NDC 54868-4813 Estradiol

NDC Product Code 54868-4813

NDC CODE: 54868-4813

Proprietary Name: Estradiol What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is a female hormone. It is used by women to help reduce symptoms of menopause (such as hot flashes, vaginal dryness). These symptoms are caused by the body making less estrogen. If you are using this medication to treat symptoms only in and around the vagina, products applied directly inside the vagina should be considered before medications that are taken by mouth, absorbed through the skin, or injected. Certain estrogen products may also be used by women after menopause to prevent bone loss (osteoporosis). However, there are other medications (such as raloxifene, bisphosphonates including alendronate) that are also effective in preventing bone loss and may be safer. These medications should be considered for use before estrogen treatment. Certain estrogen products may also be used by men and women to treat cancers (certain types of prostate cancer, breast cancer that has spread to other parts of the body) and by women who are not able to produce enough estrogen (for example, due to hypogonadism, primary ovarian failure).

NDC Code Structure

  • 54868 - Physicians Total Care, Inc.

NDC 54868-4813-0

Package Description: 4 POUCH in 1 CARTON > 1 PATCH in 1 POUCH > 24 [USP'U] in 1 PATCH

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Estradiol with NDC 54868-4813 is a product labeled by Physicians Total Care, Inc.. The product's dosage form is and is administered via form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 238003, 238004 and 242333.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • POVIDONE (UNII: FZ989GH94E)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • POVIDONE (UNII: FZ989GH94E)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Physicians Total Care, Inc.
Labeler Code: 54868
Start Marketing Date: 06-09-2003 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Estradiol Transdermal Patch

Estradiol Transdermal Patch is pronounced as (es tra dye' ole)

Why is estradiol transdermal patch medication prescribed?
Most brands of estradiol transdermal patches are used to treat hot flushes (hot flashes; sudden strong feelings of heat and sweating) and/or vaginal dryness, itching, and...
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* Please review the disclaimer below.

Estradiol Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Other

PRESCRIBING INFORMATION Estradiol
Transdermal System Continuous Delivery (Once-Weekly), USP

Table 1 provides a summary of estradiol pharmacokinetic parameters determined
during evaluation of Estradiol Transdermal System Continuous Delivery
(Once-Weekly).Table 1 Pharmacokinetic Summary (Mean Estradiol Values)EstradiolDeliveryRateSurfaceArea (cm2 )ApplicationSiteNo. ofSubjectsDosingCmax(pg/mL)Cmin(pg/mL)Cavg(pg/mL)0.0257.75Abdomen24Single3217220.0515.5Abdomen102Single7129410.131Abdomen139Single14760870.131Buttock38Single17471106The relative standard deviation of each pharmacokinetic parameter after
application to the abdomen averaged 50%, which is indicative of the considerable
intersubject variability associated with transdermal drug delivery. The relative
standard deviation of each pharmacokinetic parameter after application to the
buttock was lower than that after application to the abdomen (e.g., for Cmax 39% vs. 62%, and for Cavg 35% vs.
48%).DistributionThe 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.MetabolismExogenous 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 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.ExcretionEstradiol, estrone and estriol are excreted in the urine along
with glucuronide and sulfate conjugates.Special PopulationsGeriatricThere have not been sufficient numbers of geriatric patients
involved in clinical studies utilizing Estradiol Transdermal System Continuous
Delivery (Once-Weekly) to determine whether those over 65 years of age differ
from younger subjects in their response to Estradiol Transdermal System
Continuous Delivery (Once-Weekly).PediatricNo pharmacokinetic study for Estradiol Transdermal System
Continuous Delivery (Once-Weekly) has been conducted in a pediatric
population.GenderEstradiol Transdermal System Continuous Delivery (Once-Weekly) is
indicated for use in women only.RaceNo studies were done to determine the effect of race on the
pharmacokinetics of Estradiol Transdermal System Continuous Delivery
(Once-Weekly).Patients with Renal ImpairmentTotal estradiol serum levels are higher in postmenopausal women
with end stage renal disease (ESRD) receiving maintenance hemodialysis than in
normal subjects at baseline and following oral doses of estradiol. Therefore,
conventional transdermal estradiol doses used in individuals with normal renal
function may be excessive for postmenopausal women with ESRD receiving
maintenance hemodialysis.Patients with Hepatic ImpairmentEstrogens may be poorly metabolized in patients with impaired
liver function and should be administered with caution.Drug InteractionsIn 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.AdhesionAn open-label study of adhesion potentials of placebo transdermal
systems that correspond to the 7.75 cm2 and 15.5 cm2 sizes of Estradiol Transdermal System Continuous Delivery
(Once-Weekly) was conducted in 112 healthy women of 45 to 75 years of age. Each
woman applied both transdermal systems weekly, on the upper outer abdomen, for 3
consecutive weeks. It should be noted that lower abdomen and upper quadrant of
the buttock are the approved sites of application for Estradiol Transdermal
System Continuous Delivery (Once-Weekly).The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week
of transdermal system wear. A total of 1,654 adhesion observations were
conducted for 333 transdermal systems of each size.Of these observations, approximately 90% showed essentially no lift for both
the 7.75 cm2 and 15.5 cm2
transdermal systems. Of the total number of transdermal systems applied,
approximately 5% showed complete detachment for each size. Adhesion potentials
of the 23.25 cm2 and 31 cm2 sizes
of transdermal systems (0.075 mg/day and 0.1 mg/day) have not been
studied.Clinical StudiesEffects on vasomotor symptomsA study of 214 women 25 to 74 years old met the qualification
criteria and were randomly assigned to one of the three treatment groups: 72 to
the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch, and 72 to
placebo. Potential subjects were postmenopausal women in good general health who
experienced vasomotor symptoms. Natural menopause patients had not menstruated
for at least 12 months and surgical menopause patients had undergone bilateral
oophorectomy at least 4 weeks before evaluation for study entry. In order to
enter the 11 week treatment phase of the study, potential subjects must have
experienced a minimum of five moderate to severe hot flushes per week, or a
minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks.
Women wore the patches in a cyclical fashion (three weeks on and one week
off).During treatment, all subjects used diaries to record the number and severity
of hot flushes. Subjects were monitored by clinic visits at the end of weeks 1,
3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and 9.Adequate data for the analysis of efficacy was available from 191 subjects.
The results are presented as the mean ± SD number of flushes in each of the 3
treatment weeks of each 4 week cycle. In the 0.05 mg estradiol group, the mean
weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5 at
baseline to 20 ± 3.0 (-67.0%). The 0.1 mg estradiol group had a decline in the
mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72.0%). In
the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5 at
baseline to 46 ± 6.5 (-18.1%). Compared with placebo, the 0.05 mg and 0.1 mg
estradiol groups showed a statistically significantly larger mean decrease in
hot flushes across all treatment cycles (P less than 0.05). When the response to
treatment was analyzed for each of the three cycles of therapy, similar
statistically significant differences were observed between both estradiol
treatment groups and the placebo group during all treatment cycles.In a double-blind, placebo-controlled, randomized study of 187 women
receiving Estradiol Transdermal System Continuous Delivery (Once-Weekly) 0.025
mg/day or placebo continuously for up to three 28 day cycles, the Estradiol
Transdermal System Continuous Delivery (Once-Weekly) 0.025 mg/day dosage was
shown to be statistically better than placebo at weeks 4 and 12 for relief of
both the frequency and severity of moderate to severe vasomotor symptoms.Table 2 Mean Change from Baseline in the Number of Moderate to Severe
Vasomotor Symptoms (ITT)Treatment GroupStatisticsWeek 4Week 8Week 12E2
TDSN828468 Mean-6.45-7.69-7.56 SD4.654.764.64PlaceboN837165 Mean-5.11-5.98-5.98 SD7.438.639.69 p-ValueLess than 0.002 Less than 0.003A second active-control trial of 193 randomized subjects was supportive of
the placebo-controlled trial.Effects on bone mineral densityA two year clinical trial enrolled a total of 175 healthy,
hysterectomized, postmenopausal, non-osteoporotic (i.e., lumbar spine bone
mineral density less than 0.9 gm/cm2) women at 10 study
centers in the United States. One hundred twenty nine subjects were allocated to
receive active treatment with four different doses of estradiol patches (7.75
cm2, 15.5 cm2, 23.25 cm2, 31 cm2) and 46 subjects were
allocated to receive placebo patches. Seventy seven percent of the randomized
subjects (100 on active drug and 34 on placebo) contributed data to the analysis
of percent change of A-P spine bone mineral density (BMD), the primary efficacy
variable (see Figure 3). A statistically significant overall treatment effect at
each timepoint was noted, implying bone preservation for all active treatment
groups at all timepoints, as opposed to bone loss for placebo at all timepoints.Figure 3 Mean Percent Change from Baseline in Lumbar
Spine (A-P View) Bone Mineral Density by Treatment and Time Last Observation
Carried ForwardPercent change in BMD of the total hip (see Figure 4), was also statistically
significantly different from placebo for all active treatment groups. The
results of the measurements of biochemical markers supported the finding of
efficacy for all doses of transdermal estradiol. Serum osteocalcin levels
decreased, indicative of a decrease in bone formation, at all timepoints for all
active treatment doses, statistically significantly different from placebo
(which generally rose). Urinary deoxypyridinoline and pyridinoline changes also
suggested a decrease in bone turnover for all active treatment groups.Figure 4 Mean Percent Change from Baseline in Total
Hip by Treatment and Time Last Observation Carried ForwardFootnote: This figure is based on 74% of the randomized subjects (95 on
active drug and 34 on placebo).

Women's Health Initiative StudiesThe 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 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 3 below:Table 3 RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI (*)EventRelative RiskCE/MPA vs. Placeboat 5.2 Years(95% CI  (*,1)PlaceboN=8102Absolute Risk perCE/MPAN=850610,000 Person-yearsCHD events     Nonfatal MI     CHD death1.29 (1.02-1.63)1.32 (1.02-1.72)1.18 (0.70-1.97)3023637307Invasive breast cancer  (2)1.26 (1.00-1.59)3038Stroke1.41 (1.07-1.85)2129Pulmonary embolism2.13 (1.39-3.25)816Colorectal cancer0.63 (0.43-0.92)1610Endometrial cancer0.83 (0.47-1.47)65Hip fracture0.66 (0.45-0.98)1510Death due to cause others than the events above0.92 (0.74-1.14)4037Global Index  (3)1.15 (1.03-1.28)151170Deep vein thrombosis  (4)2.07 (1.49-2.87)1326Vertebral fractures  (4)0.66 (0.44-0.98)159Other osteoporotic fractures  (4)0.77 (0.69-0.86)170131(*)  adapted from JAMA, 2002; 288:321-333(1)  * nominal confidence intervals unadjusted from multiple looks and multiple comparisons(2)  includes metastatic and non-metastatic breast cancer with the exceptioin of in situ breast cancer(3)  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(4)  not included in Global IndexFor 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 l0,000 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.)Women's Health Initiative Memory StudyThe Women’s Health Initiative Memory Study (WHIMS), a substudy of
WHI, enrolled 4,532 predominantly postmenopausal women 65 years of age and older
(47% were age 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 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 and PRECAUTIONS,
Geriatric Use.)

Boxed Warning

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL
CANCERClose 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 of equivalent
estrogen doses. (See WARNINGS, Malignant
neoplasms, Endometrial cancer.)CARDIOVASCULAR AND OTHER RISKSEstrogens with and without 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 5
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 4 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 and 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

Estradiol Transdermal System Continuous Delivery (Once-Weekly) is designed to
release estradiol continuously upon application to intact skin. Six (7.75
cm2, 11.625 cm2, 15.5 cm2, 18.6 cm2, 23.25 cm2 and 31 cm2) systems are available to
provide nominal in vivo delivery of 0.025 mg, 0.0375
mg, 0.05 mg, 0.06 mg, 0.075 mg or 0.1 mg respectively of estradiol per day. The
period of use is 7 days. Each system has a contact surface area of either 7.75
cm2, 11.625 cm2, 15.5 cm2, 18.6 cm2, 23.25 cm2 or 31 cm2, and contains 0.97 mg, 1.46
mg, 1.94 mg, 2.33 mg, 2.91 mg or 3.88 mg of estradiol 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.
It has a molecular formula of C18H2402 and molecular weight of 272.39. The
structural formula is:The Estradiol Transdermal System Continuous Delivery (Once-Weekly) comprises
four layers. Proceeding from the visible surface toward the surface attached to
the skin, these layers are (1) a foam backing with adhesive layer, (2) a
polyester film, and (3) an acrylate adhesive matrix containing estradiol USP. A
protective liner (4) 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 (propylene glycol, povidone, anhydrous colloidal silicon dioxide,
pressure sensitive acrylic adhesive, copolymer foam, polyester film, and brown
ink) 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 mcg 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.PharmacokineticsTransdermal administration of Estradiol Transdermal System
Continuous Delivery (Once-Weekly) produces mean serum concentrations of
estradiol comparable to those produced by premenopausal women in the early
follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol
following application of the Estradiol Transdermal System Continuous Delivery
(Once-Weekly) were investigated in 197 healthy postmenopausal women in six
studies. In five of the studies Estradiol Transdermal System Continuous Delivery
(Once-Weekly) was applied to the abdomen and in a sixth study application to the
buttocks and abdomen were compared.AbsorptionThe Estradiol Transdermal System Continuous Delivery
(Once-Weekly) continuously releases estradiol which is transported across intact
skin leading to sustained circulating levels of estradiol during a 7 day
treatment period. The systemic availability of estradiol after transdermal
administration is about 20 times higher than that after oral administration.
This difference is due to the absence of first-pass metabolism when estradiol is
given by the transdermal route.In a bioavailability study, the Estradiol Transdermal System Continuous
Delivery (Once-Weekly) 7.75 cm2 was studied with the
Estradiol Transdermal System Continuous Delivery (Once-Weekly) 15.5 cm2 as reference. The mean estradiol levels in serum from the two
sizes are shown in Figure 1.Figure 1 Mean Serum 17ß-Estradiol Concentrations vs.
Time Profile following Application of a 7.75 cm2
Transdermal Patch and Application of a 15.5 cm2 Estradiol
Transdermal System Continuous Delivery (Once-Weekly) PatchDose proportionality was demonstrated for the Estradiol Transdermal System
Continuous Delivery (Once-Weekly) 7.75 cm2 transdermal
system as compared to the Estradiol Transdermal System Continuous Delivery
(Once-Weekly) 15.5 cm2 transdermal system in a 2 week
crossover study with a 1 week washout period between the two transdermal systems
in 24 postmenopausal women.Dose proportionality was also demonstrated for the Estradiol Transdermal
System Continuous Delivery (Once-Weekly) (15.5 cm2 and 31
cm2) in a 1 week study conducted in 54 postmenopausal
women. The mean steady-state levels (Cavg) of the
estradiol during the application of Estradiol Transdermal System Continuous
Delivery (Once-Weekly) 31 cm2 and 15.5 cm2 on the abdomen were about 80 pg/mL and 40 pg/mL,
respectively.In a 3 week multiple application study in 24 postmenopausal women, the 31
cm2 Estradiol Transdermal System Continuous Delivery
(Once-Weekly) produced average peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values at the end of
each wear interval (Cmin) were approximately 35 pg/mL.
Nearly identical serum curves were seen each week, indicating little or no
accumulation of estradiol in the body. Serum estrone peak and trough levels were
60 pg/mL and 40 pg/mL, respectively.In a single-dose, randomized, crossover study conducted to compare the effect
of site of application, 38 postmenopausal women wore a single Estradiol
Transdermal System Continuous Delivery (Once-Weekly) 31 cm2 system for one week on the abdomen and buttocks. The
estradiol serum concentration profiles are shown in Figure 2. Cmax and Cavg values were, respectively,
25% and 17% higher with the buttock application than with the abdomen
application.Figure 2 Observed Mean (± S.E.) Estradiol Serum
Concentrations for a One Week Application of the Estradiol Transdermal System
Continuous Delivery (Once-Weekly) (31 cm2) to the abdomen
and buttocks of 38 postmenopausal women

Indications And Usage

  • Estradiol Transdermal System Continuous Delivery (Once-Weekly),
  • USP is indicated in the: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.
  • Prevention of postmenopausal osteoporosis. When prescribing solely for the
  • Prevention of postmenopausal osteoporosis, therapy should only be considered for
  • Women at significant risk 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 IU/day to 800 IU/day
  • May also be required to ensure adequate daily intake in postmenopausal women.

Contraindications

  • Estradiol Transdermal System Continuous Delivery (Once-Weekly)
  • Should not be used in women with 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 a 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.
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly) should not be
  • Used in patients with known hypersensitivity to its ingredients.
  • Known or suspected pregnancy. There is no indication for Estradiol
  • Transdermal System Continuous Delivery (Once-Weekly) 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.Cardiovascular disordersEstrogen 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
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 strokeIn the Women’s Health Initiative (WHI) study, an increased risk
of stroke was observed in women receiving oral CE 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 vs.
30 per 10,000 women-years). The increase in risk was observed in year one and
persisted. (See CLINICAL
PHARMACOLOGY, Clinical Studies.)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
women-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 the 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
CHD events were comparable among women in the CE/MPA group and the placebo group
in HERS, HERS II, and overall.Venous thromboembolism (VTE)In the Women’s Health Initiative (WHI) study, an increased risk
of deep vein thrombosis 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 4 to 6 weeks before
surgery of the type associated with an increased risk of thromboembolism, or
during periods of prolonged immobilization.Malignant neoplasmsEndometrial cancerThe 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 unopposed estrogen users is about 2-fold to
12-fold greater than in non-users, and appears dependent on duration of
treatment and on estrogen dose. Most studies show no significant increased risk
associated with use of estrogens for less than one year. The greatest risk
appears associated with prolonged use, with increased risks of 15-fold to
24-fold for 5 to 10 years or more and this risk has been shown to persist for at
least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations 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 of equivalent estrogen dose. Adding a
progestin to estrogen therapy has been shown to reduce the risk of endometrial
hyperplasia, which may be a precursor to endometrial cancer.Breast cancerThe 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 5 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 vs. 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
vs. 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 vs. 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 healthcare provider and perform monthly breast
self-examinations. In addition, mammography examinations should be scheduled
based on patient age, risk factors, and prior mammogram results.DementiaIn the Women’s Health Initiative Memory Study (WHIMS), 4,532
generally healthy postmenopausal women 65 years of age and older were studied,
of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an
average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n =
2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of
probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95%
confidence interval 1.21 - 3.48), and was similar for women with and without
histories of menopausal hormone use before WHIMS. The absolute risk of probable
dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000
women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000
women-years. It is unknown whether these findings apply to younger
postmenopausal women. (See CLINICAL
PHARMACOLOGY, Clinical Studies and PRECAUTIONS,
Geriatric Use.)Gallbladder diseaseA 2-fold to 4-fold increase in the risk of gallbladder disease
requiring surgery in postmenopausal women receiving estrogens has been
reported.HypercalcemiaEstrogen administration may lead to severe hypercalcemia in
patients with breast cancer and bone metastases. If hypercalcemia occurs, use of
the drug should be stopped and appropriate measures taken to reduce the serum
calcium level.Visual abnormalitiesRetinal vascular thrombosis has been reported in patients
receiving estrogens. Discontinue medication pending examination if there is
sudden partial or complete loss of vision, or a sudden onset of proptosis,
diplopia, or migraine. If examination reveals papilledema or retinal vascular
lesions, estrogens should be permanently discontinued.

Precautions

  • GeneralAddition of a progestin when a woman has not had a
  • HysterectomyStudies of the addition of a progestin for 10 or more days of a
  • Cycle of estrogen administration, or daily with estrogen in a continuous
  • Regimen, have reported a lowered incidence of endometrial hyperplasia than would
  • Be induced by estrogen treatment alone. Endometrial hyperplasia may be a
  • Precursor to endometrial cancer.There are, however, possible risks that may be associated with the use of
  • Progestins with estrogens compared to estrogen-alone treatment. These include a
  • Possible increased risk of breast cancer.Elevated blood pressureIn a small number of case reports, substantial increases in blood
  • Pressure have been attributed to idiosyncratic reactions to estrogens. In a
  • Large, randomized, placebo-controlled clinical trial, a generalized effect of
  • Estrogens on blood pressure was not seen. Blood pressure should be monitored at
  • Regular intervals with estrogen use.HypertriglyceridemiaIn patients with preexisting hypertriglyceridemia, estrogen
  • Therapy may be associated with elevations of plasma triglycerides leading to
  • Pancreatitis and other complications.Impaired liver function and past history of
  • Cholestatic jaundiceEstrogens may be poorly metabolized in patients with impaired
  • Liver function. For patients with a history of cholestatic jaundice associated
  • With past estrogen use or with pregnancy, caution should be exercised and in the
  • Case of recurrence, medication should be discontinued. HypothyroidismEstrogen administration leads to increased thyroid-binding
  • Globulin (TBG) levels. Patients with normal thyroid function can compensate for
  • The increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the
  • Normal range. Patients dependent on thyroid hormone replacement therapy who are
  • Also receiving estrogens may require increased doses of their thyroid
  • Replacement therapy. These patients should have their thyroid function monitored
  • In order to maintain their free thyroid hormone levels in an acceptable
  • Range.Fluid retentionBecause estrogens may cause some degree of fluid retention,
  • Patients with conditions that might be influenced by this factor, such as a
  • Cardiac or renal dysfunction, warrant careful observation when estrogens are
  • Prescribed.HypocalcemiaEstrogens should be used with caution in individuals with severe
  • Hypocalcemia.Ovarian cancerThe CE/MPA substudy of WHI reported that estrogen plus progestin
  • Increased the risk of ovarian cancer. After an average follow-up of 5.6 years,
  • The relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95%
  • Confidence interval 0.77-3.24) but was not statistically significant. The
  • Absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000
  • Women-years. In some epidemiological studies, the use of estrogen alone, in
  • Particular for ten or more years, has been associated with an increased risk of
  • Ovarian cancer. Other epidemiologic studies have not found these
  • Associations.Exacerbation of endometriosisEndometriosis may be exacerbated with administration of
  • Estrogens. A few cases of malignant transformation of residual endometrial
  • Implants have been reported in women treated post-hysterectomy with estrogen
  • Alone therapy. For patients known to have residual endometriosis
  • Post-hysterectomy, the addition of progestin should be considered.Exacerbation of other conditionsEstrogens may cause an exacerbation of asthma, diabetes mellitus,
  • Epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic
  • Hemangiomas and should be used with caution in women with these
  • Conditions.Patient Information Physicians are advised to discuss the PATIENT
  • INFORMATION leaflet with patients for whom they prescribe Estradiol
  • Transdermal System Continuous Delivery (Once-Weekly).Laboratory TestsEstrogen administration should be initiated at the lowest dose
  • Approved for the indication and then guided by clinical response rather than by
  • Serum hormone levels (e.g., estradiol, FSH).Drug/Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet
  • Aggregation time; increased platelet count; increased factors II, VII antigen,
  • VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X
  • Complex, and beta-thromboglobulin; decreased levels of antifactor Xa and
  • Antithrombin III, decreased antithrombin III activity; increased levels of
  • Fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  • Increased thyroid-binding globulin (TBG) levels leading to increased
  • Circulating total thyroid hormone levels as measured by protein bound iodine
  • (PBI), T4 levels (by column or by radioimmunoassay) or
  • T3 levels by radioimmunoassay. T3
  • Resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are
  • Unaltered. Patients on thyroid replacement therapy may require higher doses of
  • Thyroid hormone.
  • Other binding proteins may be elevated in serum (i.e., corticosteroid
  • Binding globulin (CBG), sex hormone-binding globulin (SHBG)) leading to
  • Increased total circulating corticosteroids and sex steroids, respectively. Free
  • Hormone concentrations may be decreased. Other plasma proteins may be increased
  • (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  • Increased plasma HDL and HDL2 cholesterol subfraction
  • Concentrations, reduced LDL cholesterol concentration, and in oral formulations
  • Increased triglyceride levels.
  • Impaired glucose tolerance.
  • Reduced response to metyrapone test. Carcinogenesis, Mutagenesis, and Impairment of
  • Fertility Long-term continuous administration of estrogen, with and without
  • Progestin, in women with and without a uterus, has shown an increased risk of
  • Endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)Long-term continuous administration of natural and synthetic estrogens in
  • Certain animal species increases the frequency of carcinomas of the breast,
  • Uterus, cervix, vagina, testis, and liver.PregnancyEstradiol Transdermal System Continuous Delivery (Once-Weekly)
  • Should not be used during pregnancy. (See CONTRAINDICATIONS.)Nursing Mothers Estrogen administration to nursing mothers has been shown to
  • Decrease the quantity and quality of the milk. Detectable amounts of estrogens
  • Have been identified in the milk of mothers receiving this drug. Caution should
  • Be exercised when Estradiol Transdermal System Continuous Delivery (Once-Weekly)
  • Is administered to a nursing woman.Pediatric Use Estrogen replacement therapy has been used for the induction of
  • Puberty in adolescents with some forms of pubertal delay. Safety and
  • Effectiveness in pediatric patients have not otherwise been established. Large
  • And repeated doses of estrogen over an extended time period have been shown to
  • Accelerate epiphyseal closure, which could result in short adult stature if
  • Treatment is initiated before the completion of physiologic puberty in normally
  • Developing children. If estrogen is administered to patients whose bone growth
  • Is not complete, periodic monitoring of bone maturation and effects on
  • Epiphyseal centers is recommended during estrogen administration. Estrogen
  • Treatment of prepubertal girls also induces premature breast development and
  • Vaginal cornification, and may induce vaginal bleeding. In boys, estrogen
  • Treatment may modify the normal pubertal process and induce gynecomastia. (See
  • INDICATIONS
  • AND USAGE and DOSAGE AND
  • ADMINISTRATION.)Geriatric UseThere have not been sufficient numbers of geriatric patients
  • Involved in clinical studies utilizing Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly) to determine whether those over 65 years of age differ
  • From younger subjects in their response to Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly).In the Women’s Health Initiative Memory Study, including 4,532 women 65 years
  • Of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to
  • 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone
  • Therapy use. Women treated with conjugated estrogens plus medroxyprogesterone
  • Acetate were reported to have a 2-fold increase in the risk of developing
  • Probable dementia. Alzheimer’s disease was the most common classification of
  • Probable dementia in both the conjugated estrogens plus medroxyprogesterone
  • Acetate group and the placebo group. Ninety percent of the cases of probable
  • Dementia occurred in the 54% of women that were older than 70. (See BOXED WARNING and WARNINGS,
  • Dementia.)

Adverse Reactions

See BOXED
WARNINGS, WARNINGS and PRECAUTIONS.Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice. The adverse reaction information from
clinical trials does, however, provide a basis for identifying the adverse
events that appear to be related to drug use and for approximating rates.Summary of Most Frequently Reported Adverse Experiences/Medical Events (Greater Than or Equal To 5%) by Treatment GroupsEstradiolTransdermalSystemContinuousDelivery(Once-Weekly)AE per Body System0.025 mg/day(N=219)0.05 mg/day(N=201)0.1 mg/day(N=194)Placebo(N=72)Body as a Whole21%39%37%29%     Headache5%18%13%10%     Pain1%8%11%7%     Back Pain4%8%9%6%     Edema0.5%13.%10%6%Gastrointestinal9%21%29%18%     Abdominal Pain0.0%11%16%8%     Nausea1%5%6%3%     Flatulence1%3%7%1%Musculoskeletal7%9%11%4%     Arthralgia1%5%5%3%Psychiatric13%10%11%1%     Depression1%5%8%0%Reproductive12%18%41%11%     Breast Pain5%8%29%4%     Leukorrhea1%6%7%1%Respiratory15%26%29%14%     URTI6%17%17%8%     Pharyngitis0.5%3%7%3%     Sinusitis4%$55%3%     Rhinitis2%4%6%1%Skin and Appendages19%12%12%15%     Pruritus0.5%6%3%6%Post-marketing ExperienceThe following adverse reactions have been identified during post
approval use of Estradiol Transdermal System Continuous Delivery (Once-Weekly):
a few cases in which there were a combination of the symptoms of generalized
hives or rash with swelling of the throat or eyelid edema. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.The following additional adverse reactions have been reported with estrogen
and/or progestin therapy.Genitourinary systemChanges in vaginal bleeding pattern and abnormal withdrawal
bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in
size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in
amount of cervical secretion; changes in cervical ectropion; ovarian cancer;
endometrial hyperplasia; endometrial cancer.BreastsTenderness, enlargement, pain, nipple discharge, galactorrhea;
fibrocystic breast changes; breast cancer.CardiovascularDeep and superficial venous thrombosis; pulmonary embolism;
thrombophlebitis; myocardial infarction; stroke; increase in blood
pressure.GastrointestinalNausea, vomiting; abdominal cramps, bloating; cholestatic
jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement
of hepatic hemangiomas.SkinChloasma or melasma, which may persist when drug is discontinued;
erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair;
hirsutism; pruritus, rash.EyesRetinal vascular thrombosis, intolerance to contact lenses.Central nervous systemHeadache; migraine; dizziness; mental depression; chorea;
nervousness; mood disturbances; irritability; exacerbation of epilepsy,
dementia.MiscellaneousIncrease or decrease in weight; reduced carbohydrate tolerance;
aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido;
anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma;
increased triglycerides.

Overdosage

Serious ill effects have not been reported following acute
ingestion of large doses of estrogen-containing oral contraceptives by young
children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal
bleeding may occur in females.

Dosage And Administration

When estrogen is prescribed for a postmenopausal woman with a
uterus, progestin should also be initiated to reduce the risk of endometrial
cancer. A woman without a uterus does not need progestin. Use of estrogen, alone
or in combination with a progestin, should be with the lowest effective dose and
for the shortest duration consistent with treatment goals and risks for the
individual woman. Patients should be reevaluated periodically as clinically
appropriate (e.g., 3 month to 6 month intervals) to determine if treatment is
still necessary. (See BOXED
WARNINGS and WARNINGS.) For
women who have a uterus, adequate diagnostic measures, such as endometrial
sampling, when indicated, should be undertaken to rule out malignancy in cases
of undiagnosed persistent or recurring abnormal vaginal bleeding.Patients should be started at the lowest dose. Six (7.75 cm2, 11.625 cm2, 15.5 cm2, 18.6 cm2, 23.25 cm2 and 31 cm2) Estradiol Transdermal
Systems Continuous Delivery (Once-Weekly) are available. For the treatment of
vasomotor symptoms, treatment should be initiated with the 7.75 cm2 (0.025 mg/day) Estradiol Transdermal System Continuous
Delivery (Once-Weekly) applied to the skin once weekly. The dose should be
adjusted as necessary to control symptoms. Clinical responses (relief of
symptoms) at the lowest effective dose should be the guide for establishing
administration of the Estradiol Transdermal System Continuous Delivery
(Once-Weekly), especially in women with an intact uterus. Attempts to taper or
discontinue the medication should be made at 3 month to 6 month intervals. In
women who are not currently taking oral estrogens, treatment with Estradiol
Transdermal System Continuous Delivery (Once-Weekly) can be initiated at once.
In women who are currently taking oral estrogen, treatment with the Estradiol
Transdermal System Continuous Delivery (Once-Weekly) can be initiated one week
after withdrawal of oral therapy or sooner if symptoms reappear in less than one
week. For the prevention of postmenopausal osteoporosis, the minimum dose that
has been shown to be effective is the 7.75 cm2 (0.025
mg/day) Estradiol Transdermal System Continuous Delivery (Once-Weekly). Response
to therapy can be assessed by biochemical markers and measurement of bone
mineral density.Application of the SystemThe adhesive side of the Estradiol Transdermal System Continuous
Delivery (Once-Weekly) should be placed on a clean, dry area of the lower
abdomen or the upper quadrant of the buttock. The Estradiol
Transdermal System Continuous Delivery (Once-Weekly)
should not be applied to or near the breasts. The sites of application
must be rotated, with an interval of at least one week allowed between
applications to a particular site. The area selected should not be oily,
damaged, or irritated. The waistline should be avoided, since tight clothing may
rub and remove the system. Application to areas where sitting would dislodge the
system should also be avoided. The system should be applied immediately after
opening the pouch and removing the protective liner. The system should be
pressed firmly in place with the fingers for about 10 seconds, making sure there
is good contact, especially around the edges. If the system lifts, apply
pressure to maintain adhesion. In the event that a system should fall off, a new
system should be applied for the remainder of the 7 day dosing interval. Only
one system should be worn at any one time during the 7 day dosing interval.
Swimming, bathing, or using a sauna while using the Estradiol Transdermal System
Continuous Delivery (Once-Weekly) has not been studied, and these activities may
decrease the adhesion of the system and the delivery of estradiol.Removal of the SystemRemoval of the system should be done carefully and slowly to
avoid irritation of the skin. Should any adhesive remain on the skin after
removal of the system, allow the area to dry for 15 minutes. Then gently rubbing
the area with an oil-based cream or lotion should remove the adhesive
residue.Used patches still contain some active hormones. Each patch should be
carefully folded in half so that it sticks to itself before throwing it away.

How Supplied

Estradiol Transdermal System, 0.025 mg/day
Continuous Delivery (Once-Weekly), USP – each 7.75 cm2 system contains 0.97 mg of estradiol USP NDC 54868-5009-0    Individual Carton of 4 systemsEstradiol Transdermal System, 0.05 mg/day Continuous
Delivery (Once-Weekly), USP – each 15.5 cm2 system
contains 1.94 mg of estradiol USP NDC 54868-4811-0    Individual Carton of 4 systemsEstradiol Transdermal System, 0.1 mg/day Continuous Delivery
(Once-Weekly), USP – each 31 cm2 system contains
3.88 mg of estradiol USP NDC 54868-4813-0    Individual Carton of 4 systemsStore at 20° to 25°C (68° to 77°F). [See USP for Controlled Room
Temperature.] Do not store unpouched. Apply immediately upon removal from the
protective pouch.MYLAN PHARMACEUTICALS INC. Morgantown, WV 26505REVISED AUGUST 2008ETS:R16

Spl Patient Package Insert

  • Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly), USP PATIENT INFORMATIONRead this PATIENT INFORMATION before you start using Estradiol
  • Transdermal System Continuous Delivery (Once-Weekly), USP and read what you get
  • Each time you refill Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly), USP. There may be new information. This information does not take
  • The place of talking to your healthcare provider about your medical condition or
  • Your treatment.What is the most important information I should
  • Know about Estradiol Transdermal System Continuous Delivery (Once-Weekly) (an estrogen hormone)?Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking
  • Estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of
  • The uterus (womb). Your healthcare provider should check any unusual vaginal
  • Bleeding to find out the cause.Do not use estrogens with or without progestins to prevent heart disease,
  • Heart attacks, strokes, or dementia. Using estrogens with or without progestins may increase your chances of
  • Getting heart attack, strokes, breast cancer, and blood clots. Using estrogens
  • With progestins may increase your risk of dementia. You and your healthcare
  • Provider should talk regularly about whether you still need treatment with
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly).What is Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly)?Estradiol Transdermal System Continuous Delivery (Once-Weekly) is a medicine
  • That contains estrogen hormones.What is Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly) used for?Estradiol Transdermal System Continuous Delivery (Once-Weekly) is used after
  • Menopause to:reduce moderate to severe hot flashes. Estrogens are
  • Hormones made by a woman’s ovaries. The ovaries normally stop making estrogens
  • When a woman is between 45 to 55 years old. This drop in body estrogen levels
  • Causes the “change of life” or menopause (the end of monthly menstrual periods).
  • Sometimes, both ovaries are removed during an operation before natural menopause
  • Takes place. The sudden drop in estrogen levels causes “surgical menopause.”
  • When the estrogen levels begin dropping, some women develop very
  • Uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest,
  • Or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”).
  • In some women, the symptoms are mild, and they will not need estrogens. In other
  • Women, symptoms can be more severe. You and your healthcare provider should talk
  • Regularly about whether you still need treatment with Estradiol Transdermal
  • System Continuous Delivery (Once-Weekly).treat moderate to severe dryness, itching, and burning in
  • Or around the vagina. You and your healthcare provider should talk
  • Regularly about whether you still need treatment with Estradiol Transdermal
  • System Continuous Delivery (Once-Weekly) to control these problems. If you use
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly) only to treat
  • Your dryness, itching, and burning in and around your vagina, talk with your
  • Healthcare provider about whether a topical vaginal product would be better for
  • You.
  • Treat certain conditions in which a young woman’s ovaries
  • Do not produce enough estrogen naturally.help reduce your chances of getting osteoporosis (thin weak
  • Bones). Osteoporosis from menopause is a thinning of the bones that makes
  • Them weaker and easier to break. If you use Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly) only to prevent osteoporosis from menopause,
  • Talk with your healthcare provider about whether a different treatment or
  • Medicine without estrogens might be better for you. You and your healthcare
  • Provider should talk regularly about whether you should continue with Estradiol
  • Transdermal System Continuous Delivery (Once-Weekly).
  • Weight bearing exercise, like walking or running, and taking
  • Calcium and vitamin D supplements may also lower your chances of getting
  • Postmenopausal osteoporosis. It is important to talk about exercise and
  • Supplements with your healthcare provider before starting them.Who should not use Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly)?Do not start using Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) if you:have unusual vaginal bleeding.currently have or have had certain cancers.
  • Estrogens may increase the chances of getting certain types of cancers,
  • Including cancer of the breast or uterus. If you have or had cancer, talk with
  • Your healthcare provider about whether you should take Estradiol Transdermal
  • System Continuous Delivery (Once-Weekly).
  • Had a stroke or heart attack in the past year.currently have or have had blood clots.currently have or have had liver problems.are allergic to Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly) or any of its ingredients.
  • See section titled “What are the ingredients in Estradiol Transdermal
  • System Continuous Delivery (Once-Weekly)” at the end of this leaflet for a list
  • Of ingredients in Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly).
  • Think you may be pregnant.Tell your healthcare provider:if you are breast-feeding. The hormone in Estradiol
  • Transdermal System Continuous Delivery (Once-Weekly) can pass into your milk.
  • About all of your medical problems. Your healthcare
  • Provider may need to check you more carefully if you have certain conditions,
  • Such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus,
  • Problems with your heart, liver, thyroid, kidneys, or have high calcium levels
  • In your blood.
  • About all the medicines you take. This includes
  • Prescription and nonprescription medicines, vitamins, and herbal supplements.
  • Some medicines may affect how Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) works. Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) may also affect how your other medicines work.
  • If you are going to have surgery or will be on bed rest.
  • You may need to stop taking estrogens. How should I use Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly)?Estradiol Transdermal System Continuous Delivery (Once-Weekly) is a patch
  • That you wear on your skin. The estrogen in the Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly) passes through your skin. You must change your
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch every 7
  • Days (once a week). See the end of this leaflet for complete instructions on how
  • To use Estradiol Transdermal System Continuous Delivery (Once-Weekly).Start at the lowest dose and talk to your healthcare provider about how well
  • That dose is working for you.
  • Estrogens should be used at the lowest dose possible for your treatment only
  • As long as needed. You and your healthcare provider should talk regularly (for
  • Example, every 3 months to 6 months) about the dose you are taking and whether
  • You still need treatment with Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly). What are the possible side effects of estrogens?Less common but serious side effects include:Breast cancer
  • Cancer of the uterus
  • Stroke
  • Heart attack
  • Blood clots
  • Dementia
  • Gallbladder disease
  • Ovarian cancer These are some of the warning signs of serious side
  • Effects:Breast lumps
  • Unusual vaginal bleeding
  • Dizziness and faintness
  • Changes in speech
  • Severe headaches
  • Chest pain
  • Shortness of breath
  • Pains in your legs
  • Changes in vision
  • Vomiting Call your healthcare provider right away if you get any of these warning
  • Signs, or any other unusual symptom that concerns you.Common side effects include:Headache
  • Breast pain
  • Irregular vaginal bleeding or spotting
  • Stomach/abdominal cramps, bloating
  • Nausea and vomiting
  • Hair loss Other side effects include:High blood pressure
  • Liver problems
  • High blood sugar
  • Fluid retention
  • Enlargement of benign tumors of the uterus (“fibroids”)
  • Vaginal yeast infection These are not all the possible side effects of Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly). For more information, ask your healthcare
  • Provider or pharmacist.What can I do to lower my chances of a serious side effect
  • With Estradiol Transdermal System Continuous Delivery (Once-Weekly)?Talk with your healthcare provider regularly about whether you should
  • Continue using Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly).If you have a uterus, talk to your healthcare provider about whether the
  • Addition of a progestin is right for you.
  • See your healthcare provider right away if you get vaginal bleeding while
  • Using Estradiol Transdermal System Continuous Delivery (Once-Weekly).
  • Have a breast exam and mammogram (breast X-ray) every year unless your
  • Healthcare provider tells you something else. If members of your family have had
  • Breast cancer or if you have ever had breast lumps or an abnormal mammogram, you
  • May need to have breast exams more often.
  • If you have high blood pressure, high cholesterol (fat in the blood),
  • Diabetes, are overweight, or if you use tobacco, you may have higher chances for
  • Getting heart disease. Ask your healthcare provider for ways to lower your
  • Chances for getting heart disease. General information about safe and effective use of
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly)Medicines are sometimes prescribed for conditions that are not mentioned in
  • Patient information leaflets. Do not take Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly) for conditions for which it was not
  • Prescribed. Do not give Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) to other people, even if they have the same symptoms you have. It
  • May harm them.Keep Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly) out of the reach of
  • Children.This leaflet provides a summary of the most important information about
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly). If you would
  • Like more information, talk with your healthcare provider or pharmacist. You can
  • Ask for information about Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) that is written for health professionals. You can get more
  • Information by calling the toll free number 1-877-446-3679
  • (1-877-4-INFO-RX).What are the ingredients in Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly)?The active ingredient of Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) is estradiol. Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) also contains propylene glycol, povidone, anhydrous colloidal
  • Silicon dioxide, pressure sensitive acrylic adhesive, copolymer foam, polyester
  • Film, and brown ink (yellow iron oxide pigment, red iron oxide pigment and
  • Carbon black pigment).Instructions for UseHow and Where to Apply the Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly) PatchEach Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch is
  • Individually sealed in a protective pouch. To open the pouch, hold it with the
  • Estradiol Transdermal System Continuous Delivery (Once-Weekly) name facing you.
  • Tear from top to bottom using the right side tear notch. Tear from left to right
  • Using the top tear notch. Pull the pouch open. The Estradiol Transdermal System
  • Continuous Delivery (Once-Weekly) patch is the peach colored foam round disk
  • Attached to the clear protective release liner.Apply the sticky side of the Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) patch to a clean, dry area of the lower stomach below your belly
  • Button or the top of the buttocks (see diagram below). Do not
  • Apply the Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch
  • To your breasts. The sites of application on the lower stomach and
  • Buttocks must be rotated, allowing at least one week between applications to the
  • Same site. The site selected should not be oily, damaged, or irritated. Avoid
  • The waistline, since tight clothing may rub and remove the patch. Also, do not
  • Put the patch on areas where sitting would rub it off or loosen it. Apply the
  • Patch right after opening the pouch and removing the protective liner. Press the
  • Patch firmly in place with your fingers for about 10 seconds. Make sure that it
  • Sticks all over, especially around the edges.The Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch
  • Should be worn continuously for one week. You may wish to try different sites
  • When putting on a new patch, to find ones that are most comfortable for you and
  • Where clothing will not rub on the patch or loosen it.When to Apply the Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly)?The Estradiol Transdermal System Continuous Delivery (Once-Weekly) patch
  • Should be changed once weekly. Remove the used patch. Carefully fold it in half
  • So that it sticks to itself because used patches still contain active hormones
  • And discard it. Any adhesive that might remain on your skin can be easily rubbed
  • Off. Then place the new Estradiol Transdermal System Continuous Delivery
  • (Once-Weekly) patch on a different skin site. (The same skin site should not be
  • Used again for at least one week after removal of the patch.)Contact with water when you are bathing, swimming, or showering may affect
  • The patch. If the patch falls off, the same patch may be reapplied to another
  • Area of the lower abdomen. Make sure that there is good contact, especially
  • Around the edges. If the patch will not stick completely to your skin, put a new
  • Patch on a different area of the lower abdomen. Do not apply two patches at the
  • Same time.Estrogens should be used only as long as needed. You and your healthcare
  • Provider should talk regularly (for example, every 3 months to 6 months) about
  • Whether you still need treatment with Estradiol Transdermal System Continuous
  • Delivery (Once-Weekly).Call your doctor for medical advice about side effects. You
  • May report side effects to FDA at 1-800-FDA-1088.MYLAN PHARMACEUTICALS INC.Morgantown, WV 26505REVISED AUGUST 2008PL:ETS:R11

* Please review the disclaimer below.