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.
Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.
PHARMACOKINETICS
A. Absorption
Estradiol is well absorbed through the gastrointestinal tract. Following oral administration of Activella tablets, peak plasma estradiol concentrations are reached slowly within 5-8 hours. When given orally, estradiol is extensively metabolized (first-pass effect) to estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogens. After oral administration, norethindrone acetate is rapidly absorbed and transformed to norethindrone. It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 0.5 - 1.5 hours after the administration of Activella tablets. The oral bioavailability of estradiol and norethindrone following administration of Activella 1.0 mg/0.5 mg when compared to a combination oral solution is 53% and 100%, respectively. Administration of Activella 1.0 mg/0.5 mg with food did not modify the bioavailability of estradiol, although increases in AUC 0-72 of 19% and decreases in Cmax of 36% for norethindrone were seen.
The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of 1 Activella 1.0 mg/0.5 mg or 2 Activella 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 1.
TABLE 1: PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF Activella 1.0 MG/0.5 MG OR 2 TABLETS OF Activella 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN
| AUC = area under the curve, 0-last quantifiable sample; Cmax = maximum plasma concentration; tmax = time at maximum plasma concentration; t1/2 = half-life |
|
|
1 x Activella |
2 x Activella |
|
1.0 mg/0.5 mg |
0.5 mg/0.1 mg |
|
(n=24) |
(n=24) |
|
Mean (%CV) |
Mean* (%CV)† |
|
|
|
| Estradiol (E2) |
|
|
| AUC0-t (pg/mL*h) |
766.5 (48) |
697.3 (53) |
| Cmax (pg/mL) |
26.8 (36) |
26.5 (37) |
| tmax (h): median (range) |
6.0 (0.5-16.0) |
6.5 (0.5-16.0) |
| t1/2 (h) |
14.0 (29) |
14.5 (27) |
| Estrone‡ (E1) |
|
|
| AUC0-t (pg/mL*h) |
4469.1 (48) |
4506.4 (44) |
| Cmax (pg/mL) |
195.5 (37) |
199.5 (30) |
| tmax (h): median (range) |
6.0 (1.0-9.0) |
6.0 (2.0-9.0) |
| t1/2 (h)§ |
10.7 (44) |
11.8 (25)Þ |
| Norethindrone (NET) |
|
|
| AUC0-t (pg/mL*h) |
21043 (41) |
8407.2 (43) |
| Cmax (pg/mL) |
5249.5 (47) |
2375.4 (41) |
| tmax (h): median (range) |
0.7 (0.7-1.25) |
0.8 (0.7-1.3) |
| t1/2 (h) |
9.8 (32) |
11.4 (36) |
Following continuous dosing with once-daily administration of Activella 1.0 mg/0.5 mg, serum levels of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33-47% above levels following single dose administration. Unadjusted circulating levels of E2, E1, and NET during Activella 1.0 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.
Figure 1a: Levels of Estradiol and Estrone at Steady State During Continuous Dosing with Activella 1.0 mg/0.5 mg (n=24)
Figure 1b: Levels of Norethindrone at Steady State During Continuous Dosing with Activella 1.0 mg/0.5 mg (n=24)
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. Estradiol circulates in the blood bound to sex-hormone-binding globulin (SHBG) (37%) and to albumin (61%), while only approximately 1-2% is unbound. Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).
C. Metabolism
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 intestine 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.
Norethindrone Acetate: The most important metabolites of norethindrone are isomers of 5α-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of estradiol following single dose administration of Activella 1.0 mg/0.5 mg is 12-14 hours. The terminal half-life of norethindrone is about 8-11 hours.
E. Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
F. Drug Interactions
Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone. Similarly, no relevant interaction of norethindrone on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study.
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 result in side effects.
Clinical Studies
Effects on Vasomotor Symptoms
In a 12-week randomized clinical trial involving 92 subjects, Activella 1.0 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Activella 1.0 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).
Figure 2: Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study
In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Activella 0.5 mg/0.1 mg, 0.5 mg E2/0.25 mg NETA, or placebo for 24 weeks of treatment. The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Activella 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E2/0.25 mg NETA groups compared to placebo.
Figure 3: Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12
Effects on the Endometrium
Activella 1.0 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E2 + 0.1 mg NETA (n=294), 1 mg E2 + 0.25 mg NETA (n=291), and Activella 1.0 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects. The results of the 1 mg estradiol unopposed arm compared to Activella 1.0 mg/0.5 mg are shown in Table 2.
TABLE 2: INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND Activella 1.0 MG/0.5 MG IN A 12-MONTH STUDY
|
1 mg E2 |
Activella 1 mg E2/0.50 mg NETA |
1 mg E2/0.25 mg NETA |
1 mg E2/0.1 mg NETA |
|
(n=296) |
(n=295) |
(n=291) |
(n=294) |
| No. of subjects with histological evaluation at the end of the study |
247 |
241 |
251 |
249 |
|
|
|
|
|
| No. (%) of subjects with endometrial hyperplasia at the end of the study |
36 (14.6%) |
1 (0.4%) |
1 (0.4%) |
2 (0.8%) |
Effects on Uterine Bleeding or Spotting
During the initial months of therapy, irregular bleeding or spotting occurred with Activella 1.0 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Activella 1.0 mg/0.5 mg, about 86% of women were amenorrheic (see Figure 4).
Figure 4: Patients Treated with Activella 1.0 mg/0.5 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 - Intent to Treat Population, LOCF
Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).
In the clinical trial with Activella 0.5 mg/0.1 mg, 88% of women were amenorrheic after 6 months of treatment (See Figure 5).
Figure 5: Patients Treated with Activella 0.5 mg/0.1 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF
Effects on Bone Mineral Density
The results of two randomized, multicenter, calcium-supplemented (500-1000 mg/day), placebo-controlled, 2 year clinical trials have shown that Activella 1.0 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. While Activella 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore the BMD changes expected from treatment with Activella 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo). In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo. Approximately 58% and 67% of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DEXA).
A summary of the results comparing Activella 1.0 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 3.
TABLE 3: PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR Activella 1.0 MG/0.5 MG AND 0.5 MG E2 (Intent to Treat Analysis, Last Observation Carried Forward)
|
|
US Trial |
EU Trial |
|
Placebo |
0.5 mg E2* |
Activella
1.0 mg/0.5 mg
|
Placebo |
Activella
1.0 mg/0.5 mg
|
|
(n=37) |
(n=31) |
(n=37) |
(n=40) |
(n=38) |
|
|
|
|
|
|
| Lumbar spine |
-2.1 ± 2.9 |
2.3 ± 2.8 |
3.8 ± 3.0† |
-0.9 ± 4.0 |
5.4 ± 4.8† |
| Femoral neck |
-2.3 ± 3.4 |
0.3 ± 2.9 |
1.8 ± 4.1† |
-1.0 ± 4.6 |
0.7 ± 6.1 |
| Femoral trochanter |
-2.0 ± 4.3 |
1.7 ± 4.1 |
3.7 ± 4.3† |
0.8 ± 6.9 |
6.3 ± 7.6† |
| US = United States, EU = European |
The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg/day calcium) between Activella 1.0 mg/0.5 mg and placebo was 5.9% and between estradiol 0.5 mg and placebo was 4.4%. In the European trial (500 mg/day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3%. Activella 1.0 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for Activella 1.0 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.
Figure 6: Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for Activella 1.0 mg/0.5 mg and Estradiol 0.5 mg* (Intent to Treat Analysis with Last Observation Carried Forward)
* While Activella 0.5mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore the BMD changes expected from treatment with Activella 0.5mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg.
Effect on Bone Turnover
Activella 1.0 mg/0.5 mg reduced serum and urine markers of bone turnover with a marked decrease in bone resorption markers (e.g., urinary pyridinoline crosslinks Type 1 collagen C-telopeptide, pyridinoline, deoxypyridinoline) and to a lesser extent in bone formation markers (e.g., serum osteocalcin, bone-specific alkaline phosphatase, C-terminal propetide of type 1 collagen). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 24-month treatment period.
Treatment with 0.5 mg estradiol decreased biochemical markers of bone resorption (urinary pyridinoline, urinary deoxypyridinoline) and bone formation (bone-specific alkaline phosphatase) compared to placebo. These decreases occurred by 6 months of treatment after which the levels were maintained throughout the 24 months.
Women's Health Initiative Studies
The WHI 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 conjugated estrogens (CE 0.625 mg per day) alone or the use of oral conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg 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, 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-plus-progestin substudy was 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 estrogen-plus-progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 4 below:
TABLE 4: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-PLUS-PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS
|
| Event |
Relative Risk CE/MPA vs. Placebo |
CE/MPA |
Placebo |
|
(95% nCI) |
n = 8,506 |
n = 8,120 |
|
|
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 cancer |
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 |
The estrogen-alone substudy was also 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 5 below.
TABLE 5: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHI
|
| Event |
Relative Risk CE vs. Placebo |
CE |
Placebo |
|
(95% nCI*) |
n = 5,310 |
n = 5,429 |
|
|
Absolute Risk per 10,000 Women-years |
| CHD events |
0.95 (0.79-1.16) |
53 |
56 |
| Non-fatal MI† |
0.91 (0.73-1.14) |
40 |
43 |
| CHD death† |
1.01 (0.71-1.43) |
16 |
16 |
| Stroke |
1.39 (1.10-1.77) |
44 |
32 |
| Deep vein thrombosis† |
1.47 (1.06-2.06) |
23 |
15 |
| Pulmonary embolism† |
1.37 (0.09-2.07) |
14 |
10 |
| Invasive breast cancer† |
0.80 (0.62-1.04) |
28 |
34 |
| Colorectal cancer‡ |
1.08 (0.75-1.55) |
17 |
16 |
| Hip fracture‡ |
0.61 (0.41-0.91) |
11 |
17 |
| Vertebral fracturesठ|
0.62 (0.42-0.93) |
11 |
17 |
| Total fracturesठ|
0.70 (0.63-0.79) |
139 |
195 |
| Death due to other causes‡ |
1.08 (0.88-1.32) |
53 |
50 |
| Overall mortalityठ|
1.04 (0.88-1.22) |
81 |
78 |
| Global Index‡ |
1.01 (0.91-1.12) |
192 |
190 |
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 estrogen-alone was 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 5).
Women’s Health Initiative Memory Study
The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS) substudy of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47%, age 65 to 69 years, 35%, age 70 to 74 years, 18%, 75 years of age and older) to evaluate the effects of CE 0.625 mg plus MPA 2.5 mg daily on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of four years, 40 women in the estrogen-plus-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 1.21-3.48) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
The estrogen-alone WHIMS, a substudy of the WHI study, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45%, age 65 to 69 years, 36%, age 70 to 74 years, 19%, 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) 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.
When data from the two populations were pooled as planned in the WHIMS
