FDA recommends removing black box warning for CV risk from all testosterone product labels
Key takeaways:
- The FDA stated a warning about adverse CV outcomes with testosterone therapy can be removed based on data from the TRAVERSE trial.
- The agency also recommended adding a new warning about increased BP risk.
The FDA has recommended several labeling changes to all approved testosterone replacement therapy products based on the agency’s review of several studies, according to a release.
Among the labeling changes, the FDA recommended removing language from the black box warning of all testosterone products that stated testosterone therapy could lead to increased risk for adverse cardiovascular outcomes. As Healio previously reported, findings from the TRAVERSE trial revealed the percentage of men with hypogonadism who received transdermal 1.62% testosterone gel (AbbVie) had a similar risk for a major adverse CV event as those receiving placebo. The FDA cited the TRAVERSE trial in its labeling change and recommended adding the TRAVERSE results to testosterone products. The agency also recommended retaining limitation of use language for age-related hypogonadism.
In a company press release, Marius Pharmaceuticals said the FDA’s decision to remove the increased risk for adverse CV outcomes from the black box warning will shift the conversation about testosterone therapy from safety to its benefits.
“For years, patients have been unduly apprehensive about testosterone replacement therapy due to the black box warning, leading many to avoid a treatment that could significantly improve their health,” Shalin Shah, CEO of Marius Pharmaceuticals, said in a release. “With the removal of this warning, patients and providers can finally have an informed, evidence-based discussion about the true benefits and risks of testosterone replacement therapy. This positive shift will also accelerate Marius Pharmaceuticals’ research into additional therapeutic uses of testosterone.”
The FDA is also requiring the addition of a new warning for testosterone products regarding a risk for increased blood pressure. According to the agency’s announcement, the decision was made based on the findings of postmarket ambulatory BP studies. In March 2018, the FDA issued a requirement that postmarket ambulatory BP studies should be conducted for all testosterone products. According to the agency’s release, results from completed studies found testosterone products class-wide are tied to increased BP.
Product-specific information on increased BP must be added to testosterone labels if the product has completed its postmarket ambulatory BP study, according to the FDA.
In a press release, The Androgen Society said it welcomed the FDA’s changes to product labeling, stating the recommendations aligned with a position statement the society released on CV safety with testosterone therapy that was published in Mayo Clinic Proceedings in November.
“It is important to note that long-term studies including TRAVERSE, T4DM and the T Trials have not demonstrated BP increases at periods of 1 year or greater,” the society said in a press release. “The Androgen Society acknowledges that these findings warrant careful consideration in the implementation of BP-related labeling changes.”
References:
- Marius Pharmaceuticals helps drive FDA’s landmark testosterone label update, removing black box warning. https://www.globenewswire.com/news-release/2025/03/03/3035638/0/en/Marius-Pharmaceuticals-Helps-Drive-FDA-s-Landmark-Testosterone-Label-Update-Removing-Black-Box-Warning.html. Published March 3, 2025. Accessed March 3, 2025.
- The Androgen Society Endorses FDA's Class-Wide Labeling Changes for Testosterone Products. https://www.androgensociety.org/newsletter/press-release-march-2025. Published March 5, 2025. Accessed March 10, 2025.
Perspective
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I am pleased that the FDA cited the TRAVERSE trial with their label modifications. This was a very difficult trial to complete, and I think the results are reliable enough to conclude that there is not a major increase in cardiovascular risk with testosterone replacement therapy. However, the trial should not be overinterpreted.
There are many men obtaining testosterone outside of the parameters that we studied. We enrolled men with documented hypogonadism, defined as two testosterone levels of less than 300 ng/dL on 2 different days with symptoms associated with low levels. Trial participants were treated with one type of testosterone, transdermal 1.62% testosterone gel (AbbVie), and they were carefully titrated to raise levels into the normal range. If they went increased to above the upper limit of normal, they were back-titrated. If they reached the lowest dose and had polycythemia or other issues, then they were discontinued. That's not how testosterone is used widely. Often, it's used for men who maybe don't feel like they have the energy or the sexual performance that they had when they were 18 years old, regardless of their testosterone levels.
While I think the FDA was prudent in removing the boxed warning about increased risk for adverse CV outcomes, I am not certain if our results apply to all products. Some of the injectables may have peaks and valleys of levels, so they may have a very different kind of adverse effects.
I also want to caution that testosterone should generally not be used outside of the boundaries of what was studied in our trial. There are other adverse effects, such as an increased risk for fractures and atrial arrythmias. These adverse effects must be considered when deciding whether or not to treat a patient with testosterone.
I also agree with FDA's decision to warn about blood pressure increases. That has been observed primarily with injectable testosterone; several of the products have shown clinically important BP increases. I was also pleased that FDA is now requiring ambulatory BP monitoring be performed for new testosterone products.
The TRAVERSE trial should not be considered definitive, and I think more studies are needed. I don’t think they will be done, given the fact that so many of these products are generic. We knew we had one shot at this with the TRAVERSE trial and we did our best to get a reliable answer.
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