Femring Information
Femring ()
Femring () Description
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 CHO and the structural formula is:
The molecular weight of estradiol acetate is 314.42.
Femring () Clinical Pharmacology
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle which secretes 70 to 500 mcg of estradiol daily depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Femring () Clinical Studies
The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture or death due to other cause. The study did not evaluate the effects of CE or CE plus MPA on menopausal symptoms.
WHI Estrogen-Alone Substudy
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in .
For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See , , and .)
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 4).
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined (see Table 4).
Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for CHD [HR 0.63 () and overall mortality [HR 0.71 ()].
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.
For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 ()].
The estrogen-alone Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years to 79 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI 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. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and
mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See , and .)
The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were age 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) versus placebo was 2.05 (). The absolute risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See , and .)
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 (). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See , and .)
Femring () Indications And Usage
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.
Femring () Contraindications
Femring () should not be used in women with any of the following conditions:
Femring () Warnings
See
Femring () is used only in the vagina, however, the risks associated with oral estrogens should be taken into account.
Femring () Precautions
1. Addition of a progestin when a woman has not had a hysterectomy
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
2. Elevated blood pressure
In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.
3. Hypertriglyceridemia
In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis develops.
4. Hepatic impairment and/or a past history of cholestatic jaundice
Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T and T serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention
Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
7. Hypocalcemia
Estrogens should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
8. Exacerbation of endometriosis
A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
9. Exacerbation of other conditions
Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas, and should be used with caution in women with these conditions.
10. Vaginal use and expulsion
Femring () may not be suitable for women with conditions that make the vagina more susceptible to vaginal irritation or ulceration, or make expulsions more likely, such as narrow vagina, vaginal stenosis, vaginal infection, cervical prolapse, rectoceles and cystoceles. If local treatment of a vaginal infection is required, Femring () can remain in place during treatment.
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Estradiol acetate was assayed for mutation in four histidine-requiring strains of and in two tryptophan-requiring strains of . Estradiol acetate did not induce mutation in any of the bacterial strains tested under the conditions employed.
Femring () should not be used during pregnancy. (See .)
There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Femring () to determine whether those over 65 years of age differ from younger subjects in their response to Femring () .
The Women’s Health Initiative Study
In the Women's Health Initiative (WHI) estrogen-alone substudy (daily conjugated estrogens 0.625 mg versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.
In the WHI estrogen plus progestin substudy, there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age.
The Women’s Health Initiative Memory Study
In the Women’s Health Initiative Memory Study (WHIMS) of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in the estrogen-alone and the estrogen plus progestin groups when compared to placebo.
Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.
Femring () Adverse Reactions
See and
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In a 13-week clinical trial that included 225 postmenopausal women treated with Femring () and 108 women treated with placebo vaginal rings, adverse events that occurred at a rate of ≥ 2 percent are summarized in .
Femring () Overdosage
Overdosage of estrogen may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Femring () with institution of appropriate symptomatic care.
Femring () Dosage And Administration
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 and .)
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.
Femring () How Supplied
Each Femring () (estradiol acetate vaginal ring) is individually packaged in a pouch consisting of one side medical grade paper and the other side polyester/polyethylene laminate.
NDC 0430-6201-40 Femring () 0.05 mg/day (estradiol acetate vaginal ring) is available in single units.
NDC 0430-6202-40 Femring () 0.10 mg/day (estradiol acetate vaginal ring) is available in single units.
Femring () Storage
Store at 25˚ C (77˚ F); excursions permitted to 15˚ - 30˚ C (59˚ - 86˚ F) [see USP Controlled Room Temperature].
Femring () Patient Information
Read this PATIENT INFORMATION before you start using Femring () and read what you get each time you refill your Femring () prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Femring () Trade Carton - Femring . Mg
Femring ()
(estradiol acetate vaginal ring)
0.05 mg/day
(Contains 12.4 mg estradiol acetate to deliver the equivalent of 0.05 mg estradiol per day for three months.)
Other ingredients: barium sulfate and cured elastomer.
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F).
[see USP Controlled Room Temperature]
For intravaginal use only.
CONTENTS: 1 VAGINAL RING
Femring () Sample Carton - Femring . Mg
(estradiol acetate vaginal ring)
0.05 mg/day
(Contains 12.4 mg estradiol acetate to deliver the equivalent of 0.05 mg estradiol per day for three months.)
Other ingredients: barium sulfate and cured elastomer.
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F).
[see USP Controlled Room Temperature]
For intravaginal use only.
CONTENTS: 1 VAGINAL RING
Femring () Trade Carton - Femring . Mg
(estradiol acetate vaginal ring)
0.10 mg/day
(Contains 24.8 mg estradiol acetate to deliver the equivalent of 0.10 mg estradiol per day for three months.)
Other ingredients: barium sulfate and cured elastomer.
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F).
[see USP Controlled Room Temperature]
For intravaginal use only.
CONTENTS: 1 VAGINAL RING
Femring () Sample Carton - Femring . Mg
(estradiol acetate vaginal ring)
0.10 mg/day
(Contains 24.8 mg estradiol acetate to deliver the equivalent of 0.10 mg estradiol per day for three months.)
Other ingredients: barium sulfate and cured elastomer.
Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F).
[see USP Controlled Room Temperature]
For intravaginal use only.
CONTENTS: 1 VAGINAL RING
