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Femring

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Femring

Femring

CLINICAL PHARMACOLOGY

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle which secretes 70 to 500 mcg of estradiol daily depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

Absorption

Drug delivery from Femring (estradiol acetate) 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 is rapidly hydrolyzed to estradiol. which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (tmax) for estradiol of about 1 hour (range 0.25 to 1.5 hrs). Following the maximum concentration (Cmax), serum estradiol decreases 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.

Figure 1. Mean serum estradiol concentrations following multiple dose administration of Femring (estradiol acetate) (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)

Mean serum estradiol concentrations following multiple dose administration of Femring - Illustration

Following administration of Femring (estradiol acetate) (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 (estradiol acetate) (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 (estradiol acetate)

Dose
(as estradiol)
  Number of subjects Cmax
(pg/mL)
Tmax
(hour)
Cavg
(pg/mL)
  Estradiol1 25 1129 (25) 0.9 (41) 40.6 (26)
0.05 mg/day Estrone1 25 141 (25) 6.2 (84) 35.9 (21)
Estrone sulfate1 25 2365 (44) 9.3 (39) 494.6 (48)
Estradiol2 12 1665 (23) 0.7 (90) --4
0.10 mg/day Estradiol3 11 -- -- 76.0 (24)
Estrone3 11 -- -- 45.7 (25)
* Relative Standard Deviation, 1Study 1, 2Study 2, 3Study 3, 4-- Not determined

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 (estradiol acetate) 0.05 mg/day or Femring (estradiol acetate) 0.10 mg/day. Femring (estradiol acetate) 0.05 mg/day and Femring (estradiol acetate) 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

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)
*Denotes statistical significance at the 0.050 level.
[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.
[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.
ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval

Table 3. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF

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)
*Denotes statistical significance at the 0.050 level.
[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.
[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.
ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval

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 (estradiol acetate) 0.05 mg/day and Femring (estradiol acetate) 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 (estradiol acetate) 0.05 mg/day and Femring (estradiol acetate) 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) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture or death due to other cause. The study did not evaluate the effects of CE or CE plus MPA on menopausal symptoms.

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 4.

TABLE 4. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI

Event Relative Risk
CE vs. Placebo
(95% nCIa)
CE
n = 5,310
Placebo
n = 5,429
Absolute Risk per 10,000 Women-Years
CHD eventsb 0.95 (0.78-1.16) 54 57
  Non-fatal MIb 0.91 (0.73-1.14) 40 43
  CHD deathb 1.01 (0.71-1.43) 16 16
All Strokeb 1.33 (1.05-1.68) 45 33
  Ischemicb 1.55 (1.19-2.01) 38 25
Deep vein thrombosisb,c 1.47 (1.06-2.06) 23 15
Pulmonary embolismb 1.37 (0.90-2.07) 14 10
Invasive breast cancerb 0.80 (0.62-1.04) 28 34
Colorectal cancerd 1.08 (0.75-1.55) 17 16
Hip fractureb 0.65 (0.45-0.94) 12 19
Vertebral fracturesb,c 0.64 (0.44-0.93) 11 18
Lower arm/wrist fracturesb,c 0.58 (0.47-0.72) 35 59
Total fracturesb,c 0.71 (0.64-0.80) 144 197
Death due to other causesd,e 1.08 (0.88-1.32) 53 50
Overall mortalityb,c 1.04 (0.88–1.22) 79 75
Global Indexf 1.02 (0.92-1.13) 206 201
aNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
bResults are based on centrally adjudicated data for an average follow-up of 7.1 years.
cNot included in Global index.
dResults are based on an average follow-up of 6.8 years.
eAll deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
fA subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone were 12 more

strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See Boxed Warnings, WARNINGS, and PRECAUTIONS.)

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 4).

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined (see Table 4).

Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI 0.36-1.09) and overall mortality [HR 0.71 (95 percent CI 0.46-1.11)].

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 5. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa

Event Relative Risk
CE/MPA vs. Placebo
(95% nCIb)
CE/MPA
n = 8,506
Placebo
n = 8,102
Absolute Risk per 10,000 Women-Years
CHD events 1.23 (0.99-1.53) 41 34
  Non-fatal MIb 1.28 (1.00-1.63) 31 25
  CHD death 1.10 (0.70-1.75) 8 8
All strokes 1.31 (1.03-1.68) 33 25
  Ischemic Stroke 1.44 (1.09-1.90) 26 18
Deep vein thrombosisc 1.95 (1.43-2.67) 26 13
Pulmonary embolism 2.13 (1.45-3.11) 18 8
Invasive breast cancerd 1.24 (1.01-1.54) 41 33
Colorectal cancer 0.61 (0.42-0.87) 10 16
Endometrial cancerc 0.81 (0.48-1.36) 6 7
Cervical cancerc 1.44 (0.47-4.42) 2 1
Hip fractureb 0.67 (0.47-0.96) 11 16
Vertebral fracturesc 0.65 (0.46-0.92) 11 17
Lower arm/wrist fracturesc 0.71 (0.59-0.85) 44 62
Total fracturesc 0.76 (0.69-0.83) 152 199
Overall Mortalityc,e 1.00 (0.83-1.19) 52 52
Global Indexf 1.13 (1.02-1.25) 184 165
aResults are based on centrally adjudicated data.
bNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
cNot included in Global Index.
dIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
eAll deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
fA subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI 0.44-1.07)].

Women's Health Initiative Memory Study

The estrogen-alone Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years to 79 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See Boxed Warnings, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were age 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) versus placebo was 2.05 (95 percent CI, 1.21 to 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 Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See Boxed Warnings, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent 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 Boxed Warnings, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

Last reviewed on RxList: 6/15/2009
This monograph has been modified to include the generic and brand name in many instances.

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