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
In vitro studies suggest that within 5 minutes of administration, all estradiol acetate will be hydrolyzed to estradiol in vivo.
Absorption
Estradiol was rapidly absorbed following oral administration of estradiol acetate. Mean serum estradiol concentrations following multiple dosing are shown in Figure 1. Mean (± SD) Serum Estradiol Concentration Following Multiple-Dose Administration of Femtrace to Healthy Postmenopausal Women. Estradiol and estrone serum concentrations increased proportionally with increasing dose; the corresponding estradiol Cavg values were 23.5, 44.4 and 92.1 pg/mL for the 0.45, 0.9 and 1.8 mg doses, respectively (see Table 1. Summary of Mean (%CV)a Pharmacokinetic Parameters Following Multiple- Dose Administration of Femtrace to Healthy Postmenopausal Women (n=18)).
 Figure 1. Mean (± SD) Serum Estradiol Concentration Following Multiple-Dose Administration of Femtrace to Healthy Postmenopausal Women
Table 1. Summary of Mean (%CV)
Pharmacokinetic Parameters Following Multiple- Dose Administration of Femtrace to Healthy Postmenopausal Women (n=18) |
Estradiol Acetate Dose
|
Analyte
|
Cmax
(pg/mL)
|
tmax
(hour)
|
AUC(0-τ)
(pg·h/mL)
|
t½
(hour)
|
| 0.45 mg | Estradiol | 56.7 (57) | 0.50 | 565.0 (26) | 25.9 |
| Estrone
| 155.0 (40) | 6.0 |
2363.8 (34)
| 15.9 |
| 0.9 mg | Estradiol | 90.1 (51) | 0.43 | 1066.5 (25) | 22.2 |
| Estrone | 313.9 (25) | 5.0 |
4980.9 (32)
| 16.1 |
| 1.8 mg | Estradiol | 177.3 (55) | 0.75 | 2211.3 (26) | 21.4 |
| Estrone | 680.6 (25) | 6.0 | 11510.8 (32) | 17.6 |
|
Cmax: Maximum serum concentration
tmax: Time of Cmax
AUC(0-τ): Area under the serum concentration-time curve over the dosing interval
t½: Half-life
|
Effect of Food
The maximum serum concentration (Cmax) of estradiol following administration of 1.8 mg estradiol acetate was 36% lower in the fed state compared to the fasted state. However, the area under the serum concentration versus time curve (AUC) was comparable among the fed and fasted states.
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
Estradiol acetate is hydrolyzed in vivo to estradiol. 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.
The estradiol apparent elimination half-life value is 21 to 26 hours.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
Drug Interactions
No clinical drug-drug interaction studies with estradiol acetate have been performed. 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.
Two 12-week double-blind, placebo-controlled clinical trials were conducted to evaluate the efficacy of Femtrace in the treatment of moderate to severe vasomotor symptoms in postmenopausal women who had at least 7 moderate to severe hot flushes daily or at least 60 moderate to severe hot flushes per week before randomization. In one study, 289 postmenopausal women (mean age 53.4 years [range 41 to 68 years], 78% Caucasian) were randomized to receive either placebo, Femtrace 0.9 mg/day or Femtrace 1.8 mg/day. In the second study, 221 postmenopausal women (mean age 52.2 years [range 36 to 80 years], 80% Caucasian) were randomized to receive either placebo or Femtrace 0.45 mg/day. The results in Table 2a. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF and Table 3a. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF indicate that compared with placebo, Femtrace 0.9 mg/day and Femtrace 1.8 mg/day produced a reduction in both the frequency and severity of moderate to severe vasomotor symptoms at weeks 4 and 12. The results in Table 2b. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT (modified)a Population, LOCF and Table 3b. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT (modified)a Population, LOCF indicate that compared with placebo, Femtrace 0.45 mg/day produced a reduction in the frequency of moderate to severe vasomotor symptoms at weeks 4 and 12, and a reduction in the severity of moderate to severe vasomotor symptoms at weeks 7 and 12.
Table 2a. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF | Visit |
Placebo
(n = 94)
|
Femtrace
0.9 mg/day
(n = 100)
|
Femtrace
1.8 mg/day
(n = 95)
|
| Baseline
| | | |
| Mean (SD) | 86.1 (40.2) | 78.5 (24.9) | 82.4 (39.1) |
| | | |
| Week 4
| | | |
| Mean (SD) | 51.5 (47.2) | 24.3 (28.4) | 21.9 (25.9) |
| Mean (SE) Change from Baseline | -30.1 (3.3) | -56.5 (3.2) | -59.3 (3.4) |
| p value vs. Placebo
| - | <0.001 | <0.001 |
| | | |
| Week 12 | | | |
| Mean (SD) | 46.8 (54.6) | 17.5 (28.9) | 7.3 (15.2) |
| Mean (SE) Change from Baseline | -36.3 (3.5) | -63.9 (3.4) | -74.8 (3.6) |
| p value vs. Placebo | - | <0.001 | <0.001 |
| ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error |
Table 2b. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week – ITT (modified)
Population, LOCF | Visit |
Placebo
(n = 108)
|
Femtrace
0.45 mg/day
(n = 113)
|
| Baseline
| | |
| Mean (SD) | 85.8 (37.8) | 86.2 (34.8) |
| | |
| Week 4
| | |
| Mean (SD) | 51.5 (37.1) | 44.1 (39.5) |
| Mean (SE) Change from Baseline | -33.8 (3.5) | -41.5 (3.5) |
| p value vs. Placebo
| - | 0.014 |
| | |
| Week 12 | | |
| Mean (SD) | 43.1 (38.1) | 34.1 (40.9) |
| Mean (SE) Change from Baseline | -41.5 (3.5) | -51.2 (3.5) |
| p value vs. Placebo | - | 0.005 |
|
ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error
|
Table 3a. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT Population, LOCF | Visit |
Placebo
(n = 94)
|
Femtrace
0.9 mg/day
(n = 100)
|
Femtrace
1.8 mg/day
(n = 95)
|
| Baseline
| | | |
| Mean (SD) | 2.5 (0.2) | 2.5 (0.2) | 2.5 (0.2) |
| | | |
| Week 4
| | | |
| Mean (SD) | 2.3 (0.6) | 1.8 (1.0) | 1.9 (1.0) |
| Mean (SE) Change from Baseline | -0.2 (1.0) | -0.7 (0.1) | -0.7 (0.1) |
| p value vs. Placebo
| - | 0.001 | 0.002 |
| | | |
| Week 12 | | | |
| Mean (SD) | 2.2 (0.8) | 1.4 (1.2) | 1.0 (1.2) |
| Mean (SE) Change from Baseline | -0.3 (0.1) | -1.1 (0.1) | -1.5 (0.1) |
| p value vs. Placebo | - | <0.001 | <0.001 |
|
Note: Hot flush severity was scored using the following scale: 1 = Mild, 2 = Moderate, 3 = Severe
ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error
|
Table 3b. Mean Change from Baseline in the Severity of Moderate to Severe Vasomotor Symptoms per Week – ITT (modified)
Population, LOCF | Visit |
Placebo
(n = 108)
|
Femtrace
0.45 mg/day
(n = 113)
|
| Baseline
| | |
| Mean (SD) | 2.6 (0.2) | 2.5 (0.2) |
| | |
| Week 4
| | |
| Mean (SD) | 2.4 (0.5) | 2.3 (0.7) |
| Mean (SE) Change from Baseline | -0.2 (0.1) | -0.3 (0.06) |
| p value vs. Placebo
| - | 0.787 |
| | |
| Week 12 | | |
| Mean (SD) | 2.3 (0.8) | 1.9 (1.1) |
| Mean (SE) Change from Baseline | -0.3 (0.1) | -0.7 (0.1) |
| p value vs. Placebo | - | 0.016 |
|
Note: Hot flush severity was scored using the following scale: 1 = Mild, 2 = Moderate, 3 = Severe
ITT = intent to treat; LOCF = last observation carried forward; SD = standard deviation; SE = standard error
|
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. Relative and Absolute Risk Seen in the CE/MPA Substudy of WHIa below.
Table 4. Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI
| 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 fractures | 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”, the 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.)
|
