Estradiol Vaginal Cream Safety Information

These highlights do not include all the information needed to use estradiol vaginal cream safely and effectively. Please see full prescribing information for estradiol vaginal cream.

All estrogen products currently carry an FDA black box warning, which is the most serious warning the FDA requires. The warning alerts patients to increased risks of cancer and heart disease. However, in 2025, the FDA has announced plans to remove this black box warning from prescribing information for all estrogen products. The Menopause Society supports removal of the warning only from vaginal estrogen products, which are low-dose and not absorbed significantly throughout the body. Systemic estrogen like the estrogen pill or patch still comes with potential health risks in certain individuals that should be reviewed in detail with patients.

Estradiol vaginal cream is a form of vaginal estrogen. Like all forms of vaginal estrogen, estradiol vaginal cream is a prescription medication. It’s FDA-approved to treat moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When you receive your estradiol vaginal cream, you’ll open the box and read an FDA warning that estrogens increase risk of cancer and heart disease. These warnings have only been substantiated with higher-dose oral forms of estrogen. Women's health groups state that these warnings do not apply to vaginal estrogen and have been advocating for updated information that reflects the safety of vaginal estrogen.^[1]

Estradiol vaginal cream is prescribed in very small doses and is applied only to the affected tissues. Vaginal estradiol is not shown to carry risk of cancer and heart disease, according to analysis of information from over 161,000 women as part of the very large Women’s Health Initiative Observational Study.^[2] It can even be used by women with a history of breast cancer, provided they have approval from their oncologist.^[3]

At Interlude, we want you to feel safe and educated about your options for vaginal and urinary health in menopause and beyond. If you are considering estradiol vaginal cream, our medical team will determine if you are a good candidate for vaginal estradiol cream. We’re available 24/7 to answer any questions you may have - unlimited messaging is included with your treatment.

What does estradiol vaginal cream treat?

Estradiol vaginal cream (USP, 0.01%) is FDA-approved to treat moderate to severe dryness, itching, and burning in and around the vagina due to menopause. These changes are also known as vulvar and vaginal atrophy or the genitourinary syndrome of menopause.

What are the most important things I need to know about estradiol vaginal cream?

Boxed warning: endometrial cancer, cardiovascular disorders, breast cancer and probable dementia
Estradiol vaginal cream is considered an estrogen.
Estrogens increase the chances of getting cancer of the uterus.
Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.
Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots.
Using estrogens with progestins may increase your risk of dementia.
You and your healthcare provider should talk regularly about whether you still need treatment with estradiol vaginal cream.

Who should not take estradiol vaginal cream?

Do not use estradiol vaginal cream if you:

Have unusual vaginal bleeding
Currently have or have had certain cancers (Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol vaginal cream.)
Had a stroke or heart attack in the past year
Currently have or have had blood clots
Currently have or have had liver problems
Are allergic to estradiol vaginal cream or any of its ingredients
Think you may be pregnant

Tell your healthcare provider:

If you are breastfeeding
All of your medical problems
All the medicines you take
If you are going to have surgery or will be on bed rest.

What are the side effects of estradiol vaginal cream?

Although estradiol vaginal cream is only used in and around the vagina, the risks associated with oral estrogens should be taken into account.

Less common but serious side effects of oral estrogen include:

Breast cancer
Cancer of the uterus
Stroke
Heart attack
Blood clots
Dementia
Gallbladder disease
Ovarian cancer

These are some of the warning signs of serious side effects:

Breast lumps
Unusual vaginal bleeding
Dizziness and faintness
Changes in speech
Severe headaches
Chest pain
Shortness of breath
Pains in your legs
Changes in vision
Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

Headache
Breast tenderness
Irregular vaginal bleeding or spotting
Stomach/abdominal cramps, bloating
Nausea and vomiting
Hair loss
Vaginal burning, irritation, and itching

Other side effects:

High blood pressure
Liver problems
High blood sugar
Fluid retention
Enlargement of benign tumors of the uterus ("fibroids")
Vaginal yeast infection
Allergic reactions

These are not all the possible side effects of estradiol vaginal cream. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription products to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see the full Prescribing Information, including the BOXED WARNING, for complete safety information.

References

Pinkerton JV, Santoro N. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause. 2014;21(9):911–916.
Vinogradova Y, Coupland C, Hippisley-Cox J. Breast cancer, endometrial cancer, and cardiovascular events in recipients of low-dose vaginal estrogens. Menopause. 2018;25(1).
Vaginal estrogen use in breast cancer survivors. American Journal of Obstetrics and Gynecology. 2024.

Disclaimer: This information isn’t a substitute for professional medical advice, diagnosis, or treatment. You should never rely upon this article for specific medical advice. If you have any questions or concerns, please talk to your doctor.