Vivelle Dot Drug Information

Effects on Vasomotor Symptoms in Postmenopausal Women

In a pharmacokinetic study, Vivelle-Dot was shown to be bioequivalent to Vivelle. In 2 controlled clinical trials with Vivelle, of 356 women, 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 women was performed with Vivelle to establish the efficacy of the lowest dose of 0.0375 mg.

The baseline mean daily number of hot flushes in these 255 women 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 Vivelle 0.0375 mg Versus Placebo in a 12-week Trial 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 Vivelle (0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of vasomotor symptoms. figure2

Effects on Bone Mineral Density in Postmenopausal Women Efficacy and safety of

Vivelle 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 and non-hysterectomized, 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/cm 2 ) were enrolled in this study; 194 women were randomized to 1 of the 4 doses of Vivelle (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%) or surgically (18%) menopausal, hysterectomized (61%) or non-hysterectomized (39%) 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%) of randomized women (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. Women 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 Vivelle dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients.

All Vivelle doses were significantly superior to placebo (p < 0.05) at all time points with the exception of Vivelle 0.05 mg/day at 6 months. The highest dose of Vivelle 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 Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to placebo (p<0.05) at 24 months.

The highest Vivelle 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 Vivelle 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 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. figure3 figure4

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 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% White, 15.1% Black, 6.1% Hispanic, 3.6% 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 WHI * * 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. Þ 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. CE n = 5,310 Placebo n = 5,429 Event Relative Risk CE vs. Placebo (95% nCI † ) Absolute Risk per 10,000 Women-Years CHD events ‡ 0.95 (0.78-1.16) 54 57 Non-fatal MI ‡ 0.91 (0.73-1.14) 40 43 CHD death ‡ 1.01 (0.71-1.43) 16 16 All strokes ‡ 1.33 (1.05-1.68) 45 33 Ischemic stroke ‡ 1.55 (1.19-2.01) 38 25 Deep vein thrombosis ‡,§ 1.47 (1.06-2.06) 23 15 Pulmonary embolism ‡ 1.37 (0.90-2.07) 14 10 Invasive breast cancer ‡ 0.80 (0.62-1.04) 28 34 Colorectal cancer ¶ 1.08 (0.75-1.55) 17 16 Hip fracture ‡ 0.65 (0.45-0.94) 12 19 Vertebral fractures ‡,§ 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures ‡,§ 0.58 (0.47-0.72) 35 59 Total fractures ‡,§ 0.71 (0.64-0.80) 144 197 Death due to other causes ¶,# 1.08 (0.88-1.32) 53 50 Overall mortality ‡,§ 1.04 (0.88-1.22) 79 75 Global Index Þ 1.02 (0.92-1.13) 206 201 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-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 to 59 years of age a nonsignificant trend toward reduced risk for CHD and overall mortality. 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 CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79, 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% 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

Years *,† * 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. Þ 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. CE/MPA n = 8,506 Placebo n = 8,102 Event Relative Risk CE/MPA vs.

Placebo (95% nCI ‡ ) 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 § 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer ¶ 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer § 0.81 (0.48-1.36) 6 7 Cervical cancer § 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures § 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures § 0.71 (0.59-0.85) 44 62 Total fractures § 0.76 (0.69-0.83) 152 199 Overall mortality # 1.00 (0.83-1.19) 52 52 Global Index Þ 1.13 (1.02-1.25) 184 165 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.

Women’s Health Initiative Memory Study

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% were age 65 to 69 years of age; 36% were 70 to 74 years of age; 19% 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% 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 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 . The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years of age; 35% were 70 to 74 years of age; 18% 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 was 2.05 (95% CI, 1.21 to 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 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 . 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% 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 .