FDA Issues Boxed Warning for Fezolinetant Over Rare but Serious Liver Injury Risk

The FDA added a boxed warning for risk to fezolinetant (Veozah; Astellas Pharma US, Inc), which is the most prominent warning the agency can add to a drug. The agency warns that use of this hormone-free oral medication to control hot flashes caused by menopause is associated with significant risk for rare, serious liver injury. Pharmacists, health care providers, and patients are urged to take precautions, including regular liver blood testing, to monitor and mitigate potential risks.¹

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On September 12, 2024, the FDA issued an initial safety warning about fezolinetant prompted by a post-marketing report of a patient who experienced significant liver injury after taking the drug for approximately 40 days. According to the report, the patient had significantly elevated blood liver test values, as well as increased alanine transaminase levels exceeding 10 times the normal level, alkaline phosphatase levels exceeding 4 times the normal level, and total bilirubin levels exceeding 3 times the normal level. The patient reported experiencing symptoms including fatigue, nausea, itching, yellowing of the eyes and skin, light-colored stools, and dark urine, which are prominent signs of liver dysfunction. After discontinuing the medication, the patient's symptoms resolved and liver function normalized.^1,2

To enhance patient safety, the FDA has updated fezolinetant’s prescribing information to include hepatotoxicity based on results from 3 clinical trials, as well as the post-marketing reports made by patients. In the trials, investigators reported elevations in serum transaminase levels (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) 3 times over the normal limit (ULN) in 2.3% of women receiving fezolinetant, with an exposure-adjusted incidence rate (EAIR) of 2.7 per 100 person-years. Comparitively, in the placebo group, only 0.9% of women experienced such elevations, with an EAIR of 1.5 per 100 person-years.³

In these trials, there were no cases of serum total bilirubin above 2 times ULN observed. Women with elevated ALT or AST levels were typically asymptomatic, and their liver enzyme levels returned to or near pretreatment levels with continued treatment, dose interruption, or discontinuation. It is important to note that women with cirrhosis were not included in these trials.³

To mitigate these risks, the FDA requires baseline hepatic laboratory tests before initiating fezolinetant. This includes assessments of ALT, AST, alkaline phosphatase, and both total and direct bilirubin. Treatment should not begin in patients with ALT or AST levels at or above 2 times ULN or total bilirubin levels at or above 2 times ULN. Monthly liver function testing is mandatory during the first 3 months of therapy, followed by additional testing at 6 and 9 months.^2,3

Health care providers should discontinue the medication in cases of transaminase levels exceeding 5 times ULN or when transaminase elevations exceed 3 times ULN accompanied by total bilirubin levels exceeding 2 times ULN. It is crucial for patients to immediately stop taking fezolinetant and consult their health care provider if they experience any signs of liver damage.³

REFERENCES

1. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. FDA. December 16, 2024. Accessed December 18, 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?utm_medium=email&utm_source=govdelivery

2. FDA adds boxed warning to hot flash drug. MedPage Today. December 17, 2024. Accessed December 18, 2024. https://www.medpagetoday.com/obgyn/menopause/113436

3. FDA. Highlights of prescribing information. December 16, 2024. Accessed December 18, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216578s004lbl.pdf