FDA issues label changes for testosterone products following TRAVERSE, post-market studies

The FDA has issued class-wide labeling changes for testosterone products based on findings from the phase 4 TRAVERSE trial (NCT03518034) as well as results from required post-market ambulatory blood pressure monitoring (ABPM) studies.¹

According to the FDA, the following changes are required based on data from the ABPM studies:

• “Adding product-specific information on increased blood pressure for testosterone products with completed ABPM studies;
• Adding a new warning about increased blood pressure for testosterone products which currently do not have such a warning in their labeling.”

Additionally, the agency is recommending the following changes based on findings from TRAVERSE:

• “Adding the results of the TRAVERSE trial to all testosterone products;
• Retaining “Limitation of Use” language for age-related hypogonadism; and
• Removing language from the Boxed Warning related to an increased risk of adverse cardiovascular outcomes for all testosterone products.”

These changes clarify several prior safety warnings for testosterone products, including a 2014 warning on the reported risks of stroke, heart attack, and death in men taking these products² and a 2015 decision requiring label changes to inform of possible risks when using testosterone products for low testosterone due to aging.³

“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,” said Shalin Shah, CEO of Marius Pharmaceuticals, in a news release from the company.⁴ “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].”

Testosterone is currently approved for men who lack or have low testosterone levels in conjunction with an associated medical condition.

Testosterone is currently approved for men who lack or have low testosterone levels in conjunction with an associated medical condition.

Premarket trials

The post-market ABPM studies were initiated following premarket studies in 2016 and 2017 that suggested testosterone products (administered via subcutaneous injection and orally) may increase blood pressure. The post-market studies confirmed these results, showing that testosterone products, class-wide, led to an increase in blood pressure.

TRAVERSE trial

The TRAVERSE trial was initiated following a 2014 Joint Meeting of the Bone, Reproductive and Urologic Drugs and the Drug Safety and Risk Management Advisory Committee, which convened to discuss reports of stroke, heart attack, and death in men receiving testosterone products.

In total, the trial enrolled and randomly assigned 5204 men to transdermal 1.62% testosterone gel (n = 2601) or placebo gel (n = 2603).⁵ Patients enrolled were those most vulnerable to an increased risk of adverse cardiovascular outcomes; inclusion criteria included men aged 45 to 80 years who had preexisting or a high risk of cardiovascular disease. Participants also had reported symptoms of hypogonadism and had 2 fasting testosterone levels below 300 ng/dL.

Overall, a cardiovascular event (the first adjudicated major adverse cardiac event) was reported in 7.0% (182) patients in the testosterone arm vs 7.3% (190) in the placebo arm (HR, 0.96; 95% CI, 0.78 to 1.17; P < .001 for noninferiority). The investigators also observed “no clinically meaningful difference” between the 2 cohorts in the incidence of a secondary cardiovascular end point, which was defined as “the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.”

The incidence of pulmonary embolism was higher in the testosterone group, occurring in 0.9% of patients in the treatment arm vs 0.5% in the placebo arm. Patients in the treatment arm also experienced a higher incidence in atrial fibrillation and acute kidney injury.

Overall, the authors concluded, “In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events.”

References

1. FDA issues class-wide labeling changes for testosterone products. News release. US Food & Drug Administration. February 28, 2025. Accessed March 3, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-class-wide-labeling-changes-testosterone-products

2. FDA Drug Safety Communication: FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. News release. US Food & Drug Administration. January 31, 2014. Accessed March 3, 2025. https://wayback.archive-it.org/7993/20161022203724/http:/www.fda.gov/Drugs/DrugSafety/ucm383904.htm

3. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. News release. US Food & Drug Administration. March 3, 2015. Accessed March 3, 2025. https://wayback.archive-it.org/7993/20161022203711/http:/www.fda.gov/Drugs/DrugSafety/ucm436259.htm

4. Marius Pharmaceuticals helps drive FDA’s landmark testosterone label update, removing black box warning. News release. Marius Pharmaceuticals. Published online and accessed March 3, 2025. 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

5. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117. doi:10.1056/NEJMoa2215025