FDA asks manufacturers to remove boxed warnings from estrogen therapies, cites updated evidence

FDA Commissioner Dr. Marty Makary announced this week that the agency has asked manufacturers to remove longstanding boxed ("black box") warnings from estrogen-containing hormone replacement therapy labels, saying a review of clinical evidence and public input supports updating the most prominent warning language.

Dr. Makary said the agency reviewed petitions dating to 2016 and a more recent 2025 petition, convened internal and external experts and opened a public docket before deciding to seek label revisions. "We are not here to tell people to take hormone replacement therapy," he said, adding that the agency's action is intended to address continued fear prompted by the earlier boxed warnings. He noted the warnings were placed after the Women's Health Initiative results and broad media coverage in 2003.

The agency's staffer who led the review, Dr. Christine Wen, deputy director of the office that oversees the hormone therapy division, described specific changes the FDA is requesting from sponsors. The agency is proposing the removal from boxed language of wording related to cardiovascular disease, breast cancer and probable dementia while retaining discussion of those risks in the main body of the label. The FDA will continue to recommend a boxed warning addressing the risk of endometrial cancer for systemic estrogen-alone products. For local (vaginal) estrogen products, the agency said it will streamline and prioritize formulation-specific safety information because average systemic exposure from those products is generally lower.

The FDA cited recent and older studies in its review. Commissioner Makary referenced a 2023 review in the journal Circulation that he said found about a 30 percent reduction in all-cause mortality and a 48 percent reduction in heart-attack deaths in analyses the agency considered; agency staff stressed that benefits appear most pronounced when hormone therapy is initiated within roughly 10 years of menopause or before about age 60. "There is a nuanced window where initiation appears to be associated with more favorable cardiovascular outcomes," Makary said, while acknowledging that HRT is not appropriate for everyone — for example, some clinicians view active or prior estrogen-receptor–positive breast cancer or a history of blood clots as contraindications.

Officials said the change is a labeling recommendation that sponsors are expected to accept; the practical implementation will depend on companies' acceptance and the time needed to reprint labels and let existing pharmacy inventory cycle through. "We are not going to pull product off shelves," Makary said. Agency staff also urged professional societies, residency programs and continuing medical education providers to support clinician education so prescribers and patients can make individualized decisions.

During the question-and-answer session, the FDA reiterated that the agency will post the recording and that proposed labeling text is still under negotiation with sponsors; staff said additional questions will be addressed once proposed label language is publicly available. "We value collaboration with clinicians and professional societies to ensure appropriate use and counseling," Dr. Wen said.

The call closed with officials saying the agency will continue to review evidence and engage stakeholders; the agency noted it had solicited extensive public comment and convened external experts before making the request to sponsors.