Fezolinetant Guidelines and Emerging Data on Menopause and Liver Health
Panelists discuss why a warning about serious liver injury was added to the prescribing information for fezolinetant following a postmarketing case of drug-induced liver injury, and review updated guidelines for baseline liver testing, recommended monitoring, symptoms indicating the need to discontinue the medication, and key points for addressing patient concerns about liver health.
Episode 4
The following transcript has been edited for clarity, style, and length.
Mary Jane Minkin, MD: Lisa, let’s discuss fezolinetant, its clinical trials, and the side effects we know about. It’s officially not recommended for women with cirrhosis or severe liver disease due to concerns about liver involvement.
Before initiating fezolinetant, women are advised to undergo baseline liver function tests (LFTs), including AST, ALT, and bilirubin. The initial recommendation required AST and ALT levels to be less than twice the upper limit of normal to proceed. During clinical trials, a small number of women developed liver function abnormalities, leading to the recommendation of follow-up LFTs at 3, 6, and 9 months after starting therapy.
Some women discontinued the medication due to abnormal LFTs, but their levels eventually normalized. Others continued the medication without further issues. However, there was a recent post-marketing case where a woman developed cholestatic liver problems, including clinical signs of jaundice and GI symptoms. After discontinuing fezolinetant , her condition improved.
This incident prompted updated guidelines: LFTs should be done at baseline, monthly for the first 3 months, then at 6 and 9 months. These changes are designed to catch potential issues early. Lisa, as an internist, what are your thoughts on this?
Lisa Larkin, MD: This is an important topic. In the pivotal trials that led to fezolinetant’s approval, liver function abnormalities were closely monitored, as is standard with new drug classes. Initially, the guidelines required baseline and periodic LFTs, but as you mentioned, the monitoring protocol has since been updated.
From my conversations with OB-GYN colleagues, the need for frequent monitoring was a concern when this medication launched. OB-GYNs typically don’t see patients every 3 months or routinely monitor levels like internists do. For us, sequential LFT monitoring is a familiar practice.
As often happens, we learn more about a drug post-approval. The post-marketing case of significant LFT and bilirubin elevations led to modifications in the package insert. Now, monitoring includes baseline tests, monthly checks for the first 3 months, and then at 6 and 9 months. The patient in this case improved after discontinuing the medication, but this highlights the need for continued pharmacovigilance.
Minkin: Exactly. Thus far, in the trials for another neurokinin-3 antagonist, elinzanetant, there haven’t been significant liver function abnormalities. From my understanding, Lisa, the liver concerns with fezolinetant seem to stem from the molecule itself rather than the receptor activity. Do you agree?
Larkin: Yes, that aligns with the data. The liver issues appear intrinsic to the chemical structure of fezolinetant rather than its mechanism of action at the neurokinin-3 receptor. While this doesn’t diminish the importance of monitoring, it’s encouraging that similar drugs in this class might not carry the same risks.
