femhrt (norethindrone acetate 0.5 mg ethinyl estradiol 2.5 ug) Dailymed

Overdosage Section

Overdosage of estrogen plus progestogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of femhrt therapy with institution of appropriate symptomatic care.

Description Section

femhrt (norethindrone acetate/ethinyl estradiol tablets) is a continuous dosage regimen of a progestin-estrogen combination for oral administration.

The following strength of femhrt tablets is available:

femhrt (0.5 mg/2.5 mcg): Each oval white tablet contains 0.5 mg norethindrone acetate and 2.5 mcg ethinyl estradiol

Each tablet also contains the following inactive ingredients: calcium stearate, lactose monohydrate, microcrystalline cellulose and corn starch.

The structural formulas are as follows.



Ethinyl Estradiol [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-];Molecular Weight: 296.41Molecular Formula: C₂₀H₂₄O₂



Norethindrone Acetate [19-Norpregn-4-en-20-yn-3-one,7(acetyloxy)-, (17α)-];Molecular Weight: 340.47Molecular Formula: C₂₂H₂₈O₃

Clinical Pharmacology Section

MECHANISM OF ACTION SECTION

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, which is 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. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.

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 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, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

PHARMACODYNAMICS SECTION

Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to femhrt nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

PHARMACOKINETICS SECTION

Absorption

Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from femhrt tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of femhrt tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of femhrt tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of femhrt tablets with food.

The full pharmacokinetic profile of femhrt tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 post-menopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the femhrt 0.5/2.5 tablets and femhrt  1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet.

Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets

Table 2.  Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters^† Following Administration of 1 mg NA/10 mcg EE Tablets

	Cmax	tmax	AUC (0-24)	CL/F	t1/2
NORETHINDRONE	ng/mL	hr	ng•hr/mL	mL/min	hr
Day 1	6.0 (3.3)	1.8 (0.8)	29.7 (16.5)	588 (416)	10.3 (3.7)
Day 87	10.7 (3.6)	1.8 (0.8)	81.8 (36.7)	226 (139)	13.3 (4.5)
ETHINYL ESTRADIOL	pg/mL	hr	pg•hr/mL	mL/min	hr
Day 1	33.5 (13.7)	2.2 (1.0)	339 (113)	ND‡	ND‡
Day 87	38.3 (11.9)	1.8 (0.7)	471 (132)	383 (119)	23.9 (7.1)

†  C_max = Maximum plasma concentration; t_max = time of C_max; AUC(0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t_½ = Elimination half-life‡  ND = Not determined

Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for femhrt 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for femhrt 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively. 

The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40-62 years), in the postmenopausal population studied.

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 SHBG and albumin.

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

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 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 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 undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24 hours, respectively.

A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, women had 12 hot flushes per day upon study entry.

A total of 66 women were randomized to receive femhrt 1/5 and 66 women were randomized to the placebo group. femhrt 1/5 was shown to be statistically better than placebo at weeks 4, and 12 for relief of the frequency of moderate to severe vasomotor symptoms (see Table 3). In Table 4, femhrt 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms.

Table 3. Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week - ITT Population, LOCF

Visit	Placebo (N = 66)	femhrt 0.5/2.5 (N = 67)	femhrt 1/5 (N = 66)
Baseline [1]
Mean (SD)	76.5 (21.4)	77.6 (26.5)	70.0 (16.6)
Week 4
Mean (SD)	39.4 (27.6)	30.2 (26.1)	20.4 (22.7)
Mean Change From Baseline (SD)	-37.0 (26.6)	-47.4è   (26.1)	-49.6è   (22.1)
p-Value vs. Placebo(95 percent CI) [2]		0.041 (-20.0, -1.0)	<0.001 (-22.0, -6.0)
Week 12
Mean (SD)	31.1 (27.0)	13.8 (20.4)	11.3 (18.9)
Mean Change from Baseline (SD)	-45.3 (30.2)	-63.8è   (27.5)	-58.7è   (23.1)
p-Value vs. Placebo(95 percent CI) [2]		<0.001 (-27.0, -7.0)	<0.001 (-25.0, -5.0)
è  Denotes statistical significance at the 0.05 level [1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week pre-randomization observation period.[2] ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI - Mann-Whitney confidence interval for the difference between means (not stratified by center).ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval2 randomized women (1 in Placebo and 1 in femhrt) did not return diaries.

Table 4. Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week - ITT Population, LOCF

Visit	Placebo (N = 66)	femhrt 0.5/2.5 (N = 67)	femhrt 1/5 (N = 66)
Baseline [1]
Mean (SD)	2.49 (0.26)	2.48 (0.22)	2.47 (0.23)
Week 4
Mean (SD)	2.13 (0.74)	1.88 (0.89)	1.45 (1.03)
Mean Change from Baseline (SD)	-0.36 (0.68)	-0.59 (0.83)	-1.02¥   (1.06)
p-Value vs Placebo(95 percent CI) [2]	-	0.130 (-0.3, 0.0)	<0.001 (-0.9, -0.2)
Week 5
Mean (SD)	2.06 (0.79)	1.68 (0.99)	1.23 (1.03)
Mean Change from Baseline (SD)	-0.44 (0.74)	-0.80¥    (0.94)	-1.24¥   (1.07)
p-Value vs Placebo(95 percent CI) [2]	-	0.041 (-0.4, -0.0)	<0.001 (-1.2, -0.3)
Week 12
Mean (SD)	1.82 (1.03)	1.22 (1.11)	1.02 (1.16)
Mean Change from Baseline (SD)	-0.67 (1.02)	-1.26¥   (1.08)	-1.45¥   (1.19)
p-Value vs Placebo(95 percent CI) [2]	-	0.002 (-0.9, -0.2)	<0.001 (-1.4, -0.3)
¥  Denotes statistical significance at the 0.05 level[1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week pre-randomization observation period.[2] ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95 percent CI - Mann-Whitney confidence interval for the difference between means (not stratified by center).ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval2 randomized women (1 in Placebo and 1 in femhrt) did not return diaries.

A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of femhrt on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1,265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg ethinyl estradiol (NA/EE 0.2/1), 0.5 mg NA/2.5 mcg EE (NA/EE 0.5/2.5), femhrt 1/5 and 1 mg NA/10 mcg EE (NA/EE 1/10) or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1,265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to femhrt 1/5, 136 to NA/EE 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 femhrt 1/5, 136 NA/EE 0.5/2.5, 139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95 percent of subjects), or insufficient tissue (in approximately 5 percent of subjects). Follow-up biopsies were obtained in approximately 70 to 80 percent of patients in each arm after 12 and 24 months of therapy. Results for femhrt 1/5 and appropriate comparators are shown in Table 5.

Table 5. Endometrial Biopsy Results After 12 and 24 Months of Treatment (CHART Study, 376-359)

Endometrial Status	Placebo	femhrt		EE Alone
		0.5/2.5	1/5	2.5 mcg	5 mcg
Number of Patients Biopsied at Baseline	N = 134	N = 136	N = 143	N = 137	N = 139
MONTH 12 (Percent Patients)
Patients Biopsied (percent)	113 (84)	103 (74)	110 (77)	100 (73)	114 (82)
Insufficient Tissue	30	34	45	20	20
Atrophic Tissue	60	41	41	15	2
Proliferative Tissue	23	28	24	65	91
Endometrial Hyperplasia *	0	0	0	0	1
MONTH 24 (Percent Patients)
Patients Biopsied (percent)	94 (70)	99 (73)	102 (71)	89 (65)	107 (77)
Insufficient Tissue	35	42	37	23	17
Atrophic Tissue	38	30	33	6	2
Proliferative Tissue	20	27	32	60	86
Endometrial Hyperplasia *	1	0	0	0	2
*All patients with endometrial hyperplasia were carried forward for all time points.

The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from participant recall, was evaluated over 12 months for femhrt 1/5 and placebo arms. Results are shown in Figure 2.

Figure 2. Pa rticipants with Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward

In the 2 year study, trabecular BMD was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, 40 to 64 years of age, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to femhrt 1/5, NA/EE 0.5/2.5 or placebo. Approximately 75 percent of the women in each group completed the two-year study. All women received 1000 mg calcium in divided doses. Vitamin D was not supplemented.

As shown in Figure 3, women treated with femhrt 1/5 had an average increase of 3.1 percent in lumbar spine BMD from baseline to Month 24. Women treated with placebo had average decreases of –6.3 percent in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the femhrt 1/5 group compared with the placebo group was statistically significant.

Figure 3. Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population)



*It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two 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 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. The study 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 CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years ^{¶  #Þ}    

Event	Relative RiskCE/MPA vs. Placebo(95 percent nCI ß  )	CE/MPAn = 8,506	Placebon = 8,102
		Absolute Risk per 10,000 Women-Years
CHD events	1.23 (0.99 - 1.53)	41	34
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 (1.03 - 1.68)	33	25
Ischemic stroke	1.44 (1.09 – 1 . 90)	26	18
Deep vein thrombosis à	1.95 (1.43 - 2.67)	26	13
Pulmonary embolism	2.13 (1.45 - 3.11)	18	8
Invasive breast cancerè	1.24 (1.01 - 1.54)	41	33
Colorectal cancer	0.61 (0.42 - 0.87)	10	16
Endometrial cancer à	0.81 (0.48 - 1.36)	6	7
Cervical cancerà	1.44 (0.47 - 4.42)	2	1
Hip fracture	0.67 (0.47 - 0.96)	11	16
Vertebral fractures à	0.65 (0.46 - 0.92)	11	17
Lower arm/wrist fractures à	0.71 (0.59 - 0.85)	44	62
Total fractures à	0.76 (0.69 - 0.83)	152	199
Overall Mortality ß   ð	1.00 (0.83 - 1.19)	52	52
Global Index ø	1.13 (1.02 - 1.25)	184	165
¶  Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. #Þ  Results are based on centrally adjudicated data. ß  Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. à  Not included in "global index". è  Includes metastic and non-metastic breast cancer with the exception of in situ cancer. ð  All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. ø  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, 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 non-significant trend toward reduced risk for overall mortality (hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].

WHI Estrogen-Alone Substudy The WHI 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 63 years of age, range 50 to 79; 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 7.

Table 7. Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI^¥   

Event	Relative RiskCE vs. Placebo(95 percent nCIŒ	CEN = 5,310	Placebon = 5,429
		Absolute Risk per 10,000 Women-Years
CHD eventsœ	0.95 (0.78 - 1.16)	54	57
Non-fatal MI œ	0.91 (0.73-1.14)	40	42
CHD death œ	1.01 (0.71-1.43)	16	16
All strokesœ	1.33 (1.05-1.68)	45	33
Ischemic stroke œ	1.55 (1.19-2.01)	38	25
Deep vein thrombosisœ  Ɖ	1.47 (1.06-2.06)	23	15
Pulmonary embolismœ	1.37 (0.90-2.07)	14	10
Invasive breast cancerœ	0.80 (0.62-1.04)	28	34
Colorectal cancer*	1.08 (0.75-1.55)	17	16
Hip fractureœ	0.65 (0.45-0.94)	12	19
Vertebral fracturesœ  Ɖ	0.64 (0.44-0.93)	11	18
Lower arm/wrist fracturesœ  Ɖ	0.58 (0.47-0.72)	35	59
Total fracturesœ  Ɖ	0.71 (0.64-0.80)	144	197
Deaths due to other causes*  †	1.08 (0.88-1.32)	53	50
Overall Mortalityœ  Ɖ	1.04 (0.88-1.22)	79	75
Global Index‡	1.02(0.92-1.13)	206	201
¥  Adapted from numerous WHI publications. WHI publications can be viewed at www.nblbi.nih.gov/whi. Œ  Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. œ  Results are based on centrally adjudicated data for an average follow-up of 7.1 years. Ɖ  Not included in "global index". *  Results are based on an average follow-up of 6.8 years. †  All deaths, except from breast or colorectal cancer, definite or probable CHD, PE 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, 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 7 fewer hip fractures.⁹  The absolute excess risk of events included in the "global index" was a non-significant 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 (see Table 7).

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 therapy increased the risk of ischemic stroke, and this excess was present in all subgroups of women examined¹⁰ (see Table 7).

Timing of the initiation of estrogen-alone 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 50-59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].

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, and 18 percent were 75 years of age and older) to evaluate the effects of 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, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (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 and Precautions (5.3) , and Use in Specific Populations (8.5) ].

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age and older (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, 0.83-2.66). 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 types (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 and Precautions (5.3) , and  Use in Specific Populations (8.5) ].

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, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see  Warnings and Precautions (5.3) , and  Use in Specific Populations (8.5) ].