FDA Recklessly Removes Boxed Warning for Risk of Cardiovascular Disease From Testosterone Labels

In February 2025 the Food and Drug Administration (FDA) informed manufacturers of all testosterone products of new labeling changes.[1] Importantly, the FDA recommended removing the increased risk of adverse cardiovascular outcomes (including heart attack, stroke or death) from the boxed warning (the most prominent warning that the agency can require) of these products. Moreover, the agency will only require a general warning regarding the risk of increased blood pressure (hypertension) for all testosterone products.

The FDA made these decisions based on the results of a single post-marketing, industry-funded clinical trial (called TRAVERSE),[2] which has several limitations that we have outlined below. The agency ignored previous evidence that led it to require the cardiovascular risk boxed warning for testosterone products 10 years ago.

About testosterone products

Testosterone is an essential hormone for the growth and development of male sex organs and maintenance of secondary male characteristics. The normal blood level of testosterone in adult males ranges from 291 to 1,100 nanograms per deciliter (ng/dl). Testosterone levels decrease naturally with aging.

The FDA has approved several formulations of synthetic testosterone (see Table below for a list of these drugs that are currently on the U.S. market).

The FDA approved testosterone products as a replacement therapy only for men who have low testosterone levels because of certain medical conditions of the testicles, pituitary gland or hypothalamus that cause a condition called hypogonadism.[3] An example of these disorders is failure of the testicles to produce testosterone due to genetic problems, or damage from chemotherapy or infection.

Despite their limited approved indication, testosterone products have been used extensively off-label in men with low testosterone for no apparent reason other than aging. The benefits and safety of such unapproved use have not been established, as acknowledged by the FDA.

Table. FDA-Approved Testosterone Products

*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News

Initial cardiovascular-safety warning

In February 2014 Public Citizen’s Health Research Group petitioned the FDA to require a boxed warning regarding the increased risk of heart attacks and adverse cardiovascular events on the labels of all testosterone products.[4] This request was based on evidence from randomized clinical trials and observational studies showing that testosterone therapy increases the risks of cardiovascular disease.

In July 2014 the FDA denied our petition. Two months later, however, the agency convened an advisory committee meeting[5] to examine the same studies discussed in the petition, as well as a few others. In March 2015 the FDA acknowledged “possible” increased cardiovascular risk associated with testosterone use and required labeling changes for testosterone products about this risk. The agency also required manufacturers of testosterone products to conduct a well-designed clinical trial to examine whether there is an increased risk of heart attack or stroke among users of testosterone products.

The TRAVERSE trial and its limitations

The TRAVERSE trial was funded by AbbVie and other manufacturers of testosterone products to fulfill the FDA’s 2015 post-marketing requirement.[6] Trial investigators enrolled 5,246 men aged 45 to 85 years with an existing (or a high risk of) cardiovascular disease who reported having symptoms of hypogonadism (such as decreased libido, fatigue, or decreased frequency of shaving) and had two fasting (morning) blood tests showing low testosterone levels (less than 300 ng/dl).

The participants were randomized to receive either daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng/dl) or placebo gel for 22 months on average and were followed for 33 months on average.

Testosterone or placebo was discontinued in participants with testosterone blood levels that were higher than 750 ng/dl or had a hematocrit level (the percentage of red blood cells in a person’s blood) that exceeded 54% as well as in those who were diagnosed with prostate cancer during the trial.

During follow-up, similar proportions of participants (7%) in both groups developed a cardiovascular safety primary endpoint: any component of a composite of nonfatal heart attack or stroke, or death from cardiovascular causes.

However, testosterone users fared worse than placebo users on some secondary cardiovascular-safety outcomes. Specifically, testosterone users had a small increase in blood pressure. Nonfatal arrhythmias (irregular heartbeat) that warranted intervention occurred in 5% of testosterone users and 3% of placebo users. Atrial fibrillation (a type of irregular heart rhythm) occurred in 4% of testosterone users and 2% of placebo users. Also, 1% of testosterone users had a blood clot in the lung compared with 0.5% of those in the placebo group.

Importantly, the TRAVERSE trial has major shortcomings that limit its generalizability. Overall, there was poor adherence to the assigned daily therapy: Only 39% of participants in both groups continued using their assigned gel.

Additionally, due to dosage adjustment based on close monitoring of testosterone blood levels, testosterone users consistently had testosterone blood levels that were near the bottom (around 350 ng/dl) of the normal range throughout the trial. These levels are lower than the target blood levels generally used by clinicians in clinical practice.[7]

Moreover, the trial only examined the use of testosterone gel, excluding injectable and oral formulations. The injectable and oral formulations cause a larger increase in hematocrit levels,[8] potentially leading to a higher cardiovascular risk among testosterone users than was seen in the trial.[9]

Additional considerations

Given the established relationship between increased blood pressure and cardiovascular disease, the FDA should not have simultaneously required a warning for high blood pressure and removed the warning for cardiovascular disease. Likewise, testosterone products increase the risk of blood clots,[10] which also can increase the risk of cardiovascular disease.

In 2017 a report based on the testosterone trials (known as T Trials) found an increased volume of noncalcified plaque in coronary arteries of older men with symptomatic age-related low testosterone who used testosterone gel compared with similar men who used a placebo gel for one year.[11]

Therefore, it would have been more prudent for the FDA to keep the cardiovascular-risk warning on testosterone labels until better-designed, longer clinical trials involving various formulations provide a better understanding of the cardiovascular safety of testosterone therapy in hypogonadal men.

What You Can Do

Consider testosterone therapy only if you are a man with a confirmed diagnosis of hypogonadism due to a medical condition. In this case, discuss with your clinician whether the potential benefits from testosterone replacement therapy outweigh the risk of cardiovascular disease and other risks, such as abuse, dependence (need for higher doses) and withdrawal symptoms (including depression, fatigue, insomnia and irritability).

Otherwise, we recommend that you never use testosterone products for any unapproved reason, including treating symptoms of normal aging. Simpler and safer approaches, including exercising and maintaining a healthy weight, are more beneficial.

If you use any testosterone product, seek medical attention immediately if you experience any symptoms of a heart attack or stroke, including chest pain or pressure, trouble breathing, rapid or irregular heart rate, slurred speech, or weakness on one side of the body.

Also monitor your blood pressure closely and be alert for symptoms of blood clots in your legs (pain, edema, warmth and redness) or lungs (acute shortness of breath).
 

References

[1] Food and Drug Administration. 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. February 28, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due. Accessed June 9, 2025.

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

[3] Food and Drug Administration. 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. March 3, 2015. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM436270.pdf. Accessed June 9, 2025.

[4] Public Citizen. Petition to the FDA for black box warnings on all testosterone products. February 25, 2014. https://www.citizen.org/wp-content/uploads/2184.pdf. Accessed June 9, 2025.

[5] Public Citizen. Press release. FDA should require warnings on testosterone, Public Citizen tells advisory committee. September 17, 2014. https://www.citizen.org/news/the-fda-should-require-warnings-on-testosterone-products-public-citizen-tells-fda-advisory-committees/. Accessed June 9, 2025.

[6] Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117.

[7] Krishnan S, Aldana-Bitar J, Golub I, et al. Testosterone replacement therapy and cardiovascular risk: TRAVERSE with caution. Prog Cardiovasc Dis. 2024;86(September-October):73-74.

[8] Nackeeran S, Kohn T, Gonzalez D, et al. Association between testosterone therapy and change in hematocrit: A systematic review and network meta-analysis of randomized control trials. Fertil Steril. 2021;116(3):e358.

[9] Gagnon DR, Zhang TJ, Brand FN, et al. Hematocrit and the risk of cardiovascular disease — the Framingham Study: A 34-year follow-up. Am Hear J. 1994;127(3):674-682.

[10] Antares. Label: testosterone enanthate (XYOSTED). March 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8a3d204c-be26-49e0-8599-0ac12a272e81&type=display. Accessed June 9, 2025.

[11] Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017;317(7):708-716.