FDA Warns of Liver Injury with Veozah for Hot Flashes

The FDA is warning patients about the risk of liver injury as a result of use of Astellas’ Veozah (fezolinetant), a medicine used to treat hot flashes due to menopause. The agency has included an additional warning to the prescribing information’s existing warning about elevated liver blood test values and is requiring additional liver blood testing.

The FDA had approved Veozah in May 2023 to treat moderate to severe vasomotor symptoms, or hot flashes, caused by menopause. It works by blocking the activities of the NK3 receptor, which plays a role in the brain’s regulation of body temperature.

FDA officials said in its safety notice that this update was made after reviewing a postmarketing report of a patient with elevated liver blood test values and signs and symptoms of liver injury after taking the medicine for about 40 days.

“We also added new recommendations for patients and healthcare professionals about increasing the frequency of liver blood testing, adding monthly testing for the 2 months after starting Veozah, and then at months 3, 6, and 9 of treatment as already recommended,” the FDA said.

The postmarketing case of liver injury was made to the FDA Adverse Event Reporting System database. The patient experienced symptoms of fatigue, nausea, itching, yellow eyes and skin, light-colored stools, and dark urine after starting Veozah. Liver blood test values were elevated, including abnormal liver enzymes and bilirubin levels, which returned to normal after stopping the medication.

“We are committed to ensuring the hepatic laboratory testing protocol in the Veozah U.S. prescribing information identifies patients at risk for or experiencing symptoms of potential drug induced liver injury as early as possible and therefore have added two additional timepoints for hepatic tests to the label, testing for an additional liver value, as well as guidance on when to seek medical attention and when to discontinue Veozah,” an Astellas spokesperson said.

“Patients are advised to discontinue Veozah immediately and seek medical attention including hepatic laboratory tests when signs or symptoms may suggest liver injury, such as new onset fatigue, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or right upper quadrant pain,” the spokesperson said.

The spokesperson said that hepatic safety is tested in clinical trials for all products. In the Veozah clinical trials, the frequency of elevated liver enzymes was low across groups, and elevations were generally asymptomatic, isolated, transient and resolved on treatment or soon after study drug discontinuation.

Recent studies (SKYLIGHT 1, SKYLIGHT 2 and SKYLIGHT 4) assessed Veozah use in Hispanic/Latina women with vasomotor symptoms related to menopause compared with White women. Pooled data from these two studies found that 3% of the 415 Hispanic/Latina women in the trials at 12 weeks and 7% of Hispanic/Latina women at 52 weeks experienced drug-related adverse events, but there was no cases of what is called Hy’s law, a rule of thumb that indicates drug-induced liver injury.

The pooled phase 3 data confirm the efficacy of Veozah in Hispanic/Latina women. These data were presented recently at The Menopause Society’s annual meeting.

A separate analysis also presented at The Menopause meeting found an association between Veozah and a different safety risk: increased neoplasm, or abnormal mass. Researchers analyzed data from publicly available FDA-Clinical Reviews of SKYLIGHT 1, SKYLIGHT 2 and SKYLIGHT 4. This analysis, led by Jonathan Douxfils, Ph.D., and his colleagues at the University of Namur in Belgium, found several cases of neoplasm associated with Veozah, including 1 case among patients receiving placebo, 6 cases in patients who received Veozah 30 mg and 11 cases in patients who received Veozah 45 mg. Events occurred from 11 days to 370 posttreatment.

The Kaplan-Meier analysis revealed a significant increase in the cumulative incidence of neoplasms with a hazard ratio (HR) for neoplasms of 3.63. (A hazard ratio greater than 1 indicates a potential for harm.)

The Astellas spokesperson said the totality of the current nonclinical, clinical data and postmarketing data from the fezolinetant development program do not support a signal for an increased risk of neoplasms.

Astellas and its researchers published a response to Douxfils’ analysis in The Lancet. They argue that Douxfils and his colleagues use a meta-analysis with Peto odds ratios, which some say can lead to biased and inconsistent results.

"Studies have shown that the Peto methodology is not appropriate for investigating rare events and is not an advocated default approach for meta-analyses. Given different study designs and exposure durations, combining the SKYLIGHT studies into a meta-analysis is also not recommended and could lead to flawed interpretations.”

A spokesperson for the FDA to Formulary Watch that prior to approving Veozah, the agency had thoroughly assessed the risk of neoplasms.

"Although a higher incidence of malignancies was seen in the Veozah-treated groups compared with the placebo group, FDA concluded that this imbalance was a chance finding and that there was no evidence of a causal relationship between Veozah and malignancy," the spokesperson said. "Based on the chronology of events provided, many cases of malignancy appeared to be pre-existing, with occurrence of the malignancies likely predating treatment with Veozah. There was also a lack of biological plausibility based on a comprehensive evaluation of nonclinical information available."

A consult review by the Officer of Surveillance and Epidemology found that neoplasms seen in the clinical studies occured less than 371 days after dosing with Veozah, involve multiple anatomic sites, and are associated with higher cancer incidence than placebo across individual studies and pooled study data.

This story has been updated to include information from the FDA.