Femring
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Questions & Answers
Side Effects & Adverse Reactions
SeeBOXED WARNINGS
Femring is used only in the vagina, however, the risks associated with oral estrogens should be taken into account.
1. Cardiovascular disordersAn increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen-alone therapy. An increased risk of pulmonary embolism, DVT, stroke, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogens with or without progestins should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous thromboembolism (for example, personal history or family history of VTE, obesity and systemic lupus erythematosus) should be managed appropriately.
a. StrokeIn the Women's Health Initiative (WHI) estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens CE (0.625 mg) compared to women of the same age 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, estrogens should be discontinued immediately.
Sub-group analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in all women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES.)
b. Coronary heart diseaseIn the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. (See CLINICAL STUDIES.)
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 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. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in the HERS, the HERS II, and overall.
c. Venous thromboembolism (VTE)In the WHI estrogen-alone substudy, the risk of VTE (DVT and pulmonary embolism [PE]), was increased for women receiving daily CE (0.625 mg) compared to 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. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogens should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 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. (See CLINICAL STUDIES.) Should a VTE occur or be suspected, estrogens 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 cancerAn 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-fold greater than in nonusers, 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 all cases of 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. Breast cancerThe most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg). In the WHI estrogen-alone substudy, after an average of 7.1 years of follow-up, daily CE (0.625 mg) was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). (See CLINICAL STUDIES.)
The most important clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of 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. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 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. (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. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). 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 estrogens or among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin 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 cancerThe WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.
3. Probable DementiaIn the estrogen-alone Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg) or placebo. In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
In the WHIMS estrogen-alone ancillary study, after an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent nCI 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)
In the WHIMS estrogen plus progestin ancillary study, 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. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent nCI 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent nCI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and PRECAUTIONS, Geriatric Use.)
4. Gallbladder diseaseA 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
5. HypercalcemiaEstrogen administration may lead to severe hypercalcemia in women 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 abnormalitiesRetinal vascular thrombosis has been reported in women 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.
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
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FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Femring therapy is indicated in the:
1. Treatment of moderate to severe vasomotor symptoms due to menopause.
2. Treatment of moderate to severe vulvar and vaginal atrophy due to menopause.
History
There is currently no drug history available for this drug.
Other Information
Femring® (estradiol acetate vaginal ring) is an off-white, soft, flexible ring with a central core containing estradiol acetate.
Femring is made of cured silicone elastomer composed of dimethyl polysiloxane silanol, silica (diatomaceous earth), normal propyl orthosilicate, stannous octoate; barium sulfate and estradiol acetate. The rings have the following dimensions: outer diameter 56 mm, cross-sectional diameter 7.6 mm, core diameter 2 mm.
Femring is available in two strengths: Femring 0.05 mg/day has a central core that contains 12.4 mg of estradiol acetate, which releases at a rate equivalent to 0.05 mg of estradiol per day for 3 months. Femring 0.10 mg/day has a central core that contains 24.8 mg of estradiol acetate, which releases at a rate equivalent to 0.10 mg of estradiol per day for 3 months.
Estradiol acetate is chemically described as estra-1,3,5(10)-triene-3,17β-diol-3-acetate. The molecular formula of estradiol acetate is C20H26O3 and the structural formula is:
The molecular weight of estradiol acetate is 314.42.
Sources
Femring Manufacturers
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Physicians Total Care, Inc.
![Femring (Estradiol Acetate) Ring [Physicians Total Care, Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Femring | Physicians Total Care, Inc.
Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin.
Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. (See BOXED WARNINGS and WARNINGS.)
Two doses of Femring are available, 0.05 mg/day and 0.10 mg/day, for the treatment of moderate to severe vasomotor symptoms and/or vulvar and vaginal atrophy due to menopause.
Patients should be started at the lowest dose. The lowest effective dose of Femring has not been determined.
Instructions for UseHands should be thoroughly washed before and after ring insertion.
Femring Insertion
Insert upon removal from the protective pouch.
The opposite sides of the vaginal ring should be pressed together and inserted into the vagina. The exact position is not critical to its function. When Femring is in place, the patient should not feel anything. If the patient feels discomfort, the vaginal ring is probably not far enough inside the vagina. Gently push Femring further into the vagina.
Femring Use
Femring should remain in place for 3 months and then be replaced by a new Femring.
The patient should not feel Femring when it is in place and it should not interfere with sexual intercourse. Straining upon bowel movement may make Femring move down in the lower part of the vagina. If so, it may be repositioned with a finger.
If Femring is expelled totally from the vagina, it should be rinsed in lukewarm water and reinserted by the patient (or healthcare provider if necessary).
Femring Removal
Femring may be removed by looping a finger through the ring and pulling it out.
For patient instructions, see PATIENT INFORMATION.
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Warner Chilcott (Us), Llc
Femring | Warner Chilcott (us), Llc
Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer.
A woman without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin [see Warnings and Precautions (5.2 , 5.14)].
Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.
2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to MenopauseStart therapy with 0.05 mg/day. Dosage adjustment should be guided by the clinical response.
Therapy should be started at the lowest effective dose and the shortest duration consistent with treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals.
2.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to MenopauseStart therapy with 0.05 mg/day. Dosage adjustment should be guided by the clinical response.
Therapy should be started at the lowest effective dose and the shortest duration consistent with treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals.
![Femring (Estradiol Acetate) Ring [Warner Chilcott (Us), Llc]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=61364915-3b0b-427d-9fef-29cdcc427ec5&name=femring-11.jpg)
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