CLINICAL PHARMACOLOGY
EstroGel provides systemic estrogen replacement therapy by releasing estradiol, the major estrogenic hormone secreted by the human ovary.
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, 2 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 elevated levels of these hormones seen in postmenopausal women.
Pharmacokinetics
A. Absorption
Estradiol is transported across intact skin and into the systemic circulation by a passive diffusion process. The rate of diffusion across the stratum corneum is the rate-limiting factor. When EstroGel is applied to the skin, it dries in 2 to 5 minutes.
EstroGel 1.25 g was administered to 24 postmenopausal women once daily on the posterior surface of 1 arm from wrist to shoulder for 14 consecutive days. Mean maximal serum concentrations of estradiol and estrone on day 14 were 46.4 pg/mL and 64.2 pg/mL, respectively. The time-averaged serum estradiol and estrone concentrations over the 24-hour dose interval after administration of 1.25 g EstroGel on day 14 are 28.3 pg/mL and 48.6 pg/mL, respectively. Mean concentration-time profiles for unadjusted estradiol and estrone on day 14 are shown in Figure 1.
FIGURE 1 Mean Serum Concentration-time Profiles for Unadjusted Estradiol and Estrone After Multiple-dose Applications of 1.25 g EstroGel for 14 Days
The serum concentrations of estradiol following 2.5-g EstroGel applications (1.25 g on each arm from wrist to shoulder) appeared to reach steady state after the third daily application.
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 blood largely bound to sex hormone-binding globulin (SHBG) and 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, 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. Although the clinical significance has not been determined, estradiol from EstroGel does not go through first-pass liver metabolism.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
The apparent terminal exponential half-life for estradiol was about 36 hours following administration of 1.25 g EstroGel.
E. Special populations
EstroGel has been studied only in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
F. Drug interactions
No clinical drug-drug interaction studies have been conducted with EstroGel.
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 estrogen and may result in side effects.
G. Potential for estradiol transfer and effects of washing
The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of EstroGel once daily on the posterior surface of 1 arm from the wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered EstroGel.
The effect of application site washing on the serum concentrations of estradiol was determined in 24 healthy postmenopausal females who applied 1.25 g of EstroGel once daily for 14 consecutive days. Site washing 1 hour after the application resulted in a 22% mean decrease in average 24-hour serum concentrations of estradiol.
CLINICAL STUDIES
Effects on vasomotor symptoms
In a placebo-controlled study, 145 postmenopausal women between 29 and 67 years of age (81.4% were White) were randomly assigned to receive 1.25 g of EstroGel (containing 0.75 mg of estradiol) or placebo gel for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. A statistically significant reduction in the frequency and severity of moderate to severe hot flushes was shown at weeks 4 and 12. (See Table 1.)
TABLE 1 Mean Change from Baseline in the Number and Severity of Hot Flushes per Day, ITT Population, LOCF | Number of Hot Flushes/Day
(Moderate to Severe) | Severity Score/Day
(Mild, Moderate, Severe) |
| Placebo
n=73 | EstroGel 1.25 g
n=72 | Placebo
n=73 | EstroGel 1.25 g
n=72 |
|
* Primary timepoint
† P values from Elteren’s nonparametric test
‡ Statistically significantly different from placebo
|
Baseline
Mean (SD) |
11.01 (5.66) |
10.33 (3.07) |
2.30 (0.24) |
2.36 (0.29) |
Week 4*
Mean (SD)
Mean change from baseline (SD)
Diff. vs placebo
P value† |
5.95 (5.17)
-5.06 (4.91) |
4.43 (4.13)
-5.91 (3.68)
0.85
0.019‡ |
2.00 (0.63)
-0.31 (0.62) |
1.73 (0.73)
-0.63 (0.71)
0.32
0.005‡ |
Week 12*
Mean (SD)
Mean change from baseline (SD)
Diff. vs placebo
P value† |
5.17 (6.52)
-5.84 (4.52) |
2.79 (3.70)
-7.55 (3.52)
1.71
0.043‡ |
1.76 (0.84)
-0.54 (0.84) |
1.33 (0.97)
-1.03 (0.94)
0.49
<0.001‡ |
Effects on vulvar and vaginal atrophy
Results of the vaginal wall cytology showed a significant (P =0.001) increase from baseline in the percent of superficial epithelial cells at week 12 for 1.25 g EstroGel. In contrast, no significant change from baseline was observed in the placebo group.
Transdermal effects
In 2 controlled clinical trials, application site reactions were reported by 0.6% of patients who received 1.25 g of EstroGel. Other skin reactions, such as pruritus and rash, were also noted. (See Table 4.)
Women’s Health Initiative studies
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of 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 events, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 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. Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50-79; 75.3 percent White, 15 percent Black, 6.1 percent Hispanic, 3.5% Other), after an average follow-up of 6.8 years are presented in Table 2.
TABLE 2 Relative and Absolute Risk Seen in the Estrogen-alone Substudy of WHI | Event | Relative Risk
CE vs. Placebo
(95% nCI*) | CE
n = 5310 | Placebo
n = 5429 |
| | Absolute Risk per 10,000
Women-Years |
|
* Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
† Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
‡ Results are based on an average follow-up of 6.8 years.
§ Not included in Global Index.
|| All deaths, except from breast or colorectal cancer, definite/probable CHD, PS or cerebrovascular disease.
¶ 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
|
| CHD events† | 0.95 (0.79-1.16) | 53 | 56 |
| Nonfatal 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 (0.90-2.07) | 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 CE alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 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 2).
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 "global index," that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 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 50-79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other), are presented in Table 3 below.
TABLE 3 Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI at an Average of 5.6 Years* | Event | Relative Risk
CE/MPA vs Placebo
at 5.6 Years
(95% nCI†) | CE/MPA
n=8506 | Placebo
n=8102 |
| | Absolute Risk per 10,000
Women-Years |
|
*Results 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).
†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
|
CHD events
Non-fatal MI
CHD death | 1.24 (1.00-1.54)
1.28 (1.00-1.63)
1.10 (0.70-1.75) | 39
31
8 | 33
25
8 |
All strokes
Ischemic stroke | 1.31 (1.02-1.68)
1.44 (1.09-1.90) | 31
26 | 24
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 |
Women's Health Initiative Memory Study
The estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2947 predominantly healthy postmenopausal women aged 65 years and older (45% aged 65-69 years, 36% aged 70-74 years, and 19% aged 75 years and older) to evaluate the effects of conjugated estrogens (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% confidence interval [CI], 0.83-2.66) 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 plus progestin WHIMS substudy enrolled 4532 predominantly healthy postmenopausal women aged 65 years and older (47% aged 65-69 years, 35% aged 70-74 years, and 18% aged 75 years 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 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, 1.21-3.48) compared to placebo.
When data from the 2 populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (93% 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.)
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