Liver Safety and Monitoring in VMS Treatment
Panelists discuss how fezolinetant and elinzanetant can cause liver-related adverse events requiring careful monitoring for drug-induced liver injury, noting that patients typically recover after discontinuation and emphasizing that primary providers are ideally positioned to manage patients with complex comorbidities.
Episode 5
The following transcript has been edited for clarity, style, and length.
Tara K. Iyer, MD: Let’s talk about the newer medications available and their side effects. A lot of discussion has surrounded the liver issues associated with fezolinetant. How does this compare with elinzanetant, and what do we need to counsel patients about?
Alexa Fiffick, DO, MBS, MSCP: Common side effects of these medications include headache, nausea, diarrhea, abdominal pain, and, less commonly, insomnia and worsening hot flashes. When counseling patients, I consider whether a side effect might exacerbate their existing symptoms or introduce new concerns.
Unlike SSRIs and SNRIs, which may cause weight gain, sexual dysfunction, or daytime drowsiness, these medications are more commonly linked to headache and gastrointestinal distress. This brings us to the liver concerns with fezolinetant, which appears more likely to cause liver enzyme elevations compared to elinzanetant. While both medications target similar receptors, their different molecular structures likely account for the differences in liver toxicity profiles.
Iyer: Absolutely. We’ll need to see how the FDA's recommendations shape baseline testing and ongoing liver function monitoring if elinzanetant gets approved. Data from trials like OASIS 1 and 2, as well as preliminary findings from the 2024 Menopause Society Conference, suggest a more favorable liver safety profile. This will influence how we counsel patients on potential risks.
That said, the most common concerns remain headache, fatigue, and GI disturbances. Like with any medication, we must weigh the risks and benefits. Given how disruptive hot flashes and night sweats can be, many patients are willing to try new options, even with the possibility of mild side effects.
For fezolinetant, current recommendations include liver function tests at baseline, followed by monitoring at months 1, 2, 3, 6, and 9 during the first year of treatment. If AST or ALT levels rise significantly, discontinuing the medication is advised. Do you have any additional considerations for baseline liver testing?
Fiffick: You covered it well. Checking AST, ALT, and alkaline phosphatase levels at baseline and throughout treatment is key. Notably, in fezolinetant trials, most patients who developed liver enzyme elevations saw full resolution after stopping the medication. The one severe case was an outlier. This reinforces the importance of baseline testing—especially for patients with preexisting liver conditions. If a patient already has liver dysfunction, alternative treatments might be a better starting point.
Iyer: I agree. It’s also crucial to distinguish whether enzyme changes stem from the medication or underlying conditions. Many perimenopausal and menopausal women experience metabolic shifts, including weight gain and adverse changes in lipid profiles, which increase their risk for fatty liver disease. For example, I had a patient on fezolinetant for a long time whose ALT and AST levels rose slightly. Because we had been monitoring her regularly, we knew her existing liver condition—not the medication—was the cause, so we opted to continue treatment while keeping an eye on her levels.
Fiffick: That’s a great point. This is another reason why primary care providers—family medicine and internal medicine physicians—are ideally suited to manage menopause care. As the quarterback of a patient’s health care team, primary care clinicians have the best overall perspective to assess whether symptoms stem from an underlying condition, another medication, or a new treatment. That broad viewpoint is invaluable in guiding treatment decisions.
