Fezolinetant: NK3 Receptor Antagonist for Menopausal Hot Flushes
Fezolinetant is the first approved neurokinin 3 (NK3) receptor antagonist for the treatment of vasomotor symptoms (VMS) associated with menopause. Approved in 2023 by the FDA and EMA, it represents a novel non-hormonal approach to managing moderate to severe hot flushes and night sweats in menopausal women.
Its approval is significant for women who cannot or prefer not to use hormone replacement therapy (HRT), including those with a personal or family history of hormone-sensitive cancers. Unlike HRT, fezolinetant acts on the central nervous system rather than replacing oestrogen, targeting the thermoregulatory circuits that are dysregulated after the hormonal changes of menopause.
Mechanism of Action
The hypothalamic KNDy neurons (kisspeptin, neurokinin B, dynorphin) play a key role in thermoregulation and the neuroendocrine regulation of reproductive function. During and after menopause, oestrogen deficiency leads to hypertrophy and hyperactivity of KNDy neurons, which express NK3 receptors. Neurokinin B (NKB), secreted by KNDy neurons, acts on NK3 receptors on thermoregulatory neurons in the hypothalamus, triggering vasodilation and sweating (hot flushes). Fezolinetant selectively blocks NK3 receptors, interrupting this signalling pathway and reducing the frequency and severity of hot flushes without influencing oestrogen levels or the hypothalamic-pituitary-gonadal axis.
Indications
Fezolinetant is approved for the treatment of moderate to severe vasomotor symptoms (hot flushes, night sweats) due to menopause in adult women. It is particularly indicated for women in whom HRT is contraindicated, not tolerated, or not desired. The SKYLIGHT clinical trial programme demonstrated that fezolinetant 45 mg daily significantly reduced hot flush frequency and severity compared to placebo, with benefits maintained over twelve months.
Dosage and Administration
The approved dose is 45 mg once daily, taken orally with or without food at the same time each day. No dose titration is required. The drug can be taken in the morning or evening. Liver function tests should be performed before starting treatment and at three, six, and nine months during the first year of treatment. Fezolinetant is not recommended in moderate or severe hepatic impairment. Dose adjustment is not required for mild renal impairment; it is not recommended in severe renal impairment.
Side Effects
Hepatotoxicity is the most important safety signal identified during clinical development; elevations of liver enzymes (ALT/AST) were observed in a small proportion of patients. Monitoring of liver function is mandatory, and the drug must be discontinued if liver enzyme levels exceed three times the upper limit of normal. Abdominal pain and diarrhoea are the most common gastrointestinal adverse effects. Insomnia, hot flushes (paradoxically, at treatment initiation), and fatigue have been reported. No significant cardiovascular side effects have been identified in trials.
Interactions
Fezolinetant is metabolised primarily by CYP1A2. Strong CYP1A2 inhibitors, particularly fluvoxamine, can substantially increase fezolinetant exposure and the combination is contraindicated. Moderate CYP1A2 inhibitors (ciprofloxacin, enoxacin) should be used with caution. CYP1A2 inducers (smoking, omeprazole, rifampicin) may reduce fezolinetant levels and reduce efficacy. The combination with hepatotoxic drugs should be monitored carefully due to the additive risk of liver injury.
Special Notes
Fezolinetant is a prescription-only medicine not approved for use in men or in premenopausal women. It is not a hormonal treatment and does not protect against osteoporosis or cardiovascular disease associated with oestrogen deficiency. Women requiring protection against these conditions may still need HRT or other targeted interventions. The drug should not be used in patients with known liver disease. Regular liver enzyme monitoring is non-negotiable during treatment. The long-term safety profile beyond twelve months is still being established.
Related Topics
Frequently Asked Questions
How quickly does fezolinetant reduce hot flushes?
Clinical trials showed a significant reduction in hot flush frequency as early as the first week of treatment. The full effect developed over four to twelve weeks. In the SKYLIGHT trials, the number of moderate to severe hot flushes per day was reduced by approximately 60 percent compared to 45 percent for placebo after twelve weeks.
Can women with breast cancer history use fezolinetant?
Fezolinetant does not affect oestrogen levels and acts solely on neuronal NK3 receptors. It is not expected to stimulate hormone-sensitive cancers. However, clinical trial data in women with a history of hormone-sensitive cancers are limited, and the decision should be made in consultation with the oncologist managing the patient's cancer care.
Why is liver monitoring required during fezolinetant treatment?
During the Phase 3 clinical trials, a small number of patients experienced elevated liver enzymes on fezolinetant compared to placebo. The mechanism is not fully understood. Mandatory liver function monitoring at three, six, and nine months during the first year allows early detection of hepatotoxicity before serious liver damage occurs. The drug should be stopped if ALT or AST exceeds three times the upper limit of normal.
Sources
- EMA: Fezolinetant (Veoza) Summary of Product Characteristics 2023
- Johnson KA et al: SKYLIGHT 1 Trial. Menopause 2023
- IMS Menopause Guidelines 2023