The FDA has issued a black box warning, its most serious safety alert, for fezolinetant (Veozah; Astellas Pharma US, Inc.) due to the risk of rare but serious liver injury. This hormone-free oral medication is prescribed to manage hot flashes caused by menopause, and the FDA is urging healthcare providers and patients to take precautions, including regular liver blood testing.
The decision follows a post-marketing report of a patient experiencing significant liver injury after approximately 40 days of fezolinetant use. The patient exhibited markedly elevated liver enzyme levels, including alanine transaminase (ALT) 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. Symptoms included fatigue, nausea, itching, yellowing of the eyes and skin, light-colored stools, and dark urine, all indicative of liver dysfunction. Upon discontinuing the medication, the patient's symptoms resolved, and liver function normalized.
Clinical Trial Data and Hepatotoxicity
The FDA's updated prescribing information for fezolinetant now includes hepatotoxicity warnings based on clinical trial results and post-marketing reports. In three clinical trials, 2.3% of women receiving fezolinetant experienced elevations in serum transaminase levels (ALT and/or aspartate aminotransferase [AST]) exceeding three times the upper limit of normal (ULN), with an exposure-adjusted incidence rate (EAIR) of 2.7 per 100 person-years. In comparison, only 0.9% of women in the placebo group experienced similar elevations, with an EAIR of 1.5 per 100 person-years. No cases of serum total bilirubin exceeding two times ULN were observed in these trials. 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. The trials excluded women with cirrhosis.
Required Monitoring and Precautions
To mitigate the risk of liver injury, the FDA mandates baseline hepatic laboratory tests before initiating fezolinetant treatment, including assessments of ALT, AST, alkaline phosphatase, and total and direct bilirubin. Treatment is contraindicated in patients with ALT or AST levels at or above two times ULN or total bilirubin levels at or above two times ULN. Monthly liver function testing is mandatory during the first three months of therapy, followed by additional testing at six and nine months.
Recommendations for Healthcare Providers and Patients
Healthcare providers should discontinue fezolinetant if transaminase levels exceed five times ULN or if transaminase elevations exceed three times ULN accompanied by total bilirubin levels exceeding two times ULN. Patients are advised to immediately stop taking fezolinetant and consult their healthcare provider if they experience any signs of liver damage, such as fatigue, nausea, itching, yellowing of the eyes or skin, light-colored stools, or dark urine.
Context of Menopause Treatment
Fezolinetant, a neurokinin-3 receptor antagonist, was approved by the FDA in May 2023 as the first non-hormonal treatment for moderate to severe vasomotor symptoms (VMS) associated with menopause. It addresses the imbalance between estrogen and neurokinin B in the brain's thermoregulatory center, which is disrupted by declining estrogen levels during menopause, leading to hot flashes and night sweats. While menopausal hormone therapy is effective for symptom management, many women cannot or choose not to use hormone-based treatments.
