Are black box warnings on Hormone Replacement Therapy (HRT) medications being removed?

Black Box Warnings on Hormone Replacement Therapy Are NOT Being Removed

The FDA has NOT removed black box warnings from hormone replacement therapy (HRT) medications. The confusion likely stems from the fact that black box warnings were removed from smoking cessation medications (varenicline and bupropion) regarding neuropsychiatric events, not from HRT products 1.

Current FDA Black Box Warning Status for HRT

HRT products continue to carry black box warnings that emphasize:

• Estrogen with or without progestin should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals 1
• Increased risk of death and serious cardiovascular events when administered to target hemoglobin >12 g/dL (this applies to erythropoiesis-stimulating agents, not HRT) 1
• The black box warning on HRT specifically highlights increased risks for stroke, invasive breast cancer, dementia, and venous thromboembolism 1

What Actually Had Black Box Warnings Removed

The FDA removed black box warnings about neuropsychiatric events from smoking cessation medications:

• Varenicline (Chantix) - warnings removed 1
• Bupropion (Zyban/Wellbutrin SR) - warnings removed 1

These are tobacco cessation agents, not hormone therapy products.

Current HRT Risk Profile That Justifies Continued Warnings

Combined Estrogen-Progestin Therapy Risks:

• Increased breast cancer risk: approximately 8 additional cases per 10,000 person-years 2
• Stroke risk: demonstrated in WHI trials 1
• Venous thromboembolism: increased incidence 1
• Dementia risk: particularly in older women 1
• Does NOT reduce CHD risk: HR 1.22 (95% CI 0.99-1.51) 1

Estrogen-Only Therapy Risks:

• Reduced breast cancer risk: approximately 8 fewer cases per 10,000 person-years 2
• Stroke risk: still present 1
• Venous thromboembolism: increased 1
• Does NOT reduce CHD risk: HR 0.95 (95% CI 0.78-1.15) 1

Recent Calls for Black Box Warning Removal (Not Yet Implemented)

A 2024 research perspective proposed that FDA-approved bioidentical HRT formulations should have black box warnings removed, arguing these formulations are safe and effective 3. However, this is a proposal, not an FDA action. The authors specifically recommended:

• Removing black box warnings from bioidentical formulations 3
• Eliminating products containing medroxyprogesterone acetate (MPA) due to increased heart attack and breast cancer risks 3

This proposal has NOT been adopted by the FDA, and black box warnings remain in place.

Clinical Implications

FDA-Approved Indications Remain Limited:

• Treatment of menopausal symptoms 1
• Prevention of osteoporosis 1
• NOT approved for cardiovascular disease prevention 1

Prescribing Guidance Under Current Black Box Warning:

• Use lowest effective dose 1, 2
• Shortest duration necessary 1, 2
• Most favorable benefit-risk ratio: women <60 years old or within 10 years of menopause onset 2
• Transdermal formulations preferred when possible due to lower VTE and stroke rates 2

Common Pitfall to Avoid

Do not confuse the removal of black box warnings from smoking cessation medications with HRT products. The evidence clearly shows these are separate drug classes with different warning statuses. HRT maintains its black box warnings due to well-documented risks from large randomized controlled trials like the Women's Health Initiative 1, 3.