Femring®(estradiol acetate vaginal ring)

femring (estradiol acetateinsert, extended release 
[Warner Chilcott US, Inc.]

Rx Only

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER

Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, 2. Malignant neoplasms , a. Endometrial cancer.)

CARDIOVASCULAR AND OTHER RISKS

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, 1. Cardiovascular disorders and 3. Dementia.)

The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, 1. Cardiovascular disorders and 2. Malignant neoplasms , b. Breast cancer.)

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, 3. Dementia and PRECAUTIONS, I. Geriatric Use .)

Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. 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.

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 C20H26O3 and the structural formula is:

Image from Drug Label Content

The molecular weight of estradiol acetate is 314.41.

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.

Pharmacokinetics

Estradiol acetate is rapidly hydrolyzed to estradiol.

Absorption

Drug delivery from Femring is rapid for the first hour and then declines to a relatively constant rate for the remainder of the 3‑month dosing interval. In vitro studies have shown that this initial release is higher as the rings age upon storage. Estradiol acetate and estradiol are rapidly absorbed through the vaginal mucosa as evidenced by tmax values for estradiol of less than 1 hour. Following Cmax, serum estradiol concentrations decrease rapidly such that by 24 to 48 hours postdose, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval, see Figure 1 for results from rings stored for 16 months.

Image from Drug Label Content

Figure 1. Mean serum estradiol concentrations following multiple dose administration of Femring (0.05 mg/day estradiol) (second dose administered at 13 weeks) (inset: mean (±SD) of serum concentration-time profile for dose 1 from 0-24 hours)

Following administration of Femring (0.05 mg/day estradiol), average serum estradiol concentration was 40.6 pg/mL; the corresponding apparent in vivo estradiol delivery rate was 0.052 mg/day. Following administration of Femring (0.10 mg/day estradiol), average serum estradiol concentration was 76 pg/mL; apparent in vivo delivery rate was 0.097 mg/day. Results are summarized in Table 1 below.

Table 1. Summary of Mean (%RSD)* Pharmacokinetic Parameters for Femring
*
Relative Standard Deviation
Study 1
Study 2
§
-- Not determined
Study 3

Dose

(as estradiol)

Number

of

subjects

Cmax

(pg/mL)

Tmax

(hour)

Cavg

(pg/mL)

0.05 mg/day

Estradiol 25 1129 (25) 0.9 (41) 40.6 (26)
Estrone 25 141 (25) 6.2 (84) 35.9 (21)
Estrone sulfate 25 2365 (44) 9.3 (39) 494.6 (48)

0.10 mg/day

Estradiol 12 1665 (23) 0.7 (90) --§
Estradiol 11 -- -- 76.0 (24)
Estrone 11 -- -- 45.7 (25)

 

Consistent with the avoidance of first pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations were slightly higher than estrone concentrations.

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 to 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 proportion 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.

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Clinical Studies

Effects on vasomotor symptoms.

A 13-week double-blind, placebo-controlled clinical trial was conducted to evaluate the efficacy of 2 doses of the vaginal ring in the treatment of moderate to severe vasomotor symptoms in 333 postmenopausal women between 29 and 85 years of age (mean age 51.7 years, 77% were Caucasian) who had at least 7 moderate to severe hot flushes daily or at least 56 moderate to severe hot flushes per week before randomization. Patients were randomized to receive either placebo, Femring 0.05 mg/day or Femring 0.10 mg/day. Femring 0.05 mg/day and Femring 0.10 mg/day were shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Frequency results are shown in Table 2. Severity results are shown in Table 3.

Table 2. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week - ITT* Population, LOCF
*
ITT = intent to treat
LOCF = last observation carried forward
[1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two weeks between screening and randomization.
§
Denotes statistical significance at the 0.050 level
[2] p values and confidence intervals are from a two-way ANOVA with factors for treatment and study center for the difference between treatment groups in the mean change from baseline. Confidence intervals are adjusted for multiple comparisons within each timepoint using Dunnett’s method.
#
CI = confidence interval
Visit

Placebo

(n = 105)

Estradiol

0.05 mg/day

(n = 111)

Estradiol

0.10 mg/day

(n = 109)
Baseline [1]
Mean (SD) 83.62 (60.42) 73.83 (24.53) 75.11 (25.44)
Week 4
Mean (SD) 51.14 (51.19) 21.59§ (27.76) 11.37§ (19.43)
Mean Change from Baseline (SD) -32.48 (46.25) -52.24§ (32.92) -63.75§ (26.68)
p value vs. Placebo (95% CI) [2] - <0.001 (-30.7, -8.8) <0.001 (-42.2, -20.3)
Week 12
Mean (SD) 42.21 (41.13) 15.48§ (25.42) 8.25§ (16.58)
Mean Change from Baseline (SD) -41.41 (65.61) -58.36§ (31.36) -66.87§ (27.44)
p value vs. Placebo (95% CI#) [2] - 0.006 (-30.5, -3.4) <0.001 (-39.1, -11.8)
Table 3. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week - ITT* Population, LOCF
*
ITT = intent to treat
LOCF = last observation carried forward
[1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the average severity of MSVS during the two weeks between screening and randomization.
§
Denotes statistical significance at the 0.050 level
[2] p values and confidence intervals are from a two-way ANOVA with factors for treatment and study center for the difference between treatment groups in the mean change from baseline. Confidence intervals are adjusted for multiple comparisons within each timepoint using Dunnett’s method.
#
CI = confidence interval
Visit

Placebo

(n = 105)

Estradiol

0.05 mg/day

(n = 111)

Estradiol

0.10 mg/day

(n = 109)
Baseline [1]
Mean (SD) 2.51 (0.26) 2.46 (0.23) 2.48 (0.24)
Week 4
Mean (SD) 2.23 (0.71) 1.67§ (1.07) 1.15§ (1.14)
Mean Change from Baseline (SD) -0.28 (0.69) - 0.79§ (1.08) -1.33§ (1.10)
p value vs. Placebo (95% CI) [2] - <0.001 (-0.8, -0.2) <0.001 (-1.3, -0.8)
Week 12
Mean (SD) 2.00 (0.96) 1.41§ (1.17) 0.92§ (1.09)
Mean Change from Baseline (SD) -0.51 (0.94) -1.06 § (1.16) -1.56§(1.06)
p value vs. Placebo (95% CI#) [2] - <0.001 (-0.9, -0.2) <0.001 (-1.4, -0.7)

Effects on vulvar and vaginal atrophy.

In the same 13-week clinical trial, vaginal superficial cells increased by a mean of 16.0% and 18.9% for Femring 0.05 mg/day and Femring 0.10 mg/day, respectively, as compared to 1.11% for placebo at week 13. A corresponding reduction in parabasal cells was observed at week 13. Vaginal pH decreased for Femring 0.05 mg/day and Femring 0.10 mg/day by a mean of 0.73 and 0.60, respectively, compared to a mean decrease of 0.25 in the placebo group.

Women’s Health Initiative Studies

The Women’s Health Initiative (WHI) study enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction 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, colorectal cancer, hip fracture or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 4 below.

Table 4. Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI*
*
adapted from JAMA, 2002; 288:321-333
a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture or death due to other causes
nominal confidence intervals unadjusted for multiple looks and multiple comparisons
§
includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
not included in Global Index
Event

Relative Risk

CE/MPA vs

Placebo at 5.2 Years

(95% CI)

Placebo

N = 8102

CE/MPA

N = 8506
Absolute Risk per 10,000 Women-years

CHD events

Non-fatal MI

CHD death

1.29 (1.02 – 1.63)

1.32 (1.02– 1.72)

1.18 (0.70 – 1.97)

30

23

6

37

30

7

Invasive breast

cancer §
1.26 (1.00 – 1.59) 30 38
Stroke 1.41 (1.07 – 1.85) 21 29
Pulmonary embolism 2.13 (1.39 – 3.25) 8 16
Colorectal cancer 0.63 (0.43 – 0.92) 16 10
Endometrial cancer 0.83 (0.47 – 1.47) 6 5
Hip fracture 0.66 (0.45 – 0.98) 15 10
Death due to causes other than the events above 0.92 (0.74 – 1.14) 40 37
Global Index 1.15 (1.03 – 1.28) 151 170
Deep vein thrombosis 2.07 (1.49 – 2.87) 13 26
Vertebral fracture 0.66 (0.44 – 0.98) 15 9
Other osteoporotic fractures 0.77 (0.69 – 0.86) 170 131

For those outcomes included in the “global index”, absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 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. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Women’s Health Initiative Memory Study

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/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% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, 3. Dementia.)

INDICATIONS AND USAGE

Femring therapy is indicated in the:

  1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
  2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

CONTRAINDICATIONS

Femring should not be used in women with any of the following conditions:

  1. Undiagnosed abnormal genital bleeding.
  2. Known, suspected, or history of cancer of the breast.
  3. Known or suspected estrogen-dependent neoplasia.
  4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.
  5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
  6. Liver dysfunction or disease.
  7. Femring should not be used in patients with known hypersensitivity to its ingredients.
  8. Known or suspected pregnancy. There is no indication for Femring in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)

WARNINGS

See BOXED WARNINGS

1. Cardiovascular disorders

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity and systemic lupus erythematosus) should be managed appropriately.

a. Coronary heart disease and stroke

In the Women’s Health Initiative (WHI) study, an increase in the number of strokes was observed in women receiving CE alone compared to placebo.

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/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/MPA-treated group than in the placebo group in year 1 but not during the subsequent years. Two thousand three hundred and twenty one 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 HERS, HERS II and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism and thrombophlebitis.

b. Venous thromboembolism (VTE)

In the Women’s Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving CE alone compared to placebo.

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

2. Malignant neoplasms

a. Endometrial cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. 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 taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal 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 cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (See CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy and a smaller increased risk for estrogen alone therapy after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater and became apparent earlier with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/MPA 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 vs 25 cases per 10,000 women-years for CE/MPA 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 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA 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.

The use of 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.

3. Dementia

In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21-3.48) and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, I. Geriatric Use .)

4. Gallbladder disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

6. Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

PRECAUTIONS

A. General

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 a possible 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. Blood pressure should be monitored at regular intervals with estrogen use.

3. Hypertriglyceridemia

In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4. Impaired liver function and a past history of cholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients 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. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6. Fluid retention

Because estrogens may cause some degree of fluid retention, patients 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 individuals with severe hypocalcemia.

8. Ovarian cancer

The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

9. Exacerbation of endometriosis

Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

10. Exacerbation of other conditions

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus and hepatic hemangiomas, and should be used with caution in women with these conditions.

11. 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.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Femring.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

  1. 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.
  2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
  3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
  5. Impaired glucose tolerance.
  6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

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 Salmonella typhimurium and in two tryptophan-requiring strain of Escherichia coli. Estradiol acetate did not induce mutation in any of the bacterial strains tested under the conditions employed.

F. Pregnancy

Femring should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Femring is administered to a nursing woman.

H. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

I. Geriatric Use

Clinical studies of Femring did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, 3. Dementia.)

ADVERSE REACTIONS

See BOXED WARNINGS, WARNINGS and PRECAUTIONS.

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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

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% are summarized in Table 5.

Table 5. Incidence of AEs* Occurring in ≥ 2% of Subjects Presented in Descending Frequency of Preferred Term
*
AE = adverse event
NOS = not otherwise specified
Adverse Event

Placebo

(n = 108)

Estradiol

0.05 mg/day

(n = 113)

Estradiol

0.10 mg/day

(n = 112)
n (%) n (%) n (%)
Headache (NOS) 10 (9.3) 8 (7.1) 11 (9.8)
Intermenstrual Bleeding 2 (1.9) 9 (8.0) 11 (9.8)
Vaginal Candidiasis 3 (2.8) 7 (6.2) 12 (10.7)
Breast Tenderness 2 (1.9) 7 (6.2) 12 (10.7)
Back Pain 4 (3.7) 7 (6.2) 4 (3.6)
Genital Disorder Female (NOS) 9 (8.3) 3 (2.7) 3 (2.7)
Upper Respiratory Tract Infection (NOS) 6 (5.6) 5 (4.4) 4 (3.6)
Abdominal Distension 3 (2.8) 8 (7.1) 3 (2.7)
Vaginal discharge 9 (8.3) 2 (1.8) 3 (2.7)
Vulvovaginitis (NOS) 7 (6.5) 6 (5.3) 1 (0.9)
Nausea 5 (4.6) 3 (2.7) 2 (1.8)
Arthralgia 4 (3.7) 2 (1.8) 2 (1.8)
Sinusitis (NOS) 2 (1.9) 2 (1.8) 4 (3.6)
Uterine Pain 1 (0.9) 2 (1.8) 5 (4.5)
Nasopharyngitis 3 (2.8) 2 (1.8) 2 (1.8)
Pain in Limb 3 (2.8) 1 (0.9) 3 (2.7)
Urinary Tract Infection (NOS) 2 (1.9) 1 (0.9) 4 (3.6)
Vaginal Irritation 4 (3.7) 1 (0.9) 2 (1.8)

The following additional adverse reactions have been reported with estrogens and/or progestin therapy.

1. Genitourinary system

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.

2. Breasts

Enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.

3. Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.

4. Gastrointestinal

Vomiting, abdominal cramps; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas.

5. Skin

Chloasma or melasma which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritis, rash.

6. Eyes

Retinal vascular thrombosis; intolerance to contact lenses.

7. Central nervous system

Migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy; dementia.

8. Miscellaneous

Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need 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. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

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 moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause.

Patients should be started at the lowest dose. The lowest effective dose of Femring has not been determined.

Instructions for Use

Hands 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.

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.

Keep out of reach of children.

STORAGE

Store at 25˚C (77˚F); excursions permitted to 15˚ - 30˚C (59˚ - 86˚F) [see USP Controlled Room Temperature]

Manufactured by: Warner Chilcott UK Ltd., Larne, Northern Ireland, UK

Marketed by: Warner Chilcott (US), Inc., Rockaway, NJ 07866

6201G013

PATIENT INFORMATION

(Updated March 2005)

 

Femring® (estradiol acetate vaginal ring)

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.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT FEMRING (AN ESTROGEN PRODUCT)?

Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with Femring.

What is Femring?

Femring (estradiol acetate vaginal ring) is an off-white, soft, flexible vaginal ring with a center that contains an estrogen.

 

What is Femring used for?

Femring is used after menopause to:

Who should not use Femring?

Do not start using Femring if you:

Tell your healthcare provider:

What are the possible side effects of estrogens?

Less common but serious side effects include:

These are some of the warning signs of serious side effects:

Call your healthcare provider right away if you get any of these warning signs or any other unusual symptom that concerns you.

Common side effects include:

Other side effects include:

These are not all the possible side effects of Femring. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of a serious side effect with Femring?

How do I use Femring?

  1. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.
  2. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of Femring has not been determined. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with Femring.

    Image from Drug Label Content

 

To insert Femring into your vagina:

1. Wash and dry your hands.

2. Remove Femring from its pouch.

3. Choose the position that is most comfortable for you. For example, lying down or standing

with one leg up. (Diagrams 1a and 1b, respectively).

Image from Drug Label Content

DIAGRAM 1a

Image from Drug Label Content

DIAGRAM 1b

4. Use your thumb and index finger (pointer finger) to press the sides of the ring together. You

may find it easier to insert Femring if you twist it into a figure-of-eight shape. (Diagram 2)

Image from Drug Label Content

DIAGRAM 2

5. Use your other hand and hold open the folds of skin around your vagina. (Diagram 3)

Image from Drug Label Content

DIAGRAM 3

6. Place the tip of the ring in the vaginal opening and then use your index finger to push the

folded ring gently into your vagina. Push it up towards your lower back as far as you can.

(Diagram 4)

Image from Drug Label Content

DIAGRAM 4

If the ring feels uncomfortable, you probably did not push it into your vagina far enough. Use your index finger to push the ring as far as you can into your vagina (Diagram 5). There is no danger of Femring being pushed too far up in the vagina or getting lost.

Image from Drug Label Content

DIAGRAM 5

Femring should now be in your upper vagina (Diagram 6). The exact position of Femring in the vagina is not important for it to work.

Image from Drug Label Content

DIAGRAM 6

7. Wash your hands when you are done.

After 3 months, Femring may no longer release enough medicine to control your menopausal symptoms. To continue to have symptom relief your current Femring should be removed and replaced with a new one if you and your healthcare provider have decided that you still need treatment with Femring.

To remove Femring:

1. Wash and dry your hands.

2. Choose the position that is most comfortable for you (see Diagrams 1a and 1b).

3. Put a finger into your vagina and hook it through the ring. (Diagram 7)

Image from Drug Label Content

DIAGRAM 7

4. Gently pull downwards and forwards to remove Femring.

5. Wrap the used ring in tissue or toilet paper and put it in a trash can.

6. Wash your hands.

Insert another ring now if your healthcare provider has told you to.

If your Femring comes out of your vagina before 3 months, clean it with warm water and put it back in your vagina.

If Femring comes out often, tell your healthcare provider. Femring may not be right for you.

Call your healthcare provider if you have any problems putting Femring in your vagina or taking it out.

You may leave Femring in place if you need to use medicine for a vaginal infection.

You may leave Femring in place during sex (intercourse). If you take Femring out during intercourse or it comes out, clean it with warm water and put it back in your vagina.

If you lose your Femring, a new Femring should be put in place for 3 months.

 

General information about safe and effective use of Femring.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Femring for conditions for which it was not prescribed. Do not give Femring to other people, even if they have the same symptoms you have. It may harm them.

 

Keep Femring out of the reach of children.

This leaflet provides a summary of the most important information about Femring. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Femring that is written for health professionals. You can get more information by calling the toll free number 800-521-8813.

 

What are the ingredients in Femring?

Femring contains estradiol acetate, an estrogen. It also contains cured silicone elastomer composed of dimethyl polysiloxane silanol, silica (diatomaceous earth), normal propyl orthosilicate, stannous octoate; and barium sulfate. There are no coloring agents in Femring.

 

Rx only

Manufactured by: Warner Chilcott UK, Ltd., Larne, Northern Ireland, UK

Marketed by: Warner Chilcott (US) Inc., Rockaway, NJ 07866

6201G023


Femring (estradiol acetate)
PRODUCT INFO
Product Code 0430-6201 Dosage Form INSERT, EXTENDED RELEASE
Route Of Administration VAGINAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
estradiol acetate (estradiol) Active 12.4 MILLIGRAM  In 1 INSERT
barium sulfate Inactive  
dimethyl polysiloxane silanol Inactive  
normal propyl orthosilicate Inactive  
silica Inactive  
stannous octoate Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0430-6201-40 1 POUCH In 1 CARTON contains a POUCH
1 1 INSERT In 1 POUCH This package is contained within the CARTON (0430-6201-40)

Femring (estradiol acetate)
PRODUCT INFO
Product Code 0430-6202 Dosage Form INSERT, EXTENDED RELEASE
Route Of Administration VAGINAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
estradiol acetate (estradiol) Active 24.8 MILLIGRAM  In 1 INSERT
barium sulfate Inactive  
dimethyl polysiloxane silanol Inactive  
normal propyl orthosilicate Inactive  
silica (diatomaceous earth) Inactive  
stannous octoate Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0430-6202-40 1 POUCH In 1 CARTON contains a POUCH
1 1 INSERT In 1 POUCH This package is contained within the CARTON (0430-6202-40)

Revised: 05/2006Warner Chilcott US, Inc.