Celeste Krewson

While vasomotor symptoms (VMS) have significant adverse impacts on the quality of life in menopausal women, elinzanetant and fezolinetant have emerged as promising non-hormonal treatments to alleviate symptoms, marking significant advances in menopausal health in 2024.

Approximately 80% of menopausal women are impacted by VMS, often leading to health complications such as cardiovascular and cognitive changes, bone loss, and mood disturbances.

Elinzanetant is a dual neurokinin receptor antagonist that has shown promise toward reducing these adverse health outcomes. During the OASIS 1 and 2 trials, the safety and efficacy of this drug was investigated for managing VMS.

In clinical trials, VMS frequency and severity were both significantly reduced over 12 weeks when compared to placebo. Additionally, these effects were maintained at 26 weeks among women with moderate-to-severe VMS regardless of whether they continued elinzanetant use for the full trial or were switched from placebo at week 12.

Symptom frequency was reduced in participants taking elinzanetant as early as week 1 of the trials, and sleep disturbances were reduced by at least 50% in over 80% of participants by week 26. During the 52-week OASIS 3 trial, similar results were reported, confirming elinzanetant’s safety and efficacy.

Following submission of this data, the FDA accepted a New Drug Application (NDA) for elinzanetant in October 2024—marking a significant step forward in advancing menopausal care among US women.

An approval for elinzanetant will mark the third nonhormonal treatment optionfor moderate-to-severe VMS associated with menopause. Tolerability, efficacy, and access to hormonal options remain significant barriers to VMS treatment in many menopausal women, highlighting the importance of expanding options.

Nanette Santoro, MD, professor and E Stewart Taylor Chair of Obstetrics and Gynecology at the University of Colorado School of Medicine, provided additional information about the impact of elinzanetant for VMS in the presentation “Vasomotor Symptoms 101” at the 2024 Annual Meeting of The Menopause Society.

Nanette Santoro, MD
Credit: Colorado University

According to Santoro, VMS are the most common symptom of menopause, with a majority of women struggling with these symptoms and some being severely affected. Approximately two-thirds of menopausal women visiting the doctor’s office ask questions about their hot flashes, highlighting this symptom’s significant impact.

"For most of history, we've only had hormones,” Santoro said. “Hormones work great for hot flashes. Hormones are not bad news, they're good news. There's a lot of ways to give them, and most women can safely take them." 

However, certain women may be unable or unwilling to take hormones. These women can use selective serotonin reuptake inhibitors (SSRIs) for hot flash treatment.

Previously, SSRIs were used off-label, but now neurokinin-3 (NK3) receptor antagonists, such as elinzanetant, offer an approved treatment option. By acting on neurokinin receptors, NK3 receptor antagonists may have similar efficacy to estrogen without the increased risks or side effects of hormonal treatment.

In an interview with Contemporary OB/GYN, Santoro highlighted the benefits of fezolinetant, another NK3 receptor antagonist developed for the treatment of moderate-to-severe hot flashes in menopausal women.

 Fezolinetant is the first in class of these antagonists, providing an ideal option for patients who cannot take hormones.

These therapies target the brain’s KNDy neurons, responsible for regulating the body’s temperature. By blocking these signals, fezolinetant significantly reduces the incidence of moderate-to-severe hot flashes.

The FDA approved fezolinetant for the treatment of hot flashes associated with menopause in Spring 2023.

The drug may be taken orally at 45 mg per day. According to the FDA, the pill should be taken at the same time each day and taken as soon as possible if a patient misses their usual time.

Data has indicated a reduction in the frequency of hot flashes of 75% to 80% in patients receiving fezolinetant.

 Alongside the frequency, the severity of hot flashes is often reduced by the drug, with patients experiencing less moderate to severe hot flashes that significantly impact their quality of life.

Santoro described fezolinetant as a “breakthrough” in the menopause field in regard to side effects. Prior nonhormonal options involved antidepressants, which were discovered when used to treat depression in menopausal patients and led to a reduction in hot flashes.

The use of antidepressants for the treatment of VMS, alongside medications such as gabapentin, have off-target effects because of their primary use being for other conditions. For example, the use of antidepressants against hot flashes may lead to stomach, sexual, and mood side effects.

Gabapentin may also lead to dizziness and drowsiness. By focusing on the neurokinin receptor in the brain, fezolinetant avoids these adverse events. Current side effects linked to fezolinetant include headaches and nausea, with a rate of only 2% to 3%.

An increase in liver enzymes remains the most significant side effect associated with fezolinetant, with the FDA recommending liver function bemonitored up to 9 months in patients receiving the drug.

 However, this side effect has also only been reported in 2% to 3% of patients.

The FDA reported these risks after reviewing a postmarketing report detailing signs of liver injury in a patient after taking fezolinetant for approximately 40 days, recommending patients stop medication administration when symptoms of liver injury are present to avoid worsening the condition. This may allow liver function to return to normal.

According to the FDA, liver blood testing should be performed in patients every month for the first 2 months after starting fezolinetant, then at months 3, 6, and 9. Signs of liver problems include nausea, vomiting, unusual itching, light-colored stools, dark urine, jaundice, abdomen swelling, and right upper abdomen pain.

The FDA recommends health care professionals perform hepatic laboratory testing before prescribing fezolinetant to their patients. Additionally, patients should be warned about the risk of higher liver blood test values when they are prescribed fezolinetant.

Side effects are present in all medications when used correctly, as noted by the FDA. Individual risk will depend on patient health, diseases, other medications, and additional factors. Healthcare professionals may need to determine the individual risk of liver injury in their patients receiving fezolinetant.

This data highlights the potential of fezolinetant and other NK3 receptor antagonists in patients with breast cancer or blood clots, who are unable to receive hormonal therapy.

 Fezolinetant is best for patients who report hot flashes as their sole symptom of concern, while hormones may be the preferred option in patients with additional symptoms such as vaginal dryness.

In the future, additional compounds will be released that target the neurokinin receptor in the brain, increasing options for patients with medications that are contraindicated by fezolinetant. This highlights significant progress in non-hormonal menopause management.

“Many women still really face significant symptom burden, because there’s limitations in treatment tolerability, efficacy, and access,” said JoAnn Pinkerton, MD, a professor of obstetrics and gynecology at the University of Virginia.

 “And as such there remains a pressing need for more effective and safe treatment options for menopausal vasomotor symptom management."

Krewson C. JoAnn Pinkerton discusses elinzanetant's crucial role in VMS therapy. Contemporary OB/GYN. October 11, 2024. Accessed December 5, 2024.

https://www.contemporaryobgyn.net/view/joann-pinkerton-discusses-elinzanetant-s-crucial-role-in-vms-therapy

Fitch J. Nanette Santoro, MD: Vasomotor symptoms, treatment, and potential of elinzanetant. Contemporary OB/GYN. September 12, 2024. Accessed December 9, 2024.

https://www.contemporaryobgyn.net/view/nanette-santoro-md-vasomotor-symptoms-treatment-and-potential-of-elinzanetant

Krewson C. How fezolinetant advances non-hormonal treatment of hot flashes. Contemporary OB/GYN. December 6, 2024. Accessed December 9, 2024. 

https://www.contemporaryobgyn.net/view/how-fezolinetant-advances-non-hormonal-treatment-of-hot-flashes

FDA approves novel drug to treat moderate to severe hot flashes caused by menopause. May 12, 2023. Accessed December 17, 2024. 

https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause

FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. US Food and Drug Administration. September 12, 2024. Accessed December 17, 2024. 

https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes

Articles

Elinzanetant and fezolinetant are emerging as promising non-hormonal treatments for vasomotor symptoms (VMS) in menopausal women, offering significant advancements in menopausal health. Elinzanetant, a dual neurokinin receptor antagonist, has shown efficacy in reducing VMS frequency and severity, with the FDA accepting its New Drug Application in 2024. Fezolinetant, another NK3 receptor antagonist, has been FDA-approved since 2023, significantly reducing hot flash frequency and severity. These treatments provide alternatives for women unable or unwilling to use hormonal therapies, addressing a critical need in menopausal care.

Neurokinin-3 receptor antagonists such as elinzanetant and fezolinetant provide non-hormonal options for managing hot flashes linked to menopause.

2024 Brings Change, New Hope for Nonhormonal Management of Menopause

Pinkerton reflects on the breakthrough approval for the non-estrogen, non-hormonal daily oral drug earlier this year.

Fezolinetant Changes Menopause Management, with JoAnn Vensko Pinkerton, MD

Earlier this year, the US Food and Drug Administration (FDA) approved fezolinetant (Veozah) for the treatment of moderate to severe vasomotor symptoms associated with menopause. The indication granted to Astellas Pharma in May marked the first neurokinin 3 receptor antagonist to reach the market for managing menopausal hot flashes.

Reaction to the once-daily oral drug’s breakthrough approval among OB/GYN specialists was resonant of excitement for a novel mechanism of care to treat hot flashes—and relief for the market’s long-awaited expansion to include options like fezolinetant.

assistant editor Celeste Krewson for This Year in Medicine 2023, JoAnn Vensko Pinkerton, MD, professor of obstetrics and gynecology at the University of Virginia and a credential menopause specialist with The Menopause Society, discussed the impact of fezolinetant’s FDA approval on menopause treatment. Chief among Pinkerton’s takeaways were the non-estrogen, non-hormonal makeup of fezolinetant—as well as her own personal experiences in prescribing the therapy.

Fezolinetant and Krewson additionally review the pivotal data from the SKYLIGHT trial program supporting fezolinetant, as well as anticipation for long-term utility and rollout of the agent to real-world patients in 2023 and beyond.

Petronelli M. FDA approves fezolinetant for vasomotor symptoms. 

Published May 12, 2023. https://www.contemporaryobgyn.net/view/fda-approves-fezolinetant-for-vasomotor-symptoms

Petronelli M. 'It's about time,' fezolinetant approval and latest research showcased at annual meeting. 

Published online May 19, 2023. https://www.contemporaryobgyn.net/view/-it-s-about-time-fezolinetant-approval-and-latest-research-showcased-at-annual-meeting

Videos

Editor's note: This article originally appeared on 

Norgestrel (Opill; HRA Pharma) gained approval as the first nonprescription daily oral contraceptive by the US Food and Drug Administration (FDA) for preventing pregnancy.

“Today’s approval marks the first time a nonprescription daily oral contraceptive will be an available option for millions of people in the United States,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.

There are 6.1 million pregnancies annually in the US, of which about 50% are unintended. Adverse outcomes of unintended pregnancies include negative maternal and perinatal outcomes, such as increased preterm birth risk and decreased odds of receiving early prenatal care.

Individuals seeking contraception will be able to access norgestrel without consulting a health care provider, reducing barriers to contraception access. This may reduce the prevalence of unintended pregnancies and associated adverse outcomes.

"Of all the developed nations in the world, the US has the 

," Michael Aziz MD, MPH, maternal-fetal medicine specialist and member of the State Liaison Network for the Society for 

. "That's only gone up with the current COVID-19 pandemic."

Still, before the pandemic, the dangers of pregnancy were rising, showing disproportionate disparities. 

 are much higher than those observed in Caucasians. In addition to this, pregnancy can bring about potentially fatal obstacles for those with chronic conditions.

In 1973, norgestrel received FDA approval for prescription use, highlighting its contraceptive efficacy. The manufacturer, HRA Pharma, later applied for norgestrel to become an over-the-counter method of contraception. This required proof of safety and efficacy when used by consumers without support from a healthcare professional.

Research on norgestrel showed a significant percentage of consumers were capable of comprehending information on the Drug Facts label. Proper use of norgestrel is safe and effective, indicating it can be used as an over-the-counter product.

Efficacy of norgestrel is achieved when the product is used at the same time once daily, with efficacy decreasing if patients use medications that interact with norgestrel. Common side effects include dizziness, headaches, nausea, irregular bleeding, abdominal pain, cramps or bloating, and increased appetite.

"Today's approval is a groundbreaking expansion for women's health in the US, and a significant milestone towards addressing a key unmet need for contraceptive access," Frederique Welgryn, Perrigo Global Vice President for Women's Health said in a 

. "Perrigo is committed to making Opill, which is now the most effective method available OTC at preventing pregnancy, accessible and affordable to women and people of all ages.”

Norgestrel is not effective as emergency contraception and should not be used in patients with breast cancer or breast cancer history. It also should not be used alongside other hormonal birth control products, and use should be discontinued if pregnancy has been confirmed.

HRA Pharma will determine the price and availability timeline of norgestrel. Consumers will be able to purchase the product at convenience stores, grocery stores, drug stores, and online.

FDA approves firstnonprescription daily oral contraceptive. July 13, 2023. Accessed July 13, 2023. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-nonprescription-daily-oral-contraceptive

Grossi G. Michael Aziz, MD: Abortion Reduces Risk of Death. HCPLive. June 24, 2022. https://www.hcplive.com/view/michael-aziz-md-abortion-reduces-risk-of-death

Grossi G. Maternal Mortality Rates Highlight Alarming Inequities by State, Race/Ethnicity. HCPLive. July 3, 2023. https://www.hcplive.com/view/maternal-mortality-rates-alarming-inequities-state-race-ethnicity

Perrigo Announces U.S. FDA Approval for Opill® OTC Daily Oral Contraceptive. News Release. July 13, 2023. https://investor.perrigo.com/2023-07-13-Perrigo-Announces-U-S-FDA-Approval-for-Opill-R-OTC-Daily-Oral-Contraceptive

Individuals seeking contraception will be able to access norgestrel without consulting a health care provider, reducing barriers to contraception access.