Fezolinetant

Body Temperature; drug effects; Hot Flashes; drug therapy; Menopause; Receptors, Neurokinin-3 / antagonists & inhibitors; Skin Temperature;

Fezolinetant is an oral, non-hormonal neurokinin-3 (NK3) receptor antagonist for the treatment of moderate to severe vasomotor symptoms (VMS). Fezolinetant is approved in the USA, Europe and Australia at a dosage of 45 mg once daily.

Fezolinetant is a non-hormonal, orally administered selective antagonist of neurokinin-3 (NK3) receptors (selective neurokinin-3 (NK3) receptor antagonist) that acts specifically on the thermoregulatory centers in the hypothalamus. It is used to treat vasomotor symptoms such as hot flushes associated with the menopause.

Fezolinetant is a non-hormonal selective neurokinin 3 (NK3) receptor antagonist that blocks the binding of neurokinin B (NKB) to the kisspeptin/neurokinin B/dynorphin (KNDy) neuron. Since NKB plays a central role in the regulation of body temperature, the blockade of NK3 receptors by fezolinetant leads to a reduction in vasomotor symptoms, such as hot flushes, which often occur during menopause (Johnson KA et al. 2023).

Body temperature is regulated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the hypothalamus, which are stimulated by neurokinin B via NK3 receptors and inhibited by oestrogen. The falling estrogen level during the menopause leads to unhindered NKB signal transmission. This results in a hypertrophy of the KNDy neurons, an increased signal transmission of these neurons to the nucleus preopticus medianus (the thermoregulation center of the hypothalamus) and the activation of mechanisms of heat dissipation (e.g. skin vasodilation, sweating), which in turn results in vasomotor symptoms (VMS). By blocking NK3 receptors, fezolinetant modulates NKB signaling, inhibits the activity of KNDy neurons and neurons in the median preoptic nucleus, and reduces the frequency and severity of moderate to severe VMS associated with menopause (Ruan X et al. 2024).

Fezolinetant should be taken orally at approximately the same time each day with or without food and with liquid. The tablets are taken whole.

The most common side effects of fezolinetant in clinical trials were diarrhea (3.2%) and insomnia (3.0%).

The concomitant use of fezolinetant with medicinal products that are moderate or strong CYP1A2 inhibitors increases the Cmax in plasma as well as the AUC of fezolinetant and is therefore contraindicated.

+Hypersensitivity to the active substance or any of the other ingredients, concomitant use of moderate or strong CYP1A2 inhibitors, and in known or suspected pregnancy.

^Veoza®

Alternative therapies for VMS:

• Hormone replacement therapy (HRT): HRT is one of the most effective treatments for VMS and involves the use of estrogen alone or in combination with progesterone. However, it is not suitable for all women, especially those with certain health risks.
• Selective estrogen receptor modulators (SERMs): SERMs such as raloxifene can relieve some menopausal symptoms by binding to estrogen receptors in the body, without the risks associated with hormone replacement therapy.
• Antidepressants: Certain antidepressants, particularly those in the serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) class, can be used to relieve hot flashes.
• Gabapentin and pregabalin: These drugs, which are mainly used to treat nerve pain and epilepsy, have also been shown to be effective in reducing hot flushes.
• Herbal supplements and alternative therapies: Some women choose herbal products such as phytoestrogens (e.g. soy, red clover) or other natural supplements. However, the effectiveness and safety of these products can vary significantly.

1. Johnson KA et al. (2023) Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab 108:1981-1997.
2. Kagan R et al. (2025) Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies. Adv Ther 42:1147-1164.
3. Lederman S et al. (2023) Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomized controlled study. Lancet 401: 1091-1102.
4. Ruan X et al. (2024) Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms associated with menopause among women in East Asia: a phase 3 randomized study (MOONLIGHT I). J Int Med Res 52:3000605241247684.
5. Schaudig K et al. (2024) Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomized controlled trial. BMJ 387:e079525.