This grade answers one narrow question: how strong is the public evidence and safety record behind this drug, and how clean is its money trail and court record? It is not a verdict on whether the drug is right for you.
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than “synthetic” estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer .) CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders .) The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies . ) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WH...
INDICATIONS AND USAGE Estradiol tablets are indicated in the: Treatment of moderate to severe vasomotor symptoms associated with the menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL PHARMACOLOGY , Clinical Studies . ) The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average ...
CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Active deep vein thrombosis, pulmonary embolism or history of these conditions. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction. Liver dysfunction or disease. Estradiol tablets should not be used in patients with known hypersensitivity to its ingredients. Estradiol tablets 2 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Known or suspected pregnancy. There is no indication for estradiol tablets in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens a...
WARNINGS See BOXED WARNINGS . 1. Cardiovascular disorders Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Coronary heart disease and stroke In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing . (See CLINICAL PHARMACOLOGY, Clinical Studies .) In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receivi...
ADVERSE REACTIONS See BOXED WARNINGS , WARNINGS , and PRECAUTIONS . The following additional adverse reactions have been reported with estrogen and/or progestin therapy. 1. Genitourinary system Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea Increase in size of uterine leiomyomata Vaginitis, including vaginal candidiasis Change in amount of cervical secretion Changes in cervical ectropion Ovarian cancer; endometrial hyperplasia; endometrial cancer 2. Breasts Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer 3. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure 4. Gastrointestinal Nausea, vomiting Abdominal cramps, bloating Cholestatic jaundice Increased incidence of gallbladder disease Pancreatitis Enlargement of hepatic hemangiomas 5. Skin Chloasma or melasma that may persist when drug is discontinued Erythema multiforme Erythema nodosum Hemorrhagic eruption Loss of scalp hair Hirsutism Pruritus, rash 6. Eyes Retinal vascular thrombosis Steepening of cor...
Source: FDA SPL label for Estradiol (PharmPak, Inc.), effective 20250116. Full label on DailyMed.
These are counts of reports people filed, not rates of harm. Anyone can file one, and nobody checks whether the drug was the cause. Millions of doses are taken for every report sent, so the useful part is how this drug compares with the average across all drugs.
| 2019 | 2020 | 2021 | 2022 | 2023 | 2024 | 2025 | 2026 |
|---|---|---|---|---|---|---|---|
| 7,847 | 6,737 | 5,584 | 5,197 | 5,526 | 5,714 | 7,628 | 4,714 |
3,495 reports blaming this drug for every million Medicare prescriptions filled, which is 1.3× the typical drug on this site. (18,004 reports in 2024–2026, against 5,150,722 Medicare fills in one year. This is the one number here that accounts for how many people take the drug.)
Source: the FDA's Adverse Event Reporting System (FAERS). Reports are voluntary and unverified. Drugs that are prescribed a lot, in the news, or in lawsuits attract more reports, so the percentages are compared with the whole database to correct for that partly, not fully.
| Date | Class | Firm | Reason |
|---|---|---|---|
| 05/2026 | Class II | ANI Pharmaceuticals, Inc. | Defective Container; packets were found to be either empty or partially full. |
| 05/2024 | Class III | Zydus Pharmaceuticals (USA) Inc | Failed Impurities/Degradation Specifications. |
| 05/2024 | Class III | Zydus Pharmaceuticals (USA) Inc | Failed Impurities/Degradation Specifications. |
| 02/2023 | Class III | Padagis US LLC | Failed Content Uniformity Specifications: The Spray Content Uniformity (SCU) requirement for Standard Deviation did not meet the requirement at the 18-month stability time point. |
| 01/2022 | Class II | CARDINAL HEALTHCARE | CGMP Deviations: Products were exposed to temperatures outside of the products labeled storage conditions. |
| 04/2021 | Class II | Noven Pharmaceuticals Inc | Defective Delivery System: Out of specification for release rate testing and shear, an attribute related to the adhesive properties of the transdermal patches. As a result, patients could experience patches that do not stick well to the ski |
| 04/2021 | Class II | Noven Pharmaceuticals Inc | Defective Delivery System: Out of specification for release rate testing and shear, an attribute related to the adhesive properties of the transdermal patches. As a result, patients could experience patches that do not stick well to the ski |
| 03/2021 | Class II | Cardinal Health Inc. | CGMP Deviations: Intermittent exposure to temperature excursion during storage. |
| 10/2019 | Class II | Glenmark Pharmaceuticals Inc., USA | Defective Delivery System: complaints for difficulty in pushing the plunger of the applicator. |
| 06/2019 | Class II | Glenmark Pharmaceuticals Inc., USA | Defective Delivery System: Estradiol Vaginal Inserts USP plunger is not functioning properly. |
| 12/2018 | Class II | Glenmark Pharmaceuticals Inc., USA | Defective Delivery System: Customer complaints of malfunctioning plunger of the applicator |
| 09/2018 | Class II | Noven Pharmaceuticals, Inc. | Defective Delivery System: out of specification results for shear, an attribute related to the adhesive properties of the transdermal patches. |
Class I = reasonable probability of serious harm. Class II = temporary or reversible harm. Class III = unlikely to harm. Most generic recalls are manufacturing or labeling defects for one lot, not a verdict on the molecule.
Counts measure how much evidence exists and how transparent it is, not how big the benefit is. For that, ask your prescriber: if 100 people like me took this, how many would get better because of it, and how many would be harmed? (Doctors call these the "number needed to treat" and "number needed to harm.") It differs by condition and is the number drug ads leave out. Sources: PubMed, ClinicalTrials.gov.
In 2024, drug companies reported $140,239 in payments to US physicians and hospitals tied to this drug across 3,849 transactions (Estrogel $73,588, Femring $65,660, Estring $991).
No pending federal MDL names this drug or its brands.
Not named in any federal pharmaceutical settlement of $100M or more on record.
Sources: CMS Open Payments (Sunshine Act); Judicial Panel on Multidistrict Litigation pending docket list; DOJ settlements as tabulated on Wikipedia with links to the primary record. State-court and individual suits are not included.
| Product | Fills | $/fill |
|---|---|---|
| Estradiol | 4,055,858 | $54 |
| Estradiol (Twice Weekly) | 319,673 | $96 |
| Estradiol (Once Weekly) | 212,657 | $86 |
| Yuvafem | 203,105 | $150 |
| Dotti | 122,816 | $108 |
| Estring | 90,750 | $542 |
| Imvexxy | 34,317 | $398 |
| Lyllana | 24,542 | $113 |
Same ATC pharmacological class, graded ones first, best grade at the top. Being in the same class does not make them interchangeable for your condition; it makes them worth asking about.