Black Box Warning Added to Fezolinetant

Don't panic, here's what you need to know

Astellas

The FDA recently added a black box warning to fezolinetant (Veozah), the neurokinin-3 receptor antagonist that treats hot flashes and night sweats. Should people be concerned?

Let’s discuss.

Before we begin, check out this previous post if you want a review on fezolinetant.

What is a Black Box Warning?

This is a prominently displayed warning added to the labeling of a pharmaceutical associated with serious adverse reactions. It does not mean that the adverse reaction is common or that a cause-and-effect connection with the drug has been proven; it means there is a reasonable chance that a connection between the drug and the adverse reaction exists, and given the severity of the reaction, it’s important enough to emphasize.

Black box warnings are usually added after a drug has been approved and is out in the world. This is because most adverse reactions that lead to these warnings are typically uncommon and unlikely to be identified in the original studies used to approve the drug. The FDA has a system to identify these reactions, which worked here and that we’ll review shortly.

The most common reason for a black box warning is drug-related hepatoxicity or liver injury, which is the case here with fezolinetant.

It’s important to add that some black box warnings are ridiculous, which is unfortunate as that can lead to distrust of the system. The best example is vaginal estrogen. With systemic estrogen, there are potentially serious, albeit rare, risks with systemic use; not one study has shown these same risks with vaginal estrogen, yet frustratingly they carry the same black box warning as systemic estrogens.

What the FDA Announced Re: Fezolinetant

The black box warning about liver injury with fezolinetant was added because of a single case where the FDA concluded fezolinetant was the cause. A woman had been taking the medication for about 40 days when she developed signs and symptoms of liver injury and significantly elevated liver blood test values, confirming liver injury. The drug was stopped, her liver tests returned to normal, and she recovered.

The fact that fezolinetant could negatively affect the liver is not news because this risk was previously identified in the studies that led to FDA approval–2.3% of people who took the drug developed elevated liver enzymes (meaning 97.7% of people did not) versus 0.8% who took the placebo. These changes reverted to normal when the drug was stopped, so there was no permanent damaging effect. This was why the package labeling previously recommended checking liver enzymes before prescribing the medication and again at 3, 6, and 9 months into therapy and why people with liver disease shouldn’t take the drug.

Because of this new case, in addition to the black box or prominent nature of the warning, the latest recommendations for liver testing are an additional test at 1 and 2 months in addition to the previous testing before starting therapy and at 3, 6, and 9 months into treatment.

Here is the new language in the black box at the front of the package insert:

The language in the Canadian package insert has also changed accordingly.

Wait, This is From a Single Case?

Yes, yes, it is. This is how seriously the FDA takes drug safety. As liver injury is one of the most common severe drug reactions, the FDA has become more liberal in both issuing black box warnings and withdrawing drugs from the market due to liver-related concerns. This is believed to be the reason for the decline in pharmaceutical-related liver injury (a good thing!). In a recent review of medication-related liver failure requiring liver transplantation, all of the pharmaceuticals implicated were older medications, suggesting the newer, stricter approach to liver safety is protecting patients. The earlier healthcare professionals know to screen for the potential risk of liver injury, the sooner they can intervene when there’s an issue, preventing serious consequences, as the liver has a remarkable capacity for regeneration.

With fezolinetant, the black box warning doesn’t mean the drug is unsafe; it means that people taking the medication need to be monitored and that the system for drug safety works. It’s a shame that the press chooses inflammatory language such as the FDA “slapped a black box warning” on fezolinetant or the “FDA places its most serious warning on menopause drug due to risk fo liver injury.”

It’s worth noting that the press rarely gives the same attention to severe cases of liver injury related to supplements. For example, I recently reviewed a case of severe liver injury due to Nutrafol, which I wrote about here, or the fact that supplements are a rising cause of liver failure, which I wrote about in this post. Some estimates suggest supplements may cause up to 43% of drug-induced liver injury in the United States and 19% of drug-induced acute liver failure.

As a single case of liver injury led to a black box warning for fezolinetant, I would encourage people to consider that if the FDA regulated turmeric supplements or Nutrafol, they would also have black box warnings about liver injury, so you should treat them as if they do. In fact, lots of supplements likely deserve black box warnings, but as they have never been tested in a scientifically rigorous fashion and have no FDA approval process or post-marketing surveillance, you, the consumer, have no idea about the risk. Since my post about Nutrafol, I have heard from two people who developed abnormal liver enzymes while taking it. Has there been one case of liver injury or thirty or hundreds? With fezolinetant, I can tell you 2.3% of people will get elevated liver enzymes; with turmeric or Nutrafol or any other supplement, I can’t tell you if it is 2.3% or 23%. This is how supplements get a false image of being safer because the lack of regulation does not mean more cases of liver injury haven’t happened; there is just no standard means of reporting and tracking.

Understanding the Process of FDA Approval and Drug Safety

This is important to review because it shows how much thought and safety goes into drug development versus supplements, which have none of this testing or follow-up. Promoting supplements as supposedly safer is so egregiously false. By definition, a supplement cannot be safer because it is untested in any meaningful and rigorous way. Even when a concern is raised, there is no accountability, and nothing can be done because there is no package insert to alter or approval to revoke. Occasionally, criminal charges are filed against the manufacturer when someone dies.

The first step towards approval for a pharmaceutical is animal toxicity studies, which help a manufacturer determine whether the molecule is safe enough for human testing. These studies also provide basic information about dosing and reproductive risks and highlight any specific safety areas, such as the kidneys or the liver. When a molecule is unsafe, a company will not invest time and money in further development.

When animal studies are successful, a pharmaceutical company (typically known as the sponsor) files an investigational new drug application (IND) with the FDA. The FDA reviews the application to ensure the product meets basic safety requirements for human testing. At this point, the candidate molecule becomes an IND.

The next step is a series of clinical trials, beginning with phase 1 studies, which are safety studies. These studies determine what dose people can tolerate without getting sick or causing harm. They also provide information about how the body metabolizes the drug. Phase 1 studies may use healthy volunteers, but sometimes, they are patients with the medical condition the drug will hopefully treat.

Phase 2 clinical trials come next, and they test the dosing in patients with the medical condition, looking at both effectiveness and safety/side effects. These studies often involve hundreds of patients.

When a drug sponsor feels the phase 2 studies warrant taking the next step, they meet with the FDA to determine the best approach for phase 3 studies, which are larger and typically involve thousands of patients. Phase 3 studies should ultimately prove the best dose that balances effectiveness and safety. As they are costly and time-consuming, it is in the drug sponsor’s best interest to ensure they can answer the right questions with this work and not endanger any participants. The drug company does not want to be in the position where the FDA looks at the phase 3 data and is concerned that questions weren’t answered adequately and requests more studies to consider the drug.

When the phase 3 studies are complete, the drug’s sponsor submits a new drug application (NDA) to the FDA, which decides if the drug has an acceptable safety profile, if it works for its intended purpose, and if the benefits outweigh the risks. The FDA must approve the labeling and package insert to ensure they are clear about directions, risks, and drug interactions, and the FDA reviews the plan for manufacturing so the drug will be produced in a way that ensures it is the right strength and free from contaminants. Approximately 7% of drugs in phase 1 and 15% in phase 2 eventually get FDA approval, and there are various reasons they don’t all make it, ranging from the molecule proving too unsafe to a financial decision.

Sometimes, the drug may be effective, but there are some lingering safety concerns or even just theoretical safety concerns. In this situation, the FDA requires a risk management plan, such as post-marketing surveillance (often called phase 4 studies) or a risk evaluation and mitigation strategy (REMS), which is essentially an enhanced monitoring and safety plan.

There is also a post-marketing safety program for reporting severe adverse reactions, called MedWatch, that applies to every pharmaceutical. The information is in the fezolinetant package insert.

The FDA was alerted to the liver injury case regarding fezolinetant through MedWatch. (MedWatch also applies to dietary supplements, although, unlike pharmaceuticals, the FDA can only send a tersely worded letter about a supplement.) The FDA encourages anyone who thinks they have had an adverse reaction to a drug to ask their healthcare provider to complete the form, but anyone can fill it out (the form can be found here).

Summing it All Up

Please don’t panic about the black box warning for fezolinetant; it’s a reminder for both prescribers and the public about the risk, specifically that liver changes can occur sooner than expected; hence, blood monitoring should change accordingly. This is a sign that the drug safety system works. People should be reassured that the overall risk of abnormal liver tests with fezolinetant is low (2.3%), and we have this data because of quality randomized controlled trials.

Whenever we talk about liver injury, it’s important also to mention alcohol because women aged 40 years and older are at greater risk of alcohol-related liver injury. Even four drinks a week can result in a change in liver enzymes, and seven drinks a week increases the risk of cirrhosis, which is severe scarring of the liver. There is no recommendation to avoid alcohol with fezolinetant (alcohol isn’t mentioned in the information sheet) handout), assuming normal liver tests, of course.

In light of the recent case of liver injury associated with the supplement Nutrafol, this black box warning for fezolinetant also shows us how none of the checks and balances for medication safety exist for supplements.

References

Murphy S, Roberts R. ‘‘Black box’’ 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk. Allergy Clin Immunol 2006;117:34-9.

FDA Communication regarding Fezolinetant https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due#:~:text=FDA%20is%20warning%20that%20Veozah%20(fezolinetant)%20used%20to%20treat%20moderate,return%20liver%20function%20to%20normal

Fezolinetant Package Insert, United States, Updated 12/2024 https://www.astellas.com/us/system/files/veozah_uspi.pdf

Ghabril, Marwan; Ma, Jiayi; Patidar, Kavish R.; Nephew, Lauren; Desai, Archita P; Orman, Eric S; Vuppalanchi, Raj; Kubal, Shekhar; Chalasani, Naga. Eight‐Fold Increase in Dietary Supplement–Related Liver Failure Leading to Transplant Waitlisting Over the Last Quarter Century in the United States. Liver Transplantation 28(2):p 169-179, February 2022. | DOI: 10.1002/lt.26246

Dugal J, Malhi A, Singh Y, Hsu M, Gill A, Patel P, Tun KM. Nutrafol's Hair Gains and Liver Strains. The American Journal of Gastroenterology 119(10S):p S2733-S2734, October 2024. | DOI: 10.14309/01.ajg.0001046328.13395.e1

Lombardi N, Crescioli G, Maggini V, et al. Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports. Br J Clin Pharmacol. 2021; 87: 741–753. https://doi.org/10.1111/bcp.14460

Niemelä O, et. al. Where should the safe limits of alcohol consumption stand in light of liver enzyme abnormalities in alcohol consumers? PLoS One. 2017; 12(12): e0188574.

Simpson, Rachel F et al. Alcohol drinking patterns and liver cirrhosis risk: analysis of the prospective UK Million Women Study. The Lancet Public Health, Volume 4, Issue 1, e41 - e48