FDA Adds Black Box Warning to Fezolinetant Label, Advising of Rare but Serious Liver Injury

On December 16, the FDA added a boxed warning for rare but serious liver injury to product labeling for fezolinetant (Veozah; Astellas), an oral neurokinin-3 receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms (VMS) of menopause.

The boxed warning, the agency’s most prominent alert to prescribers and patients, increases the prominence of warnings added in September on hepatotoxicity that included requirements for increased frequency of LFT testing after initiating fezolinetant treatment.

In the Drug Safety Communication issued on September 16, the agency described details of a postmarketing report submitted to its Adverse Event Reporting System of a woman who experienced elevated LFT values and related signs and symptoms of hepatic injury within 40 days of beginning treatment with fezolinetant.

The patient’s laboratory values indicated an alanine transaminase (ALT) level more than 10 times normal, an alkaline phosphatase level more than 4 times normal, and her total bilirubin measured 3 times the average level. The primary symptoms reported were fatigue, nausea, itching, yellowed eyes and skin, light-colored stool, and dark urine. The FDA confirmed that symptoms gradually resolved and LFT values slowly normalized after fezolinetant treatment was discontinued.1

Fezolinetant was approved by the FDA as the first non-hormonal treatment for vasomotor VMS associated with menopause in May 2023. The brain’s thermoregulatory center is regulated through a balance between estrogen and neurokinin B, a balance that is disrupted by the decline in estrogen levels during menopause. The imbalance causes the well-known vasomotor symptoms experienced by many women that include hot flashes and night sweats. Fezolinetant helps restore the balance by blocking neurokinin B in the temperature control center.

Original Fezolinetant Label

The original label approved by the FDA included a warning regarding the risk of elevated hepatic transaminase that indicated concentrations 3 times the upper limit of normal (ULN) had been observed during clinical trials of fezolinetant. It called for clinicians to evaluate hepatic function and injury before initiating treatment. Therapy was contraindicated in any person with serum transaminase levels equal to or greater than 2 times ULN.2

The FDA-approved prescribing information recommended follow-up testing of ALT at 3, 6, and 9 months after initiating treatment.2According to the FDA safety communication, the agency “added new recommendations…about increasing the frequency of liver blood testing, adding monthly testing for the next 2 months after starting [fezolinetant], and then at months 3, 6, and 9 of treatment as already recommended. The updated prescribing information also instructs patients to stop the medicine immediately and contact the health care professional who prescribed the medicine if signs and symptoms of liver injury occur.1

"It’s important to note that the overall benefit-risk of Veozah has not changed and remains positive, but we want to further ensure that patients and healthcare providers are aware of the potential side effects of [fezolinetant], and the hepatic laboratory testing, as it relates to its benefit to help reduce moderate to severe vasomotor symptoms (VMS) due to menopause," Astellas said in a statement. “We remain confident in the overall safety profile of Veozah and its ability to provide appropriate patients with a nonhormonal treatment option for moderate to severe VMS due to menopause.”

Menopausal hormone therapy with combined estrogen and progestogen, or estrogen alone, is effective for symptom management. Many women, however, cannot or choose not to take the medications to ameliorate menopause-related VMS and for some the products are contraindicated.

References
1. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. FDA Drug Safety Communication. FDA. September 16, 2024. Updated December 16, 2024.Acessed December 20, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due