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Estraderm®
estradiol transdermal system
Continuous delivery for twice-weekly application
Rx only
Prescribing Information
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER.
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the
use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at
equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
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 (50-79
years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625 mg)
combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL
PHARMACOLOGY, Clinical Studies).
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 4 years of
treatment with oral conjugated equine estrogens plus medroxyprogesterone acetate relative to placebo.
It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL
PHARMACOLOGY, Clinical Studies).
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
Estraderm, estradiol transdermal system, is designed to release estradiol through a rate-limiting
membrane continuously upon application to intact skin.
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Two systems are available to provide nominal in vivo delivery of 0.05 or 0.1 mg of estradiol per day
via skin of average permeability (interindividual variation in skin permeability is approximately 20%).
Each corresponding system having an active surface area of 10 or 20 cm2 contains 4 or 8 mg of
estradiol USP and 0.3 or 0.6 mL of alcohol USP, respectively. The composition of the systems per
unit area is identical.
Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17ß-
diol.
The structural formula is
HO
H H
H
HCH3
OH
The Estraderm system comprises four layers. Proceeding from the visible surface toward the surface
attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film,
(2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an
ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF
and polyisobutylene. A protective liner (5) of siliconized polyester film is attached to the adhesive
surface and must be removed before the system can be used.
The active component of the system is estradiol. The remaining components of the system are
pharmacologically inactive. Alcohol is also released from the system during use.
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 µg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most
endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to
estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the
most abundant circulating estrogens in postmenopausal women.
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.
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In a study using transdermally administered estradiol, 0.1 mg daily, plasma levels increased by 66
pg/mL, resulting in an average plasma level of 73 pg/mL. There were no significant increases in the
concentration of renin substrate or other hepatic proteins (sex hormone-binding globulin, thyroxine-
binding globulin, and corticosteroid-binding globulin).
Pharmacokinetics
The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is
rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of
estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of
estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total
doses than does oral therapy.
Absorption
Administration of Estraderm produces mean serum concentrations of estradiol comparable to those
produced by daily oral administration of estradiol at about 20 times the daily transdermal dose. In
single-application studies in 14 postmenopausal women using Estraderm systems that provided 0.05
and 0.1 mg of exogenous estradiol per day, these systems produced increased blood levels within 4
hours and maintained respective mean serum estradiol concentrations of 32 and 67 pg/mL above
baseline over the application period. At the same time, increases in estrone serum concentration
averaged only 9 and 27 pg/mL above baseline, respectively. Serum concentrations of estradiol and
estrone returned to preapplication levels within 24 hours after removal of the system. The estimated
daily urinary output of estradiol conjugates increased 5 to 10 times the baseline values and returned to
near baseline within 2 days after removal of the system.
By comparison, estradiol (2 mg/day) administered orally to postmenopausal women resulted in
increases in mean serum concentration of 59 pg/mL of estradiol and 302 pg/mL of estrone above
baseline on the third consecutive day of dosing. Urinary output of estradiol conjugates after oral
administration increased to about 100 times the baseline values and did not approach baseline until 7-8
days after the last dose.
In a 3-week multiple-application study of 14 postmenopausal women in which Estraderm 0.05 was
applied twice weekly, the mean increments in steady-state serum concentration were 30 pg/mL for
estradiol and 12 pg/mL for estrone. Urinary output of estradiol conjugates returned to baseline within
3 days after removal of the last (6th) system, indicating little or no estrogen accumulation in the body.
Distribution
No specific investigation of the tissue distribution of estradiol absorbed from Estraderm in humans has
been conducted. 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.
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
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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.
Excretion
Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Transdermal administration produces therapeutic serum levels of estradiol with lower circulating levels
of estrone and estrone conjugates and requires smaller total doses than does oral therapy. Because
estradiol has a short half-life (~1 hour), transdermal administration of estradiol allows a rapid decline
in blood levels after an Estraderm system is removed, e.g., in a cycling regimen.
Special Populations
Estraderm was only investigated 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.
Clinical Studies
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 the use of 0.625 mg conjugated equine
estrogens (CE) per day alone and of 0.625 mg conjugated equine 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 1 below.
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Table 1, RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF
WHIa
Placebo n= 8102 CE/MPA n= 8506 Eventc Relative Risk
CE/MPA vs.
Placebo at 5.2
Years (95% CI*) Absolute Risk per 10,000 woman-years
CHD events
Non-fatal MI
CHD death
1.29 (1.02-1.63)
1.32 (1.02-1.72)
1.18 (0.70-1.97)
30
23
6
37
30
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 person-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 10,00 woman-years were 6 fewer colorectal
cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index”
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was 19 per 10,000 woman-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 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
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 4 years, 40 women in the estrogen/progestin group (45 per 10,000
woman-years) and 21 in the placebo group (22 per 10,000 woman-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.)
INDICATIONS AND USAGE
Estraderm® (estradiol transdermal system) is indicated in:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. 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.
3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be considered for women at significant risks
of osteoporosis and non-estrogen medications should be carefully considered.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise,
adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal
women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated,
calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D
supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in
postmenopausal women.
CONTRAINDICATIONS
Estrogens should not be used in individuals with any of the following conditions:
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected or history of cancer of the breast.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
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5. Active or recent (e.g. within the past year) arterial thromboembolic disease (e.g., stroke,
myocardial infarction).
6. Liver dysfunction or disease.
7. Estraderm® (estradiol transdermal system) should not be used in patients with known
hypersensitivity to its ingredients.
8. Known or suspected pregnancy. There is no indication for Estraderm 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 WARNINGS.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk of
endometrial cancer.
1. Cardiovascular disorders
Estrogen and estrogen/progestin therapy have 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
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.
a. Coronary heart disease and stroke
In the Women’s Health Initiative study (WHI), an increase in the number of myocardial infarctions and
strokes has been observed in women receiving CE compared to placebo.
In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as
non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared
to women receiving placebo (37 vs 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 vs 21 per 10,000 woman-years). The increase in risk was
observed after the first year and persisted.
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 placebo
group in year 1, 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
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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.
b. Venous thromboembolism (VTE)
In the Women’s Health Initiative study (WHI), an increase in VTE has