FDA Issues Safety Communication About Cardiovascular Risks of Testosterone Replacement

And other concise reviews of studies on men’s health
May 2015, Vol 3, No 5 - Inside Men's Health

The FDA has announced that it will require prescription testosterone product labels to include a warning about a possible increased risk of heart attacks and strokes in patients using the medication, as well as require manufacturers of these products to change the labeling so that approved uses of the medications are clear. The agency is also encouraging healthcare professionals to prescribe testosterone therapy only for men whose low testosterone levels are caused by certain medical conditions and confirmed with appropriate laboratory testing.1

According to the FDA announcement, testosterone replacement therapy is approved for men with low testosterone levels caused by disorders of the testicles, pituitary gland, or brain, which cause

hypogonadism. Genetic problems, chemotherapy, or infection may be at the root of some of these disorders.1 The agency cautioned against testosterone replacement therapy to treat age-related low testosterone.

“[The] FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging,” the announcement indicates. “The benefits and safety of this use have not been established.”

“Based on our findings, we are requiring labeling changes for all prescription testosterone products to reflect the possible increased risk of heart attacks and strokes associated with testosterone use,” the announcement continues. “Healthcare professionals should make patients aware of this possible risk when deciding whether to start or continue a patient on testosterone therapy.”

It goes on to say that patients should seek medical attention if, while using testosterone, they experience heart attack or stroke symptoms. Manufacturers of approved testosterone products will be required to conduct well-designed clinical trials that address more clearly the question of whether users of these medications are at an increased risk of heart attack or stroke.

In 2013, 2.3 million people in the United States received a prescription for testosterone, up considerably from the 1.3 million in 2009.2 Further, the most common diagnostic code related to testosterone therapy is the nonspecific diagnosis of “testicular hypofunction, not elsewhere classified”; however, only 72% of men prescribed testosterone had testosterone-level testing prior to being prescribed the hormone.2

The agency’s announcement, dated March 3, 2015, follows on the heels of a nearly unanimous September 2014 vote of 2 of its advisory committees that supported labeling to clarify medical indications for testosterone therapy, as well as a June 2014 joint statement by the FDA and the Center for Drug Evaluation and Research.2-4 The joint statement outlined a requirement for manufacturers to include in testosterone product labeling that there is a risk of venous thromboembolism, including deep vein throm­bosis and pulmonary embolism.

After hearing from medical, corporate, and government experts, as well as from the general public, members of the 2 committees voted 20 to 1 in favor of label changes stating that testosterone is only indicated in men with valid medical conditions that cause testicular dysfunction rather than men with normal, age-related hypogonadism.4 The decision was not binding, but in this case, the FDA acceded to the strength of the vote and to the precautionary principle.

The committees were charged with examining the cardiovascular safety of testosterone therapy after a paper was published showing an increased risk of stroke, heart attack, and death in older hypogonadal men.5 Other studies and meta-analyses have demonstrated both an increased and decreased risk of cardiovascular disease and/or death rate associated with testosterone. One meta-analysis demonstrated a connection between funding sources and study outcomes, stating, “in trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater…than in pharmaceutical industry funded trials.”6

Response to the announcement from the urology community has been mixed. Daniel Shoskes, MD, Professor of Surgery, Department of Surgery, Cleveland Lerner College of Medicine of Case Western Reserve University, and Director, Novick Center for Clinical and Translational Research, Glickman Urological & Kidney Insti­tute, Cleveland Clinic, is among those who are concerned. He noted concerns with the paper used as the basis for the ruling, as well as evidence that having low testosterone is a risk factor for cardiovascular health problems. Testosterone replacement therapy could mitigate that risk, he said.

“I certainly sympathize with the FDA in seeing that there are a large portion of the men who are getting testosterone therapy in the United States without getting their testosterone levels checked first and are not being monitored according to guidelines,” said Dr Shoskes. “But I am surprised and deeply disappointed in the FDA’s ruling.”


  1. US 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. www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Published March 3, 2015. Accessed April 6, 2015.
  2. US Food and Drug Administration. Testosterone replacement therapy. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM416461.pdf. Published September 17, 2014. Accessed April 6, 2015.
  3. US Food and Drug Administration. Testosterone Products: FDA/CDER statement - risk of venous blood clots. www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm402054.htm. Published June 20, 2014. Accessed April 6, 2015.
  4. 4. US Food and Drug Administration. FDA News. FDA advisory panel rejects testosterone replacement therapy. www.fdanews.com/articles/167396-fda-advisory-panels-reject-testosterone-replacement-therapy. Published September 26, 2014. Accessed April 6, 2015.
  5. 5. Vigen R, O’Donnell CI, Barón AE. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. J Am Med Assoc. 2013;310:1829-1836.
  6. 6. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108.
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