Short answer: In the label's 12-month placebo-controlled trial, the side effects seen in at least 5% of women on Vagifem and more often than on placebo were vaginal yeast infection (8% vs 3%), vulvovaginal itching (8% vs 2%), back pain (7% vs 2%) and diarrhea (5% vs 0%). Vagifem carries the estrogen boxed warning on endometrial cancer, heart and clot risks, probable dementia and breast cancer.
What Vagifem is approved for: Vagifem is an estrogen approved to treat atrophic vaginitis due to menopause (section 1.1), which the Patient Information describes as moderate to severe menopausal changes in and around the vagina.
Source
VAGIFEM (estradiol vaginal inserts), prescribing information, Patient Information and Instructions for Use. Novo Nordisk. DailyMed, version published February 12, 2025. DailyMed setid e5ad3cf6-dd96-4e64-af21-c1eee38d0b88
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, and BREAST CANCER
Estrogen-alone therapy: there is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens; adding a progestogen reduces the risk of endometrial hyperplasia, and undiagnosed persistent or recurring abnormal genital bleeding is investigated. The WHI estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis in women 50 to 79 over 7.1 years of daily oral conjugated estrogens (CE 0.625 mg), and WHIMS reported increased probable dementia in women 65 and older over 5.2 years. Estrogen plus progestin therapy: WHI reported increased risks of pulmonary embolism, deep vein thrombosis, stroke, heart attack and invasive breast cancer over 5.6 years of CE plus medroxyprogesterone acetate (MPA 2.5 mg), and WHIMS reported increased probable dementia in women 65 and older over 4 years. Neither should be used to prevent cardiovascular disease or dementia. Only oral CE (with or without MPA) was studied, so how these findings apply to lower doses, other routes or other products is not known and the risks cannot be definitively excluded. Estrogens are prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
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 Vagifem.
| Adverse reaction | Placebo N = 103 n (%) | Vagifem N = 205 n (%) |
|---|---|---|
| Back Pain | 2 (2) | 14 (7) |
| Diarrhea | 0 | 11 (5) |
| Vulvovaginal Mycotic Infection | 3 (3) | 17 (8) |
| Vulvovaginal Pruritus | 2 (2) | 16 (8) |
A 12-month placebo-controlled trial in 309 postmenopausal women. Values are number of women (%). Vulvovaginal mycotic infection means a vaginal yeast infection.
Endometrial biopsies at the end of the 12-month trial (172 women on Vagifem): one grade 2 adenocarcinoma and one complex hyperplasia without atypia. In a second 12-month open-label study (297 biopsies): one complex hyperplasia without atypia.
WHI estrogen-alone (oral CE): stroke 45 vs 33 per 10,000 women-years and deep vein thrombosis 23 vs 15. WHI estrogen plus progestin: blood clots 35 vs 17, stroke 33 vs 25 per 10,000 women-years.
WHI invasive breast cancer: relative risk 0.80 with CE alone (7.1 years); 1.24 with CE plus MPA, 41 vs 33 cases per 10,000 women-years (5.6 years).
Probable dementia in women 65 to 79: 37 vs 25 per 10,000 women-years on CE alone, 45 vs 22 on CE plus MPA; pooled relative risk 1.76.
Reported after approval with Vagifem 10 mcg: vulvovaginal burning, pain, swelling, rash or itching, vaginal ulceration, weight gain, fluid retention, depression, insomnia, worse migraine, rash and hives, breast and endometrial cancer, endometrial hyperplasia and deep vein thrombosis.
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Absorption into the body. Vagifem is for vaginal use only, but some estradiol is absorbed into the body, so the warnings for systemic estrogen-alone therapy apply.
Stroke, heart attack and blood clots. Estrogen is stopped immediately if a stroke, heart attack or blood clot occurs or is suspected, and, if feasible, 4 to 6 weeks before surgery linked to clots or during long immobilization.
Endometrial, breast and ovarian cancer. Unopposed estrogen raises endometrial cancer risk about 2 to 12 times in women with a uterus. Estrogen plus progestin raised breast cancer risk in WHI. Yearly breast exams and mammograms based on age and risk are part of the label's guidance.
Probable dementia. WHIMS found more probable dementia in women 65 to 79 on oral estrogen with or without progestin; whether this applies to younger women is unknown.
Vision problems. Blood clots in the retina have been reported with estrogens. Vagifem is paused for sudden vision loss, bulging eyes, double vision or migraine, and stopped for good if papilledema or retinal lesions are found.
Applicator abrasion. A few cases of local abrasion from the applicator have been reported, especially with severely thinned vaginal tissue.
Who should not use it. Women with undiagnosed abnormal genital bleeding, current or past breast cancer, estrogen-dependent cancer, current or past blood clots, stroke or heart attack, liver disease, clotting disorders (protein C, protein S or antithrombin deficiency) or a known allergy to Vagifem.
From the Patient Information that comes with Vagifem:
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.