Written by Keen Meds  ·  Reviewed by Licensed Clinical Providers  ·  March 1, 2026

Key Insight: The FDA's March 2025 label update removed the cardiovascular risk warning that had appeared on all testosterone medications since 2015 -- a direct consequence of TRAVERSE trial findings.

> The FDA's March 2025 label update removed the cardiovascular risk warning that had appeared on all testosterone medications since 2015 -- a direct consequence of TRAVERSE trial findings.

Medically reviewed by licensed clinical providers · March 2026

For ten years, every testosterone medication prescribed in the United States carried a black box warning -- the FDA's strongest safety label -- alerting patients and physicians to potential cardiovascular risk. That warning was removed in March 2025. The removal was not a political or industry-driven decision. It was a direct result of a large, rigorous clinical trial commissioned by the FDA itself, which found no elevated cardiovascular risk in men with hypogonadism treated with testosterone. This post explains what the label change means in practical terms -- for patients who were hesitant about TRT, for prescribers who were cautious, and for what monitoring still applies.

What a Black Box Warning Is and Why It Matters

A black box warning -- named for the bordered box that appears at the top of an FDA drug label -- is not a prohibition on prescribing. It is a required disclosure of serious or life-threatening risk. Black box warnings carry significant clinical weight: they influence physician prescribing behavior, patient acceptance of treatment, and health system guidelines.

The testosterone black box warning, added to all testosterone product labels in 2015, stated that TRT was associated with increased risk of major adverse cardiovascular events (MACE) -- including heart attack, stroke, and cardiovascular death. This warning made many physicians reluctant to initiate testosterone therapy, and many patients wary of pursuing it, even when clinical criteria for hypogonadism were clearly met.

The practical effect over the subsequent decade was substantial. Prescribing rates in men with confirmed low testosterone were affected. Patients who might have benefited from treatment declined it or were not offered it. The warning created an environment of clinical uncertainty around a therapy with otherwise strong evidence of benefit.

Why the Warning Was Added in the First Place

The 2015 black box warning was driven by two studies that raised cardiovascular concern, both of which had significant methodological limitations.

The Vigen et al. 2013 study (published in JAMA) examined medical records from veterans and reported higher rates of adverse cardiovascular events in testosterone-treated men. The study was subsequently criticized for analytical errors -- including the counterintuitive finding that some men in the "testosterone-treated" group were female, and statistical methods that may have reversed the actual direction of the association.

The Finkle et al. 2014 study (published in PLoS ONE) found elevated acute myocardial infarction rates in the period immediately after testosterone prescription. This was a pharmacoepidemiological study -- observational, with limited ability to control for confounding -- not a randomized controlled trial.

Neither study was a prospective randomized trial. Both generated enough regulatory concern that the FDA, in 2014, required manufacturers to conduct a large, prospective cardiovascular outcomes trial. That trial was TRAVERSE.

What TRAVERSE Found

The TRAVERSE trial (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) was published in the New England Journal of Medicine in 2023 (Lincoff et al.). It enrolled 5,246 men with confirmed hypogonadism and pre-existing cardiovascular disease or high cardiovascular risk, and followed them for a median of 33 months.

The primary finding: a hazard ratio of 0.96 for major adverse cardiovascular events (MACE) in the testosterone group compared to placebo. A hazard ratio below 1.0 means fewer events in the treated group; 0.96 is not statistically different from 1.0 (non-inferiority was confirmed). In plain terms, testosterone therapy did not increase the risk of heart attack, stroke, or cardiovascular death relative to placebo in this high-risk population.

This was the trial the FDA had required. Its results directly informed the March 2025 label revision.

What the Removal Actually Changes

The March 2025 label update means that testosterone medications no longer carry the black box cardiovascular warning. In practical terms, this represents a shift in the clinical and regulatory framing of TRT:

Physicians can now initiate testosterone therapy in men with confirmed hypogonadism without the explicit FDA-level signal that doing so carries elevated cardiovascular risk. For physicians who were cautious specifically because of the black box language, this represents a meaningful change in the prescribing context.

For patients, the removal signals that the cardiovascular concern that may have given them pause is no longer supported by the best available evidence. Men who deferred a conversation with their doctor -- or who were told by a physician that the cardiovascular risk outweighed the benefit -- now have an updated evidence base to bring to that discussion.

What Has Not Changed

Removing a black box warning does not eliminate all monitoring considerations. Several important points remain in effect:

Prescription requirement. Testosterone remains a Schedule III controlled substance. It still requires a physician evaluation, confirmed lab results, and a valid prescription. Nothing about the label change affects this.

The atrial fibrillation signal. TRAVERSE did confirm a modestly higher rate of atrial fibrillation in the testosterone arm (3.5% vs. 2.4% in placebo). While MACE was not elevated, men with existing atrial fibrillation or risk factors for it should discuss this finding with their treating physician.

Pulmonary embolism. TRAVERSE also showed a slightly higher rate of pulmonary embolism in the testosterone arm (0.9% vs. 0.5%). This was not statistically significant at the trial level but is an appropriate consideration in the clinical evaluation.

Polycythemia monitoring. Elevated hematocrit (polycythemia) remains the most consistently documented adverse effect of TRT. Clinical guidelines recommend monitoring hematocrit during TRT; the action threshold is greater than 54%. This monitoring requirement is unaffected by the black box removal.

Symptom plus lab diagnosis still required. The Endocrine Society's guidelines require both confirmed low testosterone (below 300 ng/dL on two separate morning fasting tests) and symptomatic presentation before initiating treatment. The regulatory update does not lower this clinical bar.

Frequently Asked Questions

Does the removal of the black box warning mean TRT is now completely risk-free?

No. The removal reflects that cardiovascular MACE risk -- previously the primary concern -- was not confirmed by TRAVERSE. Monitoring considerations remain, including hematocrit tracking for polycythemia and awareness of the atrial fibrillation signal identified in TRAVERSE. TRT is a prescription medication that requires physician supervision and periodic lab monitoring.

My doctor told me TRT was too risky because of the heart warning. Should I bring this up again?

Yes. The clinical landscape has changed based on peer-reviewed trial data. The FDA label revision is a direct reflection of the TRAVERSE results. A physician who was previously cautious based on the black box language may have a different perspective in light of the 2025 update. Bringing the TRAVERSE publication (Lincoff et al., NEJM 2023) and the label update to a follow-up consultation is a reasonable course of action.

If TRAVERSE enrolled men who already had heart disease, does it apply to healthier men?

This is a fair clinical question. TRAVERSE enrolled men with pre-existing cardiovascular disease or high risk -- a population in which any risk signal would be most apparent. The finding of no elevated MACE risk in this group provides meaningful reassurance. Studies in lower-risk populations have generally shown neutral or favorable cardiovascular outcomes as well, including the Sharma et al. veterans cohort study. However, individual risk profiles should always be discussed with a treating physician.

Updated Evidence, Clearer Path Forward

If cardiovascular concern was the reason you or your physician delayed a conversation about low testosterone, the 2025 FDA update and the TRAVERSE trial data are worth discussing at your next appointment. A blood test remains the starting point.

Keen Meds connects you with a licensed clinical team for a telehealth consultation and lab review. If your testosterone is clinically low, you receive a prescription for Testosterone Spray Rx -- delivered via Hypospray®, Keen's needle-free transdermal spray platform.

Start your Keen Testosterone Spray Program →

Medically reviewed by Licensed Clinical Providers · March 2026

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