These highlights do not include all the information needed to use Vagifem safely and effectively. See full prescribing information for Vagifem.Vagifem (estradiol vaginal tablets)Initial U.S. Approval: 1999
Vagifem Information
Company Name Novo Nordisk
Vagifem (Estradiol) 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.
Vagifem (Estradiol) Dosage Forms And Strengths
Vagifem (Estradiol) is a small, white, round, film-coated, bi-convex vaginal tablet containing 10 mcg or 25 mcg of estradiol. Each vaginal tablet is 6 mm in diameter and is administered in a disposable applicator.
Vagifem (Estradiol) Contraindications
Vagifem (Estradiol) should not be used in women with any of the following conditions:
Vagifem (Estradiol) Warnings And Precautions
An 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 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 venous thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately.
Stroke
In 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 CE (0.625 mg) 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 Should a stroke occur or be suspected, estrogens should be discontinued immediately.
Subgroup 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.
Coronary Heart Disease
In the WHI estrogen - alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen alone compared to placebo .
Subgroup analysis of women 50 to 59 years of age suggests 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 the original 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 (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.
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 . 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 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.
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold 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 1 year. The greatest risk appears associated with prolonged use, with an increased risk of 15- to 24-fold for 5 to 10 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 in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Breast Cancer
The 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 follow-up of 7.1 years, daily CE (0.625 mg) was not associated with an increased risk of invasive breast cancer .
The most important randomized 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 .
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 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.
Ovarian Cancer
The 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.
In the estrogen-alone Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to daily CE (0.625 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 .
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. 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 .
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies 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 .
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.
Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), Tlevels (by column or by radioimmunoassay) or Tlevels by radioimmunoassay. Tresin uptake is decreased, reflecting the elevated TBG. Free Tand free Tconcentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
Increased plasma HDL and HDL cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
Vagifem (Estradiol) Adverse Reactions
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial 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 12-month randomized, double-blind, parallel group, placebo-controlled study, a total of 309 postmenopausal women were randomized to receive either placebo or Vagifem (Estradiol) 10 mcg tablets. Adverse events with an incidence of ≥5% in the Vagifem (Estradiol) 10 mcg group and greater than those reported in the placebo group are listed in Table 1.
In a 12-week, randomized, double-blind, placebo-controlled study, 138 postmenopausal women were randomized to receive either placebo or Vagifem (Estradiol) 25 mcg tablets. Adverse events with an incidence of ≥5% in the Vagifem (Estradiol) 25 mcg group and greater than those reported in the placebo group are listed in Table 2.
The following adverse reactions have been reported during post approval use of Vagifem (Estradiol) 25 mcg. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Endometrial cancer, endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration
Breast cancer
Deep vein thrombosis
Diarrhea
Urticaria, erythematous/pruritic rash, genital pruritus
Aggravated migraine, depression, insomnia
Fluid retention, weight increase, drug ineffectiveness, hypersensitivity, blood estrogen increase
Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.
Vagifem (Estradiol) Drug Interactions
No drug- drug interaction studies have been conducted with Vagifem (Estradiol) .
Vagifem (Estradiol) Use In Specific Populations
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Vagifem (Estradiol) to determine whether those over 65 years of age differ from younger subjects in their response to Vagifem (Estradiol) .
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 substudies when compared to placebo .
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 .
Vagifem (Estradiol) Overdosage
Overdosage of estrogen may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of Vagifem (Estradiol) together with institution of appropriate symptomatic care.
Vagifem (Estradiol) Description
Vagifem (Estradiol) 10 mcg (estradiol vaginal tablets) are small, white, film-coated tablets containing 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. Vagifem (Estradiol) 25 mcg (estradiol vaginal tablets) are small, white, film-coated tablets containing 25.8 mcg of estradiol hemihydrate equivalent to 25 mcg of estradiol. Each tablet of Vagifem (Estradiol) 10 mcg and 25 mcg contains the following excipients: hypromellose, lactose monohydrate, maize starch and magnesium stearate. The film coating contains hypromellose and polyethylene glycol. Each Vagifem (Estradiol) tablet is 6 mm in diameter and is placed in a disposable applicator. Each tablet-filled applicator is packaged separately in a blister pack. Vagifem (Estradiol) tablets are used intravaginally. When the tablet comes in contact with the vaginal mucosa, estradiol is released into the vagina.
Estradiol hemihydrate is a white, almost white or colorless crystalline solid, chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The chemical formula is CHO • ½ HO with a molecular weight of 281.4.
Vagifem (Estradiol) 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.
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.
Absorption
Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.
In a single-center, randomized, open-label, multiple-dose, parallel group study conducted in 58 patients, Vagifem (Estradiol) 10 mcg and 25 mcg demonstrated a mean estradiol (E2) C at Day 83 of 5.5 pg/mL and 11.59 pg/mL, respectively after 12 weeks of treatment (see Tables 3 and 4).
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Use in Specific Populations
Geriatric Use: There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Vagifem (Estradiol) to determine whether those over 65 years of age differ from younger subjects in their response to Vagifem (Estradiol) .
Renal Impairment: The effect of renal impairment on the pharmacokinetics of Vagifem (Estradiol) has not been studied.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Vagifem (Estradiol) has not been studied.
Drug Interactions
Vagifem (Estradiol) Clinical Studies
Vagifem (Estradiol) 10 mcg
A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of Vagifem (Estradiol) 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean age = 57.6 years) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 50 weeks. The majority (92.9%) of the women were Caucasian (n=287), 3.2% were Black (n=10), 1.6% were Asian (n=5) and 2.2% were Other (n=7). All subjects were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH.
Relief of Vaginal Symptoms
Vagifem (Estradiol) 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 5).
Also demonstrated for Vagifem (Estradiol) 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p
Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 subjects in the Vagifem (Estradiol) 10 mcg group who had a biopsy performed at end of study, 92 subjects had endometrial tissue that was atrophic or inactive and 73 subjects had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia. Three subjects exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation.
Endometrial safety of Vagifem (Estradiol) 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 subjects who had a biopsy performed at end of study, 183 subjects had endometrial tissue that was atrophic or inactive and 111 subjects had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two subjects exhibited polyps.
Vagifem (Estradiol) 25 mcg
A placebo-controlled comparison study was done in the U.S., in which 230 women were randomized to receive either placebo, Vagifem (Estradiol) 25 mcg or 10 mcg estradiol vaginal tablets. Women inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 10 weeks. All subjects were assessed for vaginal symptoms. Vagifem (Estradiol) 25 mcg was superior to placebo in reducing the severity of a composite score of symptoms associated with atrophic vaginitis (see Table 6).
An open-label, controlled comparison study was done in Canada in which 159 women were randomized to receive either Vagifem (Estradiol) 25 mcg or a comparator drug. Two (2) grams of the comparator drug was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks; Vagifem (Estradiol) 25 mcg was administered daily for 2 weeks, then twice weekly for the remaining 22 weeks. In this study, subjects were assessed for relief of symptoms. Vagifem (Estradiol) 25 mcg was equally effective as the approved comparator product at the 2.0 gm dose in the relief of symptoms.
In the placebo-controlled study endometrial biopsies in non-hysterectomized women at week 12 were performed on 86 subjects (Vagifem (Estradiol) 25 mcg: 32 subjects, estradiol 10 mcg: 33 subjects, Placebo: 21 subjects). Of these, 3 subjects each from the Vagifem (Estradiol) 25 mcg and placebo groups and 8 from the 10 mcg estradiol group had insufficient tissue samples. Among those with biopsies that yielded sufficient tissue, results were normal with the exception of one subject in the Vagifem (Estradiol) 25 mcg group, who had a simple hyperplasia without atypia.
In the open-label study comparing Vagifem (Estradiol) 25 mcg with a comparator vaginal cream on 49 women in each treatment group, endometrial biopsies were obtained at the screening visit and at the end of treatment. At the end of the study (Week 24), all subjects in the Vagifem (Estradiol) treatment group whose biopsies yielded sufficient tissue showed an atrophic endometrium with the exception of one subject who had a proliferative endometrium.
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 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 studied. 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 causes. These substudies 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 Table 7.
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 7 fewer hip fractures. The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality
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.
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 for ischemic stroke, and this excess risk was present in all subgroups of women examined, see Table 7.
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 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 breastcancers, 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 8. 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
The estrogen-alone Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 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 both the treatment and placebo groups 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 .
The WHIMS estrogen plus progestin 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; 18 percent were 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 (95 percent CI, 1.21-3.48). 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 AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in both the treatment and placebo groups 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 .
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 .
Vagifem (Estradiol) How Supplied/storage And Handling
Each Vagifem (Estradiol) (estradiol vaginal tablets), 10 mcg and 25 mcg, is contained in a disposable, single-use applicator, packaged in a blister pack. Cartons contain 8 or 18 applicators with inset tablets.
Vagifem (Estradiol) 25 mcg
8 applicators: NDC 0169-5173-03
18 applicators: NDC 0169-5173-04
Vagifem (Estradiol) 10 mcg
8 applicators: NDC 0169-5176-03
18 applicators: NDC 0169-5176-04
Keep out of reach of children
Store at 25ºC (77ºF), excursions permitted to 15ºC-30ºC (59ºF-86ºF). Do not refrigerate.
[See USP Controlled Room Temperature.]
Vagifem (Estradiol) . Fda-approved Patient Labeling
Read this PATIENT INFORMATION before you start using Vagifem (Estradiol) and read the patient information each time you refill your Vagifem (Estradiol) 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.
Vagifem (Estradiol) Principal Display Panel - Vagifem
NDC 0169-5173-04
estradiol vaginal tablets
18 vaginal tablets
novo nordisk
Vagifem (Estradiol) Principal Display Panel - Vagifem
NDC 0169-5176-04
18 vaginal tablets
novo nordisk
