Estradiol (Page 7 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

14 CLINICAL STUDIES

14.1 Effects on Vasomotor Symptoms

In a pharmacokinetic study, estradiol transdermal system was shown to be bioequivalent to the original estradiol formulation. In 2 controlled clinical trials with the original estradiol formulation, of 356 subjects, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatment. In this original study, the 0.0375 and 0.05 mg doses, however, did not differ from placebo until approximately Week 6, therefore, an additional 12-week, placebo-controlled study in 255 patients was performed with the original estradiol formulation to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 patients was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in Figure 2.

Figure 2. Mean (SD) Change from Baseline in Mean Daily Number of Flushes for Estradiol 0.0375 mg Versus Placebo in a 12-week Trial

figure
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The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. All doses of the original estradiol formulation (0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of vasomotor symptoms.

14.2 Effects on Bone Mineral Density

Efficacy and safety of the original estradiol formulation in the prevention of postmenopausal osteoporosis have been studied in a 2-year, double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard deviations of average peak bone mass, i.e., at least 0.827 g/cm2) were enrolled in this study; 194 patients were randomized to 1 of the 4 doses of the original estradiol formulation (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.

The study population comprised naturally (82 percent) or surgically (18 percent) menopausal, hysterectomized (61 percent) or non-hysterectomized (39 percent) women with a mean age of 52 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89 percent) of randomized subjects (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Patients were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all the original estradiol formulation dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All estradiol doses were significantly superior to placebo (p<0.05) at all time points with the exception of estradiol 0.05 mg/day at 6 months. The highest dose of estradiol was superior to the 3 lower doses. There were no statistically significant differences in pairwise comparisons among the 3 lower doses. (See Figure 3)

Figure 3. Bone Mineral Density-AP Lumbar Spine Least Squares Means of Percentage Change from Baseline All Randomized Patients with at Least One Post-baseline Assessment Available with Last Post-baseline Observation Carried Forward

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Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of the original estradiol formulation were significantly superior to placebo (p<0.05) at 24 months. The highest estradiol dose was superior to placebo at all time points. A mixture of significant and nonsignificant results were obtained for the lower dose groups at earlier time points. The highest estradiol dose was superior to the 3 lower doses, and there were no significant differences among the 3 lower doses at this skeletal site. (See Figure 4)

Figure 4. Bone Mineral Density-Femoral Neck Least Squares Means of Percentage Change from Baseline All Randomized Patients with at Least One Post-baseline Assessment Available with Last Post-baseline Observation Carried Forward

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The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-telopeptides of Type 1 collagen (a marker of bone resorption) decreased numerically in most of the active treatment groups relative to baseline. However, the decreases in both markers were inconsistent across treatment groups and the differences between active treatment groups and placebo were not statistically significant.

14.3 Women’s Health Initiative Studies

The 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 the 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 causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

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; 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 3.

Table 3. 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 to 1.16)

54

57

Non-fatal MI c

0.91 (0.73 to 1.14)

40

43

CHD death c

1.01 (0.71 to 1.43)

16

16

All strokesc

1.33 (1.05 to 1.68)

45

33

Ischemic stroke c

1.55 (1.19 to 2.01)

38

25

Deep vein thrombosisc,d

1.47 (1.06 to 2.06)

23

15

Pulmonary embolismc

1.37 (0.90 to 2.07)

14

10

Invasive breast cancerc

0.80 (0.62 to 1.04)

28

34

Colorectal cancere

1.08 (0.75 to 1.55)

17

16

Hip fracturec

0.65 (0.45 to 0.94)

12

19

Vertebral fracturesc,d

0.64 (0.44 to 0.93)

11

18

Lower arm/wrist fracturesc,d

0.58 (0.47 to 0.72)

35

59

Total fracturesc,d

0.71 (0.64 to 0.80)

144

197

Death due to other causese,f

1.08 (0.88 to 1.32)

53

50

Overall mortalityc,d

1.04 (0.88 to 1.22)

79

75

Global Indexg

1.02 (0.92 to 1.13)

206

201

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

b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.

d Not included in “global index”.

e Results are based on an average follow-up of 6.8 years.

f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.

g 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. (See Table 3)

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences 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 (See Table 3)

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 [hazard ratio (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)].

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 reduction 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, 83.9 percent white, 6.8 percent black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 4. 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 to 1.53)

41

34

Non-fatal MI

1.28 (1.00 to 1.63)

31

25

CHD death

1.10 (0.70 to 1.75)

8

8

All strokes

1.31 (1.03 to 1.68)

33

25

Ischemic Stroke

1.44 (1.09 to 1.90)

26

18

Deep vein thrombosisd

1.95 (1.43 to 2.67)

26

13

Pulmonary embolism

2.13 (1.45 to 3.11)

18

8

Invasive breast cancere

1.24 (1.01 to 1.54)

41

33

Colorectal cancer

0.61 (0.42 to 0.87)

10

16

Endometrial cancerd

0.81 (0.48 to 1.36)

6

7

Cervical cancerd

1.44 (0.47 to 4.42)

2

1

Hip fracture

0.67 (0.47 to 0.96)

11

16

Vertebral fracturesd

0.65 (0.46 to 0.92)

11

17

Lower arm/wrist fracturesd

0.71 (0.59 to 0.85)

44

62

Total fracturesd

0.76 (0.69 to 0.83)

152

199

Overall mortalityf

1.00 (0.83 to 1.19)

52

52

Global Indexg

1.13 (1.02 to 1.25)

184

165

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

b Results are based on centrally adjudicated data.

c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

d Not included in “global index”.

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

f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.

g 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 nonsignificant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44 to 1.07)].

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