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Esclim

"March 14, 2013 -- Hormone replacement therapy is the most effective treatment for symptoms like hot flashes, and the benefits are likely to outweigh the risks, major medical societies say.

The statement was published in the April issue "...

Esclim

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(Generic versions may still be available.)

CLINICAL PHARMACOLOGY

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 µg 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.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism, and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

The pharmacokinetics of transdermally administered estradiol using Esclim (estradiol transdermal) have been evaluated in a total of 138 healthy postmenopausal women in 9 clinical pharmacology and biopharmaceutic studies.

Absorption

Transdermal administration of estradiol produces therapeutic serum concentrations of estradiol with lower circulating concentrations of estrone and estrone conjugates and requires smaller total doses than does oral therapy.

The in vivo estradiol daily delivery rate from Esclim (estradiol transdermal) was estimated using the baseline adjusted average serum concentrations determined from pharmacokinetic studies and an estradiol clearance value of 1600 L/day. The estimated mean in vivo transdermal delivery rates of estradiol are 0.020 mg/day, 0.051 mg/day, and 0.101 mg/day for the 11 cm,2 22 cm2 and 44 cm2 Esclim (estradiol transdermal) systems, respectively.

The bioavailability of estradiol from Esclim (estradiol transdermal) was compared with Vivelle™ in a 4-day single application randomized crossover study of Esclim (estradiol transdermal) 0.05 (22 cm2), Esclim (estradiol transdermal) 0.1 (44 cm2) and Vivelle 0.05 in 23 postmenopausal women. The mean maximum serum estradiol concentrations of 62 pg/mL and 124 pg/mL were obtained at a mean Tmax of 27 hours following application of Esclim 0.05 and Esclim 0.1, respectively. In this study, serum estradiol concentration profiles (Figure 1) and pharmacokinetic parameters (Cmax and AUC) obtained with the Esclim (estradiol transdermal) 0.1 system were twice as high as those produced by the Esclim (estradiol transdermal) 0.05 system.

Figure 1: Mean Uncorrected Serum Estradiol Concentrations After Application of Esclim (estradiol transdermal) 0.05, Esclim (estradiol transdermal) 0.1 and Vivelle 0.05 for 4 Days

In a 3-week multiple application study in 18 postmenopausal women, Esclim (estradiol transdermal) 0.05 (22 cm2) applied to the buttocks increased serum estradiol concentrations within 4 hours and maintained an average serum estradiol concentration of approximately 51 pg/mL above baseline. Trough values of approximately 27 to 35 pg/mL above the baseline were observed at the end of each application interval (3 or 4 days). Nearly identical serum estradiol concentration profiles were seen during each successive week, indicating little or no accumulation of estradiol in the body.

In a 3-day, single-application, crossover study in 12 postmenopausal women, estradiol serum concentrations were compared following application of the Esclim (estradiol transdermal) 0.05 system to sites on the buttocks (site used in clinical trials), the femoral triangle, and the upper arm. The profiles of serum estradiol concentrations from these different application sites are shown in Figure 2, and the pharmacokinetic results derived from each site are presented in Table 1.

Figure 2:Mean Uncorrected Serum Estradiol Concentrations After Application of Esclim (estradiol transdermal) 0.05 to Different Body Sites for 3 Days

Table 1: Mean Uncorrected Estradiol Pharmacokinetic Parameters After Application of Esclim 0.05 Patches to Different Body Sites

Parameter

Femoral Triangle

Upper Arm

Buttock

Cmax (pg/mL)

80.1 ± 34.9

80.2 ± 44.1

72.6 ± 36.2

Cmin72 (pg/mL)

41.6 ± 18.3

38.7 ± 15.2

34.5 ± 18.8

Cav72 (pg/mL)

49.0 ± 24.6

47.4 ± 24.3

42.8 ± 20.7

Cav96 (pg/mL)

42.8 ± 20.5

40.8 ± 19.7

37.3 ± 17.1

AUC(0-72) (pg•hr/mL)

4106 ± 1826

3825 ± 1897

3477 ± 1530

AUC(0-96) (pg•hr/mL)

4578 ± 1938

4306 ± 1925

3885 ± 1622

Linear pharmacokinetics have been demonstrated for the Esclim transdermal system. Serum estradiol concentrations following a 4-day application of the Esclim (estradiol transdermal) 0.025, 0.05, and 0.1 systems are shown in Figure 3, while the mean values for pharmacokinetic parameters from these applications are summarized in Table 2. Results for the Esclim (estradiol transdermal) 0.025 system are from 1 study, while results for Esclim (estradiol transdermal) 0.05 and 0.1 systems are from a separate study. Cmax occurred at approximately 30 hours.

Figure 3: Mean Uncorrected Serum Estradiol Concentrations After Application of Esclim (estradiol transdermal) 0.025, Esclim (estradiol transdermal) 0.05, and Esclim (estradiol transdermal) 0.1 for 4 Days

 

Table 2: Mean ± SD Uncorrected Estradiol Pharmacokinetic Parameters for Esclim Transdermal Systems Applied to the Buttocks (N = 23)

Surface Area

Estradiol Dose

Cmax

Cmina

Cavg

(cm2)

(mg/day)

(pg/mL)

(pg/mL)

(pg/mL)

11

0.025

24.5 ± 11b

15.5 ± 6.1b

17.8±6.6b

22

0.05

61.6 ± 33

26.3 ± 14

38.6 ± 21

44

0.1

124 ± 66

51.4 ± 29

74.0 ± 43

aCmin=Serum estradiol concentration at 96 hours following application. bN=17.

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. Estradiol and other naturally occurring estrogens are bound mainly to sex hormone binding globulin (SHBG), and to lesser degree to 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.

Since transdermally absorbed estradiol is not subject to first pass liver metabolism, the ratio of serum concentrations of estradiol to either of its major metabolites, estrone or estrone sulfate, is closer to those observed in premenopausal women than when administered by the oral route of administration. The clinical relevance of the estradiol to estrone ratio is presently unknown.

In a double-blind, parallel-group, placebo-controlled clinical trial using Esclim, the steady-state serum concentrations of estradiol, estrone, and estrone sulfate were measured between 24 and 72 hours after application of patch at week 13 and are presented in Table 3.

Table 3: Mean ±SD Steady State Serum Concentration of Estradiol and Its Metabolites at Week 13 Following the Application of Esclim

 

Steady State Serum Concentration

Patch

Estradiol (pg/mL)

Estrone (pg/mL)

Estrone Sulfate (ng/dL)

Placebo

19.6 ± 14.0

31a

29.7 ± 11.7

31

42.9 ± 24.0

30

0.025 mg/day

48.2 ± 27.4

22

38.7 ± 21.5

22

152.6 ± 129.7

22

0.05 mg/day

102.8 ± 63.6

24

49.0 ± 28.0

24

236.1 ± 147.1

22

0.1 mg/day

165.3 ± 116.1

28

64.9 ± 31.7

28

373.6 ± 272.0

28

anumber of subjects

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Serum concentrations of estradiol and estrone returned to baseline values within 12 to 24 hours after removal of Esclim (estradiol transdermal) .

Special Populations

No specific studies have been conducted using Esclim (estradiol transdermal) in any special populations.

Drug Interactions

No specific drug interaction studies have been conducted using Esclim (estradiol transdermal) .

Clinical Trials

In a 12-week, double-blind study evaluating the efficacy and safety of Esclim (estradiol transdermal) 0.025, 0.05, and 0.1 versus placebo in symptomatic women (average of 8 or more moderate to severe hot flushes per day), reduction in the frequency of these vasomotor symptoms was demonstrated within 4 weeks. Results from this trial are presented in Table 4 and Figure 4.

After 4 weeks of treatment, the mean reduction in the moderate to severe vasomotor symptoms (MSVS) was up to 8.6 MSVS per day in the Esclim (estradiol transdermal) 0.025 group, 9.2 and 10.2 in the Esclim (estradiol transdermal) 0.05, and Esclim (estradiol transdermal) 0.1 groups respectively, compared with 5.3 in the placebo group. After 12 weeks of treatment, this increased to 9.9 in the Esclim (estradiol transdermal) 0.025 group, 10.4 in the Esclim (estradiol transdermal) 0.05 group, and 10.7 in the Esclim (estradiol transdermal) 0.1 group and remained stable at 5.2 in the placebo group.

Table 4: Changes From Baseline in Frequency of MSVS

Week

Placebo (N=54)

Esclim 0.025 mg/day (N=48)

Esclim 0.05 mg/day (N=47)

Esclim 0.1 mg/day (N=47)

Week 0

(Baseline)

Mean ± SD

11.4 ± 3.7

11.6 ± 5.4

10.9 ± 4.2

11.2 ± 2.8

Week 4

Mean

Reduction

± SD(% Reduction)

-5.3 ± 4.1

(-48.9%)

-8.6 ± 5.7*

(-72.6%)

-9.2 ± 4.5*

(-84.4%)

-10.2 ± 2.9*

(-92.0%)

Week 8

Mean

Reduction

± SD(% Reduction)

-5.5 ± 4.7

(-51.5%)

-9.4 ± 5.7*

(-79.8%)

-10.3 ± 4.3*

(-94.0%)

-10.6 ± 2.8*

(-95.4%)

Week 12

Mean

Reduction

± SD(% Reduction)

-5.2 ± 5.1

(-50.3%)

-9.9 ± 5.8*

(-83.4%)

-10.4 ± 4.2*

(-95.3%)

-10.7 ± 2.8*

(-95.6%)

*Statistically different from placebo in mean reduction (Dunnett’s test)

Figure 4: Reduction of MSVS During Double-Blind, Placebo-Controlled Study

Maintenance of the relief of VMS over a median period of 2 years was documented in 2 open-label trials.

Last reviewed on RxList: 1/12/2005
This monograph has been modified to include the generic and brand name in many instances.

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