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Premarin Vaginal Cream

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Premarin Vaginal Cream

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, which is secreted by the adrenal cortex, to estrone by 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 follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.

Pharmacodynamics

Currently, there are no pharmacodynamic data known for PREMARIN Vaginal Cream.

Pharmacokinetics

Absorption

Conjugated estrogens are water soluble and are well-absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

A bioavailability study was conducted in 24 postmenopausal women with atrophic vaginitis. The mean (SD) pharmacokinetic parameters for unconjugated estrone, unconjugated estradiol, total estrone, total estradiol and total equilin following 7 once-daily doses of PREMARIN Vaginal Cream 0.5 g is shown in Table 2.

Table 2: Mean ± SD Pharmacokinetic Parameters of PREMARIN Following Daily Administration (7 Days) of PREMARIN Vaginal Cream 0.5 g in 24 Postmenopausal Women

Pharmacokinetic Profiles of Unconjugated Estrogens PREMARIN Vaginal Cream 0.5g
PK Parameters Arithmetic Mean ± SD Cmax
(pg/mL)
Tmax
(hr)
AUCss
(pg•hr/mL)
Estrone 42.0 ± 13.9 7.4 ± 6.2 826 ± 295
Baseline-adjusted estrone 21.9 ± 13.1 7.4 ± 6.2 365 ± 255
Estradiol 12.8 ± 16.6 8.5 ± 6.2 231 ± 285
Baseline-adjusted estradiol 9.14 ± 14.7 8.5 ± 6.2 161 ± 252
Pharmacokinetic Profiles of Conjugated Estrogens PREMARIN Vaginal Cream 0.5g
PK Parameters Cmax Tmax AUCss
Arithmetic Mean (ng/m L) (hr) (ng•hr/mL)
Total estrone 0.60 ± 0.32 6.0 ± 4.0 9.75 ± 4.99
Baseline-adjusted total estrone 0.40 ± 0.28 6.0 ± 4.0 5.79 ± 3.7
Total estradiol 0.04 ± 0.04 7.7 ± 5.9 0.70 ± 0.42
Baseline-adjusted total estradiol 0.04 ± 0.04 7.7 ± 6.0 0.49 ± 0.38
Total equilin 0.12 ± 0.15 6.1 ± 4.7 3.09 ± 1.37

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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (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 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 portion of the circulating estrogens exists 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.

Specific Populations

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

Clinical Studies

Effects on Vulvar and Vaginal Atrophy

A 12-week, prospective, randomized, double-blind placebo-controlled study was conducted to compare the safety and efficacy of 2 PREMARIN Vaginal Cream (PVC) regimens 0.5 g (0.3 mg CE) administered twice weekly and 0.5 g (0.3 mg CE) administered sequentially for 21 days on drug followed by 7 days off drug to matching placebo regimens in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The initial 12-week, double-blind, placebo-controlled phase was followed by an open-label phase to assess endometrial safety through week 52. The study randomized 423 generally healthy postmenopausal women between 44 to 77 years of age (mean 57.8 years), who at baseline had ≤ 5 percent superficial cells on a vaginal smear, a vaginal pH ≥ 5.0, and who identified a most bothersome moderate to severe symptom of vulvar and vaginal atrophy. The majority (92.2 percent) of the women were Caucasian (n = 390); 7.8 percent were Other (n = 33). All subjects were assessed for improvement in the mean change from baseline to Week 12 for the co-primary efficacy variables of: most bothersome symptom of vulvar and vaginal atrophy (defined as the moderate to severe symptom that had been identified by the woman as most bothersome to her at baseline); percentage of vaginal superficial cells and percentage of vaginal parabasal cells; and vaginal pH.

In the 12-week, double-blind phase, a statistically significant mean change between baseline and Week 12 in the symptom of dyspareunia was observed for both of the PREMARIN Vaginal Cream regimens (0.5 g twice weekly and 0.5 g daily for 21 days, then 7 days off) compared to matching placebo, see Table 3. Also demonstrated for each PREMARIN Vaginal Cream regimen compared to placebo was a statistically significant increase in the percentage of superficial cells at Week 12 (28 percent and 26 percent, respectively, compared to 3 percent and 1 percent for matching placebo), a statistically significant decrease in parabasal cells (-61 percent and -58 percent, respectively, compared to -21 percent and -7 percent for matching placebo) and statistically significant mean reduction between baseline and Week 12 in vaginal pH (-1.62 and -1.57, respectively, compared to -0.36 and -0.26 for matching placebo).

Endometrial safety was assessed by endometrial biopsy for all randomly assigned subjects at week 52. For the 155 subjects (83 on the 21/7 regimen, 72 on the twice-weekly regimen) completing the 52-week period with complete follow-up and evaluable endometrial biopsies, there were no reports of endometrial hyperplasia or endometrial carcinoma.

Table 3: Mean Change in Dyspareunia Severity Compared to Placebo MITT Population of Most Bothersome Symptom Score for Dyspareunia, LOCF

Dyspareunia PVC 0.5 g 2x/wka Placebo 0.5 g 2x/wka PVC 0.5 g 21/7b Placebo 0.5 g 21/7b
n n n n
Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Baseline 52 22 50 18
2.43 (0.76) 2.28 (1.04) 2.26 (0.99) 2.32 (0.88)
Week 12 52 21 50 18
0.88 (0.96) 1.63 (1.16) 0.77 (1.05) 1.92 (1.03)
Change from Baseline at Week 12 52 21 50 18
-1.55 (0.92) -0.62 (1.23) -1.48 (1.17) -0.40 (1.01)
P-value vs. Placebo < 0.001c -- <0.001d --
a PVC 2x/wk = apply PVC twice a week
b PVC 21/7 = apply PVC for 21 days and then 7 days of no therapy
c Comparison of PVC 2x/wk with placebo 2x/wk
d Comparison of PVC 21/7 with placebo 21/7

Women's Health Initiative Studies

The Women's Health Initiative (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 coronary heart disease [(CHD) defined as nonfatal myocardial infarction (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, pulmonary embolism (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 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 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 4.

Table 4: 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 10,000 Risk per Women-Years
CHD eventsc 0.95 (0.78–1.16) 54 57
  Non-fatal MIc 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 cancere 1.08 (0.75–1.55) 17 16
Hip fracturec 0.65 (0.45–0.94) 12 19
Vertebral fracturesc,d 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 (0.64–0.80) 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.
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/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 [see BOXED WARNINGS, and WARNINGS AND PRECAUTIONS].

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, see Table 4.10

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 50-59 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)].

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

Table 5: 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 10,000 Risk per 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 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 fracture 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
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 cancer.
f All deaths, except from breast or colorectal cancer, definite/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 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 0.441.07)].

Women's Health Initiative Memory Study

The estrogen-alone Women's Health Initiative Memory Study (WHIMS), an 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) 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 both the treatment and placebo groups 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 substudy 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 (0.625 mg) plus MPA (2.5 mg) versus placebo was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable dementia for CE (0.625 mg) plus MPA (2.5 mg) 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 both the treatment and placebo groups 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: 6/7/2011
This monograph has been modified to include the generic and brand name in many instances.

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