Short answer: In the label's 12-week placebo-controlled study, the most common Premarin Vaginal Cream side effects were breast pain (4.9% on the 21/7 regimen vs 0% on placebo), headache (3.5% vs 1.4%), pelvic pain, vulvovaginal disorder, leukorrhea and vaginitis, each under 5%. The cream carries the estrogen boxed warning on endometrial cancer, stroke, blood clots, breast cancer and probable dementia.
What Premarin Vaginal Cream is approved for: Premarin Vaginal Cream is a mixture of estrogens placed in the vagina with an applicator. It is approved to treat atrophic vaginitis and kraurosis vulvae (thinning and drying of vaginal and vulvar tissue), and to treat moderate to severe dyspareunia (painful intercourse), a symptom of vulvar and vaginal atrophy due to menopause (sections 1.1, 1.2). The label notes that some of the estrogen is absorbed into the body (section 5.1).
Source
PREMARIN (conjugated estrogens) vaginal cream, prescribing information and Patient Information. Wyeth Pharmaceuticals (Pfizer). DailyMed, version published June 2, 2025. DailyMed setid 96609623-528e-4aba-cabe-7254aed816d5
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA
Estrogen-alone therapy: a woman with a uterus who uses estrogen without a progestin has a higher risk of endometrial cancer, and unexplained or repeated abnormal bleeding is checked, including endometrial sampling when indicated. In the Women's Health Initiative (WHI), daily oral conjugated estrogens (CE) 0.625 mg alone raised the risk of stroke and deep vein thrombosis over 7.1 years, and the WHI Memory Study found a higher risk of probable dementia in women 65 and older. Estrogen plus progestin therapy: CE plus medroxyprogesterone acetate (MPA) 2.5 mg raised the risk of DVT, pulmonary embolism, stroke, heart attack, invasive breast cancer and probable dementia. Neither is to be used to prevent heart disease or dementia. Without comparable data, the label says these risks should be assumed to be similar for other doses and forms of estrogens. Estrogens are prescribed at the lowest effective dose for the shortest duration consistent with treatment goals and risks.
These are the label's own numbers from the Adverse Reactions section. Where the label compares with placebo (a dummy treatment), both columns are shown, so you can see how much more often a reaction happened on Premarin Vaginal Cream.
| Adverse reaction | PVC 21/7 (N=143) | Placebo 21/7 (N=72) | PVC 2x/week (N=140) | Placebo 2x/week (N=68) |
|---|---|---|---|---|
| Breast pain | 7 (4.9) | 0 | 3 (2.1) | 0 |
| Headache | 5 (3.5) | 1 (1.4) | 3 (2.1) | 1 (1.5) |
| Pelvic pain | 4 (2.8) | 2 (2.8) | 4 (2.9) | 0 |
| Vulvovaginal disorder | 4 (2.8) | 0 | 3 (2.1) | 2 (2.9) |
| Leukorrhea | 3 (2.1) | 1 (1.4) | 4 (2.9) | 5 (7.4) |
| Vasodilation | 3 (2.1) | 2 (2.8) | 2 (1.4) | 0 |
| Vaginitis | 2 (1.4) | 1 (1.4) | 3 (2.1) | 3 (4.4) |
| Metrorrhagia | 0 | 0 | 0 | 2 (2.9) |
| Vaginal hemorrhage | 2 (1.4) | 0 | 1 (0.7) | 1 (1.5) |
| Pruritus | 2 (1.4) | 1 (1.4) | 1 (0.7) | 0 |
| Dysuria | 2 (1.4) | 0 | 0 | 0 |
| Vaginal moniliasis | 2 (1.4) | 0 | 0 | 0 |
12-week double-blind study of postmenopausal women. PVC 21/7 is 0.5 g of cream daily for 21 days then 7 days off; PVC 2x/week is 0.5 g twice weekly; each had its own matching placebo. Cells are number of women (percent). Shown are rows at 2% or more in any group.
In a 52-week study of the cream alone (0.5 g twice weekly, or daily for 21 days then 7 days off), there was no evidence of endometrial hyperplasia or endometrial cancer; 155 women had evaluable biopsies at week 52 (14.1).
At week 12, superficial vaginal cells rose 28% (21/7) and 26% (twice weekly) vs 3% and 1% on placebo, and vaginal pH fell by 1.62 and 1.57 vs 0.36 and 0.26.
WHI CE alone vs placebo, per 10,000 women-years: stroke 45 vs 33; VTE 30 vs 22; DVT 23 vs 15. CE plus MPA vs placebo: stroke 33 vs 25; DVT 26 vs 13; pulmonary embolism 18 vs 8.
WHIMS, women 65 to 79: probable dementia 37 vs 25 cases per 10,000 women-years on CE alone (relative risk 1.49), and 45 vs 22 on CE plus MPA (relative risk 2.05).
Reported after approval: abnormal bleeding or spotting, pelvic pain, fibroid growth, vaginal yeast infection, cystitis-like symptoms, vulvovaginal burning, irritation and itching, endometrial hyperplasia and cancer, breast tenderness and enlargement, blood clots, heart attack, stroke, nausea, hair loss, migraine, mood changes, weight change and hypersensitivity.
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Who should not use it. Women with undiagnosed abnormal genital bleeding, current or past breast cancer, estrogen-dependent cancer, active or past DVT, pulmonary embolism, stroke or heart attack, a known anaphylactic reaction or angioedema to Premarin, liver impairment or disease, or protein C, protein S or antithrombin deficiency or other clotting disorders.
Absorption into the body. Some of the estrogen in the cream is absorbed into the bloodstream, so the label says the warnings, precautions and side effects of oral Premarin are taken into account.
Blood clots, stroke and heart attack. Estrogen alone raised the risk of stroke and DVT; estrogen plus progestin raised the risk of pulmonary embolism, DVT, stroke and heart attack. Treatment is stopped right away if one occurs or is suspected, and if feasible 4 to 6 weeks before surgery linked to clots.
Endometrial, breast and ovarian cancer. Estrogen without a progestin raises endometrial cancer risk 2 to 12 times in women with a uterus. CE plus MPA raised invasive breast cancer risk in the WHI, and hormone therapy has been linked to more abnormal mammograms and to ovarian cancer.
Probable dementia. In women 65 to 79, probable dementia was more common on CE alone and on CE plus MPA than on placebo. Whether this applies to younger women is unknown.
Gallbladder, calcium, vision and blood pressure. Estrogens are linked to a 2- to 4-fold rise in gallbladder disease needing surgery (5.5), severe high calcium in breast cancer spread to bone (5.6), retinal blood clots (5.7), rare blood pressure rises (5.9) and high triglycerides with pancreatitis (5.10).
Allergic reactions and other conditions. Anaphylaxis and angioedema have been reported with oral Premarin. Estrogens can raise thyroid hormone needs, cause fluid retention and low calcium in hypoparathyroidism, and worsen endometriosis, hereditary angioedema, asthma, diabetes, epilepsy, migraine, porphyria, lupus and liver hemangiomas (sections 5.12 to 5.18).
Condoms and diaphragms. The cream has been reported to weaken latex condoms, and may weaken and contribute to the failure of latex or rubber condoms, diaphragms or cervical caps.
From the Patient Information that comes with Premarin Vaginal Cream:
Dose Track has a side-effect log. Each entry records the symptom, a severity (none, mild, moderate, severe or life-threatening), the date and an optional note, and can be tied to a specific dose or logged on its own. The history screen shows what you logged over time, which makes it easier to tell your prescriber when a reaction started and whether it is easing. The app records what you enter; it does not judge whether a symptom is serious. For anything on the label's call-your-doctor list, call your doctor.
This page is what the FDA label says, in plain words. It is not medical advice. Follow your prescriber, and ask them or your pharmacist about anything here.