FDA Issues New Labeling Changes Clarifying Safety of Testosterone Products Following Clinical Trials

The FDA has informed sponsors of products containing testosterone, a hormone critical to the development of male growth and masculine features, that the agency is issuing new labeling changes to current language to clarify important safety information regarding the risk of adverse cardiovascular outcomes in patients.¹

Multiple formulations of testosterone products are approved by the FDA. | Image Credit: © Aleksandra Gigowska - stock.adobe.com

These changes follow the submission of results from multiple investigations, including the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE; NCT03518034) clinical trial and required postmarketing ambulatory blood pressure (ABPM) studies. In TRAVERSE, investigators found that in men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone replacement therapy was noninferior to placebo regarding the incidence of major adverse cardiac events (7.0% versus 7.3%; hazard ratio [HR]: 0.96; 95% CI, 0.78-1.17; P < .001).^2,3

Correspondingly, the FDA recommended ABPM studies in 2016 and 2017 as part of the premarket development of 2 different testosterone products—one administered through subcutaneous injection and another administered orally. The results from these studies were consistent in indicating concerns regarding heightened blood pressure with the use of testosterone products. In 2018, the FDA required individual ABPM studies for all testosterone products; the results of these studies confirmed an increase in blood pressure with the use of all class-wide testosterone products.¹

Based on the results of TRAVERSE, the FDA issued new recommended changes to current labeling language for testosterone products. According to the FDA’s news release, these include 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 a heightened risk of adverse cardiac outcomes for all testosterone products.¹

Furthermore, required changes to current labeling language were announced by the FDA in accordance with the results of the ABPM studies. These include adding product-specific guidance on increased blood pressure for testosterone products that underwent full ABPM studies and adding a new warning about increased blood pressure for testosterone products that do not currently have a warning for the issue in their labeling, according to the FDA’s news release.¹

The deliberations that led to these label changes first began following increased reports of adverse cardiovascular outcomes—such as stroke, heart attack, and death—in men taking FDA-approved testosterone products. Following a Joint Meeting of the Bone, Reproductive, and Urologic Drugs and the Drug Safety and Risk Management Advisory Committee in September 2024, the agency recommended an industry-ride clinical trial—TRAVERSE—to assess the safety of these products in men with age-related hypogonadism.¹

Multiple prior actions have been taken by the FDA regarding the safety of testosterone products. These include a January 2014 Drug Safety Communication (DSC) that warned of reported risks of stroke, heart attack, and death in men taking FDA-approved testosterone products, and a March 2015 DSC that informed consumers of mandated labeling changes and urged caution when using testosterone products.^1,4,5

Multiple formulations of testosterone products are available to consumers and approved by the FDA, including oral, topical gel, transdermal patch, buccal system—through application to the upper gum or inner cheek—and injection formulations. Testosterone is only approved by the FDA for use in men who lack or have low testosterone levels in conjunction with an associated condition, according to experts. Pharmacists, health care professionals, and patients must be aware of adverse events when taking testosterone products and make any reports to the FDA.¹

REFERENCES

1. FDA. FDA issues class-wide labeling changes for testosterone products. News Release. Released February 28, 2025. Accessed March 4, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-class-wide-labeling-changes-testosterone-products

2. 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

3. ClinicalTrials.gov. A study to evaluate the effect of testosterone replacement therapy (TRT) on the incidence of major adverse cardiovascular events (MACE) and efficacy measures in hypogonadal men (TRAVERSE). National Library of Medicine. Last Updated March 13, 2024. Accessed March 4, 2025. https://clinicaltrials.gov/study/NCT03518034

4. FDA. FDA Drug Safety Communication: FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. News Release. Released January 31, 2014. Accessed March 4, 2025. https://wayback.archive-it.org/7993/20161022203724/http:/www.fda.gov/Drugs/DrugSafety/ucm383904.htm

5. FDA. 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. Released March 3, 2015. Accessed March 4, 2025. https://wayback.archive-it.org/7993/20161022203711/http:/www.fda.gov/Drugs/DrugSafety/ucm436259.htm