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.
Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation.
Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.
A. Absorption
Administration of Climara Pro to postmenopausal women produces mean maximum estradiol concentrations in serum in about 2 to 2.5 days. Estradiol concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12-24 hours after the first application.
In one study, steady state estradiol concentrations in serum were measured during week 4 in 44 healthy, postmenopausal women during four consecutive Climara Pro applications of two formulations (0.045 mg estradiol/0.03 mg levonorgestrel and 0.045 mg estradiol/0.015 mg levonorgestrel) to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of estradiol and estrone Cmax and AUC parameters. A summary of Climara Pro single and multiple applications estradiol, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 1.
Table 1: Summary of Mean Pharmacokinetic Parameters | All mean parameters are arithmetic means except Tmax which is expressed as the median. |
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Summary of Mean (± SD) Pharmacokinetic Parameters Following a Single
Application of Climara Pro in 24 Healthy Postmenopausal Women
|
| Parameter | Units | Estradiol | Estrone | Levonorgestrel |
|
Single application
Week 1 Data
| | | | |
| Cave | Pg/mL | 37.7 ± 10.4 | 41 ± 15 | 136 ± 52.7 |
| Cmax | Pg/mL | 54.3 ± 18.9 | 43.9 ± 14.9 | 138 ± 51.8 |
| Tmax | Hours | 42 | 84 | 90 |
| Cmin | Pg/mL | 27.2 ± 7.66 | 32.6 ± 14.3 | 110 ± 41.7 |
| AUC | Pg.h/mL | 6340 ± 1740 | 6890 ± 2520 | 22900 ± 8860 |
|
Summary of Mean (± SD) Pharmacokinetic Parameters (Week 4) Following
Four Consecutive Weekly Applications of Climara Pro in
44 Healthy Postmenopausal Women
|
|
Multiple application
Week 4 Data
| | | | |
| Cave | Pg/mL | 35.7 ± 11.4 | 45.5 ± 62.6 | 166 ± 97.8 |
| Cmax | Pg/mL | 50.7 ± 28.6 | 81.6 ± 252 | 194 ± 111 |
| Tmax | Hours | 36 | 48 | 48 |
| Cmin | Pg/mL | 33.8 ± 28.7 | 72.5 ± 253 | 153 ± 69.6 |
| AUC | Pg.h/mL | 6002 ± 1919 | 7642 ± 10518 | 27948 ± 16426 |
At steady state, Climara Pro maintains during the application period an average serum estradiol concentration of 35.7 pg/mL as depicted in Figure 1.
 Figure 1: Mean Estradiol Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara Pro
Following the application of the Climara Pro transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Climara Pro maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Climara Pro are summarized in Table 1.
 Figure 2: Mean Levonorgestrel Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Climara Pro
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 the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Climara Pro mean (± SD) SHBG concentrations declined from a predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.
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.
The most important metabolic pathway for levonorgestrel occurs in the reduction of the Δ4- and the 3-oxo-group as well as hydroxylations at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β -tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17β -sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum estradiol concentrations decline rapidly with a mean (± SD) terminal half-life of 3± 0.67 hours.
Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (± SD) terminal half-life for levonorgestrel was determined to be 28 ± 6.4 hours.
E. Special Populations
Climara Pro has been studied only in healthy postmenopausal women.
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 may result in side effects.
Hydroxylation of levonorgestrel is a conversion step which is mediated by cytochrome P450 enzymes. Based on in-vitro and in-vivo studies, it can be assumed that CYP3A, CYP2E and CYP2C are involved in the metabolism of levonorgestrel. Likewise, inducers or inhibitors of these enzymes may either, respectively, decrease the therapeutic effects or result in side effects.
G. Adhesion
A study of the adhesion potential of Climara Pro was conducted in 104 healthy women of 45-75 years of age. Each woman applied a placebo patch, containing only the Climara Pro adhesive without active ingredient, to the upper outer abdominal areas weekly for three weeks. The adhesion assessment was done visually on Days 2, 4, 5, 6 and 7 of each of the three weeks using a four-point scale. The mean scores ranked in the highest category possible on the 0 to 4 scale demonstrating clinically acceptable adhesion performance.
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CLINICAL STUDIES
Effects on vasomotor symptoms
The efficacy of 0.045 mg estradiol/0.03 mg levonorgestrel administered weekly versus placebo in the relief of moderate to severe vasomotor symptoms in postmenopausal women was studied in one 12-week clinical trial (n=183, average age 52.1 ± 4.93, 82% Caucasian). The 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the number and severity of moderate to severe hot flushes. See Tables 2 and 3. Climara Pro and the 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength are bioequivalent in terms of estradiol delivery. (See CLINICAL PHARMACOLOGY, Absorption)
Table 2: Summary of Mean Daily Number of Moderate to Severe Hot Flushes-ITTITT= Intent to –Treat population | Baseline A subject was included at baseline only if the subject had a post-baseline mean score. The post-baseline mean score required 3 days in one week. | Week 4 | Week 8 | Week 12 |
| Placebo | nn= Number of subjects in a treatment group in a cycle; Number of subjects varied from cycle to cycle due to missing data | 88 | 82 | 73 | 69 |
| Mean (SD)SD= standard deviation |
10.80
(5.803) |
6.13
(4.311) |
5.35
(4.095) |
5.59
(4.930) |
|
Mean Change
from baseline (SD) | NA |
-4.23
(4.374) |
-4.80
(4.448) |
-4.55
(5.407) |
| 0.045/.03 | n | 92 | 88 | 80 | 73 |
| Mean (SD) |
10.13
(3.945) |
2.69
(4.455) |
1.22
(2.804) |
1.06
(3.187) |
|
Mean Change
from baseline (SD) | NA |
-7.40
(4.715) |
-8.68
(4.715) |
-8.82
(4.336) |
| p-Value p-Value for comparison to placebo, adjusted by the method of Bonferroni | | NA | <0.001 p <0.025 | NA | <0.001 |
Table 3: Summary of Mean Severity of Moderate to Severe Hot Flushes-ITTITT= Intent to Treat population | | Baseline A subject was included at baseline only if the subject had at least 1 post-baseline value. |
Week 4
(day 7) |
Week 8
(day 7) |
Week 12
(day 7) |
| Placebo | nn= Number of subjects in a treatment group in a cycle; Number of subjects varied from cycle to cycle due to missing data | 89 | 76 | 68 | 57 |
| Mean (SD)SD= standard deviation Severity scores are–: 1 = Mild, 2 = Moderate, 3 = Severe. Mean severity of hot flushes by day is [(2X number of moderate hot flushes) + (3X number of severe hot flushes)] / total number of moderate to severe hot flushes on that day. If no moderate to severe hot flush was indicated, the mean severity was 0. |
2.42
(0.282) |
1.99
(0.875) |
1.93
(0.955) |
1.80
(1.034) |
|
Mean Change
from baseline
(SD) | NA |
-0.40
(0.865) |
-0.48
(0.922) |
-0.57
(1.044) |
| 0.045/.03 | n | 92 | 83 | 72 | 55 |
| Mean (SD) |
2.48
(0.295) |
1.10
(1.191) |
0.82
(1.226) |
0.44
(0.960) |
|
Mean Change
from baseline
(SD) | NA |
-1.40
(1.164) |
-1.67
(1.245) |
-2.06
(1.005) |
| p-Value p-Value for comparison to placebo, adjusted by the method of Bonferroni | | NA | <0.001 p <0.025 | NA | <0.001 |
Effects on the endometrium
In a 1-year clinical trial of 412 postmenopausal women (with intact uteri) treated with a continuous regimen of Climara Pro or with an continuous estradiol-only transdermal system, results of evaluable endometrial biopsies show that no hyperplasia was seen with Climara Pro. Table 4 below summarizes these results (Intent-to-Treat populations).
Table 4: Incidence of Endometrial Hyperplasia during Continuous Combined treatment with Climara Pro, Intent-to-Treat Population |
Climara Pro
E2 0.045mg / LNG 0.015mg
|
Estradiol
E2 0.045mg |
| nN = number of intent-to-treat subjects = 210 | n = 202 |
| No. of Patients with Biopsies at > 6 months Defined as at least 180 days of treatment | 124 | 139 |
| No. of Patients with Biopsies at 1 year Defined as > 323 days of treatment | 102 | 110 |
| No. (%) of Patients with Hyperplasia Includes hyperplasia occurring at any time after initiation of treatment as a proportion of patients with biopsies at 1 year | 0 (0%) p < 0.0167 P-value for comparison to unopposed estradiol dose using the Fisher Exact test. P-values were adjusted by the method of Bonferroni. | 19 (17.3%) |
| 95% Confidence Interval | 0 - 3.55% | 9.75 - 24.79% |
Effects on uterine bleeding or spotting
The effects of Climara Pro on uterine bleeding or spotting, as recorded using an interactive voice response system, were evaluated in one 12-month clinical trial. Results are shown in Figure 3.
 Figure 3: Cumulative proportion of subjects at each cycle with no bleeding/ spotting through the end of cycle 13 Last Observation Carried Forward
Percent based upon the number of subjects with data
Last non-missing cycle carried forward through cycle 13
Bleeding associated with endometrial biopsies not included
Effects on bone mineral density
The effects on bone mineral density (BMD) were studied in a randomized, double-blind, placebo-controlled clinical trial of transdermal systems (patches) containing only estradiol (E2). The patients were postmenopausal women with hysterectomies, 40-83 years of age (mean=51.4 years), and 77.3% Caucasian. Patients received calcium supplements if they appeared deficient on a questionnaire. Vitamin D supplements were not given.
A total of 154 patients were randomized in a 2:2:3 ratio to weekly application of 22 cm2 patches containing 2.2 mg E2, 4.4 mg E2, or placebo, for 728 days of continuous treatment (26 28-day cycles). Only the results for the estradiol dose in Climara Pro (4.4 mg E2) and for placebo are presented.
Statistically significant increases in the primary efficacy variable, BMD of the lumbar spine (A-P view, L2- L4), were seen for 4.4 mg E2 compared to placebo (see Table 5 and Figure 4). BMD was also measured at the hip (total, non-dominant side) and radius (midshaft, non-dominant side) with statistically significant treatment effects only observed for the hip (see Table 5).
Table 5: Mean Bone Mineral Density (Standard Deviation)Intent-to-treat population with on-treatment efficacy data | 4.4 mg E2E2=estradiol; LOCF= Last Observation Carried Forward | Placebo |
|
Total Lumbar Spine
Baseline (g/cm2) |
n=36
1.1 (0.2) |
n=46
1.1 (0.2) |
| % Change from baseline LOCF | +1.7% (4.4) | -2.9% (3.8) |
| P-value compared to placebo | <0.0001 | |
|
Total Hip
Baseline (g/cm2) |
n=36
0.97 (0.1) |
n=48
0.94 (0.1) |
| % Change from baseline LOCF | +1.3% (4.2) | -0.9% (5.2) |
| P-value compared to placebo | 0.05 | |
 Figure 4: Percent Change From Baseline in Bone Mineral Density (g/cm2) of Lumbar Spine (A-P View, L2–L4) by Treatment Group and Cycle (Mean ± SE)*
* Data in the figure is for 21 patients on 4.4 mg E2 and 27 placebo patients who completed the study; approximately 44% of randomized patients.
The lumbar spine BMD data were analyzed according to baseline estradiol levels. Estimated treatment effects for 4.4 mg E2 were approximately twice as large in the subgroup with baseline estradiol levels <5 pg/mL as in the subgroup with baseline estradiol levels ≥ 5 pg/mL.
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled a total of 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 the use of oral conjugated estrogens (CE 0.625 mg) plus 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 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, 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 CE/MPA substudy was stopped early because, according to the 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, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5:
Table 6: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI Adapted from JAMA, 2002; 288:321-333 |
| Event 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 |
Relative Risk
CE/MPA vs placebo
at 5.2 Years
(95% CINominal confidence intervals unadjusted for multiple looks and multiple comparisons)
|
CE/MPA
n = 8,506
|
Placebo
n = 8,102
|
| Absolute Risk per 10,000 Women-Years |
|
CHD events
Non-fatal MI
CHD death |
1.29 (1.02-1.63)
1.32 (1.02-1.72)
1.18 (0.7-1.97) | 37 | 30 |
| 30 | 23 |
| 7 | 6 |
| Invasive breast cancerIncludes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer | 1.26 (1-1.59) | 38 | 30 |
| Stroke | 1.41 (1.07-1.85) | 29 | 21 |
| Pulmonary embolism | 2.13 (1.39-3.25) | 16 | 8 |
| Colorectal cancer | 0.63 (0.43-0.92) | 10 | 16 |
| Endometrial cancer | 0.83 (0.47-1.47) | 5 | 6 |
| Hip fracture | 0.66 (0.45-0.98) | 10 | 15 |
| Death due to causes other than the events above | 0.92 (0.74-1.14) | 37 | 40 |
| Global Index | 1.15 (1.03-1.28) | 170 | 151 |
| Deep vein thrombosis Not included in global index | 2.07 (1.49-2.87) | 26 | 13 |
| Vertebral fractures | 0.66 (0.44-0.98) | 9 | 15 |
|
Other osteoporotic
fractures | 0.77 (0.69-0.86) | 131 | 170 |
For those outcomes included in the WHI "global index", the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 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. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
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 percent white, 15 percent black, 6.1 percent Hispanic), after an average follow-up of 6.8 years are presented in Table 6.
Table 7. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHIAdapted from JAMA, 2004; 291:1701-1712 | EventNot included in global index | Relative Risk Nominal confidence intervals unadjusted for multiple looks and multiple comparisons
CE vs. Placebo
at 6.8 Years
(95% CI) | CE
n = 5,310 | Placebo
n = 5,429 |
| Absolute Risk per 10,000 Women-Years |
| CHD events | 0.91 (0.75-1.12) | 49 | 54 |
| Nonfatal MI | 0.89 (0.70-1.12) | 37 | 41 |
| CHD death | 0.94 (0.65-1.36) | 15 | 16 |
| Invasive breast cancer | 0.77 (0.59-1.01) | 26 | 33 |
| Stroke | 1.39 (1.10-1.77) | 44 | 32 |
| Pulmonary embolism | 1.34 (0.87-2.06) | 13 | 10 |
| Colorectal cancer | 1.08 (0.75-1.55) | 17 | 16 |
| Hip fracture | 0.61 (0.41-0.91) | 11 | 17 |
| Death due to causes other than the events above | 1.08 (0.88-1.32) | 53 | 50 |
| Global index 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 | 1.01 (0.91-1.12) | 190 | 192 |
|
| Deep vein thrombosis | 1.47 (1.04-2.08) | 21 | 15 |
| Vertebral fractures | 0.62 (0.42-0.93) | 11 | 17 |
| Total fractures | 0.70 (0.63-0.79) | 139 | 195 |
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 was 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.)
Women's Health Initiative Memory Study
The estrogen plus progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were age 65 to 69 years, 35 percent were 70 to 74 years, and 18 percent 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 estrogen/progestin 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 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, I. Geriatric use).
The estrogen-alone WHIMS substudy enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent were age 65 to 69 years, 36 percent were 70 to 74 years, and 19 percent were 75 years of age and older) to evaluate the effects of CE.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 estrogen 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 estrogen alone group was 1.49 (95% CI, 0.83 to 2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, 3. Dementia and PRECAUTIONS, I. Geriatric use.)
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