FDA Removes Black Box Warning on Hormone Therapy

US health authorities have announced the first steps to remove the black box warning on estrogen products prescribed to treat menopausal symptoms.

The warning was added to products in 2003 when data from a large government study of women’s health, known as the Women’s Health Initiative (WHI), showed that hormone therapy was linked to an increased risk of a number of diseases, including breast cancer, heart disease, blood clots and potentially dementia.

Women’s health experts say the risks were misinterpreted and do not accurately reflect the study data. The result: In subsequent years, many women and the doctors who treated them avoided hormone therapy to treat menopausal symptoms such as hot flashes, night sweats and mood changes.

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Dr. Marty Makary, commissioner of the U.S. Food and Drug Administration (FDA), said the agency convened a panel of experts in July to review and make recommendations on the warning label. The FDA’s internal experts on the subject then reviewed the experts’ opinions and decided to remove the black box warning. Manufacturers of estrogen products will now reprint their product labels.

Many women’s health experts have long supported removing the black box warning, particularly for certain forms of estrogen. Vaginal estrogen products, prescribed to women who experience vaginal dryness after menopause which can increase the risk of urinary tract infections, are applied topically and urologists have argued that the risk described in the black box warning is less applicable to these forms.

“Globally, I would say removing the black box warning on the label is long overdue,” says Dr. Kathleen Jordan, chief medical officer of Midi Health, a virtual health care company that provides services to 20,000 women in quarantine each week. “Experts agree that this overstates the risk from estrogens, and particularly low-dose vaginal estrogens, whose systemic absorption is negligible and the risks associated with them are minimal to minimal.”

Experts at the American College of Obstetrics and Gynecology (ACOG) say other forms of hormone therapy, such as the patch or pill, result in different exposures to the body and therefore have different risk profiles. The risk-benefit discussion for these forms should therefore be different.

“The ACOG guidelines are not changing due to the removal of the black box warning,” says Dr. Stella Dantas, ACOG immediate past president and obstetrician-gynecologist at Northwest Kaiser Permanente. The group still recommends that if women ages 50 to 59 experience menopausal symptoms such as hot flashes or night sweats, vaginal dryness, or difficulty sleeping, they should talk with their doctor about whether hormone therapy makes sense.

This conversation should include consideration of a woman’s family and personal history of breast cancer and other health factors. “We know that hormone therapy can really help women treat their symptoms,” says Dantas. “However, how we counsel them and achieve shared decision-making on whether the benefits outweigh the risks” also depends on the woman’s personal and family history.

The hormonal therapy available today for women is different in many ways from the therapy studied in the WHI. Under WHI, women received oral estrogen and a synthetic progestin, whereas today, most doctors start with an estrogen patch and use a different form of progesterone that is more like the natural hormone and is more “breast neutral,” Jordan says.

Dantas says the population of women in the WHI study was also very different from those who would typically receive hormone treatments today. The WHI study included women who were older on average and about a decade past menopause. “They were not being treated for menopausal symptoms and were already postmenopausal, so the negative effects of lower estrogen levels on their arteries and other systems had already started to occur,” she says. “Whereas today we’re talking about treating women for menopausal symptoms and we’re now using medications that don’t have the same risk profiles.”

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Dantas, however, says the way hormone therapy is administered — by pill or patch — is important and could result in different levels of exposure and risk to the body. While most experts agree that vaginal estrogens do not warrant the black box warning — the FDA’s strongest warning — oral and patch versions of estrogens are designed to disperse more widely throughout the body and therefore pose a different level of risk.

“If I had a wish list, it would include a broader review process to reevaluate what systemic estrogen therapy labeling should be,” she says. “I think removing the black box warning for vaginal creams and rings is different from removing more systemic therapies like oral estrogens, because they have a different risk profile, but are confounded. I think there is data now, so we should be able to extrapolate and show if there is a difference between the transdermal patch and vaginal estrogens, and see what the best warning would be for patients.”

Experts also caution that beyond menopausal symptoms, it’s unclear what benefits hormone therapy might provide. Makary noted that hormone therapy could help women treat a number of other health problems associated with postmenopause, including heart disease and osteoporosis. “There are now profound long-term health benefits that few people, even doctors, know about,” he said. “With few exceptions, there is perhaps no other drug in the modern era that improves women’s health outcomes on a population level than hormone therapy. »

Although there is promising data suggesting that women taking hormone therapy may reduce their risk of bone fractures and heart disease in particular, the evidence is not strong enough for women to rely on hormones as a primary strategy to combat these health problems. “There are other medications for osteoporosis and other medications to control cholesterol,” Dantas says. “Hormone therapy should not be a primary treatment for other illnesses or conditions. It is really about treating the symptoms of menopause.”