- Fezolinetant and elinzanetant are new drugs that have been approved to treat hot flushes and night sweats
- This article summarises safety and efficacy studies of fezolinetant and elinzanetant
- It also looks at how fezolinetant and elinzanetant work, side effects and interactions with other medications and supplements
What are fezolinetant and elinzanetant?
Fezolinetant (brand name Veoza) and elinzanetant (brand name Lynkuet) are new drugs that have been approved in the UK to treat moderate to severe vasomotor symptoms in menopausal women aged 45 to 60 years [1,2]. In the UK, both drugs are currently only available on private prescription.
Fezolinetant has also been approved in the United States, Europe, and many other countries. Elinzanetant has also been approved in the United States, Australia and Canada.
Some studies have shown that around 75% of perimenopausal and menopausal women experience hot flushes and night sweats (also known as vasomotor symptoms), which can disrupt sleep and adversely affect mood. However, they are not the most common or most troublesome symptom Balance app users have reported that brain fog is the most common, with mood issues also more commonly experienced.
RELATED: Handling hot flushes and night sweats
How do they work?
Vasomotor symptoms are thought to be caused by increased activity in KNDy neurones (pronounced ‘candy’ neurones), in the thermoregulatory centre of your brain, in an area called the hypothalamus. KNDy is short for Kisspeptin, Neurokinin B and Dynorphin. These are three neurotransmitters (chemicals made by your brain which allow nerves to communicate with each other) that work together to induce release of gonadotrophin releasing hormone (GnRH). GnRH is a hormone made in your hypothalamus, and it is important for reproduction, regulation of your menstrual cycle and control of levels of the hormones progesterone, estradiol and testosterone.
When levels of these hormones fluctuate and fall, this can affect the hypothalamus, causing KNDy neurons to become more active, and your brain’s temperature control centre overly sensitive. This can lead to hot flushes and night sweats occurring.
The neurokinin 3 receptor is a receptor on cells that respond to the KNDy neurones when they are activated. Fezolinetant and elinzanetant both work as neurokinin receptor antagonists – meaning they block this receptor on the cells, which then block the KNDy neurones working.
Although there are many neurokinin receptors in your hypothalamus, there are also neurokinin receptors in other areas of your brain and spinal cord, so this means other functions of your brain can be blocked with these drugs. Interestingly, neurokinin receptors are also in your ovaries and womb as well as in other tissues in your body. They are present in your digestive, cardiovascular, and immune systems. They are expressed on many cell types, such as neurons, smooth muscle cells, and immune cells, playing a role in functions like pain transmission, secretion, and muscle contraction.
The effects of blocking these receptors elsewhere in your brain and throughout your body have not been fully assessed nor researched.
RELATED: Could it be perimenopause? How hormones influence the brain
How effective are these drugs?
A study of 10 controlled trials, involving 4,663 postmenopausal women, compared the efficacy of fezolinetant and elinzanetant with placebo in managing vasomotor symptoms. Both treatments were found to reduce the frequency of vasomotor symptoms by 50% or more, with elinzanetant producing faster effects and improving menopause-specific quality of life [3]. However, higher doses of both drugs increased the risk of adverse effects (read more on side effects below).
A more recent randomised, placebo-controlled trial, OASIS-3, of 628 women found that after 12 weeks, 74% of women had a reduction of hot flushes while taking elinzanetant [4]. However, 47% of women who were given a placebo also reported a reduction of hot flushes. By week 50, women taking elinzanetant experienced 1.4 moderate to severe vasomotor events per day, compared to 3.5 by the women taking a placebo.
There have not been studies comparing HRT (which is the gold standard treatment for menopausal symptoms) with fezolinetant or elinzanetant. Also there have not been any long-term studies involving women who have had breast cancer taking either of these drugs.
RELATED: Hot flush drug Fezolinetant
What are the side effects?
Interestingly, one of the noted side effects of fezolinetant is hot flushes. These drugs can block production of progesterone, estradiol and testosterone so may worsen menopausal symptoms in some women.
In a clinical trial, 2.1% of women taking fezolinetant developed signs of liver damage (elevated levels of liver enzymes) that resolved when the drug was stopped [1]. However, most women who developed abnormal liver function in the trials had no symptoms. Liver function must be monitored before and during treatment in all patients taking fezolinetant.
Kisspeptin is a protein in your body that also works to reduce spread of cancer so blocking it may lead to detrimental effects, especially in people who have had cancer in the past. One paper reported an increased incidence of cancer in women treated with fezolinetant compared with placebo [5]. This is a concern as currently this drug is being marketed as a drug to prescribe to women who have had breast cancer in the past.
Common side effects of elinzanetant include fatigue, drowsinesss, headache, diarrhoea and muscle spasms.
While some trial participants developed elevated liver enzyme levels while taking elinzanetant, no serious liver injuries were reported in studies that lasted up to one year.
Can I take these drugs if I've had cancer?
These drugs are being marketed mainly to women who have had breast cancer in the past. However, the safety and efficacy, especially for long-term use, of taking these drugs after breast cancer are unknown as the studies have not been undertaken.
The OASIS-3 trial that explored the use of elinzanetant (mentioned above) excluded women with current or recent history of cancer.
Another study, OASIS-4, involved women taking endocrine therapy for hormone receptor (HR)-positive breast cancer [6]. This found elinzanetant led to a significantly lower daily frequency of moderate-to-severe vasomotor symptoms, a greater decrease in sleep disturbances, and a greater increase in menopause-related quality-of-life than placebo. However, the authors noted that longer term assessment of this cohort is needed, and that recurrence of breast cancer and survival were not prespecified outcomes in this trial, so it’s important to have future studies that assess these outcomes.
Who can take it?
You should avoid taking fezolinetant if you take ciprofloxacin, an antibiotic; fluvoxamine, an antidepressant; and ethinyl estradiol, an oral estrogen in many types of contraceptive pill and some oral HRT formulations.
Liquorice, and certain supplements such as St John’s Wort, green tea and grape seed extract should also be avoided.
Taking fezolinetant at the same time as HRT has not been studied, and it is not recommended to use fezolinetant and HRT together [1].
Elinzanetant is not suitable if you are pregnant or may become pregnant, have liver problems or a history of seizures.
What’s the bottom line?
The most effective evidence-based treatment for perimenopausal and menopausal symptoms, including vasomotor symptoms, is HRT, because it targets the underlying cause. Also, HRT is bone, heart and neuro-protective, and reduces all-cause mortality by 30% [7].
Fezolinetant and elinzanetant have been approved to treat moderate to severe vasomotor symptoms in menopausal women. These drugs do not treat other menopausal symptoms, have not been tested against gold standard treatment (HRT) and we don’t yet have long-term data regarding their impact on cardiovascular and bone health, or breast cancer incidence.
Even if these drugs work to reduce or stop vasomotor symptoms in women, this does not mean that other symptoms will improve nor that there are any health benefits from taking these drugs.
The most effective evidence-based treatment for perimenopausal and menopausal symptoms, including vasomotor symptoms, is hormone replacement therapy (HRT), because HRT targets the underlying cause (low hormone levels). Women who take hormones have a lower future risk of diseases, which has not been shown for women who are prescribed these medications.
You can download visual aids illustrating the benefits and risks of HRT here.
A decision to treat women with a past history of cancer should be based on an individualised assessment of the relative risks and benefits.
To enable women to make an informed treatment choice of these neurokinin receptor antagonists, they should be aware that the available safety data is limited, and an increased incidence of cancer was observed in a clinical trial that has not yet been fully evaluated.
