Estradiol is an active pharmaceutical ingredient in the Natural and Semisynthetic Estrogens, Plain group (G03CA). The information below is compiled per regulator from the product labels on record, with direct links to the original documents.
GBOfficial regulatory label· revised March 13, 2026[1]
• Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women. • Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
4) The experience treating women older than 65 years is limited.
How to take
CACanada· Health Canada
32 products
Uses
CAOfficial regulatory label· revised March 22, 2025[2]
g. hot flushes, sleep disturbances and vulvar and vaginal atrophy. The above indication is only for women with intact uteri since the regimen includes a progestin whose role is to prevent endometrial hyperplasia/carcinoma. 1 Pediatrics Pediatrics: ESTALIS is not indicated for use in children.
2 Geriatrics Geriatrics (> 65 years of age): No clinical studies were conducted to evaluate the effect of ESTALIS on women more than 65 years old. Therefore, ESTALIS is not recommended in women over 65 years of age.
How to take
USUnited States· FDA
16 products
Uses
USOfficial regulatory label· revised April 13, 2026[3]
INDICATIONS AND USAGE
01% is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.
How to take
US
Drug interactions
Known interactions involving Estradiol. Select one for details. This list is informational and not a complete interaction checker.
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[1]MHRA (UK) · PL283970016 · revised March 13, 2026
[2]Health Canada (DPD) · 02241835 · revised March 22, 2025
[3]FDA DailyMed · 0137d491-6917-40… · revised April 13, 2026 [PDF]
[4]OpenFDA adverse-event reports (US), 12 months ending June 4, 2026.
Information on this page is compiled from public regulatory records. Drugvu is not affiliated with any regulator or pharmaceutical manufacturer. This is not medical advice. Always consult a qualified healthcare professional.
GBOfficial regulatory label· revised March 13, 2026[1]
Posology Oestrogel should be administered daily on a continuous basis. Dosing in women without a uterus Oestrogel is an estrogen-only product particularly indicated for women without a uterus. Oestrogel should be administered daily on a continuous basis.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women. Dosing in women with an intact uterus In women with a uterus, consideration should be given to the addition of a progestagen including progesterone for at least 12 to 14 days every month / 28-day cycle to reduce the risk of endometrial hyperplasia and carcinoma.
Oestrogel should be administered daily on a continuous sequential basis. 5 mg estradiol) is the usual starting dose, which in the majority of women will provide effective relief of symptoms. 0 mg estradiol). 4) should be used.
Initiation of treatment:
Women who have never taken HRT and are post-menopausal or have very infrequent menstrual cycles: • Treatment with Oestrogel can be started on any day. Switching from a continuous oestrogen-progestogen combined HRT: • Treatment with Oestrogel can be started on any day of the cycle.
Switching from a cyclic or continuous sequential HRT treatment: • Finish the therapeutic sequence before beginning treatment with Oestrogel. 5 mg estradiol) once daily. The lowest effective dose for the prevention of osteoporosis is not known.
Method of administration For local cutaneous use. The gel should be applied by the patient herself, not by anyone else, and skin contact, particularly with a male partner, should be avoided for one hour after application. Wash hands with soap and water after applying the gel.
Washing the skin or contact with other skin products should be avoided until at least one hour after application of Oestrogel. Secondary exposure to estradiol can potentially occur as a result of passive transfer following skin-to-skin contact.
4). g. on the arms and shoulders, or inner thighs. A thin layer of the gel should be applied to the entire arm on the inside and outside from wrist to shoulder or inner thigh. The area of application should be as large as possible. Oestrogel should NOT be applied on or near the breasts or on the vulval region.
A frequent change in application sites is recommended.
Application Areas:
Arms from wrist to shoulder Inner thighs Oestrogel must be allowed to dry for 5 minutes before covering the skin with clothing. If the patient forgets to apply a dose and it is more than 12 hours until the next dose, the missed dose should be applied and normal dosing resumed the next day.
If the next dose is less than 12 hours away, it is best just to wait and apply the next dose normally. Forgetting a dose may increase the likelihood of break-through bleeding and spotting. Patients should be advised not to apply two doses at the same time.
Elderly people As for adults. The experience treating women older than 65 years is limited. Paediatric population There is no relevant use of Oestrogel in children aged less than 12 years.
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
GBOfficial regulatory label· Adverse reactions· revised March 13, 2026[1]
Undesirable effects are generally mild and rarely require treatment withdrawal. Undesirable effects, if any, usually occur during the first months of treatment. Adverse effects have been ranked under headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100; ≤ 1/10); uncommon (≥ 1/1,000; ≤ 1/100); rare (≥ 1/10,000; ≤ 1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).
Table 1:
Adverse Reaction Tabulation based on the Frequency Report for Estradiol total spontaneous cumulative MeDRA Term Frequency calculations based on the Frequency Report for Estradiol total spontaneous cumulative ADRs: 20,193 ADR Frequency report - 01/01/1900 - 07/31/2023 Adverse reactions – preferred termsOrgan System Class Very Common (≥10) (No adverse reactions noted for this frequency) Common (≥1/100, <1/10) Uncommon (≥1/1000, <1/100) Rare (≥1/10000 to ≤1/1000) Very rare (<1/10,000) Frequency not known (No adverse reactions noted for this frequency) Metabolism and nutrition disorders Glucose intolerance Psychiatric disorders Depression, Mood swings Change in libido Nervous system disorders Headache Vertigo, migraine Aggravation of epilepsy Gastrointestinal disorders Nausea, abdominal pain Flatulence, vomiting Eye disorders Contact lens intolerance Vascular disorders Venous thromboembolic disease Arterial hypertension Hepatobiliary disorders Liver function test abnormalities, cholestasis and jaundice Skin and subcutaneous tissue disorders Pruritus Skin discolouration, acne Musculoskeletal and connective tissue disorders Bone pain Reproductive system and breast disorders Breast swelling/pain, breast enlargement, dysmenorrhoea , menorrhagia, metrorrhagia, leucorrhoea discharge, endometrial hyperplasia increased volume of uterine fibroids, leiomyoma, vaginitis/vaginal candidiasis General disorders and administration Site conditions Weight change (increase or decrease), water retention with peripheral oedema Asthenia Anaphylactic reaction (in women a history of allergic reaction) Breast cancer risk • An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.
• The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestogen combinations. 4). • Absolute risk estimations based on results of the largest randomised placebocontrolled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.
Largest meta-analysis of prospective epidemiological studies Estimated additional risk of breast cancer after 5 years’ use in women with BMI 27 (kg/m2) Age at start HRT (years) Incidence per 1000 never- users of HRT over a 5 year period (50- 54 years) * Risk ratio .
0 *: Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2).
Note:
Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately. 8 *Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2).
Note:
Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately. 5) +4 (0 – 9) *: WHI study in women with no uterus, which did not show an increase in risk of breast cancer.
‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users. Endometrial cancer risk Postmenopausal women with a uterus The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. 2). 4). 56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.
3-3-fold increased […]
GBOfficial regulatory label· Warnings and precautions· revised March 13, 2026[1]
This medicine is for external use only and should not therefore be swallowed. Care should be taken to ensure cleanliness of the skin and hands during application. Do not apply to damaged skin. For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life.
In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk. Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited.
Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women. Medical Examination and Follow-Up Before initiating or reinstituting HRT, a complete personal and family medical history should be taken.
Physical (including pelvic and breast) examination should be guided by this and by contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman.
Women should be advised what changes in their breasts should be reported to their doctor or nurse (see “Breast cancer” below). g. mammography should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions Which Need Supervision If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. g. g. 3) and in the following situations: • Jaundice or deterioration in liver function • Significant increase in blood pressure • New onset of migraine-type headache • Pregnancy Warnings: Endometrial hyperplasia and carcinoma In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods.
8). After stopping treatment risk may remain elevated for at least 10 years. The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non- hysterectomised women prevents the excess risk associated with oestrogenonly HRT.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
GBOfficial regulatory label· Contraindications· revised March 13, 2026[1]
g. g. g. g. angina, myocardial infarction); • Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal; • Porphyria
This is not medical advice. Consult a qualified healthcare professional.
CAOfficial regulatory label· revised March 22, 2025[2]
1 Dosing Considerations • For initiation and maintenance of treatment, the lowest effective dose should always be used. • Hormone replacement therapy (HRT) involving either estrogen alone or estrogen- progestogen combined therapy should only be continued as long as the benefits outweigh the risks for the individual.
• ESTALIS is used as a continuous treatment (uninterrupted application twice weekly). • In women who are not currently taking oral estrogens, treatment with ESTALIS (NETA/estradiol-17ß) can be initiated at once. In women who are currently taking oral estrogen, treatment with ESTALIS can be initiated on reappearance of menopausal symptoms, following discontinuation of oral therapy.
Combination progestin/estrogen regimens are indicated for women with intact uteri. Two ESTALIS (NETA/estradiol-17ß) patches are available: 140 mcg norethindrone acetate with 50 ESTALIS® (Norethindrone Acetate and Estradiol-17ß) Page 6 of 48 Unclassified / Non classifié mcg estradiol per day (9 cm2) and 250 mcg norethindrone acetate with 50 mcg estradiol per day (16 cm2).
For all regimens, the requirement for hormone replacement therapy for menopausal symptoms should be reassessed periodically. Attempts to taper or discontinue the medication should be made at 3- to 6-month intervals. 2 Recommended Dose and Dosage Adjustment Continuous Combined Regimen: ESTALIS 140/50 or ESTALIS 250/50 mcg per day (16 cm2) is worn continuously on the abdomen or buttocks.
A new patch should be applied twice weekly during a 28-day cycle. Irregular uterine bleeding may occur particularly in the first 6 months, but generally decreases with time, and often to an amenorrheic state. If irregular uterine bleeding persists and uterine pathology has been ruled out by appropriate diagnostic measures, it may be more appropriate instead to prescribe ESTALIS using a sequential regimen.
No studies were performed in patients with renal and hepatic impairment. All estrogen preparations are contraindicated in the patients with severe hepatic impairment (see 2 CONTRAINDICATIONS). ESTALIS is not indicated for use in children.
4 Administration Patch Application The physician should discuss the most appropriate placement of the patch with the patient. Immediately after removal of a patch from the pouch and removal of one-half of the protective liner, the adhesive side of the ESTALIS patch should be placed on a clean, dry area of intact skin and peel off the remaining one-half of the protective liner.
The area selected should not be oily, damaged or irritated, and not exposed to the sun. The site selected should also be one at which little wrinkling of the skin occurs during movement of the body (buttocks and lower abdomen). The waistline should be avoided, since tight clothing may dislodge the patch.
The patch should be pressed firmly in place with the palm of the hand for at least 10 seconds, making sure there is good contact, especially around the edges. In the event that a patch should fall off, it can be reapplied. If it fails to adhere, then a new patch may be applied.
In either case, the original treatment schedule should be continued. Patches should not be applied to the same skin site for at least one week. ESTALIS must not be applied to the breasts to avoid potentially harmful effects on the breast tissue.
5 Missed Dose Patients who miss applying a patch of ESTALIS should apply a new patch as soon as possible. The subsequent patch should be applied according to the original treatment schedule. The ESTALIS® (Norethindrone Acetate and Estradiol-17ß) Page 7 of 48 Unclassified / Non classifié interruption of treatment might increase the likelihood of recurrence of symptoms and breakthrough bleeding and spotting.
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
CAOfficial regulatory label· Adverse reactions· revised March 22, 2025[2]
1 Adverse Reaction Overview See 7 WARNINGS AND PRECAUTIONS regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives. The following adverse reactions have been reported with estrogen/progestin combinations in general.
Blood and lymphatic system disorders:
Altered coagulation tests (see
CAOfficial regulatory label· Warnings and precautions· revised March 22, 2025[2]
Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. Carcinogenesis and Mutagenesis Breast Cancer Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer.
In the estrogen plus progestin arm of the WHI trial, among 10,000 women over a one-year period, there were: • 8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo). 1) vs. 04) and were at a more advanced stage compared with those diagnosed in the placebo group.
The percentage of women with abnormal mammograms ESTALIS® (Norethindrone Acetate and Estradiol-17ß) Page 9 of 48 Unclassified / Non classifié (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group.
This difference appeared at year one and persisted in each year thereafter. In the estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.
It is recommended that estrogens with or without progestins not be given to women with existing breast cancer or those with a previous history of the disease (see 2 CONTRAINDICATIONS). There is a need for caution in prescribing estrogens with or without progestins for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (breast nodules, fibrocystic disease of the breast, abnormal mammograms and/or atypical hyperplasia at breast biopsy).
Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated. It is recommended that women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.
The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of WHI-trial) be discussed with the patient and weighed against its known benefits.
Instructions for regular self-examination of the breasts should be included in this counselling. Endometrial Hyperplasia & Endometrial Carcinoma Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.
The risk of endometrial hyperplasia/carcinoma in users of unopposed estrogens who have intact uteri is greater than in non-users and appears to depend on the duration of treatment and the estrogen dose. The greatest risk appears to be associated with prolonged use.
It has been shown that adequate concomitant progestogen therapy lowers the incidence of endometrial hyperplasia and therefore the potential risk of endometrial carcinoma associated with prolonged use of estrogen therapy (see 10 CLINICAL PHARMACOLOGY, Coadministration of Progestins).
ESTALIS® (Norethindrone Acetate and Estradiol-17ß) Page 10 of 48 Unclassified / Non classifié Ovarian Cancer Some recent epidemiologic studies have found that the use of hormone replacement therapy (estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has been associated with an increased risk of ovarian cancer.
Epidemiologic evidence from a meta- analysis suggests that while the risk of ovarian cancer diminishes over time after discontinuation, the risk is still significantly increased more than five years (median time of 10 years since last use) after stopping long duration hormone therapy (median duration of treatment of nine years) for serous or endometrioid tumours.
Hepatocellular Carcinomas Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral contraceptives. The causal relationship of this malignancy to these drugs is not known. Cardiovascular The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women’s Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women.
The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women. WHI trial findings In the combined estrogen plus progestin arm of the WHI trial, among 10,000 women over a one- year period, there were: • 8 more cases of stroke (29 on combined HRT versus 21 on placebo) • 7 more cases of CHD (37 on combined HRT versus 30 on placebo).
In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10,000 women over a one-year period, there were/was: • 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo) • no statistically significant difference in the rate of CHD.
5 mg medroxyprogesterone acetate (MPA) […]
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
CAOfficial regulatory label· Contraindications· revised March 22, 2025[2]
ESTALIS is contraindicated in: • Patients with known or suspected hypersensitivity to this drug or to any ingredient in the formulation or to any component of the patch. For a complete listing, see 6 DOSAGE FORMS, STRENGHTS, COMPOSITION AND PACKAGING.
• Patients with known or suspected estrogen-dependent or progestin-dependent malignant neoplasia such as endometrial cancer. • Patients with endometrial hyperplasia • Patients with known, suspected or past history of breast cancer • Patients with known or suspected pregnancy • Patients with active or past history of confirmed venous thromboembolism (such as deep venous thrombosis or pulmonary embolism) or active thrombophlebitis • Patients with known thrombophilic disorders • Patients with liver dysfunction or disease as long as liver function tests have failed to return to normal.
g. stroke, myocardial infarction, coronary heart disease) • Patients with Porphyria • Patients with partial or complete loss of vision from ophthalmic vascular disease • Patients with Classical Migraine • Patients who are breastfeeding ESTALIS® (Norethindrone Acetate and Estradiol-17ß) Page 5 of 48 Unclassified / Non classifié
This is not medical advice. Consult a qualified healthcare professional.
01% alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should reevaluate periodically as clinically appropriate to determine if treatment is still necessary.
For treatment of vulvar and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. For women who have a uterus, adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal genital bleeding.
Usual Dosage:
The usual dosage range is 2 to 4 g (marked on the applicator) daily for one or two weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance dosage of 1 g, one to three times a week, may be used after restoration of the vaginal mucosa has been achieved.
NOTE:
The number of doses per tube will vary with dosage requirements and patient handling.
This is not medical advice. Consult a qualified healthcare professional.
Most-reported reactions to the US regulator (12 mo to June 4, 2026): 9,125 reports total. [4]
Product Adhesion Issue 1,105
Device Adhesion Issue 861
Drug Ineffective 624
No Adverse Event 571
Off Label Use 506
Nausea 481
Headache 445
Fatigue 406
Product Dose Omission Issue 382
Circumstance Or Information Capable Of Leading To Medication Error 320
Dizziness 318
Diarrhoea 303
Side effects & warnings
USOfficial regulatory label· Adverse reactions· revised April 13, 2026[3]
ADVERSE REACTIONS
See BOXED WARNINGS, WARNINGS and PRECAUTIONS . 01%. The warnings, precautions, and adverse reactions associated with oral estrogen treatment should be taken into account. The following adverse reactions have been reported with estrogen and/or progestin therapy.
1 . Genitourinary System Abnormal uterine bleeding or spotting; dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in cervical secretion; cystitis-like syndrome; application site reactions of vulvovaginal discomfort including burning and irritation; genital pruritus; ovarian cancer; endometrial hyperplasia; endometrial cancer.
2 . Breasts Tenderness, enlargement, pain, nipple discharge, fibrocystic breast changes; breast cancer. 3 . Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; myocardial infarction; stroke; increase in blood pressure.
4 . Gastrointestinal Nausea, vomiting; abdominal cramps, bloating; increased incidence of gallbladder disease. 5 . Skin Chloasma that may persist when drug is discontinued; loss of scalp hair; hirsutism; rash. 6 . Eyes Retinal vascular thrombosis, intolerance to contact lenses.
7 . Central Nervous System Headache; migraine; dizziness; mental depression; nervousness; mood disturbances; irritability; dementia. 8 . Miscellaneous Increase or decrease in weight; glucose intolerance; edema; arthralgias; leg cramps; changes in libido; urticaria; exacerbation of asthma; increased triglycerides; hypersensitivity.
gov/medwatch.
USOfficial regulatory label· Warnings and precautions· revised April 13, 2026[3]
WARNINGS
See BOXED WARNINGS . 01%. The warnings, precautions, and adverse reactions associated with oral estrogen treatment should be taken into account. 1. Cardiovascular Disorders An increased risk of stroke and DVT has been reported with estrogen-alone therapy.
An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. , personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
a. 625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted [see CLINICAL STUDIES ]. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years) 3 . 5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see CLINICAL STUDIES ]. The increase in risk was demonstrated after the first year and persisted 3 .
Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. b. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI and CHD death) was reported in women receiving estrogen-alone compared to placebo 4 [see CLINICAL STUDIES ].
625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years) 3 . 5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years) 3 . An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see CLINICAL STUDIES ].
5 mg) demonstrated no cardiovascular benefit. 1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years.
Two thousand, three hundred and twenty one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. 8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.
c. 625 mg)-alone compared to women receiving placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 5 [see CLINICAL STUDIES ].
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
USOfficial regulatory label· Contraindications· revised April 13, 2026[3]
CONTRAINDICATIONS
01% should not be used in women with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected, or history of cancer of the breast. 3. Known or suspected estrogen-dependent neoplasia. 4. Active DVT, PE or history of these conditions.
5. Active arterial thromboembolic disease (for example, stroke, MI) or a history of these conditions. 6. 01%. 7. Known liver dysfunction or disease. 8. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.
9. Known or suspected pregnancy.
This is not medical advice. Consult a qualified healthcare professional.
Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis.
Breast cancer The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or oestrogen-only HRT, that is dependent on the duration of taking HRT. 8). Oestrogen-only therapy The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT.
8). Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
HRT, especially oestrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. Ovarian cancer Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women oestrogen-only or combined oestrogen-progestogen HRT which becomes apparent within 5 years of use and diminishes over time after stopping.
8). e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than […]
Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. 5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated.
The increase in VTE risk was observed during the first year and persisted 6 [see CLINICAL STUDIES ]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
2. Malignant Neoplasms a. Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose.
Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
b. 625 mg)-alone. 80) 7 [see CLINICAL STUDIES ]. 5 mg). 6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.
24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. 86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. 09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo.
5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups 8 [see CLINICAL STUDIES ].
Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use.
One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy.
Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy.
However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
c. Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. 24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years 9 . A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer.
The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. 50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs.
greater than 5 years [median of 10 years] of use before the cancer diagnosis). 48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.
3. 625 mg)-alone or placebo. 2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. 66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years 10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use ].
5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. 48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years 10 [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use ].
60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 10 [see PRECAUTIONS, Geriatric Use ]. 4. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
5. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
6. Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine.
If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. 7. Anaphylactic Reaction and Angioedema Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered estrogen and require emergency medical management, have been reported in the postmarketing setting.
Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted. Angioedema involving the tongue, larynx, face, hands and feet requiring medical intervention has occurred postmarketing in patients taking orally-administered estrogen.
If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with oral estrogen should not receive oral estrogen again.
8. Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.