30 mg Total^d (n = 1103)	Fezolinetant 45 mg Total^e (n = 1100)
SSRIs (total)	74 (7.8%)	86 (7.8%)	64 (5.8%)
Citalopram / citalopram hydrobromide	27 (2.8%)	20 (1.8%)	25 (2.3%)
Escitalopram / escitalopram oxalate	13 (1.4%)	16 (1.5%)	14 (1.3%)
Fluoxetine / fluoxetine hydrochloride	10 (1.1%)	20 (1.8%)	11 (1.0%)
Paroxetine / paroxetine hydrochloride	5 (0.5%)	7 (0.6%)	4 (0.4%)
Sertraline / sertraline hydrochloride	21 (2.2%)	26 (2.4%)	12 (1.1%)
SNRIs (total)	31 (3.3%)	36 (3.3%)	33 (3.0%)
Desvenlafaxine / desvenlafaxine succinate monohydrate	3 (0.3%)	4 (0.4%)	3 (0.3%)
Duloxetine / duloxetine hydrochloride	12 (1.3%)	11 (1.0%)	14 (1.3%)
Levomilnacipran hydrochloride	1 (0.1%)	0	0
Venlafaxine / venlafaxine hydrochloride	15 (1.6%)	21 (1.9%)	16 (1.5%)

^aConcomitant medications are defined as any medications that participants took after the first dose of study medication and either up to 30 days from last dose of study drug or first dose of study drug during the extension period, whichever came sooner.

^bSAF: All randomized participants assessed according to the treatment they received at first dose.

^c Placebo includes 175 participants from SKYLIGHT 1 and 167 participants from SKYLIGHT 2 who received placebo for 12 weeks, and 610 participants who received placebo for 52 weeks in SKYLIGHT 4.

^d Fezolinetant 30 mg Total includes 152 participants who received fezolinetant 30 mg for 40 weeks (re-randomized after Week 12 from placebo to fezolinetant 30 mg for the active treatment extension period in SKYLIGHT 1 and 2), and 951 participants who received fezolinetant 30 mg for 52 weeks in SKYLIGHT 1, 2 and 4.

^e Fezolinetant 45 mg Total includes 151 participants who received fezolinetant 45 mg for 40 weeks (re-randomized after Week 12 from placebo to fezolinetant 45 mg for the active treatment extension period in SKYLIGHT 1 and 2), and 949 participants who received fezolinetant 45 mg for 52 weeks in SKYLIGHT 1, 2, and 4.

Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. FDA. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed 3JUN2024.
Lexidrug Online. Inhibitors and Inducers of Cytochrome P450 Enzymes (Lexi-Drugs). Available at: https://online.lexi.com/lco/action/home. Accessed 19APR2024.
Drug Interactions Flockhart Table^TM. Indiana University. Available at: https://drug-interactions.medicine.iu.edu/MainTable.aspx. Accessed 19APR2024.
VEOZAH [package insert]. Northbrook, IL, USA: Astellas Pharma, Inc. Available at: https://www.astellas.com/us/system/files/veozah_uspi.pdf.
Lexicomp Online. Inhibitors and Inducers of Cytochrome P450 Enzymes (Lexi-Drugs). Available at: https://online.lexi.com/lco/action/home.
Data on file.