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.
A. 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. 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) for results from rings stored for 16 months .
 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. Summary of Mean (%RSD)* Pharmacokinetic Parameters for Femring below.
Table 1. Summary of Mean (%RSD)* Pharmacokinetic Parameters for Femring |
Dose
(as estradiol) | |
Number
of
subjects |
Cmax
(pg/mL) |
Tmax
(hour) |
Cavg
(pg/mL) |
|
0.05 mg/day
| Estradiol1 | 25 | 1129 (25) | 0.9 (41) | 40.6 (26) |
| Estrone1 | 25 | 141 (25) | 6.2 (84) | 35.9 (21) |
| Estrone sulfate1 | 25 | 2365 (44) | 9.3 (39) | 494.6 (48) |
|
0.10 mg/day
| Estradiol2 | 12 | 1665 (23) | 0.7 (90) | --4 |
| 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.
B. 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.
C. 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.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
E. Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
F. 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.
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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. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF. Severity results are shown in Table 3. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF.
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 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 in two substudies 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 (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 CE/MPA), 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 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% White, 15.1% Black, 6.1% Hispanic, 3.6% Other) after an average follow-up of 6.8 years, are presented in TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHI below.
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 (0.79-1.16) | 53 | 56 |
| Non-fatal MI b | 0.91 (0.73-1.14) | 40 | 43 |
| CHD death b | 1.01 (0.71-1.43) | 16 | 16 |
| Strokec | 1.39 (1.10-1.77) | 44 | 32 |
| Deep vein thrombosisb,d | 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 cancerc | 1.08 (0.75-1.55) | 17 | 16 |
| Hip fracturec | 0.61 (0.41-0.91) | 11 | 17 |
| Vertebral fracturesc,d | 0.62 (0.42-0.93) | 11 | 17 |
| Total fracturesc,d | 0.70 (0.63-0.79) | 139 | 195 |
| Death due to other causesc,e | 1.08 (0.88-1.32) | 53 | 50 |
| Overall mortalityc,d | 1.04 (0.88–1.22) | 81 | 78 |
| Global Indexc,f | 1.01 (0.91-1.12) | 192 | 190 |
| 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. |
| cResults are based on an average follow-up of 6.8 years. |
| dNot included in Global Index. |
| 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 six fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant two 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.)
Final adjudicated results for CHD events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) in women receiving CE alone compared with placebo (see TABLE 4. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHI).
The CE/MPA substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28).
For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were six more CHD events, seven more strokes, ten more PEs, and eight more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were seven fewer colorectal cancers and five fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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, 3.9% Other), after an average follow-up of 5.6 years are presented in TABLE 5. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-PLUS-PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa below.
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 | 1.24 (1.00-1.54) | 39 | 33 |
| Non-fatal MI | 1.28 (1.00-1.63) | 31 | 25 |
| CHD death | 1.10 (0.70-1.75) | 8 | 8 |
| All strokes | 1.31 (1.02-1.68) | 31 | 24 |
| Ischemic Stroke | 1.44 (1.09-1.90) | 26 | 18 |
| Deep vein thrombosis | 1.95 (1.43-2.67) | 26 | 13 |
| Pulmonary embolism | 2.13 (1.45-3.11) | 18 | 8 |
| Invasive breast cancerc | 1.24 (1.01-1.54) | 41 | 33 |
| Invasive colorectal cancer | 0.56 (0.38-0.81) | 9 | 16 |
| Endometrial cancer | 0.81 (0.48-1.36) | 6 | 7 |
| Cervical cancer | 1.44 (0.47-4.42) | 2 | 1 |
| Hip fracture | 0.67 (0.47-0.96) | 11 | 16 |
| Vertebral fractures | 0.65 (0.46-0.92) | 11 | 17 |
| Lower arm/wrist fractures | 0.71 (0.59-0.85) | 44 | 62 |
| Total fractures | 0.76 (0.69-0.83) | 152 | 199 |
| aResults are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95% nCI 0.82-1.18). |
| bNominal confidence intervals unadjusted for multiple looks and multiple comparisons. |
| cIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. |
Women’s Health Initiative Memory Study
The estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45%, age 65 to 69 years; 36%, 70 to 74 years; 19%, 75 years of age and older) to evaluate the effects of CE 0.625 mg daily on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen-alone group was 1.49 (95% CI 0.83–2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, 3. Dementia and PRECAUTIONS, I. Geriatric use.)
The estrogen-plus-progestin WHIMS substudy 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.
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% 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, 3. Dementia and PRECAUTIONS, I. Geriatric use..)
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