The Boxed Warning: How Cardiovascular Language Got on the Label, and How It Came Off

In September 2014 the FDA convened a joint advisory committee following increased reports of stroke, heart attack and death in men taking approved testosterone products. That meeting produced a recommendation for an industry-wide clinical trial. Cardiovascular risk language went onto testosterone labels — and on 28 February 2025, the FDA removed language from the Boxed Warning related to an increased risk of adverse cardiovascular outcomes for all testosterone products.[1]

Two clarifications before the history, because both are routinely muddled.

First, testosterone gels carry more than one boxed warning. The one that came off in 2025 was the cardiovascular language. Topical gels also carry a boxed warning about secondary exposure — testosterone transferring from treated skin to a child or partner — and that one is unaffected by any of this.[2] It is covered separately in the transfer warning.

Second, a warning is not a ban. Testosterone remained approved and prescribable throughout.

How the language got there

The evidence behind the warning was not a single decisive study. It was three contested ones in close succession.

• 2010 — the TOM trial was stopped early after 23 men on testosterone had cardiovascular adverse events against 5 on placebo, in 209 frail older men. Its authors wrote that the trial's size and unique population prevent broader inferences.[3]
• 2013 — Vigen and colleagues reported an association between testosterone therapy and mortality, myocardial infarction and stroke in a retrospective VA cohort.[4]
• 2013 — a systematic review and meta-analysis pooled placebo-controlled trials of testosterone and cardiovascular events.[5]

None was a randomised trial powered for cardiovascular outcomes. Together they were enough to move a regulator, which is the pattern examined in how contested evidence became a label change.

Notably, evidence pointing the other way appeared in the same window: Sharma and colleagues analysed 83,010 veterans and found normalisation of testosterone associated with reduced myocardial infarction and mortality.[6]

The trial the FDA asked for

The September 2014 advisory committee's recommendation was for an industry-wide trial assessing safety in men with age-related hypogonadism.[1] That trial became TRAVERSE — an FDA-required postmarketing safety study conducted by a consortium led by the manufacturers of AndroGel and Androderm.[7]

It tracked serious major adverse cardiovascular outcomes in more than 5,200 men receiving at least one dose of AndroGel 1.62%. Published in June 2023:

7.0% of men in the AndroGel group had a major adverse cardiovascular event, compared with 7.3% in the placebo group. FDA determined that the results did not demonstrate a new safety signal or trend in adverse cardiovascular outcomes with testosterone use.[7]

The trial itself is covered in the TRAVERSE main trial.

What the 2025 action actually did

On 28 February 2025 the FDA informed sponsors of labeling changes following its review of TRAVERSE and of required postmarket ambulatory blood pressure monitoring studies.[1] The changes were not simply a removal.

Led by TRAVERSE, the FDA recommended:

• adding the TRAVERSE results to all testosterone products
• retaining the "Limitation of Use" language for age-related hypogonadism
• removing the Boxed Warning language about increased risk of adverse cardiovascular outcomes[1]

Led by the blood pressure studies, the FDA also required:

• adding product-specific information on increased blood pressure for products with completed ABPM studies
• adding a new warning about increased blood pressure for products that did not already carry one[1]

That second half is the part almost no coverage mentioned. One warning came off and another went on. The FDA had recommended ABPM studies in 2016 and 2017 for two products given by different routes, and consistent results raised concerns that testosterone could increase blood pressure.[1]

Anyone describing February 2025 as "the FDA removed the warning" is describing half the action. The full picture is in what the 2025 labeling change did.

Bottom line

Cardiovascular language entered the testosterone Boxed Warning on evidence that was individually weak and collectively persuasive, and it left after a 5,200-man randomised trial the FDA itself had asked for. The secondary-exposure boxed warning on gels is a different warning and is still there.

The honest summary of the arc is not that the sceptics were wrong. It is that the question was answered properly, nine years after it was raised — and that a blood pressure warning arrived on the same day the cardiovascular one departed.

References

7 sources

1. U.S. Food and Drug Administration. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. fda.gov
2. U.S. Food and Drug Administration. AndroGel (testosterone gel) 1% — prescribing information, including BOXED WARNING: secondary exposure to testosterone. Reference ID 021015s044. 2019. accessdata.fda.gov
3. Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010;363(2):109–122. doi:10.1056/NEJMoa1000485 · PMID 20592293
4. Vigen R, O'Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829–1836. doi:10.1001/jama.2013.280386 · PMID 24193080
5. Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108. doi:10.1186/1741-7015-11-108 · PMID 23597181
6. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706–15. doi:10.1093/eurheartj/ehv346 · PMID 26248567
7. U.S. Food and Drug Administration. Testosterone Information — postmarket drug safety information for patients and providers, including the TRAVERSE results and the June 2026 requested prescribing-information updates. fda.gov