Combipatch (Estradiol / Norethindrone Acetate) - Description and Clinical Pharmacology

DESCRIPTION

CombiPatch^® (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol, an estrogen, and norethindrone acetate (NETA), a progestational agent, continuously upon application to intact skin.

Two systems are available, providing the following in vivo delivery rates of estradiol and NETA.

1NETA = norethindrone acetate. 2Based on in vivo/in vitro flux data, delivery of both components per day via skin of average permeability (interindividual variation in skin permeability is approximately 20 percent).
System Size	Estradiol (mg)	NETA1 (mg)	Nominal Delivery Rate2 (mg per day) Estradiol / NETA
9 cm2 round	0.62	2.7	0.05/0.14
16 cm2 round	0.51	4.8	0.05/0.25

Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular weight of estradiol is 272.39 and the molecular formula is C₁₈H₂₄O₂.

NETA USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of NETA is 340.47 and the molecular formula is C₂₂H₂₈O₃.

The structural formulas for estradiol and NETA are:

CombiPatch is comprised of 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film backing, (2) an adhesive layer containing estradiol, NETA, acrylic adhesive, silicone adhesive, oleic acid NF, povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the adhesive surface and must be removed before the system can be used.

The active components of the system are estradiol USP and NETA USP. The remaining components of the system are pharmacologically inactive.

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 in the 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 the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics
Absorption

Estradiol: Estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Administration of CombiPatch every 3 to 4 days in postmenopausal women produces average steady-state estradiol serum concentrations of 45 to 50 pg/mL, which are equivalent to the normal ranges observed at the early follicular phase in premenopausal women. These concentrations are achieved within 12 to 24 hours following CombiPatch application. Minimal fluctuations in serum estradiol concentrations are observed following CombiPatch application, indicating consistent hormone delivery over the application interval.

In 1 study, serum concentrations of estradiol were measured in 40 healthy, postmenopausal women throughout 3 consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table 1.

Table 1. Mean (SD) Serum Estradiol and Estrone Concentrations (pg/mL) at Steady-State (Uncorrected for Baseline Levels)

Estradiol
System Size	Dose Estradiol/NETA (mg per day)	Cmax	Cmin	Cavg
9 cm2	0.05/0.14	71 (32)	27 (17)	45 (21)
16 cm2	0.05/0.25	71 (30)	37 (17)	50 (21)
Estrone
9 cm2	0.05/0.14	72 (23)	49 (19)	54 (19)
16 cm2	0.05/0.25	78 (22)	58 (22)	60 (18)

Norethindrone: Progestins used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Norethindrone steady-state concentrations are attained within 24 hours of application of the CombiPatch transdermal delivery systems. Minimal fluctuations in serum norethindrone concentrations are observed following CombiPatch treatment, indicating consistent hormone delivery over the application interval. Serum concentrations of norethindrone increase linearly with increasing doses of NETA.

In 1 study, serum concentrations of norethindrone were measured in 40 healthy, postmenopausal women throughout 3 consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table 2.

Table 2. Mean (SD) Serum Norethindrone Concentrations (pg/mL) at Steady-State

System Size	Dose Estradiol/NETA (mg per day)	Cmax	Cmin	Cavg
9 cm2	0.05/0.14	617 (341)	386 (137)	489 (244)
16 cm2	0.05/0.25	1060 (543)	686 (306)	840 (414)

Distribution

Estradiol: 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 albumin.

Norethindrone: In plasma, norethindrone is bound approximately 90 percent to SHBG and albumin.

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 a 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 portion 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: NETA is hydrolyzed to the active moiety, norethindrone, in most tissues including skin and blood. Norethindrone is primarily metabolized in the liver.

Excretion

Estradiol: Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Estradiol has a short elimination half-life of approximately 2 to 3 hours; therefore, a rapid decline in serum levels is observed after the CombiPatch estradiol/NETA transdermal system is removed. Within 4 to 8 hours serum estradiol concentrations return to untreated, postmenopausal levels (less than 20 pg/mL).

Concentration data from Phase II and III studies indicate that the pharmacokinetics of estradiol did not change over time, suggesting no evidence of the accumulation of estradiol following extended patch wear periods (up to 1 year).

Norethindrone: The elimination half-life of norethindrone is reported to be 6 to 8 hours. Norethindrone serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the CombiPatch transdermal delivery system.

Concentration data from Phase II and III studies indicate that the pharmacokinetics of norethindrone did not change over time, suggesting no evidence of the accumulation of norethindrone following extended patch wear periods (up to 1 year).

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

CLINICAL STUDIES

Effects on Vasomotor Symptoms

In 2 clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), CombiPatch was administered for 3 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch was applied throughout the 3 cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle^® 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; CombiPatch was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch at all doses as compared to placebo (intent-to-treat population). (See Tables 3 and 4.)

Table 3. Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch^® Continuous Combined Transdermal Therapy

1Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA). 2Represents the milligrams of estradiol/NETA delivered daily by each system. 3Population represents those patients who had baseline and endpoint observations. 4The intensity of hot flushes was evaluated on a scale of 0 to 9 (none=0, mild=1-3, moderate= 4-6, severe=7-9). 5P value versus placebo = <0.001. 6Total number of patients with available data is 56. 7Total number of patients with available data is 50.
	CombiPatch ® Continuous Combined		Placebo
Adjusted Mean Change from Baseline1	0.05/0.14 mg per day2 n=57	0.05/0.25 mg per day2 n=52	n=51
Number of Hot Flushes3	-9.35	-8.95	-6.2
Daily Intensity of Hot Flushes3,4	-4.65,6	-5.05	-2.87

Table 4. Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch^® Continuous Sequential Transdermal Therapy

1Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA). 2Represents the milligrams of estradiol/NETA delivered daily by each system. 3Population represents those patients who had baseline and endpoint observations. 4The intensity of hot flushes was evaluated on a scale of 0 to 9 (none=0, mild=1-3, moderate= 4-6, severe=7-9). 5P value versus placebo = <0.001.
	CombiPatch ® Continuous Combined		Placebo
Adjusted Mean Change from Baseline1	0.05/0.14 mg per day2 n=54	0.05/0.25 mg per day2 n=59	n=53
Number of Hot Flushes3	-9.35	-9.55	-5.5
Daily Intensity of Hot Flushes3,4	-4.45	-4.55	-2.1

Effects on the Endometrium

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications.

CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after 1 year of therapy in 2 Phase II clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of CombiPatch alone (Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system (Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after 1 year of therapy with either CombiPatch regimen than with the estradiol-only transdermal system. Tables 5 and 6 summarize these results (intent-to-treat populations).

Table 5. Incidence of Endometrial Hyperplasia in a Continuous Combined CombiPatch^® Regimen

1Represents milligrams of estradiol/NETA delivered daily by each system. 2Biopsy after 12 cycles of treatment or hyperplasia before cycle 12. 3Comparison of continuous combined regimen versus estradiol-only patch was significant (p <0.001). 4This patient had hyperplasia at baseline. 5One of 39 patients had hyperplasia in an endometrial polyp.
	CombiPatch® Continuous Combined		Vivelle® Continuous
	0.05/0.14 mg per day1	0.05/0.25 mg per day1	0.05 mg per day
Number of Patients with Biopsies2	123	98	103
Number (%) of Patients with Hyperplasia	1 (<1%)3	1 (1%)3,4	39 (38%)5

Table 6. Incidence of Endometrial Hyperplasia in a Continuous Sequential CombiPatch^® Regimen

1Represents milligrams of estradiol/NETA delivered daily by each system. 2Biopsy after 12 cycles of treatment or hyperplasia before cycle 12. 3Comparison of continuous sequential regimen versus estradiol-only patch was significant (p <0.001). 4This patient had hyperplasia at baseline. 5This patient had hyperplasia in an endometrial polyp.
	CombiPatch® Continuous Sequential		Vivelle® Continuous
	0.05/0.14 mg per day1	0.05/0.25 mg per day1	0.05 mg per day
Number of Patients with Biopsies2	117	114	115
Number (%) of Patients with Hyperplasia	1 (<1%)3,4	1 (<1%)3,5	23 (20%)

Effects on Uterine Bleeding or Spotting

With the Continuous Combined regimen, of the women treated with CombiPatch and who completed the 1-year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53 percent and 39 percent for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of 4 and 6 days for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. (See Figure 1)

Figure 1. Incidence of Cumulative Amenorrhea* in CombiPatch^® Continuous Combined Transdermal Therapy by Cycle Over a 1-Year Period (Intent-to-Treat Population)
*Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study.

Women’s Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in 2 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 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, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive 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 years; 83.9 percent white, 6.8 percent black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 7. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years^a,b

Event	Relative Risk CE/MPA vs. Placebo (95% nCIc)	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
Nonfatal MI	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 thrombosisd	1.95 (1.43–2.67)	26	13
Pulmonary embolism	2.13 (1.45–3.11)	18	8
Invasive breast cancere	1.24 (1.01–1.54)	41	33
Colorectal cancer	0.61 (0.42–0.87)	10	16
Endometrial cancerd	0.81 (0.48–1.36)	6	7
Cervical cancerd	1.44 (0.47–4.42)	2	1
Hip fracture	0.67 (0.47–0.96)	11	16
Vertebral fracturesd	0.65 (0.46–0.92)	11	17
Lower arm/wrist fracturesd	0.71 (0.59–0.85)	44	62
Total fracturesd	0.76 (0.69–0.83)	152	199
Overall mortalityf	1.00 (0.83–1.19)	52	52
Global Indexg	1.13 (1.02–1.25)	184	165
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
bResults are based on centrally adjudicated data.
cNominal confidence intervals (CI) unadjusted for multiple looks and multiple comparisons.
dNot included in “global index”.
eIncludes metastatic and nonmetastatic breast cancer, with the exception of in situ breast cancer.
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
gA 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 plus progestin 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 to 59 years of age a nonsignificant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI 0.44 to 1.07)].

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 63 years of age, range 50 to 79 years; 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 8.

Table 8. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI^a

Event	Relative Risk CE vs. Placebo (95% nCIb)	CE n=5,310	Placebo n=5,429
		Absolute Risk per 10,000 Women-Years
CHD eventsc	0.95 (0.78–1.16)	54	57
Nonfatal MIc	0.91 (0.73–1.14)	40	43
CHD deathc	1.01 (0.71–1.43)	16	16
All strokesc	1.33 (1.05–1.68)	45	33
Ischemic strokec	1.55 (1.19–2.01)	38	25
Deep vein thrombosisc,d	1.47 (1.06–2.06)	23	15
Pulmonary embolismc	1.37 (0.90–2.07)	14	10
Invasive breast cancerc	0.80 (0.62–1.04)	28	34
Colorectal cancere	1.08 (0.75–1.55)	17	16
Hip fracturec	0.65 (0.45–0.94)	12	19
Vertebral fracturesc,d	0.64 (0.44–0.93)	11	18
Lower arm/wrist fracturesc,d	0.58 (0.47–0.72)	35	59
Total fracturesc,d	0.71 (0.64–0.80)	144	197
Death due to other causese,f	1.08 (0.88–1.32)	53	50
Overall mortalityc,d	1.04 (0.88–1.22)	79	75
Global Indexg	1.02 (0.92–1.13)	206	201
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
bNominal CI unadjusted for multiple looks and multiple comparisons.
cResults are based on centrally adjudicated data for an average follow-up of 7.1 years.
dNot included in “global index”.
eResults are based on an average follow-up of 6.8 years.
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
gA 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 was 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.

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.

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 for ischemic stroke, and this excess was present in all subgroups of women examined.

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 to 59 years of age, a nonsignificant trend toward reduced risk for CHD [HR 0.63 (95 percent, CI 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)].

Women’s Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; 18 percent were 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 plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer disease (AD), vascular dementia (VaD) and mixed type (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 WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use)

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone 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 to 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 AD, VaD and mixed type (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 WARNINGS, Probable 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 to 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 WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use)