May 29, 2017
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Vagifem

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Vagifem




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 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, 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.

Pharmacodynamics

Currently, there are no pharmacodynamic data known for Vagifem.

Pharmacokinetics

Absorption

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

In a single-center, randomized, open-label, multiple-dose, parallel group study conducted in 58 patients, Vagifem 10 mcg and 25 mcg demonstrated a mean estradiol (E2) Cave at Day 83 of 5.5 pg/mL and 11.59 pg/mL, respectively after 12 weeks of treatment (see Tables 3 and 4).

Table 3: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses* of Vagifem 10 mcg

  E2 E1 E1S
AUC0-24 (h•pg/mL) Cave (0-24) (pg/mL) %CV† AUC0-24 (h•pg/mL) Cave (0-24) (pg/mL) %CV† AUCo-24 (h•pg/mL) Cave (0-24) (pg/mL) %CV†
Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93 53.57
Day 14 176.49 7.35 43.69 496.14 2o.67 30.88 6323.41 263.48 50.07
Day 83 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76
*Patients received vaginal tablets as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks.
†CV: Coefficient of Variance for both AUC0-24 and Cave(0-24)

Table 4: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses* of Vagifem 25 mcg

Uncorrected for baseline, N† =28 or 27
  E2 E1 E1S
AUC0-24 (h•pg/mL) Cave (0-24) (pg/mL) %CV‡ AUC0-24 (h•pg/mL) Cave (0-24) (pg/mL) %CV‡ AUC0-24 (h•pg/mL) Cave (0-24) (pg/mL) %CV‡
Day 1 495.27 2o.64 25.7o 567.o7 23.63 28.96 5738.32 239.1o 47.72
Day 14 466.63 19.44 33.53 662.94 27.62 24.36 7725.9o 321.91 43.67
Day 83 278.27 11.59 61.83 5oo.o6 2o.84 34.99 411o.84 171.29 51.38
*Patients received vaginal tablets as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks.
†N=28 for treatment before Day 14 and N=27 for treatments from Day 14.
‡CV: Coefficient of Variance for both AUC0-24 and Cave(0-24)

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.

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 the 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 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.

Excretion

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

Use In Specific Populations

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

Clinical Studies

Effects On Atrophic Vaginitis

Vagifem 10 mcg

A 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of Vagifem 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n=287), 3.2 percent were Black (n=10), 1.6 percent were Asian (n=5) and 2.2 percent were Other (n=7). All subjects were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: a composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on a vaginal smear; and vaginal pH.

Relief Of Vaginal Symptoms

Vagifem 10 mcg was statistically superior to placebo in reducing the severity of a composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 5).

Table 5: Mean Change from Baseline to Week 12 in a Composite Score of Most Bothersome Symptoms Compared to Placebo – ITT Population*

  Placebo Vagifem 10 mcg
ITT Population*
N 93 190
Baseline mean composite score 2.29 2.35
Change from baseline at Week 12 (LOCF) -0.84 -1.20
p-value versus Placebo --- 0.002
* All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation.

Also demonstrated for Vagifem 10 mcg compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p < 0.001), a statistically significant decrease in parabasal cells at Week 12 (-37.0 percent compared to -9.3 percent for matching placebo, p < 0.001), and a statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p < 0.001).

Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 subjects in the Vagifem 10 mcg group who had a biopsy performed at end of study, 92 subjects had endometrial tissue that was atrophic or inactive and 73 subjects had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade 2 and one case of complex hyperplasia without atypia. Three subjects exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation.

Endometrial safety of Vagifem 10 mcg was additionally evaluated in a second, 12 month, open-label, multicenter safety study. Of the 297 subjects who had a biopsy performed at end of study, 183 subjects had endometrial tissue that was atrophic or inactive and 111 subjects had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two subjects exhibited polyps.

Vagifem 25 mcg

A placebo-controlled comparison study was done in the U.S., in which 230 women were randomized to receive either placebo, Vagifem 25 mcg or 10 mcg estradiol vaginal tablets. Women inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 10 weeks. All subjects were assessed for vaginal symptoms. Vagifem 25 mcg was superior to placebo in reducing the severity of a composite score of symptoms associated with atrophic vaginitis (see Table 6).

An open-label, controlled comparison study was done in Canada in which 159 women were randomized to receive either Vagifem 25 mcg or a comparator drug. Two (2) grams of the comparator drug was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks; Vagifem 25 mcg was administered daily for 2 weeks, then twice weekly for the remaining 22 weeks. In this study, subjects were assessed for relief of symptoms. Vagifem 25 mcg was equally effective as the approved comparator product at the 2.0 gm dose in the relief of symptoms.

Table 6: Mean Change from Baseline to Week 7 and Week 12 in a Composite Score of Symptoms Compared to Placebo – ITT Population*

  Placebo Vagifem 25 mcg
ITT Population*
N 47 91
Baseline mean 1.93 1.85
Change from baseline at Week 7 (LOCF) -0.85 -1.22
Change from baseline at Week 12 (LOCF) -0.83 -1.33
p-value versus Placebo - Week 7 (LOCF) --- 0.016
p-value versus Placebo - Week 12 (LOCF) --- 0.005
* All randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation.

In the placebo-controlled study endometrial biopsies in non-hysterectomized women at week 12 were performed on 86 subjects (Vagifem 25 mcg: 32 subjects, estradiol 10 mcg: 33 subjects, Placebo: 21 subjects). Of these, 3 subjects each from the Vagifem 25 mcg and placebo groups and 8 from the 10 mcg estradiol group had insufficient tissue samples. Among those with biopsies that yielded sufficient tissue, results were normal with the exception of one subject in the Vagifem 25 mcg group, who had a simple hyperplasia without atypia.

In the open-label study comparing Vagifem 25 mcg with a comparator vaginal cream on 49 women in each treatment group, endometrial biopsies were obtained at the screening visit and at the end of treatment. At the end of the study (Week 24), all subjects in the Vagifem treatment group whose biopsies yielded sufficient tissue showed an atrophic endometrium with the exception of one subject who had a proliferative endometrium.

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 causes. These substudies did not evaluate the effects of CEalone 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 7.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI*

Event Relative Risk CE vs. Placebo (95% nCI† ) CE
n=5,310
Placebo
n=5,429
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
*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.
ÞA 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 non-significant 5 events per 10,000 womenyears. 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-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 [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].

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 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 8. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 8: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years*,†

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 IndexÞ 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 cancer.
#All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
ÞA 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 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)].

Women’s Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately 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 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, and Use In Specific Populations].

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; 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 versus placebo was 45 versus 22 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, and Use in Specific Populations].

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, and Use in Specific Populations].

REFERENCES

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; 21:817-828.

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: 8/1/2016
This monograph has been modified to include the generic and brand name in many instances.

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