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Climara PRO (Estradiol / Levonorgestrel Transdermal) - Description and Clinical Pharmacology

 
 



PRESCRIBING INFORMATION

Climara Pro®

(Estradiol/Levonorgestrel Transdermal System)

Rx only

DESCRIPTION

Climara Pro® (Estradiol/Levonorgestrel Transdermal System) is an adhesive-based matrix transdermal patch designed to release both estradiol and levonorgestrel, a progestational agent, continuously upon application to intact skin.

The 22 cm2 Climara Pro system contains 4.4 mg estradiol and 1.39 mg levonorgestrel and provides a nominal delivery rate (mg per day) of 0.045 estradiol and 0.015 levonorgestrel.

Estradiol USP has a molecular weight of 272.39 and the molecular formula is C18H24O2.

Levonorgestrel USP has a molecular weight of 312.4 and a molecular formula of C21H28O2.

The structural formulas for estradiol and levonorgestrel are:

The Climara Pro system comprises 3 layers. Proceeding from the visible surface towards the surface attached to the skin, these layers are (1) a translucent polyethylene backing film, (2) an acrylate adhesive matrix containing estradiol and levonorgestrel, and (3) a protective liner of either siliconized or fluoropolymer coated polyester film. The protective liner is attached to the adhesive surface and must be removed before the system can be used.

The active components of the system are estradiol and levonorgestrel. The remaining components of the system (acrylate copolymer adhesive and polyvinylpyrrolidone/vinyl acetate copolymer) 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.

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.

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

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

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.

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-ITT
Baseline Week 4 Week 8 Week 12
Placebo n 1 88 82 73 69
Mean (SD) 2

10.8

(5.803)

6.13

(4.311)

5.35

(4.095)

5.59

(4.93)

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  NA <0.001 3 NA <0.001

1 n= Number of subjects in a treatment group in a cycle; Number of subjects varied from cycle to cycle due to missing data
2 SD= standard deviation
3 p <0.025

Table 3: Summary of Mean Severity of Moderate to Severe Hot Flushes-ITT
Baseline 1

Week 4

(day 7)

Week 8

(day 7)

Week 12

(day 7)

Placebo n 89 76 68 57
Mean (SD)

2.42

(0.282)

1.99

(0.875)

1.93

(0.955)

1.8

(1.034)

Mean Change

from baseline

(SD)

NA

-0.4

(0.865)

-0.48

(0.922)

-0.57

(1.044)

0.045/.03 n 92 83 72 55
Mean (SD)

2.48

(0.295)

1.1

(1.191)

0.82

(1.226)

0.44

(0.96)

Mean Change

from baseline

(SD)

NA

-1.4

(1.164)

-1.67

(1.245)

-2.06

(1.005)

p-Value NA <0.001 [] NA <0.001[]

ITT= Intent to Treat population; n= Number of subjects in a treatment group in a cycle; 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.

Number of subjects varied from cycle to cycle due to missing data

1 A subject was included at baseline only if the subject had at least 1 post-baseline value.

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 0.015 mg

Estradiol

E2 0.045 mg

n 1 = 210 n = 202
No. of Patients with Biopsies at ≥6 months 124 139
No. of Patients with Biopsies at 1 year  102 110
No. (%) of Patients with Hyperplasia  0 (0%)  19 (17.3%)
95% Confidence Interval 0 - 3.55% 9.75 - 24.79%

1 N = number of intent-to-treat subjects

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

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)
4.4 mg E2 Placebo

Total Lumbar Spine

Baseline (g/cm2)

n=36

1.1 (0.2)

n=46

1.1 (0.2)

% Change from baseline LOCF 1 +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

1 LOCF=Last Observation Carried Forward

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)*

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 6:

Table 6: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI
Event 1

Relative Risk

CE/MPA vs placebo

at 5.2 Years

(95% CI)

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 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 2 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

1  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
2  Not included in global index

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 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 7.

Table 7. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-ALONE SUBSTUDY OF WHI
Event 1 Relative Risk
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
Non-fatal 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 (1.1-1.77) 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 1.01 (0.91-1.12) 192 190
Deep vein thrombosis 1.47 (1.04-2.08) 21 15
Vertebral fractures 0.62 (0.42-0.93) 11 17
Total fractures 0.7 (0.63-0.79) 139 195

1 Not included in global index

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, 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, Dementia and PRECAUTIONS, Geriatric Use)

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