Short answer: In the label's 12-week placebo-controlled study, the most common Divigel side effects were irregular bleeding (metrorrhagia, 9.6% on 1.0 g a day vs 1.6% on placebo), breast tenderness (8.8% vs 1.6%), vaginal yeast infection, nasopharyngitis and upper respiratory infection. Application site reactions were under 1%. The boxed warning covers endometrial cancer with estrogen alone in women with a uterus.
What Divigel is approved for: Divigel is an estrogen gel approved to treat moderate to severe hot flashes (vasomotor symptoms) due to menopause (section 1.1). The label says timing matters for the overall benefit and risk, and to consider starting it in women under 60 or within 10 years of menopause onset (section 2.1).
Source
DIVIGEL (estradiol gel) 0.1% for topical use, prescribing information and Patient Information. Vertical Pharmaceuticals. DailyMed, version published March 5, 2026. DailyMed setid 59e610dc-883e-4f07-9ec6-a5841b0bf9fb
WARNING: ENDOMETRIAL CANCER WITH UNOPPOSED ESTROGEN IN WOMEN WITH A UTERUS
A woman with a uterus who uses estrogen without a progestogen has a higher risk of endometrial cancer. Adding a progestogen has been shown to lower the risk of endometrial hyperplasia, which may come before endometrial cancer. Menopausal women with abnormal genital bleeding of unknown cause are checked, including with endometrial sampling when indicated, to rule out cancer. The February 2026 label removed the earlier boxed items on cardiovascular disorders, breast cancer and probable dementia; blood clots, stroke and breast cancer are now covered in Warnings and Precautions (5.1, 5.2).
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 Divigel.
| Adverse reaction | Divigel 0.25 g/day (N=122) | Divigel 0.5 g/day (N=123) | Divigel 1.0 g/day (N=125) | Placebo (N=125) |
|---|---|---|---|---|
| Nasopharyngitis | 7 (5.7) | 5 (4.1) | 6 (4.8) | 5 (4.0) |
| Upper respiratory tract infection | 7 (5.7) | 3 (2.4) | 2 (1.6) | 2 (1.6) |
| Vaginal mycosis (yeast infection) | 1 (0.8) | 3 (2.4) | 8 (6.4) | 4 (3.2) |
| Breast tenderness | 3 (2.5) | 7 (5.7) | 11 (8.8) | 2 (1.6) |
| Metrorrhagia (irregular bleeding) | 5 (4.1) | 7 (5.7) | 12 (9.6) | 2 (1.6) |
Adverse reactions reported by more than 5% of patients in any treatment group. 495 postmenopausal women. Values are number of women (percent).
In the 12-week placebo-controlled study, application site reactions were seen in less than 1% of women.
WHI estrogen-alone trial (oral CE 0.625 mg), women 50 to 79: DVT 23 vs 15 per 10,000 women-years on placebo (relative risk 1.48); stroke 45 vs 34 (relative risk 1.35); pulmonary embolism 14 vs 10. In women 50 to 59: DVT 13 vs 8, pulmonary embolism 10 vs 6, stroke 16 vs 17.
Endometrial cancer risk with estrogen alone in a woman with a uterus is about 2 to 12 times that of non-users, and 15 to 24 times with 5 to 10 years or more of use, persisting at least 8 to 15 years after stopping.
Breast cancer: in WHI, CE alone was not linked to more invasive breast cancer (28 vs 35 per 10,000 women-years, relative risk 0.79). A meta-analysis of 24 studies found a relative risk of 1.33 with 5 to 14 years of current estrogen-only use. Ovarian cancer relative risk was 1.37 with current estrogen-only use in a meta-analysis of 17 studies.
Washing the application site with soap and water 1 hour after use lowered average 24-hour estradiol exposure by 30 to 38%.
Reported after approval: missed or painful periods, ovarian cyst, vaginal discharge, breast enlargement in men, palpitations, flatulence, itchy rash, hives, retinal vein occlusion, tremor, joint pain, application site rash, fatigue, insomnia, muscle spasms and weight gain, among others.
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, current or past DVT, pulmonary embolism, stroke or heart attack, liver impairment or disease, protein C, protein S or antithrombin deficiency or other clotting disorders, or a known allergic reaction to Divigel.
Blood clots and stroke. The WHI estrogen-alone trial found more pulmonary embolism, DVT and stroke. Divigel is stopped right away if one occurs or is suspected and, if feasible, at least 4 to 6 weeks before surgery linked to clots or during long immobilization. Only oral CE 0.625 mg was studied, so how the findings apply to a gel is not known.
Endometrial, breast and ovarian cancer. Estrogen alone raises endometrial cancer risk in women with a uterus. Breast exams and mammography are recommended, and estrogen alone has been linked to more abnormal mammograms. Meta-analyses link current estrogen-only use to breast and ovarian cancer.
Estrogen plus progestogen. Adding a progestogen lowers endometrial hyperplasia, but combined use carries risks that differ from estrogen alone, described in the progestogen's own label.
Gallbladder disease. A 2- to 4-fold rise in gallbladder disease needing surgery has been reported in postmenopausal women taking estrogens.
Vision problems. Blood clots in the retina have been reported. Divigel is stopped pending exam for sudden vision loss, bulging eyes, double vision or migraine, and permanently if papilledema or retinal vessel lesions are found.
Triglycerides, liver and calcium. In women with high triglycerides, estrogen can raise them and cause pancreatitis (5.8). Divigel is stopped if jaundice from bile blockage returns (5.9). Estrogen can cause severe high calcium in breast cancer that has spread to bone (5.5) and low calcium in hypoparathyroidism (5.12).
Thyroid, fluid and other conditions. Women on thyroid hormone may need higher doses. Estrogen can cause fluid retention and may worsen endometriosis, hereditary angioedema, asthma, diabetes, epilepsy, migraine, porphyria, lupus and liver hemangiomas (sections 5.10 to 5.15).
Flammable gel and transfer to others. Divigel contains alcohol, so fire, flame and smoking are avoided until it has dried. Estradiol can pass to another person through skin contact, so contact is avoided until the gel is dry and the site is covered with clothing (section 5.19).
From the Patient Information that comes with Divigel:
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.