The FDA's Boxed Warning for Liver Injury
Following a review of postmarketing data, the U.S. Food and Drug Administration (FDA) added a Boxed Warning—the most serious type of warning—to the prescribing information for Veozah (fezolinetant). This decision, announced in December 2024, followed a specific case of severe drug-induced liver injury that occurred within 40 days of a patient starting the medication. The patient experienced a significant elevation in liver enzymes and bilirubin levels, along with symptoms such as fatigue, nausea, and jaundice. The patient's symptoms and liver values gradually returned to normal after discontinuing Veozah.
The Importance of Regular Liver Monitoring
To mitigate the risk of serious liver injury, the FDA has issued new recommendations for liver function monitoring during Veozah treatment. Healthcare providers must order specific hepatic laboratory tests at baseline and at intervals during the first year of treatment. This schedule includes testing before starting treatment, and then monthly for the first three months, and again at months six and nine.
How to Recognize Liver Problems
Patients on Veozah must be vigilant for signs and symptoms that could indicate a liver problem. The FDA advises patients to immediately stop taking the medication and contact their healthcare provider if they notice any of the following:
- New or worsening fatigue: Feeling more tired than usual.
- Nausea and vomiting: Unexplained or persistent stomach upset.
- Unusual itching: Itching without a rash.
- Jaundice: Yellowing of the skin or the whites of the eyes.
- Dark urine: Urine that is a darker color than normal.
- Pale stools: Feces that are lighter in color than usual.
- Abdominal pain: Pain in the right upper abdomen.
If these symptoms occur, a doctor will perform blood tests to assess liver function and determine if it is safe to continue the treatment.
Comparing Liver Risks: Veozah vs. Placebo in Clinical Trials
During clinical trials for Veozah, the incidence of elevated liver enzymes was higher in patients taking Veozah compared to those taking a placebo, though no serious liver injury was reported during this phase. A comparison of these findings is shown below.
| Adverse Event | Veozah (45 mg) | Placebo |
|---|---|---|
| Incidence of Elevated Hepatic Transaminases (>3x ULN) | 2.3% of patients (n=1100) | 0.9% of patients (n=952) |
| Incidence Rate (per 100 person-years) | 2.7 | 1.5 |
| Asymptomatic Elevations | Yes, elevations generally returned to baseline with or without continuation of treatment. | Yes |
| Elevated Bilirubin (>2x ULN) | No elevations observed in clinical trials. | No elevations observed in clinical trials. |
Veozah and Pre-existing Liver Conditions
Due to the risk of hepatotoxicity, Veozah is contraindicated in women with known cirrhosis. This precaution is in place because Veozah's metabolism can be affected by liver function. Studies have shown increased drug exposure in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. For this reason, the medication has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). A doctor will carefully evaluate a patient's liver health before prescribing Veozah and may opt for an alternative treatment if liver problems are present.
Drug Interactions Affecting Liver Health
Veozah is primarily metabolized in the liver by the enzyme CYP1A2. Certain medications, known as CYP1A2 inhibitors, can interfere with this metabolic process. When taken with Veozah, these inhibitors can increase the concentration of fezolinetant in the blood, potentially increasing the risk of adverse effects, including liver-related issues. Due to this risk, concomitant use with CYP1A2 inhibitors is a contraindication for Veozah. Examples of CYP1A2 inhibitors include:
- Fluvoxamine (used to treat obsessive-compulsive disorder)
- Ciprofloxacin (an antibiotic)
- Cimetidine (a medication for ulcers and heartburn)
Patients should provide a complete list of all medications and supplements to their healthcare provider to screen for potential interactions before starting Veozah.
Conclusion: Balancing Benefits and Risks
While Veozah offers a nonhormonal option for treating moderate to severe menopausal hot flashes, the potential for rare but serious liver problems cannot be overlooked. The FDA's Boxed Warning emphasizes the need for careful monitoring and patient education. Adherence to the recommended liver function testing schedule and prompt communication with a healthcare provider about any potential liver-related symptoms are essential for safely managing treatment. Ultimately, the decision to use Veozah involves weighing its benefits against the risks, in close consultation with a medical professional, particularly for those with pre-existing liver conditions.
