Introduction

The climacteric comprises the transitional period from the reproductive to the nonreproductive stage in women and extends from 40 to 65 years of age (1). It is usually divided into two phases: the menopausal transition/perimenopause (from the onset of climacteric symptoms to menopause) and postmenopause (beginning at menopause, which in turn is subdivided into an early stage—the first five years of postmenopause—and a second late stage, starting five years after menopause and lasting until death) (1-3).

Menopause occurs at the end of the menopausal transition and marks the beginning of postmenopause (1,2). It is recognized after 12 months without menstrual cycles associated with permanent and physiological ovarian insufficiency (3). In general, it is defined as the “permanent cessation of menstruation, determined retrospectively after 12 consecutive months of amenorrhea, with no pathological causes” (2,4).

Worldwide, menopause occurs at around 49 years of age, depending on geographic and ethnic variation (5). In Latin America, it occurs between 47 and 50 years of age (6), which is consistent with Colombian women (2,4,7). If the average life expectancy in women is 78 years, most will spend approximately one-third of their lives in postmenopause (2,4). Considering 50 years as the age at menopause, around 25 million women will go through it each year. It is estimated that in 1990 there were 467 million postmenopausal women worldwide, with a mean age of about 60 years. Thus, by 2030, the global population of menopausal and postmenopausal women is projected to increase to 1.2 billion, with 47 million new women each year (8).

Vasomotor symptoms (VMS), commonly referred to as hot flashes and night sweats, are the main symptoms of menopause and are also the symptoms for which women most frequently seek treatment. Up to 80% of women experience them during the menopausal transition (2,9); however, a systematic review found prevalence rates ranging from 22% to 63% in Asia, 36% to 50% in the United States, and 74% in Europe (10).

Most women rate their VMS as moderate to severe (9), with an average duration of 7.4 years (11). Accordingly, these bothersome symptoms can affect women’s quality of life through sleep problems, fatigue, anxiety, and depression, thereby impairing their ability to work and perform daily activities (12-14).

According to Ameye et al. (15), most women are not currently treating their VMS, perhaps because of the belief that menopause is a natural aging process, lack of knowledge about the different therapeutic options, or concerns about the potential adverse/side effects and safety of existing treatments (16,17).

Treatment options for VMS include hormonal therapy and nonhormonal therapy, as well as complementary and alternative therapies (lifestyle changes, healthy eating, exercise, nutraceuticals, acupuncture, aromatherapy, phytotherapy, neurokinin 3 receptor antagonists, cognitive behavioral therapy, mindfulness, yoga, regenerative therapies, etc.) (18-21).

For years, menopausal hormone therapy (MHT) has been considered the first-line treatment option because it is the most effective for relieving moderate to severe VMS (22). Despite this, both patients and healthcare professionals have expressed concerns about its long-term safety, which has led to a global decline in its use as first-line therapy (23-25). Nonhormonal medications, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for hot flashes, or gabapentin for night sweats, have also been recommended for women who cannot or do not wish to take MHT; however, they are often insufficient to relieve symptoms and may be associated with intolerable side effects (26-28).

In general, nonhormonal medications are not approved for the treatment of VMS, as their use is recommended off-label. However, in recent years, a new nonhormonal option has emerged, known as fezolinetant, a nonhormonal neurokinin 3 (NK3) receptor antagonist for the treatment of moderate to severe VMS (18). It acts by inhibiting neuronal impulses originating in the thermoregulatory center of the hypothalamus, an area of the brain innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are stimulated by the neuropeptide neurokinin B (29). Currently, the SKYLIGHT 2 and 4 trials statistically demonstrate the safety and acceptability of fezolinetant, with relatively few adverse effects (30,31). Hence, it is already available and approved in many countries, including the United States and Europe, at a dose of 45 mg once daily (32,33). Therefore, this study aims to evaluate the efficacy and safety of fezolinetant in order to offer a new nonhormonal alternative for the treatment of vasomotor symptoms.

Materials and Methods

The only indication for the use of fezolinetant is the treatment of moderate to severe VMS associated with menopause (29-31). The final research question of this study was: does the use of fezolinetant have a positive or negative influence on women? This question was refined through consultation with experts in climacteric/menopause, who agreed on the need to restrict the systematic search to the use of fezolinetant in menopausal women with VMS. The following inclusion criteria were considered:

Type of intervention: fezolinetant was the term of interest, followed by efficacy, safety, and the presence of adverse/side effects.

Type of studies: the search was limited to randomized clinical trials, observational studies, meta-analyses, and literature reviews that evaluated the efficacy and safety of fezolinetant in menopausal women, with full text available for complete assessment and inclusion in the review, with no language restriction; published between January 1, 1985, and June 30, 2025.

Type of population: studies including menopausal women with VMS. Studies with fewer than 20 participants, animal studies, women with cancer, preliminary reports without complete data, opinion articles, editorials, and letters to the editor were excluded.

Evidence synthesis and summary: the results of the selected studies are presented in summary tables and described narratively in the text. A qualitative synthesis of the findings is provided, highlighting: a) reduction in the frequency and severity of VMS, b) safety and adverse/side effects, c) improvement in quality of life, and d) improvement in sleep disturbances.

Search Strategy

A systematic search of the medical literature was conducted using the following databases: CENTRAL, the Cochrane Database of Systematic Reviews (Wiley platform), Embase (Elsevier), Google Scholar, MEDLINE via PubMed, and SciELO.

The guidelines for defining the population using free text and controlled vocabulary were established through free and standardized search terms (MeSH and DeCS). These were: climacteric, menopause [MeSH], and therapeutics. The terms combined using the Boolean operator OR were: neurokinin B and neurokinin-1 receptor antagonists. Finally, the group of search terms defining the population of interest was combined with the free and standardized search terms using the Boolean operator AND.

Likewise, a manual “snowball” search was performed, starting from the reference list of each selected article, in search of other publications that met the previously established selection criteria.

Ethical Considerations

In accordance with Article 11 of Resolution 8430 of 1993 (34), as this is a review of the scientific literature, it is considered research without risk.

Results

The search of the databases yielded a total of 3,762 references. Subsequently, after removing duplicates, 983 references remained, of which 414 met the inclusion criteria based on title and abstract and were selected for full-text assessment. Figure 1 details the PRISMA flowchart for reference screening.

Efficacy

Fezolinetant has been shown to be effective for the treatment of moderate to severe VMS in women considered unsuitable for MHT at an oral dose of 45 mg once daily (18,30,35). It blocks neurokinin B signaling, normalizing the activity of kisspeptin, neurokinin B, and dynorphin neurons in the hypothalamus to reduce the frequency and severity of VMS, which is associated with improved quality of life (35-38).

Up to the time of the present review, fezolinetant had demonstrated efficacy for the treatment of moderate to severe VMS associated with menopause in the phase 3 studies SKYLIGHT 1 (39) and SKYLIGHT 2 (30), which included a 12-week placebo-controlled period followed by an active-treatment extension to 52 weeks. To further investigate the clinical benefits of fezolinetant for the treatment of moderate to severe VMS, a phase 3b trial (DAYLIGHT) was conducted (37), which included a 24-week placebo-controlled period and enrolled a population considered unsuitable for hormone therapy.

In the long term, the safety of fezolinetant was also investigated in the 52-week randomized, double-blind, phase 3 SKYLIGHT 4 study, with a total of 1,830 participants (31). The results of SKYLIGHT 4 confirm the safety and tolerability of fezolinetant over 52 weeks and support its continued use (Table 1).

Table 1 synthesizes the evidence by summarizing the results of the selected studies (RCTs) and provides an overall picture of the efficacy of fezolinetant for VMS. A clear consistency was identified both in the efficacy of the drug and in its validation. All the collected findings reinforce that fezolinetant is positioned as an excellent, viable, nonhormonal alternative for the treatment of VMS.

Fezolinetant reduced the frequency and severity of VMS in phase 3, randomized, placebo-controlled clinical trials in healthy menopausal women (SKYLIGHT 1 and 2) and in women unsuitable for MHT (DAYLIGHT). The effect on VMS translated positively into improvements in menopause-related quality of life, as well as in sleep disturbances and sleep impairment (43).

Given that the risks associated with hormone use may limit this option in some women, neurokinin B inhibitors such as fezolinetant act on the physiological cause of VMS, and with the approval of fezolinetant, healthcare professionals and patients now have an additional nonhormonal treatment option for menopause-associated VMS (44).

Safety

Clinical trials have shown that fezolinetant is superior to placebo in reducing the frequency and severity of VMS. Adverse/side effects associated with fezolinetant include headache (the most frequent: 5%-10%) (45) and gastrointestinal disorders, as well as elevations in hepatic transaminase levels (43). Safety data have been encouraging across all studies, especially in the 52-week clinical trials (SKYLIGHT 4 and MOONLIGHT 3) (44).

With fezolinetant, alanine aminotransferase or aspartate aminotransferase values >3 times the upper limit of normal have been reported in up to 1.4% of women, and it has generally been found to be safe and well tolerated over a 52-week period (46).

In the SKYLIGHT studies, adverse events with fezolinetant were similar to those observed with placebo. The most frequent were headache, fatigue, insomnia, nausea, abdominal pain, and diarrhea (30,31,42,44). In the SKYLIGHT 4 safety study (31), adverse events led to treatment discontinuation in 4.3% of the placebo group and 5.1% of the fezolinetant group. Liver enzymes increased in 5.5% of participants who received fezolinetant, compared with 4.9% in the placebo group. Table 2 describes the systematic reviews and meta-analyses on the efficacy and safety of fezolinetant in the treatment of VMS.

In a study that evaluated the safety and tolerability of fezolinetant in women with menopause-related VMS, a pooled analysis was performed using data from three 52-week phase 3 trials (SKYLIGHT 1, 2, and 4). A total of 952 participants received placebo, 1,100 received fezolinetant 45 mg, and 1,103 received fezolinetant 30 mg. Adverse events occurred in 55.3%, 62.9%, and 65.4%, respectively. The most frequent adverse events in participants treated with fezolinetant included upper respiratory tract infection (7.7%-8.3%), headache (6.8%-8.2%), COVID-19 infection (5.8%-6.1%), back pain (3.1%-3.7%), arthralgia (2.9%-3.2%), diarrhea (2.3%-3.2%), urinary tract infection (2.9%-3.4%), insomnia (2.0%-3.0%), and elevated hepatic transaminases (1.5%-2.3%).

The incidence of serious drug-related adverse events and associated treatment discontinuations was low. In women who developed elevated transaminases, these were typically asymptomatic and transient; they resolved after discontinuation of the drug, with no evidence of severe liver injury. Endometrial safety results, based on the exposure-adjusted analysis of benign and non-benign neoplasms, showed no increased risk compared with placebo (51).

Discussion

The present study provides an exhaustive systematic review of the scientific literature to evaluate the efficacy and safety of fezolinetant in postmenopausal women with moderate to severe VMS. Its effect is exerted directly on the thermoregulatory center of the hypothalamus to inhibit VMS associated with decreased estrogen levels by blocking the action of neurokinin B (29,43). It is marketed as 45-mg tablets for oral administration once daily (37,52). Fezolinetant (VEOZAH™) was developed by Astellas Pharma Inc. and received its first approval in the United States in May 2023 for the treatment of moderate to severe VMS (53).

The efficacy of fezolinetant was documented in the major clinical trials conducted (SKYLIGHT 1-3 and 2-4) (31,42,51), which were double-blind studies involving postmenopausal women presenting with moderate to severe VMS at a mean event rate of at least 7 times per day. They were administered fezolinetant or placebo for 12 weeks to assess whether symptom frequency and severity were reduced.

At the end, women in the placebo group were switched to fezolinetant, and all participants continued treatment for an additional 40 weeks. In the two trials conducted in Europe and the United States, 339 women were randomly assigned to receive fezolinetant 30 mg daily, 341 to receive fezolinetant 45 mg daily, and 342 to receive placebo. In both trials, fezolinetant rapidly reduced the mean daily frequency of VMS. After 12 weeks, pooled data from the two trials showed that fezolinetant 30 mg reduced symptom frequency from 10.94 to 4.63 events per day, whereas fezolinetant 45 mg reduced it from 11.10 to 4.27 events per day. In the placebo group, the reduction was from 11.04 to 6.79. Additionally, a decrease in VMS severity was observed compared with placebo, especially with fezolinetant 45 mg. During the extension period of both trials, symptoms improved in women from the placebo group who switched to fezolinetant 30 mg or fezolinetant 45 mg, and symptom improvement was maintained in all patients (31,39).

In the analysis by Nappi et al. (54), a ≥50% reduction in VMS frequency was achieved at week 12, as well as reductions of 23% and 11% in women receiving fezolinetant 45 mg and 30 mg, respectively, compared with the placebo group. In addition, 8% and 4% more participants receiving fezolinetant 45 mg and 30 mg, respectively, compared with those receiving placebo, experienced a 100% reduction in VMS frequency from baseline to week 12.

The effect of fezolinetant on sleep disturbances and sleep impairment in women with VMS was pooled in the SKYLIGHT 1 and 2 studies (patients aged ≥40 to ≤65 years were included). Assessments were performed at baseline and at weeks 4 and 12. A total of 1,022 women were randomized. The results showed improvements in sleep disturbance with fezolinetant 30 mg and 45 mg versus placebo (week 12: −0.6; 95% CI = −1.7 to 0.4 for 30 mg and −1.5 [−2.5 to −0.5] for 45 mg) (55). In these phase 3, double-blind investigations, fezolinetant had a beneficial effect on sleep disturbance and sleep impairment after treatment of VMS.

Regarding the safety of fezolinetant, the 12-week, phase 3, double-blind, placebo-controlled clinical trial with a 40-week active-treatment extension conducted by Johnson et al. (30) showed that serious treatment-related adverse events were infrequent, reported by 2%, 1%, and 0% of participants receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. This is consistent with the study by Takamatsu et al. (56) in Japan and that by Ruan et al. (57) in China. The latter, among 301 participants in a phase 3, randomized, double-blind study of postmenopausal women with moderate to severe VMS (minimum mean frequency in the 10 days before randomization: ≥7/day or 50/week), observed serious adverse events in 0.7% of participants receiving fezolinetant between weeks 1 and 12, compared with 1.3% of those receiving placebo, which supports the safety of fezolinetant.

In summary, fezolinetant reduces moderate to severe vasomotor symptoms from the first day of treatment, with statistically significant effects compared with placebo and with other nonhormonal treatments, along with a favorable tolerability profile and few side effects. This was reported in the systematic review by Cieri-Hutcherson et al. (58). In three RCTs of fezolinetant, they demonstrated a reduction in the frequency/severity of VMS, improvement in menopause-specific quality-of-life scores, and improvement in sleep quality at weeks 4 and 12, compared with placebo, without serious adverse events.

In the present narrative review, it is clear that fezolinetant is both effective and safe in the treatment of menopause-associated VMS, which often negatively affect the daily lives of the women who experience them, and that it is an ideal first-line therapy for women who are not candidates for MHT. Many times, these women seek nonhormonal therapeutic alternatives, but these are usually ineffective, costly, and unsatisfactory.

It is necessary to continue long-term research with larger numbers of participants in order to establish the safety of fezolinetant after several years of continuous use. Additionally, studies in population subgroups of women with preexisting or specific conditions such as cancer, obesity, diabetes, among others, are needed in order to develop personalized recommendations centered on holistic medicine. Another important point is the urgent need for comparative studies with MHT, as well as with other nonhormonal therapies, in order to draw more precise conclusions regarding its reported efficacy.

The main strength of this research lies in the use of a systematic review methodology to search for and synthesize the available evidence on a specific question. The fact that randomized clinical studies were taken into account represents another strength in support of its validity. The extensive search of the scientific literature, expanded through the “snowball” technique, sought to identify other publications relevant to the study. On the other hand, the use of synthesis and summary tables of the publications facilitates communication and understanding of the results. The available and selected meta-analyses from the recent literature help support and develop a narrative review of relevant scientific quality.

With respect to the weaknesses of this study, it should be noted that, as a narrative review, it lacks standardization, which makes it prone to bias. However, in this specific investigation, that effect is not substantial, because almost all the included studies have a high proportion of direct-evidence level. Since no Colombian population was included in the studies evaluated, this constitutes a potential limitation, although unavoidable in the absence of such studies, and it may have only a marginal effect on the final results.

Conclusions

Fezolinetant effectively reduces the frequency and severity of moderate to severe VMS and sleep disturbances in postmenopausal women because it is well tolerated and shows no concerning safety signals.

The results highlight the usefulness of fezolinetant as an effective therapeutic option for women with contraindications to MHT or who decide not to use it. The nonhormonal mechanism of action of fezolinetant, as well as its efficacy and safety, with a positive impact on quality of life and improvement in sleep disturbances, places it among the first-line treatment options for women with VMS who are seeking reliable alternatives to MHT.

Acknowledgments

To Dr. Sandra Milena Sánchez Gutiérrez and Dr. José Luis Cubides, for their valuable support in my professional training, thanks to which I have been able to enter the world of scientific research.

References

Notes

Funding Este estudio no recibió financiación de ningún tipo. Es producto del esfuerzo económico del autor.

Conflicto de intereses: none declared.

Author notes

^a Correspondence author: espitiafranklin71@gmail.com

Additional information

How to cite: Espitia-De La Hoz FJ. Fezolinetant: Neurokinin 3 (NK3) Receptor Antagonist for the Treatment of Vasomotor Symptoms of Menopause. Univ Med. 2026;67. https://doi.org/10.11144/Javeriana.umed67.fnra

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