Physician Package Insert
`NDA 20, 847 (ESCLIM® estradiol transdermal system}
`
`Page 1
`
`ESCLIM®
`
`estradiol transdermal system
`
`Continuous delivery for twice—weekly application
`
`Prescribing information
`
`1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF
`
`ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
`
`Close clinical surveillance of all women taking estrogens is important. Adequate
`
`diagnostic measures,
`
`including endometrial
`
`sampling when indicated should be
`
`undenaken to rule out malignancy in all cases of undiagnosed persistent or recurring
`
`abnormal vaginal bleeding. There is no evidence that “natural” estrogens are more or
`
`less hazardous than “synthetic” estrogens at equiestrogenic doses.
`
`2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY
`
`There is no indication for estrogen therapy during pregnancy or during the immediate
`
`postpartum period. Estrogens are ineffective for the prevention or treatment of
`
`threatened or habitual abortion. Estrogens are not
`
`indicated for the prevention of
`
`postpartum breast en gorgement.
`
`Estrogen therapy during pregnancy is associated with an increased risk of congenital
`
`defects in the reproductive organs of the fetus, and possibly other birth defects. Studies
`
`of women who received diethylstilbestrol (DES) during pregnancy have shown that
`
`female offspring have an increased risk of vaginal adenosis, squamous cell dysplasia of
`
`the uterine cervix, and clear cell vaginal cancer later in life; male offspring have an
`
`increased risk of urogenital abnormalities and possibly testicular cancer later in life. The
`
`1985 DES Task Force concluded that use of DES during pregnancy is associated with
`
`a subsequent
`
`increased risk of breast cancer in the mothers, although a causal
`
`relationship remains unproven and the observed level of excess risk is similar to that for
`a number of other breast cancer risk factors.
`
`
`
`
`
`Reference: NDA #20-847
`
`l-"'ersion: Final
`
`Edition Date: August 3, 1998
`
`Noven Pharmaceuticals, Inc.
`EX2009
`
`0001
`
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`|PR2018~00174
`
`

`

`Physician Package Insert
`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`Pave 2
`
`DESCRIPTION
`
`The Esclim estradiol transdermal system contains estradiol
`
`in a polymeric adhesive. The system is
`
`designed to release FEB—estradiol continuously upon application to intact skin.
`
`Five systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.075 or 0.1 mg
`
`of estradiol per day via skin of average permeability. Each corresponding system having an active
`
`surface area of 11, 16.5, 22, 33 or 44 cm2 contains 5, 7.5, 10, 15 or 20 mg of estradiol USP,
`
`respectively.
`
`The composition of the systems per unit area is identical.
`
`Estradiol USP (NB—estradiol) is a white, crystalline powder, chemically described as estra—l , 3, 5 (10)
`
`OH
`
`The molecular formula of estradiol is C18 H24 02. The molecular weight is 272.39.
`
`H O
`
`Esclirn transdermal systems are composed of a soft, flexible, rectangular foam backing material with
`
`rounded corners, covered on one side with a self—adhesive polymer matrix which contains estradiol
`
`and pharmacologically inactive components. The adhesive surface is covered by a transparent
`
`protective release liner as shown in the diagram below.
`
`
`
`‘— Non removable backing film
`
`
`
`
`+— Adhesive polymeric matrix
`‘—
`Peelable protective release liner
`
`The active component of the system is estradiol. The remaining components of the system (EVA
`
`copolymers, ethylcellulose, octyldodecanol, dipropylene glycol, polyester protective release liner) are
`
`pharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`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
`
`Reference: NDA #20-847
`
`Version: Final
`0002
`
`Edition Date: August 3. 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 3
`
`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 ug
`
`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.
`
`Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH)
`
`and follicle stimulating hormone (FSH)
`
`through a negative feedback mechanism and estrogen
`
`replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal
`women.
`
`Pharmacokinetics
`
`The pharmacokinetics of transdermally administered estradiol using Esclim have been evaluated in a
`
`total of 138 healthy postmenopausal women in nine clinical pharmacology and biopharmac-eutic
`
`studies.
`
`Absorption
`
`Transdermal administration of estradiol produces therapeutic serum concentrations of estradiol with
`
`lower circulating concentrations of estrone and estrone conjugates and requires smaller total doses
`
`than does oral therapy.
`
`The in viva estradiol daily delivery rate from Esclim was estimated using the baseline adjusted average
`
`serum concentrations determined from pharmacokinetic studies and an estradiol clearance value of
`
`1600 leay. The estimated mean in vivo transdermal delivery rates of estradiol are 0.020 mgfday,
`
`0.051 mg/day, and 0.101 mg.day for the l 1 cm2 , 22 cm2 and 44 cm2 Esclim systems, respectively.
`
`The bioavailability of estradiol from Esclim was compared with VivelleTM in a 4-day single application
`
`randomized crossover study of Esclim 0.05 (22 cmz), Esclim 0.1 (44 cm2) and Vivelle 0.05 in 23
`
`postmenopausal women. The mean maximum serum estradiol concentrations of 62 pgi’ml and 124
`
`pg/ml were obtained at a mean Tmax of 27 hours following application of Esclim 0.05 and Esclim 0.1,
`
`respectively.
`
`In this study, serum estradiol concentration profiles (Figure 1) and pharmacokinetic
`
`parameters (CW and AUC) obtained with the Esclim 0.1 system were twice as high as those produced
`
`by the Esclim 0,05 system.
`
`Reference: NDA #20-847
`
`Version: Final
`0003
`
`Billion Date: August 3, 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 4
`
`Figure 1: Mean Uncorrected Serum Estradiol Concentrations After Application
`
`of
`
`Esclim 0.05, Esclim 0.1 and Vivelle 0.05 for 4 Days
`
`120-
`
`100'
`
`80
`
`20-
`
`60-
`
`40-
`
`+ Esclimw 0.05
`
`+ Esclimw 0.1
`
`_[3. .VivelleTM 0.05
`
`Time (days)
`
`In a 3-week multiple application study in 18 postmenopausal women, Esclim 0.05 (22 cm2) applied to
`
`the buttocks increased serum estradiol concentrations within 4 hours and maintained an average serum
`
`estradiol concentration of approximately 51 pgme above baseline. Trough values of approximately
`
`27 to 35 pg/mL above the baseline were observed at the end of each application interval (3 or 4 days).
`
`Nearly identical serum estradiol concentration profiles were seen during each successive week,
`
`indicating little or no accumulation of estradiol in the body.
`
`In a 3-day, single-application, crossover study in 12 postmenopausal women, estradiol serum
`
`concentrations were compared following application of the Esclim 0.05 system to sites on the buttocks
`
`(site used in clinical trials), the femoral triangle, and the upper arm. The profiles of serum estradiol
`
`concentrations from these different application sites are shown in Figure 2, and the pharmacokinetic
`
`results derived from each site are presented in Table 1.
`
`Reference: NDA #20-847
`
`Version: Final
`0004
`
`Edition Date: August 3, 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 5
`
`Figure 2: Mean Uncorrected Serum Estradiol Concentrations After Application of ESCLIM
`
`0.05 to Different Body Sites for 3 Days
`
`
`
`—|— Femoral triangle (Upper Inner Thigh)
`
`' 'X'
`
`'Upper arm + Buttock
`
`Tlme {days}
`
`Table 1: Mean Uncorrected Estradiol Pharmacokinefic Parameters after Application of
`
`ESCLIM 0.05 Patches to Different Body Sites
`
`Femoral Triangle
`
`Upper Arm
`
`Buttock
`
`Cm“ (pgian
`
`80.1 :1: 34.9
`
`80.2 :1: 44.1
`
`C1nin72{pgmlL)
`
`41.6 i 18.3
`
`38.7 i152
`
`
`
`Cav96(Pg/1“Ll
`
`AUC(0_72}
`
`(pg-hrhnL)
`
`AUC(0_96}
`
`(pg-hrimL)
`
`42.3 i: 20.5
`
`4106 i 1826
`
`(
`4578 at U38
`
`40.8 :1: 19.7
`(
`3825 d: 18)?
`
`L
`4306 :1: 1)25
`
`7'16 :1: 36.2
`
`34.5 :: 18.8
`
`37.3 117.1
`__
`3477 __ 1530
`
`_
`3885 _
`
`Reference: NDA #20-847
`
`Version: Final
`0005
`
`Edition Dare: August 3. 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 6
`
`Linear pharmacokinetics have been demonstrated for the Esclim transdermal system. Serum estradiol
`
`concentrations following a 4-day application of the Esclim 0.025, 0.05, and 0.1 systems are shown in
`
`Figure 3, while the mean values for pharmacokinetic parameters from these applications are
`
`summarized in Table 2. Results for the Esclim 0.025 system are from one study, while results for
`
`Esclim 0.05 and 01 systems are from a separate study. Cmax occurred at approximately 30 hours.
`
`Figure 3: Mean Uncorrected Serum Estradiol Concentrations After Application of ESCLIM
`
`0.025, ESCLIM 0.05 and ESCLIM 0.1 for 4 Days
`
`12E]I -
`
`100 '
`
`so -
`
`60
`
`40 -
`
`20 -
`
`o
`
`
`
`o
`
`1
`
`2
`
`Time (days)
`
`.
`3
`
`4
`
`5
`
`—><-— Esclim” 0.025
`
`—D— Esclim” 0.05 + Esclim” 0.1
`
`Table 2: Mean i SD Uncorrected Estradiol Pharmacokinetic Parameters
`
`for Esclim
`
`Transdermal Systems Applied to the Buttocks (N = 23)
`
`Surface area
`
`Estradio] Dose
`
`(cm‘)
`
`(mg/day)
`
`
`
`Cmg
`
`(00'le
`
`aC‘m.-1.=Ser11n1| estradiol concentration at 96 hours following application. bN = 17
`
`Reference: NDA #20-847
`
`Version: Final
`0006
`
`Edition Date: August 3. 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 7
`
`Distribution
`
`The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are
`
`widely distributed in the body and are generally found in higher concentrations in the sex hormone
`
`target organs. Estradiol and other naturally occurring estrogens are bound mainly to sex hormone
`
`binding globulin (SHBG), and to lesser degree to 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
`
`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.
`
`Since transdermally absorbed estradiol is not subject to first pass liver metabolism, the ratio of serum
`
`concentrations of estradiol to either of its major metabolites, estrone or estrone sulfate, is closer to
`
`those observed in premenopausal women than when administered by the oral route of administration.
`
`The clinical relevance of the estradiol to estrone ratio is presently unknown.
`
`In a double-blind, parallel-group placebo-controlled clinical trial using Esclim, the steady-state serum
`
`concentrations of estradiol, estrone and estrone sulfate were measured between 24 and ”i2 hours after
`
`application of patch at week 13 and are presented in Table 3.
`
`Reference: NDA #20-847
`
`Version: Final
`0007
`
`Edition Dare: August 3. 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transderrnal system)
`
`Physician Package Insert
`
`Page 8
`
`Table 3: Mean 3: SD Steady State Serum Concentration of Estradiol and Its Metabolites at
`
`Week 13 Following the Application of Esclim
`
`
`Steady State Serum Concentration
`
`Estradiol
`
`Estrone
`
`(pg/mL)
`
`(pgimL)
`
`Estrone
`
`Sulfate
`
`(ng/dL)
`
`Placebo
`
`19.6 a 14.0
`
`29.2 a 11.2
`
`42.9 i 24.0
`
`30
`31
`31"
`
`
`
`
`0025 rug/day
`
`005 [mg/day
`
`0} trig/day
`
`43.2 a: 27.4
`22
`
`102.3 i 63.6
`24
`
`33.7 i 21.5
`22
`
`49.0 a 23.0
`24
`
`152.6 :t 12971
`22
`
`236.1 i 142.1
`22
`
`165.3 i 116.]
`28
`
`64.9 d: 31.7
`28
`
`373.6 i 2—120
`28
`
`“munber of subjects
`
`Excretion
`
`Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
`
`Serum concentrations of estradiol and estrone returned to baseline values within 12 to 24 hours after
`
`removal of Esclim.
`
`Special Populations
`
`No specific studies have been conducted using Esclim in any special populations.
`
`Drug Interactions
`
`No specific drug interaction studies have been conducted using Esclim.
`
`Clinical Trials
`
`In a 12—week, double—blind study evaluating the efficacy and safety of Esclim 0,025, 0.05, and 0.1
`
`versus placebo, in symptomatic women (average of 8 or more moderate to severe hot flushes per day),
`
`reduction in the frequency of these vasomotor symptoms was demonstrated within 4 weeks. Results
`
`from this trial are presented in Table 4 and Figure 4.
`
`Reference: NDA #20-847
`
`Version: Final
`0008
`
`Edm'rm Dore: AugIISI 3. 1998
`
`

`

`Physician Package Insert
`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`Pa 8 9
`
`After 4 weeks of treatment,
`
`the mean reduction in the moderate to severe vasomotor symptoms
`
`(MSVS) was up to 8.6 MSVS per day in the Esclim 0.025 group, 9.2 and 10.2 in the Esclim 0.05 and
`
`Esclim 0.1 groups respectively, compared with 5.3 in the placebo group. After 12 weeks of treatment,
`
`this increased to 9.9 in the Esclim 0.025 group, 10.4 in the Esclim 0.05 group and 10.? in the Esclim
`
`0.1 group and remained stable at 5.2 in the placebo group.
`
`Table 4:
`
`Changes from Baseline in Frequency of MSVS
`
`Placebo
`
`Esclim
`
`Esclim
`
`Esclim
`
`Week
`
`Week 0
`
`(Baseline)
`McaniSD
`Week 4
`Mean Reduction i SD
`
`% Reduction}
`Week 8
`Mean Reduction i SD
`
`(% Reduction]
`Week 12
`Mean Reduction 1r SD
`
`(% Reduction]
`
`(N=54)
`
`0025 lug/day
`(N=48)
`
`0.05 mgfday
`tN=47)
`
`0.1 mgiday
`(N=47)
`
`11.43517
`
`ll.6i5.4
`
`109:4.2
`
`ll.2i2.8
`
`-5.3 i 4.]
`
`(48.9%)
`
`-5.5 i 4,?
`
`(61.5%}
`
`-5.2 i 5.1
`
`(-50.39%)
`
`-8.6 :r 5.7*
`
`{-"i2.6%)
`
`-9.4 :r 57*
`
`(-79.8%)
`
`-9.9 i 58*
`
`(-83.41%)
`
`-9.2 i 45*
`
`-10.2 i 29*
`
`{-84.4%)
`
`(-92.0%)
`
`-l().3 ir 43*
`
`-l().6 i 28*
`
`(-94.0911)
`
`(-95.61%)
`
`-10.4 1r 42*
`
`-10.7 i 28*
`
`[-95.3%)
`
`(05.6%)
`
`*Statistieally different difference from placebo in mean reduction (Dunnett’s test)
`—><— Esclimw 0.1
`
`Figure 4: Reduction of MSVS During Double—Blind, Placebo—Controlled Study
`
`Weeks of Treatment
`
`
`.12
`
`+ placebo + Esclim‘u 0,025
`
`- ,3- .Escum"° 0.05
`
`Reference: NDA #20-847
`
`Version: Final
`0009
`
`Edition Date: August 3. 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 10
`
`Maintenance of the relief of VMS over a median period of 2 years was documented in two open—label
`
`trials.
`
`INDICATIONS AND USAGE
`
`Esclim (estradiol transdermal system) is indicated in the following:
`
`I.
`
`2.
`
`3.
`
`Treatment of moderate to severe vasomotor symptoms associated with the menopause. There is no
`
`adequate evidence that estrogens are effective for nervous symptoms of depression that might
`
`occur during menopause and they should not be used to treat these conditions.
`
`Treatment of vulva] and vaginal atrophy.
`
`Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
`
`CONTRAINDICATIONS
`
`Patients with known hypersensitivity to any of the components of the therapeutic system should not
`
`use Esclim_ Estrogens shOuld not be used in individuals with any of the following conditions:
`
`1. Known or suspected pregnancy (see Boxed Warning). Estrogen may cause fetal harm when
`
`administered to a pregnant woman.
`
`. Undiagnosed abnormal genital bleeding.
`
`. Known or suspected cancer of the breast except in appropriately selected patients being treated for
`
`metastatic disease.
`
`. Known or suspected estrogen—dependent neoplasia.
`
`. Active thrombophlebitis or thromboembolic disorders.
`
`WARNINGS
`
`1. Induction of Maiignani Neoplasms. Some studies have suggested a possible increased incidence of
`
`breast cancer in those women taking estrogen therapy at higher doses or for prolonged periods of
`
`time. The majority of studies, however, have not shown an association with the usual doses used
`
`for estrogen replacement therapy. Women on this therapy should have regular breast examinations
`
`and should be instructed in breast self—examination. The reported endometrial cancer risk among
`
`unopposed estrogen users is about 2 to 12—fold 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 1 year. The greatest risk appears associated with
`
`prolonged use with increased risks of 15 to 24—fold for 5 to 10 years or more. In three studies,
`
`persistence of risk was demonstrated for 8 to over 15 years afier cessation of estrogen treatment. In
`
`one study, a significant decrease in the incidence of endometrial cancer occurred 6 months after
`
`Reference: NDA #20-847
`
`Version: Final
`0010
`
`Edition Dare: August 3, 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 11
`
`estrogen withdrawal. Concurrent progestin therapy may offset this risk, but the overall health
`
`impact in postmenopausal women is not known (see PRECAUTIONS).
`
`Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital
`
`reproductive tract disorders. In female offspring, there is an increased risk of vaginal adenosis,
`
`squamous cell dysplasia of the cervix, and clear cell vaginal cancer later in life; in males, urogenital
`
`and possibly testicular abnormalities. Although some of these changes are benign, it is not known
`
`whether they are precursors of malignancy.
`
`2. Gallbladder Disease. Two studies have reported a 2 to 4—fold increase in the risk of surgically
`
`confirmed gallbladder disease in postmenopausal women receiving oral estrogen replacement
`
`therapy, similar to the 2—fold increase previously noted in users of oral contraceptives.
`
`3. Cardiovascular Disease. 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.
`
`These risks cannot necessarily be extrapolated from men to women, However,
`
`to avoid the
`
`theoretical cardiovascular risk to women caused by high estrogen doses, the dose for estrogen
`
`replacement therapy should not exceed the lowest effective dose.
`
`4. Elevated Blood Pressure. Occasional blood pressure increases during estrogen replacement therapy
`
`have been attributed to idiosyncratic reactions to estrogens. More often, blood pressure has
`
`remained the same or has dropped. Postmenopausal estrogen use does not increase the risk of
`
`stroke. Nonetheless, blood pressure should be monitored at regular intervals with estrogen use,
`
`especially if high doses are used. Ethinyl estradiol and conjugated estrogens have been shown to
`
`increase renin substrate. In contrast to these oral estrogens, transderrnalIy—administered estradiol
`
`does not affect renin substrate.
`
`5. Hwercalcemia. Administration of estrogen may lead to severe hypercalcemia in patients with
`
`breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate
`
`measures taken to reduce the serum calcium level.
`
`PRECAUTIONS
`
`General
`
`1. Addilien (y'a Progestin. Studies of the addition of a progestin for 10 or more days of a cycle of
`
`estrogen administration have reported a lowered incidence of endometrial hyperplasia than would
`
`be induced by estrogen treatment alone. Morphological and biochemical studies of endometria
`
`Reference: NDA #20-847
`
`Version: Final
`001 1
`
`Edlllon Dale: August 3, I998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 12
`
`suggest
`
`that
`
`IO to 14 days of progestin are needed to provide maximal maturation of the
`
`endometrium and to reduce the likelihood of hyperplastic changes.
`
`There are however, possible risks that may be associated with the use of progestins in estrogen
`
`replacement regimens. These include:
`
`(I) adverse effects on lipoprotein metabolism (lowering HDL and raising LDL), which could
`
`diminish the purported cardioprotective effect of estrogen therapy (see PRECAUTIONS,
`
`below);
`
`(2) impairment of glucose tolerance; and
`
`(3) possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiological
`
`data are available to address this point (see PRECAUTIONS, below).
`
`The choice of progestin, its dose and its regimen may be important in minimizing these adverse
`
`effects, but these issues will require further study before they are clarified.
`
`2. Cardiovascular Risk. A causal relationship between estrogen replacement therapy and reduction of
`
`cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of
`
`added pro gestins on this putative benefit is not yet known.
`
`In recent years, many published studies have suggested that
`
`there may be a cause—effect
`
`relationship between postmenopausal oral estrogen replacement therapy without added progestius
`
`and a decrease in cardiovascular disease in women_ Although most of the observational studies
`
`which assessed this statistical association have reported a 20% to 50% reduction in coronary heart
`
`disease risk and associated mortality in estrogen takers, the following should be considered when
`
`interpreting these reports:
`
`(1) Because only one of these studies was randomized and it was too small to yield statistically
`
`significant results, all relevant studies were subject to selection bias. Thus,
`
`the apparently
`
`reduced risk of coronary artery disease cannot be attributed with certainty to estrogen
`
`replacement therapy. It may instead have been caused by lifcustyle and medical characteristics
`
`of the women studied with the result that healthier women were selected for estrogen therapy.
`
`In general, treated women were of higher socio—economic and educational status, more slender,
`
`more physically active, more likely to have undergone surgical menopause, and less likely to
`
`have diabetes than the untreated women. Although some studies attempted to control for these
`
`selection factors,
`
`it
`
`is common for properly—designed randomized trials to fail
`
`to confirm
`
`benefits suggested by less rigorous study designs. Thus ongoing and future large—scale
`
`randomized trials may fail to confirm this apparent benefit.
`
`(2) Current medical practice often includes the use of concomitant progestin therapy in women
`
`with intact uteri
`
`(see PRECAUTIONS and WARNINGS). While the effects of added
`
`Raicreuce: NDA #20-847
`
`Version: Final
`001 2
`
`Edition Date: August 3, I998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 13
`
`progestins on the risk of ischemic heart disease are not known, all available progestins reverse
`
`at least some of the favorable effects of estrogens on HDL and LDL levels.
`
`(3) While the effects of added progestins on the risk of breast cancer are also unknown, available
`
`epidemiologic evidence suggests that progestins do not
`
`reduce, and may enhance,
`
`the
`
`moderately increased breast cancer incidence that has been reported with prolonged estrogen
`
`replacement therapy (see WARNINGS, above).
`
`Because relatively long—term use of estrogens by a woman with a uterus has been shown to induce
`
`endometrial cancer, physicians often recommend that women who are deemed candidates for
`
`hormone replacement should take progestins as well as estrogens. When considering prescribing
`
`concomitant estrogens and progestins for hormone replacement therapy, physicians and patients are
`
`advised to carefully weigh the potential benefits and risks of the added progestin. Large—scale
`
`randomized, placebo—controlled, prospective clinical trials are required to clarify these issues.
`
`3. Physical Examination. A complete medical and family history should be taken prior to the initiation
`
`of any estrogen therapy. The pre—treatment and periodic physical examinations should include
`
`special reference to blood pressure, breasts, abdomen, and pelvic organs and should include a
`
`Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than 1 year
`
`without re—examining the patient.
`
`4. Hypercoaguiabi/iiy. Some studies have shown that women taking estrogen replacement therapy
`
`have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears
`
`dose and duration dependent and is less pronounced than that associated with oral contraceptive
`
`use. Also, postmenopausal women tend to have increased coagulation parameters at baseline
`
`compared to premenopausal women. There is some suggestion that low—dose postmenopausal
`
`mestranol may increase the risk of thromboembolism, although the majority of studies (primarily of
`
`users of conjugated estrogens) report no such increase. There is insufficient
`
`information on
`
`hypercoagulability in women who have had previous thromboembolic disease.
`
`5. Familial Hyperiipoproreinemia. Estrogen therapy may be associated with massive elevations of
`
`plasma triglycerides leading to pancreatitis and other complications in patients with familial defects
`
`of lipoprotein metabolism.
`
`6. Fiuid Retention. Because estrogens may cause some degree of fluid retention, conditions that might
`
`be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction,
`
`require careful observation.
`
`7. Uterine Bieeding and Mastodynia. Certain patients may develop undesirable manifestations of
`
`estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
`
`Reference: NDA #20-847
`
`Version: Final
`001 3
`
`Edition Date: August 3, 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 14
`
`8. Impaired Liver Function. Estrogens may be poorly metabolized in patients with impaired liver
`
`function and should be administered with caution.
`
`Information for the Patient
`
`See text of Patient Package Insert, which appears after the HOW SUPPLIED section.
`
`Laboratory Tests
`
`Estrogen administration should generally be guided by clinical response at the smallest dose, rather
`
`than laboratory monitoring, for relief of symptoms for those indications in which symptoms are
`
`observable.
`
`Drug/Laboratory Tests Interactions
`
`Some of these drug/laboratory test interactions have been observed only with estrogen—progestin
`
`combinations (oral contraceptives):
`
`l. 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 anti—factor Xa
`
`and antithrombin III; decreased antithrombin III activity;
`
`increased levels of fibrinogen and
`
`fibrinogen activity; increased plasminogen antigen and activity.
`
`2. Increased thyroid—binding globulin (TBG) leading to increased circulating total thyroid hormone, as
`
`4 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.
`
`3. Other binding proteins may be elevated in serum, i,e. corticosteroid binding globulin (CBG), sex
`
`hormone—binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids
`
`respectively, Free or biologically active hormone concentrations are unchanged. Other plasma
`
`proteins may be increased (angiotensinogen/renin substrate, alpha—l—antitrypsin, ceruloplasmin).
`
`4. Increased plasma HDL and HDL—2
`
`subfraction concentrations,
`
`reduced LDL cholesterol
`
`concentration, increased triglyceride levels.
`
`5. Impaired glucose tolerance.
`
`6. Reduced response to metyrapone test.
`
`Reference: NDA #20-847
`
`Version: Final
`001 4
`
`Edition Date: August 3, I998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`7. Reduced serum folate concentration.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Page 15
`
`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 (see
`
`CONTRAINDICATIONS and WARNINGS).
`
`Pregnancy Category X
`
`Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and Boxed Warning).
`
`Nursing Mothers
`
`As a general principle, the administration of any drug to nursing mothers should be done only when
`
`clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to
`
`nursing mothers has been shown to decrease the quantity and quality of the milk.
`
`ADVERSE REACTIONS
`
`See WARNINGS and Boxed Warning regarding the potential adverse effects on the fetus,
`
`the
`
`induction of malignant neoplasms, gallbladder disease, cardiovascular disease, elevated blood pressure
`
`and hypercalcemia.
`
`Skin irritation:
`
`In controlled clinical studies with Esclim, the most commonly reported adverse events
`
`were topical reactions of erythema andfor pruritis at the application site.
`
`In general these reactions
`
`caused patients little or no discomfort, and led to premature discontinuation of treatment in 0.9%
`
`(31317) of patients in these trials. The rate of application site reactions, based on 8,135 applications of
`
`the 0.025, 0.05, and 0.1 Esclim systems in these trials was 6.1 per 100 applications (4.9, 5.4, 10.7 for
`
`the three Esclim doses respectively) compared to 6.2 in the placebo treated patients (2,014
`
`applications).
`
`In a placebo-controlled trial of Esclim 0.025, 0.05, and 0.1 conducted in 196 patients in the US, the
`
`adverse events reported by at least 5% of patients in one or more of the treatment groups are shown in
`
`Table 5.
`
`Raft'rence: NDA #20-847
`
`Version: Final
`001 5
`
`Edfrion Date: August 3, I998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 16
`
`Table 5
`Incidence of Adverse Events }5% in a
`
`Placebo-Controlled Study of Esclim
`Data are Expressed as % of Treatment Group
`
`Placebo
`
`Esclim
`
`Esclim
`
`Esclim
`
`0.025 mgiday
`0.05 tngiday
`0.1 tngiday
`
`Adverse Event
`{N=54)
`(N=48)
`(N=4?)
`(N=47)
`Breast Pain
`3.?
`25.0
`44.7
`46.8
`Headache
`22.2
`18.8
`8.5
`6.4
`Infection
`7.4
`10.4
`10.6
`8.5
`
`Injury Accident
`Anxiety
`Emotional Lability
`Arthalgia
`Flu Syndrome
`Joint Disorder
`Prurilis
`Rhinitis
`Abdominal Pain
`General Edema
`
`Moniiia Vagina
`Nausea
`
`Peripheral Edema
`Sinusitis
`Asthenia
`Back Pain
`Diarrhea
`
`Dysmenorrhea
`Enlarged Abdomen
`Enlarged Breast
`Rash
`Anemia
`Gaeroenterilis
`
`Hyperlipemia
`Leukorrhea
`Paresthesia
`
`3.7
`0
`1.9
`1.9
`7.4
`0
`1.9
`1.9
`9.3
`1.9
`
`5.6
`1.9
`
`0
`7.4
`1,9
`3.?
`1.9
`
`0
`0
`0
`5.6
`0
`1.9
`
`5.6
`0
`1.9
`
`10.4
`8.3
`8.3
`6.3
`6.3
`6.3
`6.3
`6.3
`4.2
`4.2
`
`4.2
`4.2
`
`4.2
`4.2
`2.1
`2.1
`2.1
`
`2. I
`2.1
`2.1
`2.1
`0
`0
`
`0
`0
`{l
`
`4.3
`2.]
`2. 1
`2.1
`6.4
`0
`12.8
`4.3
`10.6
`6.4
`
`8.5
`10.6
`
`2.1
`2.1
`10.6
`2.1
`8.5
`
`2. I
`2.]
`2.1
`4.3
`6.4
`0
`
`0
`12.8
`6. 4
`
`2.1
`0
`6.4
`4.3
`8.5
`0
`0
`4.3
`2. 1
`6.4
`
`4.3
`8.5
`
`6.4
`4.3
`6.4
`6.4
`0
`
`6.4
`6.4
`8.5
`2.1
`4.3
`6.4
`
`2. l
`0
`0
`
`Urogenital Adverse Events:
`
`(See Precautions: Addition of a progestin):
`
`In the US placebo-
`
`controlled study, 72 patients were included who had intact uteri. As expected, after 12-13 weeks of
`
`continuous unopposed therapy, findings of endometrial hyperplasia (diagnosed either by endometrial
`
`biopsy andior ultrasonography) were increased with increasing doses of estradiol (placebo:
`
`0;“ 18
`
`patients; Esclim 0.025:
`
`lil4 (2.1%); Esclim 0.05: 12:22 (54.5%); Esclim 0.1: 10:18 (55.6%).
`
`In
`
`the 86 patients who had not previously undergone a total hysterectomy, vaginal bleeding was also
`
`increased with increasing doses of estradiol (placebo: 2i21 patients (9.5%); Esclim 0.025:
`
`6i19
`
`(31.6%); Esclim 0.05: W25 (56.0%); Esclim 0,1: 12m (57.1%).
`
`Reference: NDA #20-847
`
`Version: Final
`001 6
`
`Edition Date: August 3, 1998
`
`

`

`NBA 20, 847 (ESCLIM® estradiol transdermal system)
`
`Physician Package Insert
`
`Page 17
`
`In two long-term studies involving a total of 488 patients treated for a mean duration of 618 days and
`
`up to 3.5 years, the nature and incidence of adverse events did not change with prolonged duration of
`treatment.
`
`The following additional adverse reactions hav