FDA outlines narrower, age-focused menopausal hormone therapy labels after WHI reanalysis

The FDA said it has revised how risks are presented for menopausal hormone therapy (MHT), narrowing boxed warnings and tailoring safety language to specific drug categories and age cohorts to help clinicians counsel patients.

Dr. Aisha Johnson, deputy director for safety and associate director for labeling in the Office of New Drugs, told attendees at an FDA Grand Rounds webinar that labels will now separate risk information for four MHT categories — systemic estrogen plus progestogen (EP), systemic estrogen alone, topical low‑dose vaginal estrogen alone, and progestogen alone — rather than repeating class-wide boxed warnings that may not apply to lower‑exposure products.

The changes follow long‑term analyses of the Women’s Health Initiative (WHI) trials and related meta‑analyses, Johnson said. She emphasized the agency will add WHI subgroup data for women ages 50–59 and advise clinicians that timing of initiation matters: "consider initiating MHT in women less than 60 years old or less than 10 years since menopause onset," Johnson said. That guidance reflects the WHI subgroup finding that absolute risk differences for many adverse outcomes were smaller in younger cohorts than in the overall trial population.

Why it matters: The WHI trials, which enrolled more than 27,000 women with an average age of 63, led to widespread changes in labeling after interim analyses found increased risks of breast cancer, stroke and venous thromboembolism. Those 2002–2004 results coincided with rapid declines in MHT use. FDA presenters said the new labels aim to present risk and benefit information more precisely for the patients who typically seek MHT for vasomotor symptoms (VMS).

Key label updates and rationale - Dementia: Dr. Johnson said the risk of probable dementia will be removed from the boxed warnings of both estrogen‑plus‑progestogen and estrogen‑alone labels and instead retained in geriatric‑use and clinical‑studies sections for older patients, reflecting evidence from WHIMS and later subgroup studies showing little or no increased cognitive risk in younger cohorts.

- Breast cancer: The agency will remove invasive breast cancer from the boxed warning for estrogen‑plus‑progestogen products while retaining breast‑cancer information in warnings and precautions. Johnson said that subgroup analyses of WHI (age 50–59) and meta‑analyses showed a smaller absolute risk difference in younger women, and that screening and the established symptomatic benefit of MHT for VMS informed the change.

- Cardiovascular and VTE risks: The boxed warning language has been reallocated by drug category. For example, the agency removes certain risks (DVT, PE, stroke, MI) from boxed warnings for some categories while keeping them in warnings and precautions as appropriate, with the changes guided by age‑stratified risk differences in WHI data.

- Endometrial cancer and topical products: The risk of endometrial cancer for unopposed systemic estrogen remains boxed for systemic estrogen‑alone products but is removed from estrogen‑plus‑progestogen and topical vaginal estrogen labels because progestogen mitigates uterine risk and topical products typically have lower systemic exposure.

- Lowest‑dose/shortest‑duration advisory: FDA removed the blanket boxed recommendation to use the lowest dose for the shortest duration and replaced it with more specific timing guidance tied to patient age and time since menopause.

Evidence base and process Dr. Nicholas Hazen, an OB‑GYN medical officer in the Office of New Drugs, reviewed the historical context: observational studies in the 1980s–1990s suggested cardiovascular benefit, but randomized trials (HERS, WHI) were designed to test causation and showed mixed results and specific safety signals. Hazen noted WHI could detect rare outcomes and that the combined estrogen‑plus‑progestogen arm showed a 26% relative increase in breast cancer translating to an absolute risk increase of about one additional case per 1,000 women per year in the trial population.

During the webinar, Johnson said the agency relied on subgroup analyses of WHI, long‑term follow‑up studies and meta‑analyses to calibrate risk language toward the populations most likely to use MHT for symptomatic relief.

Q&A highlights and implementation In response to a question about counseling patients, Dr. Christina Chang of the Center for Drug Evaluation and Research said FDA added explicit risk numbers to help clinicians explain magnitude of harms and benefits: "We put in relative risk and we put in the risk difference — for example, the risk of five additional cases of blood clots per 10,000 women per year," Chang said.

Asked whether companies are legally required to adopt FDA’s requested labeling changes, Chang said, "No, the companies are not required by law to comply with our requests," but added many companies have responded. She noted that, in February, FDA approved revised labeling for six products out of 29 targeted products (one previously listed product had been withdrawn).

What the changes do not do FDA presenters emphasized they are not concluding MHT is categorically safe or unsafe for all patients; rather, the agency is clarifying how risks differ by drug formulation and patient age and providing clinicians with subgroup risk data to inform shared decision‑making. Dr. Chang reiterated that the WHI trials were conducted and analyzed appropriately for their prevention endpoints but enrolled an older cohort than typical symptomatic MHT users.

Next steps and context The agency opened a public docket in 2025 that received over 2,900 comments and has been reviewing industry responses and finalizing labels. FDA encouraged clinicians and interested members of the public to consult the updated prescribing information posted on its website for examples of the revised labels across the four MHT categories.

The webinar concluded with thanks to authors and reviewers in OND and the Office of Surveillance and Epidemiology; presenters said FDA will continue to monitor evidence and update labeling where appropriate.