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CombiPatch

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CombiPatch

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

Absorption

Estradiol: Estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Administration of CombiPatch (estradiol, norethindrone acetate transdermal system) every 3 to 4 days in postmenopausal women produces average steady-state estradiol serum concentrations of 45 to 50 pg/mL, which are equivalent to the normal ranges observed at the early follicular phase in premenopausal women. These concentrations are achieved within 12 to 24 hours following CombiPatch (estradiol, norethindrone acetate transdermal system) application. Minimal fluctuations in serum estradiol concentrations are observed following CombiPatch (estradiol, norethindrone acetate transdermal system) application, indicating consistent hormone delivery over the application interval.

In one study, serum concentrations of estradiol were measured in 40 healthy, postmenopausal women throughout three consecutive CombiPatch (estradiol, norethindrone acetate transdermal system) applications to the abdomen (each dose was applied for three 3.5 day periods). The corresponding pharmacokinetic parameters are summarized in Table I below.

Table I. Mean (SD) Serum Estradiol and Estrone Concentrations (pg/mL) at Steady-State [Uncorrected for Baseline Levels]
Estradiol
System Size Dose Estradiol / NETA (mg per day) Cmax Cmin Cavg
9 sq cm 0.05 / 0.14 71 (32) 27 (17) 45 (21)
16 sq cm 0.05 / 0.25 71 (30) 37 (17) 50 (21)
Estrone
9 sq cm 0.05 / 0.14 72 (23) 49 (19) 54 (19)
16 sq cm 0.05 / 0.25 78 (22) 58 (22) 60 (18)

Norethindrone : Progestins used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Norethindrone steady state concentrations are attained within 24 hours of application of the CombiPatch (estradiol, norethindrone acetate transdermal system) transdermal delivery systems. Minimal fluctuations in serum norethindrone concentrations are observed following CombiPatch (estradiol, norethindrone acetate transdermal system) treatment, indicating consistent hormone delivery over the application interval. Serum concentrations of norethindrone increase linearly with increasing doses of norethindrone acetate.

In one study, serum concentrations of norethindrone were measured in 40 healthy, postmenopausal women throughout three consecutive CombiPatch (estradiol, norethindrone acetate transdermal system) applications to the abdomen (each dose was applied for three 3.5 day periods). The corresponding pharmacokinetic parameters are summarized in Table II below.

Table II. Mean (SD) Serum Norethindrone Concentrations (pg/mL) at Steady-State
System Size
Dose Estradiol / NETA (mg per day)
Cmax
Cmin
Cavg
9 sq cm 0.05 / 0.14
617 (341)
386(137)
489(244)
16 sq cm 0.05 / 0.25
1060(543)
686(306)
840(414)

Distribution

Estradiol : 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.

Norethindrone : In plasma, norethindrone is bound approximately 90% to SHBG and albumin.

Metabolism

Estradiol : 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. Transdermally delivered estradiol is metabolized only to a small extent by the skin and bypasses the first-pass effect seen with orally administered estrogen products. Therapeutic estradiol serum levels with lower circulating levels of estrone and estrone conjugates are achieved with smaller transdermal doses (daily and total) as compared to oral therapy.

Norethindrone : Norethindrone acetate is hydrolyzed to the active moiety, norethindrone, in most tissues including skin and blood. Norethindrone is primarily metabolized in the liver; however, transdermal administration significantly decreases metabolism because hepatic first-pass effect is avoided.

Excretion

Estradiol : Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Estradiol has a short elimination half-life of approximately 2 to 3 hours; therefore, a rapid decline in serum levels is observed after the CombiPatch estradiol/norethindrone acetate transdermal system is removed. Within 4 to 8 hours serum estradiol concentrations return to untreated, postmenopausal levels (<20 pg/mL).

Concentration data from Phase II and III studies indicate that the pharmacokinetics of estradiol did not change over time, suggesting no evidence of the accumulation of estradiol following extended patch wear periods (up to 1 year).

Norethindrone : The elimination half-life of norethindrone is reported to be 6 to 8 hours. Norethindrone serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the CombiPatch (estradiol, norethindrone acetate transdermal system) transdermal delivery system.

Concentration data from Phase II and III studies indicate that the pharmacokinetics of norethindrone did not change over time, suggesting no evidence of the accumulation of norethindrone following extended patch wear periods (up to 1 year).

Special Populations

CombiPatch (estradiol, norethindrone acetate transdermal system) has been studied only in postmenopausal women.

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. Johns 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.

Adhesion

Averaging across six clinical trials lasting 3 months to one year, of 1287 patients treated, CombiPatch (estradiol, norethindrone acetate transdermal system) transdermal systems completely adhered to the skin nearly 90% of the time over the 3- to 4-day wear period. Less than 2% of the patients required reapplication or replacement of systems due to lifting or detachment. Only two patients (0.2%) discontinued therapy during clinical trials due to adhesion failure.

CLINICAL STUDIES

Effects on vasomotor symptoms.

In two clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), CombiPatch (estradiol, norethindrone acetate transdermal system) was administered for three 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch (estradiol, norethindrone acetate transdermal system) was applied throughout the three cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; CombiPatch (estradiol, norethindrone acetate transdermal system) was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch (estradiol, norethindrone acetate transdermal system) at all doses as compared to placebo (intent-to-treat population). [See tables below.]

Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch Continuous Combined Transdermal Therapy
Adjusted Mean Change from Baseline1
CombiPatch
Placebo
Continuous 0.05/0.14 mg per day2 n = 57
Combined 0.05/0.25 mg per day2 n = 52
n = 51
Number of Hot Flushes3
-9.35
-8.95
-6.2
Daily Intensity of Hot Flushes3,4
-4.65,6
-5.05
-2.8 7
1 Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA).
2 Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
3 Population represents those patients who had baseline and endpoint observations.
4 The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9).
5 P value versus placebo = <0.001.
6 Total number of patients with available data is 56.
7 Total number of patients with available data is 50.

 

Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch Continuous Sequential Transdermal Therapy
Adjusted Mean Change from Baseline1
CombiPatch
Placebo
Continuous 0.05/0.14 mg per day2 n = 54
Sequential 0.05/0.25 mg per day2 n = 59
n = 53
Number of Hot Flushes3
-9.35
-9.55
-5.5
Daily Intensity of Hot Flushes3,4
-4.45
-4.55
-2.1
1 Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA).
2 Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
3 Population represents those patients who had baseline and endpoint observations.
4 The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9).
5 P value versus placebo = <0.001.

EFFECTS ON THE ENDOMETRIUM

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications.

CombiPatch (estradiol, norethindrone acetate transdermal system) was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after 1 year of therapy in two Phase II clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of CombiPatch (estradiol, norethindrone acetate transdermal system) alone (Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch (estradiol, norethindrone acetate transdermal system) transdermal system (Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after 1 year of therapy with either CombiPatch (estradiol, norethindrone acetate transdermal system) regimen than with the estradiol-only transdermal system. The tables below summarize these results (intent-to-treat populations).

Incidence of Endometrial Hyperplasia in a Continuous Combined CombiPatch Regimen
 
CombiPatch
Vivelle
 
Continuous 0.05 / 0.14 mg per day1
Combined 0.05 / 0.25 mg per day1
Continuous 0.05 mg per day
No. of Patients with Biopsies2
123
98
103
No. (%) of Patients with Hyperplasia
1 (<1%)3
1 (1%)3,4
39 (38%)5
1 Represents milligrams of estradiol / NETA delivered daily by each system.
2 Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
3 Comparison of continuous combined regimen versus estradiol-only patch was significant (p value <0.001).
4 This patient had hyperplasia at baseline.
5 One of 39 patients had hyperplasia in an endometrial polyp.

 

Incidence of Endometrial Hyperplasia in a Continuous Sequential CombiPatch Regimen
 
CombiPatch
Vivelle
Continuous 0.05 / 0.14 mg per day1
Sequential 0.05 / 0.25 mg per day1
Continuous 0.05 mg per day
No. of Patients with Biopsies2
117
114
115
No. (%) of Patients with Hyperplasia
1 (<1%)3,4
1 (<1%)3,5
23 (20%)
1 Represents milligrams of estradiol / NETA delivered daily by each system.
2 Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
3 Comparison of continuous sequential regimen versus estradiol-only patch was significant (p value <0.001).
4 This patient had hyperplasia at baseline.
5 This patient had hyperplasia in an endometrial polyp.

Effects on uterine bleeding or spotting.

With the Continuous Combined regimen, of the women treated with CombiPatch estradiol/norethindrone acetate transdermal system and who completed the one year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53% and 39% for the CombiPatch (estradiol, norethindrone acetate transdermal system) 0.05/0.14 mg per day and CombiPatch (estradiol, norethindrone acetate transdermal system) 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding, usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of 4 and 6 days for the CombiPatch (estradiol, norethindrone acetate transdermal system) 0.05/0.14 mg per day and CombiPatch (estradiol, norethindrone acetate transdermal system) 0.05/0.25 mg per day treatment groups, respectively.

Incidence of Cumulative Amenorrhea* in CombiPatch (estradiol, norethindrone acetate transdermal system) Continuous Combined Transdermal Therapy by Cycle over a One-Year Period (Intent-to-Treat Population)

*Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study.

Information regarding lipid effects.

In the CE/MPA substudy of the WHI (n=16,608 predominantly healthy postmenopausal women) hormone therapy lowered the level of low-density lipoprotein (LDL) cholesterol and increased the level of high-density lipoprotein (HDL), yet an increased risk of coronary heart disease events was observed. Therefore, estrogens and progestins should not be used for the prevention of cardiovascular disease. (See BOXED WARNING and CLINICAL PHARMACOLOGY, Clinical Studies)

The results of clinical trials conducted in a 90% Caucasian population at low risk for cardiovascular disease showed that compared to Vivelle (an estrogen-alone treatment), CombiPatch (estradiol, norethindrone acetate transdermal system) demonstrated significantly greater reductions in total cholesterol (TC) concentrations. Mean high density lipoprotein-cholesterol (HDL-C) values, however, decreased after one year of CombiPatch (estradiol, norethindrone acetate transdermal system) therapy whereas they were noted to increase in Vivelle users. Shifts in mean TC/HDL-C were minimal after one year of therapy in both Vivelle and CombiPatch (estradiol, norethindrone acetate transdermal system) treatment groups. Decreases in triglycerides were observed in both CombiPatch (estradiol, norethindrone acetate transdermal system) regimens.

The following tables summarize lipid parameters from these two clinical trials in 955 postmenopausal women (with intact uteri) after 1 year of therapy. Subjects were treated with (i) a continuous regimen of CombiPatch (estradiol, norethindrone acetate transdermal system) alone (Continuous Combined regimen), (ii) a sequential CombiPatch (estradiol, norethindrone acetate transdermal system) regimen consisting of an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch (estradiol, norethindrone acetate transdermal system) transdermal system (Continuous Sequential regimen), or (iii) a continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The values below represent mean percent change from baseline in patients with data at baseline and 1 year.

Lipid Profile Values, Adjusted Mean Percent Change from Baseline after One Year of Continuous Combined CombiPatch Transdermal Therapy
Lipid Parameter (%)
CombiPatch
Vivelle
Continuous 0.05 / 0.14 mg per day1n = 122
Combined 0.05 / 0.25 mg per day1n = 99
Continuous 0.05 mg per day n = 79
Total Cholesterol
-5.4%2
-8.6%3
-2.0%
HDL-C
-3.1%3
-9.1%3
+7.3%
LDL-C
-4.6%4
-7.6%5
-3.4%
Triglycerides
-4.6%
-9.5%
-6.7%
1 Represents milligrams of estradiol/NETA delivered daily by each system.
2 Comparison with estradiol-only patch was significant (p <0.05).
3 Comparison with estradiol-only patch was significant (p <0.001).
4 Total number of patients with available data is 121.
5 Total number of patients with available data is 97.

 

Lipid Profile Values, Adjusted Mean Percent Change from Baseline after One Year of Continuous Sequential CombiPatch Transdermal Therapy
Lipid Parameter (%)
CombiPatch
Vivelle
Continuous 0.05 / 0.14 mg per day1 n = 117
Sequential 0.05 / 0.25 mg per day1 n = 115
Continuous 0.05 mg per day n = 105
Total Cholesterol
-4.1%2
-9.0%3
-1.0%
HDL-C
-4.7%3
-8.9%3
+0.9%
LDL-C
-1.2%4
-6.8%2,5
-2.0%6
Triglycerides
-8.2%3
-14.1%3
+13.2%
1 Represents milligrams of estradiol/NETA delivered daily by each system.
2 Comparison with estradiol-only patch was significant (p<0.05).
3 Comparison with estradiol-only patch was significant (p<0.001).
4 Total number of patients with available data is 116.
5 Total number of patients with available data is 114.
6 Total number of patients with available data is 103.

Womens Health Initiative Studies

The Womens 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 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) 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 III below.

Table III, RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHIa
Eventc
Relative Risk CE/MPA vs. Placebo at 5.2 Years (95% CI*)
Placebo n= 8102
CE/MPA n= 8506
Absolute Risk per 10,000 women-years
CHD events
1.29 (1.02-1.63)
30
37
Non-fatal MI
1.32 (1.02-1.72)
23
30
CHD death
1.18 (0.70-1.97)
6
7
Invasive breast cancerb
1.26 (1.00-1.59)
30
38
Stroke
1.41 (1.07-1.85)
21
29
Pulmonary embolism
2.13 (1.39-3.25)
8
16
Colorectal cancer
0.63 (0.43-0.92)
16
10
Endometrial cancer
0.83 (0.47-1.47)
6
5
Hip fracture
0.66 (0.45-0.98)
15
10
Death due to causes other than the events above
0.92 (0.74-1.14)
40
37
Global indexc
1.15 (1.03-1.28)
151
170
Deep vein thrombosisd
2.07 (1.49-2.87)
13
26
Vertebral fracturesd
0.66 (0.44-0.98)
15
9
Other osteoporotic fracturesd
0.77 (0.69-0.86)
170
131
a adapted from JAMA, 2002: 288: 321-333
b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c 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.
d not included in Global index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

For those outcomes included in the "global index", 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.)

Womens Health Initiative Memory Study

The Womens Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were aged 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of oral CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) 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 and WARNINGS, Dementia.)

Last reviewed on RxList: 10/5/2006
This monograph has been modified to include the generic and brand name in many instances.

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