August 4, 2015
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Angeliq

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Angeliq




CLINICAL PHARMACOLOGY

Mechanism Of Action

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 (E2) 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 will 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 concentrations of these gonadotropins seen in postmenopausal women.

DRSP is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro, drospirenone has antiandrogenic activity, but no glucocorticoid, antiglucocorticoid, estrogenic, or androgenic activity. Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacodynamics

No clinical pharmacology studies have been conducted for Angeliq.

Pharmacokinetics

Absorption

Serum concentrations of DRSP reach peak concentrations approximately 1 hour after administration of Angeliq and mean absolute bioavailability of DRSP ranges from 76–85%. Following oral administration, the median Tmax of serum estradiol was approximately 2 hours after dosing with Angeliq and Tmax ranged between 0.3-10 hours.

The pharmacokinetics of DRSP are dose proportional within the dose range of 0.25–4 mg. Following daily dosing of Angeliq, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for DRSP and estradiol were 2.3 and 2.0, respectively, following multiple doses of 0.5 mg DRSP/1 mg E2, and 2.6 and 1.6, respectively, following multiple doses of 0.25 mg DRSP/0.5 mg E2. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with Angeliq (0.5 mg DRSP/1 mg E2) for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 0.25 mg DRSP/0.5 mg E2 or 0.5 mg DRSP/1 mg E2 at steady state is presented in Table 3.

Figure 1: Mean (± SD) steady state serum drospirenone and estradiol concentrations following daily oral administration of 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol

Mean (± SD) steady state serum drospirenone and estradiol concentrations following daily oral administration of 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol - Illustration

Table 3: Mean (± SD) Steady State Pharmacokinetic Parameters after Administration of Tablets Containing 0.25 or 0.5 mg Drospirenone and 0.5 or 1 mg Estradiol

Parameter Unit 0.25 mg DRSP/0.5 mg E2 0.5 mg DRSP/1 mg E2
Drospirenone (DRSP) N=12 N=17
Cmax ng/mL 5.70 (1.42) 8.50 (1.63)
Tmax h 0.992 (0.667 - 1.03) 1.02 (1 - 2.03)
AUC (0-24) ng•h/mL 48.5 (13.7) 84.3 (19.7)
h N/A 39.2a (8.5)
Estradiol (E2)
C max pg/mL 29.7 (6.80) 63.7 (24.2)
Tmax h 2.33 (0.32 - 10) 2.01 (0.5 - 6.02)
AUC (0-24) pg•h/mL 515.4 (142.0) 882 (267)
h N/A 20.5 (2.67)
Estrone (E1)
C max pg/mL 165.7 (40.4) 362 (122)
Tmax h 3.98 (1.98 - 7.05) 6 (3.99 - 10)
AUC (0-24) pg•h/mL 2839 (658) 5561 (1689)
h N/A 19.9 (2.10)

Except for Tmax, the mean PK results of DRSP, E2, and E1 are displayed as the arithmetic mean and standard deviation (SD, in parentheses). For Tmax the median and range are provided. Cmax=Maximum observed serum concentration Tmax=time to reach Cmax AUC (0-24)=area under the serum concentration-time curve from 0 h up to 24 h after daily multiple administration t½=half-life N/A=Not available
aN=16

Effect of Food

The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of Angeliq. However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake.

Distribution

The mean volume of distribution of DRSP is 4.2 L/kg. DRSP does not bind to SHBG or CBG but binds about 97% to other serum proteins. 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 SHBG (37%) and to albumin (61%), while only approximately 1%–2% is unbound.

Metabolism

Mean clearance of DRSP is 1.2 mL/min/kg. DRSP is extensively metabolized after oral administration. The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active. DRSP is also subject to oxidative metabolism catalyzed by CYP 3A4.

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 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

DRSP serum concentrations are characterized by a terminal elimination half-life of approximately 36–42 hours. Excretion of DRSP was nearly complete after 10 days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates. Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Use in Specific Populations

Geriatric

No pharmacokinetic studies were conducted for Angeliq in the geriatric population.

Pediatric

No pharmacokinetic studies were conducted for Angeliq in a pediatric population.

Gender

Angeliq is indicated for use in women only.

Race

No studies were done to determine the effect of race on the pharmacokinetics of Angeliq.

Hepatic Impairment

Angeliq is contraindicated in patients with hepatic impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Renal Impairment

Angeliq is contraindicated in patients with renal impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effects of DRSP on serum potassium concentrations were investigated in female subjects (n=28, age 30-65 years) with creatinine clearance (CLcr) ≥ 80 mL/min (11 patients), and CLcr of 50-79 mL/min (10 patients) and CLcr of 30-49 mL/min (7 patients). All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations were on average 37% higher in the group with CLcr of 30-49 mL/min compared to those in the group with normal renal function (CLcr ≥ 80 mL/min). Serum DRSP concentrations in the group with CLcr of 50–79 mL/min were comparable to those in the group with CLcr ≥ 80 mL/min. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in 5 of the 7 subjects who continued use of potassium sparing drugs during the study, individual mean serum potassium concentrations increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

Drug Interactions

No formal drug interaction studies have been conducted for Angeliq.

Effects of Drospirenone on Other Drugs: Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies, DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme.

The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the systemic clearance of the CYP2C19 substrate omeprazole (40 mg) and the CYP2C19 product 5-hydroxy-omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.

Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy, postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of 3 mg DRSP/day.

Based on the available results of in vivo and in vitro studies, it can be concluded that, at clinical dose concentration, DRSP is unlikely to inhibit significantly CYP enzymes.

There is a potential for an increase in serum potassium in women taking drospirenone with other drugs that may affect electrolytes, such as ACE inhibitors, angiotensin receptor blockers, or NSAIDs.

Electrolytes were studied in 230 postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker. Of these, 26 patients had a creatinine clearance > 50 mL/min to < 80 mL/min. Patients were given 1 mg E2 and 3 mg DRSP (n=112) or placebo (n=118) over 28 days. Non-diabetic patients also received ibuprofen 1200 mg/day for 5 days during the study. There was a single case of serum potassium > 6 mEq/L and a single case of serum sodium < 130 mEq/L on treatment, both occurring following five days of ibuprofen therapy in two women taking E2/DRSP. Serum potassium concentrations ≥ 5.5 mEq/L were observed in 8 (7.3%) E2/DRSP-treated subjects (3 diabetic and 5 non-diabetic) and in 3 (2.6%) placebo-treated subjects (2 diabetic and 1 non-diabetic). After 28 days of exposure, the mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium concentrations ≥ 5.5 mEq/L had cardiovascular adverse events.

A drug-drug interaction study of DRSP 3 mg/E2 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations > 5.5 mEq/L).

Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials.

Effects of Other Drugs on Estrogens and Progestins: In vitro and in vivo studies have shown that estrogens and progestins are metabolized partially by CYP3A4. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism [see DRUG INTERACTIONS]. In a clinical drug-drug interaction study conducted in 18 premenopausal women, once daily co-administration of DRSP 3 mg/E2 1.5 mg combination tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a 2.30-fold (90% CI: 2.08-2.54) increase of the AUC (0-24) and a 1.66-fold (90% CI: 1.50-1.84) increase of Cmax for DRSP. The E2 exposure [that is, AUC (0-24) and Cmax] was unaffected by ketoconazole, although the AUC(0-24) and Cmax for E1 increased 1.39-fold (90% CI: 1.27-1.52) and 1.32-fold (90% CI: 1.23-1.42), respectively.

Clinical Studies

Effects On Vasomotor Symptoms

Angeliq 0.25 mg DRSP/0.5 mg E2

The efficacy of Angeliq 0.25 mg DRSP/0.5 mg E2 for reducing the frequency and severity of moderate to severe vasomotor symptoms was evaluated in a randomized, double-blind, placebo-controlled trial. A total of 735 postmenopausal women ≥ 40 years of age with a minimum of 7 to 8 moderate to severe hot flashes daily or 50 to 60 moderate to severe hot flashes weekly were randomized to one of the two doses of Angeliq, including DRSP 0.25 mg/0.5 mg E2, estrogen monotherapy, or placebo. The median age of study subjects was 53 years and 68% were Caucasian. Efficacy for vasomotor symptoms was assessed during the 12 weeks of treatment. Compared to placebo, subjects receiving Angeliq 0.25 mg DRSP/0.5 mg E2 achieved statistically significant reduction in the frequency and severity of moderate to severe vasomotor symptoms at Week 4 and at Week 12. The mean difference in daily reduction of frequency of hot flushes between Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo were approximately -2 episodes at Week 4 and -3 episodes at Week 12. Table 4 shows the mean number of hot flushes in the Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo groups and the treatment difference between Angeliq 0.25 mg DRSP/0.5 mg E2 and placebo treatment at Week 4 and at Week 12.

Table 4: Summary Tabulation Of The Number Of Hot Flushes Per Day – Mean Values And Comparisons Between the Active Treatment Group and the Placebo Group, Last Observation Carried Forward

Treatment No. of Hot Flushes/Day
Time Period (week) Baseline Mean Mean Change from Baseline* Difference from Placebo (95% CI) p-Values vs. Placebo*
DRSP/E2 (0.25 mg/0.5 mg) [n=175]
Week 4 10.68 -5.46 -2.02
(-2.89, -1.16)
< 0.0001
Week 12 10.68 -7.71 -3.17
(-3.97, -2.37)
< 0.0001
Placebo [n=176]
Week 4 10.53 -3.44 - -
Week 12 10.53 -4.54 - -
* Mean change from baseline, difference from placebo, 95% confidence interval, and p-value based on an ANCOVA model with treatment and pooled center as factors and baseline measurement as covariate

Angeliq 0.5 mg DRSP/1 mg E2

Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the Angeliq combination product with a currently marketed 1 mg E2 product. The multiple-dose bioequivalence study evaluated the bioequivalence of E2 from a tablet containing DRSP (2 mg) and E2 (1 mg) relative to E2 1 mg tablet. Angeliq 0.5 mg DRSP/1 mg E2 tablets met the criteria for bioequivalence to the E2 1 mg comparator.

Effects On Endometrium

Angeliq 0.25 mg DRSP/0.5 mg E2

In a one year clinical trial, 661 postmenopausal subjects were treated with Angeliq 0.25 mg DRSP/0.5 mg E2 (N=489) or a comparator drug (N=172). Endometrial biopsies were performed on 407 (83.2%) subjects in the Angeliq group during the treatment period. No endometrial hyperplasias occurred during or after one year of treatment. See Table 5.

Angeliq 0.5 mg DRSP/1 mg E2

In a one year clinical trial of 1,142 postmenopausal subjects treated with 1 mg E2 alone or 1 mg E2 + 0.5, 1, 2, or 3 mg DRSP, endometrial biopsies were performed on 966 (84.6%) subjects during the treatment period. Eight subjects in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, 3 complex hyperplasia with no cytological atypia, and 1 complex hyperplasia with cytological atypia), and one subject in the 1 mg E2+2 mg DRSP group developed simple hyperplasia with no cytological atypia. Table 5 shows that there were no diagnoses of endometrial hyperplasia in the Angeliq group.

Table 5: Incidence of Endometrial Hyperplasia after up to 12 Months of Treatment

  E2 1 mg Angeliq 0.25 mg DRSP/ 0.5 mg E2 Angeliq 0.5 mg DRSP/ 1 mg E2
Total No. Subjects Treated 226 489 227
Total No. of On-Treatment Biopsies* 197 (87.2%) 407 (83.2%) 191 (84.1%)
Hyperplasia 8 (4%) 0 (0%) 0 (0%)
*Includes evaluable and unevaluable endometrial biopsy results

Effects On Uterine Bleeding Or Spotting

Angeliq 0.5 mg DRSP/1 mg E2 and Angeliq 0.25 mg DRSP /0.5 mg E2 were evaluated in separate one-year clinical trials investigating the endometrial safety in postmenopausal women with an intact uterus.

Over 12 months in the double-blind trials, the proportions of women with any bleeding or spotting decreased over time. At one year, approximately 22% of women treated with Angeliq 0.5 mg/E2 1.0 mg and 15% of women treated with Angeliq 0.25 mg/E2 0.5 mg had any uterine bleeding or spotting. See Figure 2.

Figure 2: Proportion of Subjects with Any Bleeding/spotting by Month of Angeliq Use

Proportion of Subjects with Any Bleeding/spotting by Month of Angeliq Use - Illustration

Women's Health Initiative Studies

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. 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 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 Yearsa,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
Non-fatal MI 1.28 (1.02-1.632) 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 fracturec 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

Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Results are based on centrally adjudicated data.

Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

Not included in “global index.”

Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.

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.

Timing of the initiation of estrogen 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 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CT 0.44-1.07)].

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 age of 63 years, 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 WHIa

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
  Non-fatal MI 0.91 (0.73-1.14) 40 43
  CHD deathc 1.01 (0.71-1.43) 16 16
All strokec 1.33 (1.05-1.68) 45 33
  Ischemicc 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 cancerc 1.08 (0.75-1.55) 17 16
Hip fracturec 0.65 (0.45-0.94) 12 19
Vertebral fractures c 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 (0.64-0.8) 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

a) Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.

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.

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 was 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 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 risk was present in all subgroups of women examined.10

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 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 CT 0.461.11)].

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, and 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 1.21-3.48). The absolute risk of probable dementia for CE plus MPA was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's 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 AND PRECAUTIONS, and Use In Specific Populations].

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 age 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) 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 type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and 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 and Use in Specific Populations].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall RR 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, and Use in Specific Populations].

REFERENCES

8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.

9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817828.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

Last reviewed on RxList: 7/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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