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Elestrin (Estradiol Transdermal) - Description and Clinical Pharmacology

 
 



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DESCRIPTION

Elestrin® (estradiol gel) contains 0.06% estradiol in a hydroalcoholic gel base. The gel is applied onto the skin in a thin layer. The recommended area of application is the upper arm to shoulder (approximately 320 cm2). One pump actuation delivers Elestrin® in a unit dose of 0.87 g, which contains 0.52 mg of estradiol. The 0.87 g dose provides systemic delivery of 0.0125 mg of estradiol daily. The 1.7 g dose, two pump actuations, provides systemic delivery of 0.0375 mg daily.

Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17-diol, (17β)-. It has a molecular formula of C18H24O2•½H2O and molecular weight of 281.4.

The structural formula is:

The active component of Elestrin® is estradiol. The remaining components of the gel (ethanol, propylene glycol, diethylene glycol monoethyl ether, carbomer 940, triethanolamine, edetate disodium, and purified water) are pharmacologically inactive.

CLINICAL PHARMACOLOGY

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 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 hormones seen in postmenopausal women.

Pharmacokinetics

A. Absorption

Steady-state serum concentrations of estradiol are achieved in approximately 3 days following daily application of Elestrin® to the upper arm.

Pharmacokinetic parameters for estradiol on Day 14 following daily application of 0.87 g or 1.7 g of Elestrin® are summarized in Table 1. The nominal mean delivery rates of estradiol using the baseline-adjusted average serum concentrations from pharmacokinetic studies using 0.87 g/day and 1.7 g/day are 0.012 mg/day and 0.041 mg/day, respectively.

TABLE 1 - Summary of Unadjusted PK Parameters for Estradiol after 14 Days of Dosing
  Pharmacokinetic
Parameter
 
0.87 g Elestrin®
(0.52 mg/d Estradiol)
Mean
1.7 g Elestrin®
(1.04 mg/d Estradiol)
Mean

a Tmax shown as median (range)

AUC0-24 (pg'hr/mL) 335.2 940.2
Cmax (pg/mL) 21.6 66.7
Cave (pg/mL) 15.4 39.2
Cmin (pg/mL) 9.4 21.1
Tmax (h)a 18 (1 – 20) 4 (1 – 20)
Fluctuation Index 0.80 1.16
E2:E1 ratio 0.53 0.98

Mean concentrations of estradiol over a 24-hour period on Day 14 are shown in Figure 1.

Application of sunscreen 10 minutes before application of Elestrin® increased the exposure to estradiol by approximately 55%. No significant change in estradiol exposure was observed when sunscreen was applied 25 minutes after application of Elestrin. In the same study, prolonged (7 days) concomitant application of sunscreen to the site of Elestrin® application increased exposure to estradiol by about 2-fold, regardless of whether it was applied before or after application of Elestrin®.

B. 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 blood largely bound to sex hormone binding globulin (SHBG) and albumin.

C. 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 intestine 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.

D. Excretion

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

E. Special Populations

Elestrin® has been studied only in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment or any other special populations.

F. Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in side effects.

G. Estradiol Transfer

The potential for estradiol transfer between treated postmenopausal female subjects and their untreated male partners was evaluated. Two and 8 hours after women applied 2.6 g Elestrin® to one arm (12 women per time point), they engaged in direct arm-to-arm contact with a male partner for 5 minutes. No significant changes in estradiol pharmacokinetic parameters were observed in the male partners after contact.

Less than 10% of the estradiol dose was measured on the skin at 2 and 8 hours after application. After washing the application site with soap and water at 8 hours after application, about 1% of the dose of estradiol was measurable.

CLINICAL STUDIES

Effects On Vasomotor Symptoms

A randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of 12-week treatment with three different daily doses of Elestrin® for the treatment of vasomotor symptoms in 484 postmenopausal women between 28 and 74 years of age (mean 54 years; 83-88% Caucasian per group) who had at least 60 moderate-to-severe hot flushes per week at baseline. Subjects applied placebo, Elestrin® 0.87 g (0.52 mg estradiol), 1.7 g (1.04 mg estradiol), or 2.6 g (1.56 mg estradiol) once daily to the upper arm. Reduction in both the frequency and severity of moderate-to-severe hot flushes was statistically significant for the Elestrin® 1.7 g/day dose compared to placebo at week 4. Statistically significant reductions in both the frequency and severity of moderate-to-severe hot flushes when compared to placebo were delayed for the Elestrin® 0.87 g/day dose to week 5. Both the 0.87 g/day and 1.7 g/day doses were statistically significant compared to placebo at week 12. The reductions in frequency and severity are shown in Table 2.

TABLE 2 - Mean Change From Baselinea in the Number and Severity of Hot Flushes after Elestrin® Treatment
Evaluation Placebo
(N=137)
Elestrin®
0.87 g/day
(N=136)
Elestrin®
1.7 g/day
(N=142)

a Differences from baseline based on LS means derived from the ANCOVA model with factors for baseline, treatment, site, and treatment-by-baseline interaction.

b Unadjusted means and standard deviations, based on the first 14 days of the Screening Period.

c Severity score: 1=mild, 2=moderate, 3=severe.

SD: standard deviation

#P= ns, *P<0.01, **P<0.001, ***P<0.0001 for treatment comparison with placebo (Dunnett's test).

Number of Daily Hot Flushes      
Baseline (Mean ± SD)b 13.5 ± 4.5 13.3± 4.6 13.1 ± 6.5
  Mean Change: Week 4 -5.1 -6.5# -8.0***
  Week 5 -5.1 -7.5* -8.8***
  Week 12 -5.4 -8.5*** -10.0***
Daily Hot Flush Severityc      
  Baseline (Mean ± SD)b 2.4 ± 0.3 2.4 ± 0.3 2.4 ± 0.3
  Mean Change: Week 4 -0.2 -0.5# -0.7***
  Week 5 -0.2 -0.5* -0.8***
  Week 12 -0.3 -0.8*** -1.2***

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or in combination with medroxyprogesterone acetate (MPA 2.5 mg) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the estrogen plus progestin substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The estrogen alone substudy was stopped early because an increased risk of stroke was observed. Results of the estrogen alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 6.8 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)
Placebo
n = 5,429
CE
n = 5,310
Absolute Risk per 10,000 Women-Years

a Adapted from JAMA. 2004;291:1701-1712.

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

e Not included in Global Index.

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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

CHD eventsc 0.95 (0.79-1.16) 56 53
  Non-fatal MI c 0.91 (0.73-1.14) 43 40
  CHD death c 1.01 (0.71-1.43) 16 16
Invasive breast cancerc 0.80 (0.62-1.04) 34 28
Stroked 1.39 (1.10-1.77) 32 44
Deep vein thrombosisc,e 1.47 (1.06-2.06) 15 23
Pulmonary embolismc 1.37 (0.90-2.07) 10 14
Colorectal cancerd 1.08 (0.75-1.55) 16 17
Hip fractured 0.61 (0.41-0.91) 17 11
Vertebral fracturesd,e 0.62 (0.42-0.93) 17 11
Total fracturesd,e 0.70 (0.63-0.79) 195 139
Death due to other causesd,f 1.08 (0.88-1.32) 50 53
Overall mortalityd,e 1.04 (0.88-1.22) 78 81
Global indexd,g 1.01 (0.91-1.12) 190 192

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 0.625 mg alone were 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

The CE/MPA substudy was also stopped early because, according to predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) after an average follow-up of 5.6 years, are presented in Table 4:

TABLE 4 - Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI at an Average of 5.6 Yearsa

a   Results are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95% nCI 0.82-1.18).

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

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

Eventc Relative Risk
CE/MPA vs. Placebo
(95% nCIb )
Placebo
n = 8,102
CE/MPA
n = 8,506
Absolute Risk per 10,000 Women-Years
CHD events 1.24 (1.00-1.54) 33 39
  Non-fatal MI 1.28 (1.00-1.63) 25 31
  CHD death 1.10 (0.70-1.75) 8 8
Invasive breast cancerc 1.24 (1.01-1.54) 33 41
All Stroke 1.31 (1.02-1.68) 24 31
Ischemic Stroke 1.44 (1.09-1.90) 18 26
Deep vein thrombosis 1.95 (1.43-2.67) 13 26
Pulmonary embolism 2.13 (1.45-3.11) 8 18
Invasive Colorectal cancer 0.56 (0.38-0.81) 16 9
Endometrial cancer 0.81 (0.48-1.36) 7 6
Cervical cancer 1.44 (0.47-4.42) 1 2
Hip fracture 0.67 (0.47-0.96) 16 11
Vertebral fractures 0.65 (0.46-0.92) 17 11
Lower arm/wrist fractures 0.71 (0.59-0.85) 62 44
Total fractures 0.76 (0.69-0.83) 199 152

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/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28). (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Women's Health Initiative Memory Study

The estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were aged 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 5.2 years, 28 women in the CE-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the CE-alone group was 1.49 (95% confidence interval [CI], 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)

The CE/MPA WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the CE/MPA group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21-3.48) compared to placebo.

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, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia , and PRECAUTIONS, Geriatric Use .)

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