Physicians Welcome Testosterone Labeling Changes

A decade ago, questions about the cardiovascular safety of testosterone replacement therapy prompted the US Food and Drug Administration (FDA) to require manufacturers to conduct new studies assessing the safety of products containing the hormone.

Results of those studies in hand, the agency announced on February 28 that the labels for all testosterone products must change. 

For one, products must note they can increase blood pressure. Studies involving ambulatory blood pressure monitoring “confirmed an increase in blood pressure with use of all testosterone products, class-wide,” the FDA said. Some products already include this risk on their labels.

Other labeling changes are more reassuring, however. Boxed warnings about the risk for adverse cardiovascular events that appear on the labels of some testosterone products can be removed. 

Instead, labels should reference results from the TRAVERSE trial, which showed similar rates of cardiovascular events including myocardial infarction and stroke in patients who received testosterone or placebo over a 2-year period.

Guidance about which testosterone therapy is indicated for — men with primary or hypogonadotropic hypogonadism — remains unchanged. Labels will continue to note the safety and efficacy of testosterone has not been established in children or men with age-related hypogonadism. 

Thomas Blackwell, MD, an internist with The University of Texas Medical Branch in Galveston, Texas, said he expects the new labeling could lead to more men with coronary artery disease and low testosterone receiving treatment to correct the deficiency. 

“Some cardiologists, not all, have been reluctant to agree with testosterone replacement therapy because of that black box warning,” Blackwell told Medscape Medical News. “With that being removed, you are going to see a big roadblock taken away so that more men can benefit from testosterone therapy.” 

FDA-Mandated Trial 

Prescriptions for testosterone products fell after a pair of studies in 2013 and 2014 linked the use of testosterone replacement therapy to an increased risk for stroke and myocardial infarction. 

The FDA issued an alert to healthcare professionals and patients about the potential hazard, and labels were updated to note some but not all studies had shown testosterone therapy might increase the risk for adverse cardiovascular events.

In addition, regulators required further study of testosterone’s safety, which led to TRAVERSE. Investigators in 2023 reported reassuring cardiovascular safety results from the trial, which enrolled more than 5200 men with hypogonadism at high risk for heart disease. Participants were randomly assigned to receive daily transdermal testosterone gel or placebo. Testosterone did not increase the risk for myocardial infarction, stroke, or death from cardiovascular causes in the study. 

Atrial fibrillation, acute kidney injury, and pulmonary embolism were more common in men who received testosterone, however. More fractures occurred in the testosterone group as well.

Use Carefully Controlled 

Steven Nissen, MD, chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic in Cleveland, chaired the TRAVERSE trial. He said he agrees with the FDA’s labeling changes, adding the evidence does not support a boxed warning for testosterone. 

Still, Nissen said TRAVERSE should not be misinterpreted to suggest testosterone is safe for everybody under all circumstances. “We showed that it could be used safely in a carefully controlled environment,” Nissen told Medscape Medical News.

Men in the trial gradually increased the medication until their testosterone levels reached a normal range. “If they went too high, we back titrated or even in some cases stopped the drug,” Nissen said. 

“What we did not show is that if you take men who do not like the way they feel at their age and give them testosterone, that’s a good thing or that it is safe,” he said. 

Nissen characterized any improvements in symptoms like sexual function during the study as small. 

“Testosterone is not a wonder drug for aging men, and it is important for people to have reasonable expectations,” he said. “Yes, if your testosterone is low and you have a lot of symptoms, you might want to try it. But don’t expect to feel like you did when you were 18 years old.” 

‘Sea Change’

Other recent studies, including one by Blackwell, have supported the safety of testosterone.

He and his colleagues analyzed medical records from more than 133,000 men with hypogonadism and found testosterone replacement therapy was associated with lower rates for mortality, atrial fibrillation, stroke, and prostate cancer.

Testosterone “actually may reduce your risk for many of these problems,” Blackwell said. “It is really a sea change in the way of thinking about it.”

If patients experience mild elevations in blood pressure with testosterone replacement therapy, medication could help relieve hypertension, Blackwell said. 

“We do not start anybody on therapy with any drug and not follow them,” Blackwell said. “If we put you on a drug, we want to make sure that it’s having the effects that we want it to have.”

Off-Label Use Predominates 

Martin M. Miner, MD, founder of the Men’s Health Center at The Miriam Hospital in Providence, Rhode Island, said increases in blood pressure seen with testosterone in the ambulatory pressure studies “were relatively small but they were present.”

Use of oral and subcutaneous testosterone products were associated with an average increase in systolic blood pressure of about 4 mm Hg and a diastolic rise of 1-1.5 mm Hg. 

“Any increase in blood pressure is significant because any increase in blood pressure could potentially increase what the FDA is concerned about, which is major adverse cardiovascular events,” Miner said. “Even small increases can increase that risk.”

The FDA’s announcement does not affect one aspect of prescribing testosterone Miner said torments him as a physician: Off-label use. 

When Miner sees patients who could benefit from treatment, almost 80% of the time the prescription is off label. Most have low testosterone levels resulting from comorbid conditions like obesity, rather than problems related to the testes, hypothalamus, or parathyroid gland, for which a prescription for testosterone is indicated, he said.

“We can certainly treat patients with off-label medications, but it’s not comforting to know that everything that you are doing is off label,” Miner said.

Further studies could someday broaden the indications, Blackwell said.

“All of these things evolve over time,” Blackwell said. “This is a step, but this isn’t necessarily where it’s going to end for testosterone.”

Marius Pharmaceuticals, which markets Kyzatrex (testosterone undecanoate) capsules, indicated further studies of testosterone could be coming.

Shalin Shah, CEO of the company, said in a news release the labeling changes will “accelerate Marius Pharmaceuticals’ research into additional therapeutic uses of testosterone.”

In September, Marius urged regulators to remove the boxed warning on its drug, which was approved in 2022.

“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 therapy, Shah said.

Miner has consulted for Antares Pharma, which markets a testosterone injection. The Cleveland Clinic Center for Clinical Research received funding from pharmaceutical companies to perform clinical trials that Nissen works on, but Nissen does not accept personal compensation from the companies. AbbVie and other companies funded TRAVERSE.