Estring Information
Estring ()
Estring () Warnings
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See and and .)
The Women's Health Initiative (WHI) estrogen alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with daily oral conjugated estrogens (CE 0.625 mg) relative to placebo. (See and .)
The estrogen plus progestin WHI substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. (See and and .)
The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See and and .)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estring () Description
Estring () ® (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form the ring. When placed in the vagina, Estring () releases estradiol, approximately 7.5 mcg per 24 hours, in a consistent stable manner over 90 days. Estring () has the following dimensions: outer diameter 55 mm; cross-sectional diameter 9 mm; core diameter 2 mm. One Estring () should be inserted into the upper third of the vaginal vault, to be worn continuously for three months.
Estradiol is chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular formula of estradiol is CHOand the structural formula is:
The molecular weight of estradiol is 272.39.
Estring () 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.
Estring () Clinical Studies
Two pivotal controlled studies have demonstrated the efficacy of Estring () (estradiol vaginal ring) in the treatment of postmenopausal urogenital symptoms due to estrogen deficiency.
In a U.S. study where Estring () was compared with conjugated estrogens vaginal cream, no difference in efficacy between the treatment groups was found with respect to improvement in the physician's global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving Estring () and cream, respectively) and in the patient's global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving Estring () and cream, respectively) after 12 weeks of treatment. In an Australian study, Estring () was also compared with conjugated estrogens vaginal cream and no difference in the physician's assessment of improvement of vaginal mucosal atrophy (79 percent and 75 percent for Estring () and cream, respectively) or in the patient's assessment of improvement in vaginal dryness (82 percent and 76 percent for Estring () and cream, respectively) after 12 weeks of treatment.
In the U.S. study, symptoms of dysuria and urinary urgency improved in 74 percent and 65 percent, respectively, of patients receiving Estring () as assessed by the patient. In the Australian study, symptoms of dysuria and urinary urgency improved in 90 percent and 71 percent, respectively, of patients receiving Estring () as assessed by the patient.
In both studies, Estring () and conjugated estrogens vaginal cream had a similar ability to reduce vaginal pH levels and to mature the vaginal mucosa (as measured cytologically using the maturation index and/or the maturation value) after 12 weeks of treatment. In supportive studies, Estring () was also shown to have a similar significant treatment effect on the maturation of the urethral mucosa.
Endometrial overstimulation, as evaluated in non-hysterectomized patients participating in the U.S. study by the progestogen challenge test and pelvic sonogram, was reported for none of the 58 (0 percent) patients receiving Estring () and 4 of the 35 patients (11 percent) receiving conjugated estrogens vaginal cream.
Of the U.S. women who completed 12 weeks of treatment, 95 percent rated product comfort for Estring () as excellent or very good compared with 65 percent of patients receiving conjugated estrogens vaginal cream, 95 percent of Estring () patients judged the product to be very easy or easy to use compared with 88 percent of cream patients, and 82 percent gave Estring () an overall rating of excellent or very good compared with 58 percent for the cream.
The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (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) (nonfatal myocardial infarction [MI], silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The 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 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 6.8 years are presented in Table 2.
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 was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See , , and .)
Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no overall difference from primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see ).
Centrally adjudicated results for stroke events from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtypes or severity, including fatal strokes, in women receiving CE alone compared to placebo. Estrogen alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined (see ).
The estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 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 (relative risk [RR] 1.15, 95 percent nCI 1.03–1.28).
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/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See and .)
Results of the estrogen plus progestin substudy, which included 16,608 women (average of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 3. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
The estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95 percent CI, 0.83–2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See and .)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI, 1.21–3.48) compared to placebo.
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 CI, 1.19–2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See and .)
Estring () Indications And Usage
Estring () (estradiol vaginal ring) is an estrogen indicated for the treatment of moderate to severe urogenital symptoms due to postmenopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).
Estring () Contraindications
Estring () vaginal ring should not be used in women with any of the following conditions:
Estring () Warnings
Estring () is a vaginal administered product with low systemic absorption following continuous use for 3 months (see ). The estrogen plus progestin substudy of WHI utilized systemically-absorbed oral estrogen/progestin. However, the warnings, precautions, and adverse reactions associated with oral estrogen and/or progestin therapy should be considered in the absence of comparable data with other dosage forms of estrogens and/or progestins.
Estring () Precautions
Estring () 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 patients involved in studies utilizing Estring () to determine whether those over 65 years of age differ from younger subjects in their response to Estring () .
In the estrogen alone substudy of the Women's Health Initiative (WHI) study, 46 percent (n = 4,943) of subjects were 65 years of age and older, while 7.1 percent (n = 767) of subjects were 75 years of age and older. There was a higher relative risk (daily CE 0.625 mg versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older.
In the estrogen alone substudy of the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years of age, was randomized to receive daily conjugated estrogens (CE 0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women-years compared with placebo.
Of the total number of subjects in the estrogen plus progestin substudy of WHI, 44 percent (n = 7,320) were 65 years of age and older, while 6.6 percent (n = 1,095) were 75 years of age and older. In women 75 years of age and older compared to women less than 75 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.
In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomized to receive CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.
Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease.
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 CI, 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 and .)
Estring () 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 the two pivotal controlled studies, discontinuation of treatment due to an adverse event was required by 5.4 percent of patients receiving Estring () and 3.9 percent of patients receiving conjugated estrogens vaginal cream. The most common reasons for withdrawal from Estring () treatment due to an adverse event were vaginal discomfort and gastrointestinal symptoms.
The adverse events reported with a frequency of 3 percent or greater in the two pivotal controlled studies by patients receiving Estring () or conjugated estrogens vaginal cream are listed in Table 4.
Other adverse events (listed alphabetically) occurring at a frequency of 1 to 3 percent in the two pivotal controlled studies by patients receiving Estring () include: anxiety, bronchitis, chest pain, cystitis, dermatitis, diarrhea, dyspepsia, dysuria, flatulence, gastritis, genital eruption, urogenital pruritus, hemorrhoids, leg edema, migraine, otitis media, skin hypertrophy, syncope, toothache, tooth disorder, urinary incontinence.
Estring () Overdosage
Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. Treatment of overdose consists of discontinuation of Estring () together with institution of appropriate symptomatic care.
Estring () Dosage And Administration
One Estring () (estradiol vaginal ring) is to be inserted as deeply as possible into the upper one-third of the vaginal vault. The ring is to remain in place continuously for three months, after which it is to be removed and, if appropriate, replaced by a new ring. The need to continue treatment should be assessed at 3 or 6 month intervals.
Should the ring be removed or fall out at any time during the 90-day treatment period, the ring should be rinsed in lukewarm water and re-inserted by the patient, or, if necessary, by a physician or nurse.
Retention of the ring for greater than 90 days does not represent overdosage but will result in progressively greater underdosage with the attendant risk of loss of efficacy and increasing risk of vaginal infections and/or erosions.
Estring () How Supplied
Each Estring () (estradiol vaginal ring) is individually packaged in a heat-sealed rectangular pouch consisting of three layers, from outside to inside: polyester, aluminum foil, and low density polyethylene, respectively. The pouch is provided with a tear-off notch on one side.
NDC 0013-2150-36 Estring () (estradiol vaginal ring) 2 mg - available in single packs.
Estring ()
Estring () Patient Information
Read this PATIENT INFORMATION before you start using Estring () and read the patient information each time you refill your Estring () prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms and their treatment.
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Estring () Principal Display Panel - Mg Ring Carton
