estradiol and norethindrone acetate
Dosage Form: patch, extended release
CombiPatch
T2005-16/T2006-59
101932-6
CombiPatch®
(estradiol/norethindrone acetate transdermal system)
Rx only
Prescribing Information
Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular Disorders and Dementia.)
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during five years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular Disorders and Malignant Neoplasms, Breast Cancer).
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during four years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
CombiPatch® (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol and norethindrone acetate (NETA), a progestational agent, continuously upon application to intact skin.
Two systems are available, providing the following delivery rates of estradiol and norethindrone acetate.
| System Size | Estradiol (mg) | NETA1 (mg) | Nominal Delivery Rate2 (mg per day) Estradiol/NETA |
| 9 sq cm round | 0.62 | 2.7 | 0.05/0.14 |
| 16 sq cm round | 0.51 | 4.8 | 0.05/0.25 |
1 NETA = norethindrone acetate.
2 Based on in vivo/in vitro flux data, delivery of both components per day via skin of average permeability (interindividual variation in skin permeability is approximately 20%).
Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular weight of estradiol is 272.39 and the molecular formula is C18H24O2.
Norethindrone acetate USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of norethindrone acetate is 340.47 and the molecular formula is C22H28O3.
The structural formulas for estradiol and norethindrone acetate are
CombiPatch transdermal systems are comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film backing, (2) an adhesive layer containing estradiol, norethindrone acetate, acrylic adhesive, silicone adhesive, oleyl alcohol, oleic acid NF, povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the adhesive surface and must be removed before the system can be used.
The active components of the system are estradiol USP and norethindrone acetate USP. The remaining components of the system 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
Absorption
Estradiol: Estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Administration of CombiPatch every three to four 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 application. Minimal fluctuations in serum estradiol concentrations are observed following CombiPatch 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 applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table I below.
| 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 transdermal delivery systems. Minimal fluctuations in serum norethindrone concentrations are observed following CombiPatch 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 applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table II below.
| 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 | 1,060 (543) | 686 (306) | 840 (414) |
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 two to three hours; therefore, a rapid decline in serum levels is observed after the CombiPatch estradiol/norethindrone acetate transdermal system is removed. Within four to eight 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 one year).
Norethindrone: The elimination half-life of norethindrone is reported to be six to eight hours. Norethindrone serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the CombiPatch 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 one year).
Special Populations
CombiPatch 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. 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.
Adhesion
Averaging across six clinical trials lasting three months to one year, of 1,287 patients treated, CombiPatch 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 was administered for three 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch 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 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 at all doses as compared to placebo (intent-to-treat population). (See tables below.)
| CombiPatch® Continuous Combined | Placebo | ||
| Adjusted Mean Change from Baseline1 | 0.05/0.14 mg per day2 n=57 | 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 | -2.87 |
- Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA).
- Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
- Population represents those patients who had baseline and endpoint observations.
- 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).
- P value versus placebo = <0.001.
- Total number of patients with available data is 56.
- Total number of patients with available data is 50.
| CombiPatch® Continuous Sequential | Placebo | ||
| Adjusted Mean Change from Baseline1 | 0.05/0.14 mg per day2 n=54 | 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 |
- Means were adjusted for imbalance among treatment groups and investigators (least squares
mean from ANOVA). - Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
- Population represents those patients who had baseline and endpoint observations.
- 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). - P value versus placebo = <0.001.
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 was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after one 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 alone (Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch 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 one year of therapy with either CombiPatch regimen than with the estradiol-only transdermal system. The tables below summarize these results (intent-to-treat populations).
| CombiPatch® Continuous Combined | Vivelle® Continuous | ||
| 0.05/0.14 mg per day1 | 0.05/0.25 mg per day1 | 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 |
- Represents milligrams of estradiol/NETA delivered daily by each system.
- Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
- Comparison of continuous combined regimen versus estradiol-only patch was significant (p value <0.001).
- This patient had hyperplasia at baseline.
- One of 39 patients had hyperplasia in an endometrial polyp.
| CombiPatch® Continuous Sequential | Vivelle® Continuous | ||
| 0.05/0.14 mg per day1 | 0.05/0.25 mg per day1 | 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%) |
- Represents milligrams of estradiol/NETA delivered daily by each system.
- Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
- Comparison of continuous sequential regimen versus estradiol-only patch was significant (p value <0.001).
- This patient had hyperplasia at baseline.
- This patient had hyperplasia in an endometrial polyp.
With the Continuous Combined regimen, of the women treated with CombiPatch 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 0.05/0.14 mg per day and CombiPatch 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 four and six days for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively.
Incidence of Cumulative Amenorrhea* in CombiPatch® 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 demonstrated significantly greater reductions in total cholesterol (TC) concentrations. Mean high density lipoprotein-cholesterol (HDL-C) values, however, decreased after one year of CombiPatch 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 treatment groups. Decreases in triglycerides were observed in both CombiPatch regimens.
The following tables summarize lipid parameters from these two clinical trials in 955 postmenopausal women (with intact uteri) after one year of therapy. Subjects were treated with (i) a continuous regimen of CombiPatch alone (Continuous Combined regimen), (ii) a sequential CombiPatch regimen consisting of an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch 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 one year.
| CombiPatch® Continuous Combined | Vivelle® Continuous | ||
| Lipid Parameter (%) | 0.05/0.14 mg per day1 n=122 | 0.05/0.25 mg per day1 n=99 | 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% |
- Represents milligrams of estradiol/NETA delivered daily by each system.
- Comparison with estradiol-only patch was significant (p <0.05).
- Comparison with estradiol-only patch was significant (p <0.001).
- Total number of patients with available data is 121.
- Total number of patients with available data is 97.
| CombiPatch® Continuous Sequential | Vivelle® Continuous | ||
| Lipid Parameter (%) | 0.05/0.14 mg per day1 n=117 | 0.05/0.25 mg per day1 n=115 | 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% |
- Represents milligrams of estradiol/NETA delivered daily by each system.
- Comparison with estradiol-only patch was significant (p <0.05).
- Comparison with estradiol-only patch was significant (p <0.001).
- Total number of patients with available data is 116.
- Total number of patients with available data is 114.
- Total number of patients with available data is 103.
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 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.
| Eventc | Relative Risk CE/MPA vs. Placebo at 5.2 Years (95% CI*) | Placebo n=8,102 | CE/MPA n=8,506 |
| Absolute Risk per 10,000 Women-Years | |||
| CHD Events | 1.29 (1.02-1.63) | 30 | 37 |
| Nonfatal 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 |
aAdapted 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 seven more CHD events, eight more strokes, eight more PEs, and eight more invasive breast cancers, while absolute risk reductions per 10,000 women-years were six fewer colorectal cancers and five 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 WARNING, WARNINGS, and PRECAUTIONS.)
Women’s Health Initiative Memory Study
The 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% 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 equine estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of four 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 WARNING and WARNINGS, Dementia.)
INDICATIONS AND USAGE
In women with an intact uterus, CombiPatch is indicated for the following:
- Treatment of moderate to severe vasomotor symptoms associated with the menopause.
- Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause.
When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
- Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
CONTRAINDICATIONS
CombiPatch should not be used in women under any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of cancer of the breast.
- Known or suspected estrogen-dependent neoplasia.
- Active deep vein thrombosis, pulmonary embolism or history of these conditions.
- Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
- Liver dysfunction or disease.
- CombiPatch should not be used in patients with known hypersensitivity to its ingredients.
- Known or suspected pregnancy. There is no indication for CombiPatch in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS).
WARNINGS
See BOXED WARNING.
Cardiovascular Disorders
Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens/progestins should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
Coronary Heart Disease and Stroke
In the Women’s Health Initiative (WHI) study, an increase in the number of strokes was observed in women receiving CE alone compared to placebo.
In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 versus 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 versus 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year one, but not during the subsequent years. Two thousand three hundred and twenty-one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and in the placebo group in HERS, HERS II, and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
Venous Thromboembolism (VTE)
In the Women’s Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE compared to placebo.
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
If feasible, estrogens should be discontinued at least four to six weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Malignant Neoplasms
Breast Cancer
The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen-alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen-alone and/or estrogen/progestin-combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 versus 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.
The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Endometrial Cancer
The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among users of unopposed estrogen is about 2- to 12-fold or greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than on
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