Fezolinetant (Veozah®): A Comprehensive Pharmacological and Clinical Monograph on the First-in-Class NK3 Receptor Antagonist for Vasomotor Symptoms

Introduction and Drug Profile

Overview of Fezolinetant as a First-in-Class Neurokinin-3 (NK3) Receptor Antagonist

Fezolinetant, marketed under the brand names Veozah and Veoza, represents a significant therapeutic innovation in the management of menopausal symptoms.[1] It is a first-in-class, orally administered, small-molecule, selective neurokinin-3 (NK3) receptor antagonist.[1] Its development and approval mark a paradigm shift away from traditional hormonal approaches, offering a novel, non-hormonal mechanism of action that directly targets the neurobiological underpinnings of vasomotor symptoms (VMS).[4]

The pathophysiology of VMS, colloquially known as hot flashes and night sweats, involves a complex interplay of neuroendocrine signals within the hypothalamus. Fezolinetant's mechanism is precisely targeted to this central pathway, offering a new therapeutic strategy for a condition that can persist for a median duration of 7.4 years and is the most common reason women seek medical treatment for menopausal issues.[5] Developed by Astellas Pharma following its acquisition from Ogeda, fezolinetant addresses a substantial unmet medical need for the large population of women who either have contraindications to hormone therapy (HT) or choose to avoid it due to safety and tolerability concerns, such as an increased risk of stroke, venous thromboembolism, or hormone-dependent cancers like breast cancer.[1] The U.S. Food and Drug Administration (FDA) has recognized its novelty by designating it a first-in-class medication.[1]

Approved Indication

Fezolinetant is specifically indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.[1] This indication is based on a robust clinical development program that demonstrated its efficacy in reducing both the frequency and severity of hot flashes and night sweats.

Nomenclature and Identification

To ensure unambiguous identification across scientific literature, regulatory filings, and clinical practice, the various names and identifiers for fezolinetant are consolidated below. This comprehensive reference is essential for linking early-stage development data, where the compound may be referred to by its code (e.g., ESN-364), with clinical trial registrations and final prescribing information.

Table 1: Drug Identification and Nomenclature for Fezolinetant

Identifier Type	Value	Source(s)
International Nonproprietary Name (INN)	Fezolinetant	1
Brand Names	Veozah, Veoza	1
Development Codes	ESN-364, ESN364, AS-3472693-00	7
DrugBank Accession Number	DB15669	1
CAS Number	1629229-37-3	1
PubChem CID	117604931	1
UNII	83VNE45KXX	1
ChEMBL ID	CHEMBL3608680	1
ChEBI ID	CHEBI:229236	1
KEGG ID	D11976	1
EPA CompTox Dashboard ID	DTXSID601103615	1

Chemical and Physical Properties

Fezolinetant is a synthetic organic compound belonging to several chemical classes, including triazolopyrazines, monofluorobenzenes, thiadiazoles, and benzamides.[7] Its specific structure is fundamental to its high affinity and selectivity for the NK3 receptor. The key physicochemical properties, which predict its behavior as a drug molecule, are summarized in the table below. Notably, fezolinetant adheres to Lipinski's Rule of Five, with zero violations, which is predictive of good oral bioavailability and membrane permeability—critical attributes for an orally administered drug that must act within the central nervous system.[11]

Table 2: Chemical and Physical Properties of Fezolinetant

Property	Value	Source(s)
IUPAC Name	(4-fluorophenyl)-triazolo[4,3-a]pyrazin-7-yl]methanone	1
Chemical Formula	C16​H15​FN6​OS	1
Molar Mass	358.40 g·mol⁻¹	1
Physical Form	Solid	12
Solubility	Soluble in DMSO	12
XLogP	4.12	11
Hydrogen Bond Acceptors	6	11
Hydrogen Bond Donors	0	11
Rotatable Bonds	3	11
Canonical SMILES	C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C	1
InChI	InChI=1S/C16H15FN6OS/c1-9-13-19-20-14(15-18-10(2)21-25-15)23(13)8-7-22(9)16(24)11-3-5-12(17)6-4-11/h3-6,9H,7-8H2,1-2H3/t9-/m1/s1	1
InChIKey	PPSNFPASKFYPMN-SECBINFHSA-N	1

Comprehensive Pharmacological Profile

Mechanism of Action: Targeting the Hypothalamic Thermoregulatory Center

The therapeutic effect of fezolinetant is rooted in its ability to modulate the activity of a specific group of neurons in the brain that are central to the body's thermoregulation. The pathophysiology of menopausal VMS is now understood to originate in the hypothalamic thermoregulatory center, which is innervated by a population of neurons known as KNDy neurons (expressing kisspeptin, neurokinin B, and dynorphin).[2]

In the premenopausal state, a delicate balance exists: estrogen provides an inhibitory tone to these KNDy neurons, while the neuropeptide neurokinin B (NKB) provides a stimulatory signal. This equilibrium maintains normal body temperature regulation.[2] During the menopausal transition, the decline in circulating estrogen levels disrupts this balance. The loss of estrogen's inhibitory feedback leads to hypertrophy and hyperactivity of the KNDy neurons.[2]

This heightened neuronal activity, driven by the now unopposed stimulatory action of NKB binding to its receptor, the neurokinin-3 (NK3) receptor (also known as the Neuromedin-K receptor), dysregulates the thermoregulatory center.[2] The brain incorrectly perceives the body as being overheated and triggers potent heat dissipation mechanisms, such as peripheral vasodilation (flushing) and sweating.[2] These physiological responses manifest clinically as hot flashes and night sweats.

Fezolinetant acts as a selective antagonist at the NK3 receptor.[1] By competitively blocking NKB from binding to the NK3 receptor on KNDy neurons, fezolinetant directly dampens this neuronal hyperactivity.[2] This action helps to restore a more balanced state within the thermoregulatory center, thereby reducing the frequency and intensity of VMS.[2] This targeted, non-hormonal mechanism addresses the root neurological cause of VMS, representing a fundamental advance over previous therapeutic approaches.[4]

Pharmacodynamics

Fezolinetant's pharmacodynamic profile is characterized by its high affinity and selectivity for its molecular target, which translates into potent in vivo effects.

Receptor Affinity and Selectivity

In vitro studies have demonstrated that fezolinetant binds with high affinity to the human NK3 receptor, with a reported equilibrium dissociation constant (Ki​) of 25 nM and a half-maximal inhibitory concentration (IC50​) of 20 nM.[1] A critical feature of its profile is its selectivity. Fezolinetant's binding affinity for the NK3 receptor is more than 450-fold higher than its affinity for the related NK1 and NK2 receptors.[2] This high degree of selectivity is crucial, as it minimizes the potential for off-target effects that could arise from interactions with other neurokinin receptor subtypes, contributing to a more favorable safety profile.

In Vivo Effects and Central Nervous System Penetration

The NKB/NK3 signaling pathway is also implicated in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. Consistent with this, loss-of-function mutations in the genes encoding NKB and the NK3 receptor are associated with idiopathic hypogonadotropic hypogonadism.[1] Accordingly, NK3 receptor antagonists like fezolinetant have been shown to dose-dependently suppress luteinizing hormone (LH) secretion in both preclinical models and humans.[1]

However, the therapeutic effect of fezolinetant on VMS is understood to be independent of its modulatory actions on the HPG axis and downstream sex hormone production.[1] This distinction is fundamental to its classification as a non-hormonal therapy and is what differentiates it from agents like GnRH modulators or estrogens. Its ability to effectively cross the blood-brain barrier is a key pharmacokinetic property that enables its central mechanism of action. This attribute distinguishes it from earlier-generation NK3 receptor antagonists, such as osanetant and talnetant, which showed limited tangible effects on central nervous system pathways, likely due to less favorable pharmacokinetic profiles.[7]

Pharmacokinetics (ADME)

The pharmacokinetic profile of fezolinetant supports a convenient once-daily oral dosing regimen. Its absorption, distribution, metabolism, and excretion (ADME) properties have been well-characterized in healthy women.

Absorption

Following oral administration, fezolinetant is readily absorbed, with the median time to reach peak plasma concentration (Tmax​) occurring at approximately 1.5 hours (range: 1 to 4 hours).[7] The maximum concentration (

Cmax​) and area under the curve (AUC) increase proportionally over a dosage range of 20 to 60 mg once daily. Steady-state plasma concentrations are achieved rapidly, after just two once-daily doses, with minimal drug accumulation observed.[7]

Distribution

Fezolinetant has a mean apparent volume of distribution (Vz​/F) of 189 L, suggesting distribution into tissues beyond the plasma volume.[7] Its binding to plasma proteins is moderate, at approximately 51%.[14]

Metabolism

Fezolinetant undergoes extensive metabolism before excretion. In vitro studies using human recombinant cytochrome P450 enzymes and human liver microsomes have identified CYP1A2 as the primary enzyme responsible for its metabolism.[14] CYP2C9 and CYP2C19 play minor roles.[14] The primary metabolic pathway involves conversion to ES259564, a major but pharmacologically inactive metabolite.[16] This heavy reliance on a single primary metabolic pathway has significant clinical implications for drug-drug interactions.

Excretion

The elimination of fezolinetant and its metabolites occurs primarily through the renal route. Following a single oral dose, approximately 77% of the administered radioactivity is recovered in the urine and about 15% is recovered in the feces.[7] The drug is almost completely metabolized prior to excretion, as very little is excreted in its unchanged form (1.1% in urine and 0.1% in feces).[7] The apparent clearance at steady state (

CL/F) is 10.8 L/h.[7] The effective half-life is approximately 9.6 hours, which is consistent with and supportive of the recommended once-daily dosing schedule.[14]

Table 3: Key Pharmacokinetic Parameters of Fezolinetant

Parameter	Value	Source(s)
Median Time to Peak Concentration (Tmax​)	1.5 hours	7
Apparent Volume of Distribution (Vz​/F)	189 L	7
Apparent Clearance (CL/F)	10.8 L/h	7
Effective Half-life (t1/2​)	9.6 hours	14
Plasma Protein Binding	51%	14
Primary Metabolic Enzyme	CYP1A2	14
Primary Route of Elimination	Renal (as metabolites)	7

The pharmacological profile of fezolinetant reveals two defining characteristics that shape its clinical use. First, its mechanism of action as a non-hormonal agent provides a significant safety advantage over traditional therapies by avoiding direct modulation of sex hormone pathways. This is evidenced by long-term safety studies showing no adverse effects on endometrial health or bone mineral density, which are primary areas of concern with hormonal agents.[17] This profile makes fezolinetant a uniquely suitable option for women with contraindications to HT, such as a history of breast cancer, a population specifically evaluated in clinical trials.[8]

Second, its pharmacokinetic profile is dominated by its reliance on a single metabolic enzyme, CYP1A2. This creates a significant vulnerability to drug-drug interactions. A dedicated clinical study demonstrated this profound effect: co-administration with fluvoxamine, a strong CYP1A2 inhibitor, resulted in a dramatic 939% increase in fezolinetant exposure (AUC).[16] This finding is the direct pharmacological basis for the strict contraindication against using fezolinetant with any CYP1A2 inhibitor, regardless of its strength (weak, moderate, or strong).[2] Conversely, the same study showed that smoking, a moderate CYP1A2

inducer, decreased fezolinetant exposure by more than 50%.[16] This suggests that individuals who smoke may experience substantially reduced efficacy, a critical point for patient counseling and managing therapeutic expectations. Thus, while the drug's mechanism is its greatest strength, its metabolism is its most significant liability.

Clinical Efficacy and Development Program

Overview of the BRIGHT SKY™ Phase 3 Program

The clinical development of fezolinetant was anchored by the comprehensive BRIGHT SKY™ program, which collectively enrolled over 3,000 individuals across the United States, Canada, and Europe.[4] This extensive program was designed to rigorously evaluate the efficacy and safety of fezolinetant for its target indication. It comprised two pivotal, replicate 52-week efficacy and safety trials (SKYLIGHT 1™ and SKYLIGHT 2™), a dedicated 52-week long-term safety study (SKYLIGHT 4™), and a specialized Phase 3b trial (DAYLIGHT) focused on women considered unsuitable for hormone therapy.[4]

Pivotal Efficacy Trials: SKYLIGHT 1™ (NCT04003155) & SKYLIGHT 2™ (NCT04003142)

The cornerstone of the efficacy data comes from the identical SKYLIGHT 1 and SKYLIGHT 2 trials. These were large-scale, randomized, double-blind, placebo-controlled studies. Each trial enrolled women aged 40 to 65 years who were experiencing a minimum average of seven moderate to severe VMS per day.[24] Participants were randomized in a 1:1:1 ratio to receive either placebo, fezolinetant 30 mg, or fezolinetant 45 mg orally once daily. The primary efficacy analysis was conducted after a 12-week placebo-controlled period, which was followed by a 40-week active treatment extension period to gather longer-term data.[4]

The studies successfully met all four co-primary efficacy endpoints, which were the mean change from baseline in the frequency and severity of moderate-to-severe VMS at both week 4 and week 12, compared to placebo.[8]

The results from SKYLIGHT 2 provide a clear example of the magnitude of the effect. For the approved 45 mg dose, fezolinetant demonstrated a statistically significant mean change from baseline versus placebo in VMS frequency of -2.55 episodes per day at week 4 and -2.53 episodes per day at week 12 (p<0.001 for both timepoints).[31] For VMS severity, the mean change versus placebo was -0.29 at both week 4 and week 12 (p<0.001).[31] Pooled data presented to the European Medicines Agency showed that after 12 weeks of treatment, the 45 mg dose resulted in an average reduction of 63% in VMS frequency from baseline, a clinically meaningful improvement compared to the 40% reduction observed in the placebo group.[10]

A consistent and clinically important finding across the trials was the rapid onset of action. Statistically significant improvements in VMS frequency and severity compared to placebo were observed as early as the first week of treatment, with some analyses showing effects within the first few days.[8] This rapid relief is a highly desirable attribute for patients suffering from disruptive symptoms.

Efficacy in Hormone Therapy-Ineligible Populations: The DAYLIGHT Study (NCT05033886)

To confirm the efficacy of fezolinetant in a key target population, the Phase 3b DAYLIGHT study was conducted. This trial specifically enrolled women who were considered unsuitable for hormone therapy, either due to medical contraindications, a history of side effects, or an informed personal choice to avoid hormones.[8] The study design was notable for its extended 24-week placebo-controlled period, providing more robust data on sustained efficacy.[8]

The DAYLIGHT study successfully met its primary endpoint. At 24 weeks, treatment with fezolinetant 45 mg resulted in a statistically significant and clinically meaningful reduction in the frequency of moderate-to-severe VMS compared to placebo, with a least squares mean difference of –1.93 episodes per day (p<0.001).[8] This trial confirmed that the rapid onset of action seen in the SKYLIGHT studies was replicated in this population and that the therapeutic effect was well-maintained throughout the 24-week treatment period.[8]

Impact on Patient-Reported Outcomes (PROs)

Beyond the primary endpoints of VMS frequency and severity, the clinical development program also assessed the impact of fezolinetant on key patient-reported outcomes, including sleep and overall quality of life.

Sleep Disturbance

Given that night sweats are a primary driver of sleep disruption in menopausal women, improvement in sleep was a key secondary area of investigation. The results, however, were not uniformly consistent across all trials. The DAYLIGHT study demonstrated a clear and statistically significant benefit, showing a greater reduction in sleep disturbance in the fezolinetant group compared to placebo at week 24, as measured by the PROMIS SD-SF 8b total score (least squares mean difference –2.5; p<0.001).[8]

In contrast, while the SKYLIGHT 1 study also observed improvements in sleep, its key secondary endpoint for sleep disturbance did not achieve statistical significance at the 12-week timepoint.[30] This discrepancy suggests a complex relationship between VMS and sleep. While fezolinetant effectively reduces VMS-related awakenings, it may not fully address other co-existing contributors to insomnia during menopause, such as anxiety or primary sleep disorders. This is an important nuance for managing patient expectations; fezolinetant is a highly effective treatment for VMS, which can secondarily improve sleep, but it is not a primary hypnotic agent.

Quality of Life

Treatment with fezolinetant demonstrated a consistent and positive impact on overall quality of life. Analyses using the Menopause-Specific Quality of Life (MENQOL) questionnaire showed that fezolinetant produced statistically significant and clinically meaningful improvements compared to placebo. These improvements were observed as early as week 4 and were sustained through the full 52 weeks of the extension studies.[24]

Table 4: Summary of Primary Efficacy Outcomes in Phase 3 Trials (Fezolinetant 45 mg vs. Placebo)

Trial	Endpoint	Timepoint	Mean Difference vs. Placebo (95% CI)	p-value	Source(s)
SKYLIGHT 2	Change in VMS Frequency (episodes/day)	Week 12	-2.53	<0.001	31
SKYLIGHT 2	Change in VMS Severity (scale)	Week 12	-0.29	<0.001	31
DAYLIGHT	Change in VMS Frequency (episodes/day)	Week 24	-1.93 (-2.64 to -1.22)	<0.001	8
DAYLIGHT	Change in VMS Severity (scale)	Week 24	-0.39 (-0.57 to -0.21)	<0.001	8

The clinical data package for fezolinetant is robust, demonstrating consistent, rapid, and sustained efficacy in reducing the cardinal symptoms of menopause across a large and diverse patient population. The successful outcomes in two replicate pivotal trials, further confirmed over a longer duration in a difficult-to-treat, HT-ineligible population, form the solid foundation of its therapeutic value. This strong efficacy signal is what allows clinicians and patients to consider its use, even in the context of its complex safety profile.

Safety, Tolerability, and Risk Management

The safety profile of fezolinetant is a critical component of its overall clinical assessment. While generally well-tolerated in long-term studies with a favorable profile regarding hormonal-related risks, its use is defined by a rare but serious risk of hepatotoxicity, which has led to significant regulatory action and mandates a strict risk management protocol.

Hepatotoxicity: A Critical Assessment of the Boxed Warning

From its early clinical development, a signal for potential liver effects was identified. In pooled data from three large clinical trials, elevations in serum aminotransferases (alanine aminotransferase and/or aspartate aminotransferase) to levels greater than three times the upper limit of normal (>3x ULN) were observed in 2.3% of women receiving the 45 mg dose of fezolinetant, compared to 0.9% of women receiving placebo.[2] During the trials, these transaminase elevations were generally asymptomatic, isolated, and reversible, with levels returning to baseline either with continued treatment or upon discontinuation.[2] No cases meeting the criteria for severe drug-induced liver injury (Hy's Law) were reported in the clinical trial program.[17]

However, following its market approval, post-marketing surveillance identified rare but serious cases of hepatotoxicity.[1] These cases involved clinically apparent liver injury with jaundice. Patients presented with symptoms including fatigue, nausea, pruritus, and yellowing of the skin or eyes, accompanied by markedly elevated liver enzymes (transaminases up to 50x ULN) and bilirubin (up to 5x ULN).[34]

This new post-marketing evidence prompted decisive regulatory action. In September 2024, the U.S. FDA issued a Drug Safety Communication, and by December 2024, it mandated the addition of a Boxed Warning to the U.S. prescribing information.[1] A Boxed Warning is the FDA's most stringent warning and is used to highlight risks that are particularly serious. This action elevated the prominence of the existing warning on hepatotoxicity and established a mandatory, more frequent schedule for liver function monitoring for all patients receiving the drug.[35]

Long-Term Safety Profile: The SKYLIGHT 4™ Study (NCT04003389)

The SKYLIGHT 4 study was a large, 52-week, randomized, placebo-controlled trial involving over 1,800 women, designed specifically to assess the long-term safety and tolerability of fezolinetant.[3] The findings from this study are crucial as they provide reassurance regarding potential risks often associated with therapies for menopausal symptoms.

Endometrial Health

The study met its primary endpoint for endometrial safety. The incidence of endometrial hyperplasia and endometrial malignancy was evaluated via endometrial biopsies and was found to be within the pre-specified safety limits defined by the FDA. In the 45 mg group, one case of endometrial hyperplasia (0.5%) was reported, with no cases of malignancy. In the 30 mg group, one case of malignancy (0.5%) was reported, with no cases of hyperplasia. No cases of either were found in the placebo group.[17] Furthermore, there were no clinically meaningful changes in endometrial thickness as measured by transvaginal ultrasound over the 52-week period.[17]

Bone Mineral Density (BMD)

A key concern with non-hormonal treatments that might affect the HPG axis is the potential for adverse effects on bone health. The SKYLIGHT 4 study demonstrated that over 52 weeks, changes in bone mineral density at the hip and spine, as well as changes in trabecular bone score, were similar between the fezolinetant-treated groups and the placebo group.[17] This finding indicates that fezolinetant does not appear to have an adverse impact on bone health.

Overall Tolerability

The overall incidence of treatment-emergent adverse events (TEAEs) was comparable across all groups. TEAEs were reported in 63.9% of participants in the fezolinetant 45 mg group and 64.1% of participants in the placebo group.[17] The most commonly reported TEAEs were headache and COVID-19, consistent with placebo.[3] The rate of discontinuation due to adverse events was also similar across groups.[17]

Common Adverse Reactions

Based on pooled data from the Phase 3 clinical trials, the most common adverse reactions that occurred in at least 2% of patients treated with fezolinetant and at a higher incidence than placebo are summarized below.

Table 5: Common Treatment-Emergent Adverse Reactions (≥2% and >Placebo) in Pooled Phase 3 Trials

Adverse Reaction	Fezolinetant 45 mg (n=609) n (%, EAIR)	Placebo (n=610) n (%, EAIR)	Source(s)
Abdominal pain	26 (4.3%, 5.2)	13 (2.1%, 2.7)	2
Diarrhea	24 (3.9%, 4.8)	16 (2.6%, 3.4)	2
Insomnia	24 (3.9%, 4.8)	11 (1.8%, 2.3)	2
Back pain	18 (3.0%, 3.6)	13 (2.1%, 2.7)	2
Hot flush	15 (2.5%, 3.0)	10 (1.6%, 2.1)	2
Hepatic transaminase elevation	14 (2.3%, 2.8)	5 (0.8%, 1.1)	2
EAIR = exposure-adjusted incidence rate per 100 person-years.

Contraindications and Key Drug Interactions

The safety profile and pharmacokinetic properties of fezolinetant have led to several absolute contraindications:

1. Known Cirrhosis: Fezolinetant has not been studied in women with cirrhosis, and given the risk of hepatotoxicity, it is contraindicated in this population.[2]
2. Severe Renal Impairment or End-Stage Renal Disease: The drug is contraindicated in individuals with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m², as exposure to its metabolite increases in this population.[2]
3. Concomitant Use with CYP1A2 Inhibitors: Due to the profound increase in fezolinetant exposure when co-administered with CYP1A2 inhibitors, their concurrent use is strictly contraindicated. This applies to weak, moderate, and strong inhibitors of the enzyme.[2]

The overall safety profile of fezolinetant is bifurcated. On one hand, the long-term data from SKYLIGHT 4 provide strong reassurance regarding its non-hormonal nature, showing a favorable profile for endometrial and bone health—areas of significant concern with traditional HT. This is a major advantage. On the other hand, this favorable profile is overshadowed by the rare but serious risk of idiosyncratic drug-induced liver injury. The FDA's decision to add a Boxed Warning fundamentally alters the drug's risk perception, signaling to prescribers that this is a medication requiring careful patient selection and active, ongoing safety monitoring. Therefore, the clinical decision to use fezolinetant must be centered on a direct weighing of the benefits of VMS relief against the potential risk of liver injury and the patient's ability to adhere to the mandatory monitoring schedule.

Dosing, Administration, and Clinical Monitoring

The practical application of fezolinetant in a clinical setting is straightforward in terms of dosing but requires strict adherence to a safety monitoring protocol due to the risk of hepatotoxicity.

Recommended Dosage and Administration

The approved dosage of fezolinetant is one 45 mg tablet taken orally once daily.[20] The tablet should be administered at approximately the same time each day to maintain consistent plasma concentrations. It can be taken with or without food.[14] It is critical that patients are instructed to

swallow the tablet whole with liquid; it should not be cut, crushed, or chewed.[14]

For a missed dose, the patient should be advised to take it as soon as they remember, unless the next scheduled dose is less than 12 hours away. In that case, the missed dose should be skipped, and the patient should resume their regular schedule the following day.[14]

Mandatory Hepatic Monitoring Protocol

The Boxed Warning for hepatotoxicity necessitates a rigorous and non-negotiable liver function monitoring schedule for all patients prescribed fezolinetant. Adherence to this protocol is essential for the safe use of the medication.

Baseline Evaluation

Before initiating therapy, a comprehensive panel of baseline hepatic laboratory tests must be performed. This panel must include serum ALT, AST, alkaline phosphatase (ALP), and bilirubin (total and direct).[2] Fezolinetant

must not be started if baseline ALT or AST levels are at or above two times the upper limit of normal (≥2x ULN) or if total bilirubin is elevated (e.g., ≥2x ULN).[2]

Follow-up Monitoring During Treatment

Once treatment is initiated, follow-up hepatic laboratory tests are required at regular intervals:

• Monthly for the first 3 months of therapy.
• Then at 6 months and 9 months after initiation.[2]

Criteria for Discontinuation and Patient Counseling

Specific criteria are in place for discontinuing the drug due to liver enzyme elevations. Fezolinetant must be discontinued immediately if:

• Transaminase elevations are greater than five times the ULN (>5x ULN).
• Transaminase elevations are greater than three times the ULN (>3x ULN) and the total bilirubin level is greater than two times the ULN (>2x ULN).[14]

Patient education is a critical component of the risk management strategy. All patients must be counseled to discontinue fezolinetant immediately and seek medical attention, including urgent hepatic laboratory testing, if they experience any signs or symptoms suggestive of liver injury. These include new onset fatigue, decreased appetite, nausea, vomiting, pruritus (itching), jaundice (yellowing of skin or eyes), pale stools, or dark urine.[14]

Table 6: Required Hepatic Monitoring Schedule for Fezolinetant Therapy

Timepoint	Required Tests	Action/Threshold	Source(s)
Baseline (Pre-initiation)	ALT, AST, ALP, Bilirubin (Total & Direct)	Do not start if: ALT/AST ≥2x ULN or Total Bilirubin ≥2x ULN.	2
Month 1	ALT, AST, ALP, Bilirubin (Total & Direct)	Monitor for elevations.	20
Month 2	ALT, AST, ALP, Bilirubin (Total & Direct)	Monitor for elevations.	20
Month 3	ALT, AST, ALP, Bilirubin (Total & Direct)	Monitor for elevations.	2
Month 6	ALT, AST, ALP, Bilirubin (Total & Direct)	Monitor for elevations.	2
Month 9	ALT, AST, ALP, Bilirubin (Total & Direct)	Monitor for elevations.	2
As needed	ALT, AST, ALP, Bilirubin (Total & Direct)	Perform immediately if patient reports symptoms of liver injury.	14

Regulatory History and Market Context

Timeline of Key Regulatory Milestones

Fezolinetant's journey from a novel investigational compound to a marketed therapy involved key regulatory reviews and approvals in major global markets, as well as significant post-marketing safety updates.

U.S. Food and Drug Administration (FDA)

• June 23, 2022: Astellas submitted the New Drug Application (NDA) to the FDA.[37]
• August 18, 2022: The FDA accepted the NDA for review.[37]
• May 12, 2023: Fezolinetant received its initial FDA approval for the treatment of moderate to severe VMS due to menopause.[1]
• September 12, 2024: The FDA issued a Drug Safety Communication, adding a warning to the label regarding the rare occurrence of serious liver injury based on post-marketing reports.[1]
• December 16-17, 2024: The FDA strengthened the warning by adding a Boxed Warning to the prescribing information, highlighting the risk of hepatotoxicity and mandating an updated, more frequent monitoring schedule.[35]

European Medicines Agency (EMA)

• September 29, 2022: The EMA accepted the Marketing Authorisation Application (MAA) for review.[22]
• October 13, 2023: The Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion, recommending approval.[23]
• December 7, 2023: The European Commission granted marketing authorisation for fezolinetant (Veoza) throughout the European Union.[1]

Current and Future Research Directions

A significant and promising area of ongoing research for fezolinetant is its potential use in women with breast cancer who are receiving adjuvant endocrine therapy.[19] Treatments such as tamoxifen and aromatase inhibitors are highly effective for hormone receptor-positive breast cancer but frequently induce severe VMS as a side effect. For these women, hormone therapy to manage the VMS is contraindicated.

A Phase 3, randomized, placebo-controlled, double-blind clinical trial (NCT06440967) is currently recruiting participants to investigate the efficacy and safety of fezolinetant specifically in this population.[19] The study is enrolling women with stage 0 to 3 breast cancer who are on stable endocrine therapy and experiencing at least seven moderate to severe hot flashes per day. The trial has an estimated primary completion date in late 2026, with full study completion anticipated in 2028.[44]

Successful outcomes from this trial would represent a major clinical advance. It would provide a targeted, evidence-based, non-hormonal treatment for a highly symptomatic and vulnerable patient population that currently has very limited effective options. A positive result would solidify fezolinetant's role as a critical therapy for women with contraindications to HT and further define its place in the therapeutic landscape.

Expert Synthesis and Conclusion

Integrated Analysis of the Benefit-Risk Profile

Fezolinetant presents a compelling but complex benefit-risk profile that requires careful clinical judgment. The benefit is unequivocally clear and robust: it offers rapid, sustained, and clinically meaningful relief from moderate to severe vasomotor symptoms, a condition that can severely impair sleep, mood, and overall quality of life for millions of women. This therapeutic benefit is particularly pronounced and valuable for the significant population of women for whom traditional hormone therapy is not a safe or desired option. The strength of the efficacy data, demonstrated across multiple large-scale, placebo-controlled trials, is the primary driver of its clinical value.

This benefit must be weighed against a risk that is singular in nature but significant in its potential severity: a rare but documented potential for serious, idiosyncratic drug-induced liver injury. While fezolinetant is otherwise well-tolerated, with an excellent long-term safety profile regarding endometrial and bone health, the risk of hepatotoxicity—underscored by an FDA Boxed Warning—is the central safety concern. This risk necessitates a demanding and resource-intensive hepatic monitoring protocol that is a non-negotiable component of its safe use.

Positioning in the Therapeutic Landscape for Menopausal VMS

Given its unique profile, fezolinetant is not positioned as a universal replacement for hormone therapy. For many younger, healthy perimenopausal women without contraindications, low-dose HT remains a highly effective, well-established, and appropriate standard of care.

Instead, fezolinetant carves out a distinct and critical niche as a specialized first-line or essential second-line therapy for specific, well-defined patient populations:

1. Women with absolute contraindications to hormone therapy: This includes survivors of hormone-sensitive cancers (e.g., breast cancer), women with a history of venous thromboembolism, or those with other conditions where estrogens are contraindicated. For these patients, fezolinetant may be the most effective option available.
2. Women who have failed or cannot tolerate hormone therapy: This includes individuals who experience persistent VMS despite HT or who develop intolerable side effects.
3. Women who make an informed choice to avoid hormonal treatments: For personal or other reasons, many women prefer a non-hormonal approach, and fezolinetant provides a highly effective, mechanistically targeted option.

The decision to prescribe fezolinetant must be a collaborative one, emerging from a shared decision-making process between the clinician and the patient. This discussion must frankly and transparently weigh the proven benefits for VMS against the potential liver risks and the absolute requirement for strict adherence to the blood monitoring schedule.

Concluding Remarks

Fezolinetant is a landmark achievement in the field of women's health. It represents the successful clinical translation of a novel understanding of the neuroendocrine control of thermoregulation into a targeted, effective therapy. As the first-in-class NK3 receptor antagonist approved for VMS, it has forged a new, non-hormonal path for managing a common and burdensome condition of menopause.

However, its clinical utility is fundamentally tempered by its safety profile. Its ultimate impact on clinical practice will be determined not just by its impressive efficacy, but by the real-world implementation and success of the risk management strategies mandated to ensure its benefits can be realized safely. Fezolinetant is a powerful and valuable therapeutic tool, but one that demands respect, caution, and unwavering diligence from both the prescribers who recommend it and the patients who receive it.

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