`NDA20, 847 (ESCLIM® estradiol transdermal system)
`
`Page |
`
`ESCLIM”
`
`estradiol transdermal system
`
`Continuous delivery for twice-weekly application
`
`Prescribing information
`
`
`
`1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF
`
`ENDOMETRIAL CARCINOMAIN POSTMENOPAUSAL WOMEN.
`
`Close clinical surveillance of all women taking estrogens is important. Adequate
`diagnostic measures,
`including endometrial
`sampling when indicated should be
`undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring
`abnormal vaginal bleeding. There is no evidence that “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
`postpartum breast engorgement.
`
`indicated for the prevention of
`
`Estrogen therapy during pregnancy is associated with an increased risk of congenital
`defects in the reproductive organsof the fetus, and possibly other birth defects. Studies
`of women whoreceived diethylstilbestrol (DES) during pregnancy have shown that
`female offspring have an increased risk of vaginal adenosis, squamouscell dysplasia of
`the uterine cervix, and clear cell vaginal cancer later in life; male offspring have an
`increasedrisk of urogenital abnormalities and possibly testicular cancer later in life. The
`1985 DES Task Force concluded that use of DES during pregnancyis associated with
`a subsequent
`increased risk of breast cancer in the mothers, although a causal
`relationship remains unproven and the observed level of excessrisk is similar to that for
`a number ofother breast cancer risk factors.
`
`
`
`Reference: NDA #20-847
`
`Version: Final
`
`Edition Date: August 3, 1998
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2009
`Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-00174
`
`
`
`Physician Package Insert
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 2
`
`DESCRIPTION
`
`in a polymeric adhesive. The system is
`The Esclim estradiol transdermal system contains estradiol
`designed to release 178—estradiol continuously upon application to intact skin.
`
`Five systems are available to provide nominalin 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 (178-estradiol) is a white, crystalline powder, chemically described as estra—1, 3, 5 (10)
`
`OH
`
`The molecular formula of estradiol is C] g H74 O>. The molecular weight is 272.39.
`
`HO
`
`Esclim transdermal systems are composedofa soft, flexible, rectangular foam backing material with
`rounded comers, 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 shownin 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
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 3
`
`Physician Package Insert
`
`equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen andis
`substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary
`source of estrogen in normally cycling adult womenis the ovarian follicle, which secretes 70 to 500 ig
`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
`abundantcirculating 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 biopharmaceutic
`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 doesoral therapy.
`
`The in vivo 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 L/day. The estimated mean in vivo transdermal delivery rates of estradiol are 0.020 mg/day,
`0.051 mg/day, and 0.101 mg.day for the 11 cm’, 22 cm’ and 44 cm” Esclim systems, respectively.
`
`The bioavailability of estradiol from Esclim was compared with Vivelle™ in a 4-day single application
`randomized crossover study of Esclim 0.05 (22 cm’), Esclim 0.1 (44 cm’) and Vivelle 0.05 in 23
`postmenopausal women. The mean maximum serum estradiol concentrations of 62 pg/ml and 124
`pg/ml were obtained at a mean T,,,x 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 (Cmax 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
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 4
`
`Physician Package Insert
`
`Figure 1: Mean Uncorrected Serum Estradiol Concentrations After Application
`Esclim 0.05, Esclim 0.1 and Vivelle 0.05 for 4 Days
`
`of
`
`120>
`
`—t— Esclim® 0.05
`
`Time (days)
`—g-Esclim® 0.1
`
`—@ -Vivelle™ 0.05
`
`In a 3-week multiple application study in 18 postmenopausal women, Esclim 0.05 (22 cm’) applied to
`the buttocks increased serum estradiol concentrations within 4 hours and maintained an average serum
`estradiol concentration of approximately 51 pg/mL above baseline. Trough values of approximately
`27 to 35 pg/mL abovethe 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 ofestradiol 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 eachsite are presented in Table 1.
`
`Reference: NDA #20-847
`
`Version: Final
`0004
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 5
`
`Physician Package Insert
`
`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
`
`Time (days)
`
`Table 1: Mean Uncorrected Estradiol Pharmacokinetic Parameters after Application of
`ESCLIM 0.05 Patches to Different Body Sites
`
`FemoralTriangle|_Upper Arm
`Cmax (pe/mb)
`80.1 234.9
`80.24441
`72,64 36.2
`
`Cann (pelmL)
`41.6 £183
`38.74 15.2
`34.5 +188
`
`
`
`Cayog (pg/mL)
`AUC(9.72)
`(pgehr/mL)
`AUC(0.96)
`(pgehr/mL)
`
`42.8 + 20.5
`4106 + 1826
`
`C
`4578 + 1938
`
`40.8 + 19.7
`¢
`3825 + 1897
`
`C
`4306 + 1925
`
`37.3417.1
`a
`3477 + 1530
`
`of
`3885 + 1622
`
`Reference: NDA #20-847
`
`Version: Final
`0005
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 6
`
`Physician Package Insert
`
`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 0.1 systems are from a separate study. Cymax 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
`
`120 5
`
`80 -
`
`60
`
`40 -
`
`20 -
`
`0
`
`100 >
`
`0
`
`1
`
`2
`
`;
`3
`
`—< Esclim” 0.025
`
`Time (days)
`—1 Esclim” 0.05
`
`4
`
`5
`
`—a—Esclim® 0.1
`
`Table 2: Mean + SD Uncorrected Estradiol Pharmacokinetic Parameters
`Transdermal Systems Applied to the Buttocks (N = 23)
`
`for Esclim
`
`Surface area
`
`Estradiol Dose
`
`Cua
`
`Ci.
`
`Cag
`
`:
`
`(mg/day)
`
`0,025
`
`(pg/mL)
`
`24.5+11°
`
`(pg/mL)
`
`(pg/mL)
`
`17.8+6.6
`
`
`
`124 + 66
`
`51.4429
`
`74,0 + 43
`
`*Cynin=Serum estradiol concentration at 96 hours following application. "N= 17
`
`Reference: NDA #20-847
`
`Version: Final
`0006
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 7
`
`Physician Package Insert
`
`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 womena 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 absorbedestradiol 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 72 hoursafter
`
`application of patch at week 13 and are presented in Table 3.
`
`Reference: NDA #20-847
`
`Version: Final
`0007
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 8
`
`Physician Package Insert
`
`Table 3: Mean + SD Steady State Serum Concentration of Estradiol and Its Metabolites at
`Week13 Following the Application of Esclim
`
`
`
`
`
`Steady State Serum Concentration
`
`Estradiol
`
`(pg/mL)
`
`Estrone
`
`(pg/mL)
`
`Estrone
`
`Sulfate
`(ng/dL)
`
`Placebo
`
`19.6 + 14.0
`
`29.7+£11.7
`
`42.9 + 24.0
`
`30
`31
`31°
`
`0.025 mg/day
`48.2+27.4
`38.7+21.5
`152.6 + 129.7
`22
`22
`22
`
`0.05 mg/day
`
`0.1 mg/day
`
`102.8 + 63.6
`24
`
`165.3 + 116.1
`28
`
`49.0 + 28.0
`24
`
`64.9 + 31.7
`28
`
`236.1 + 147.1
`ae
`
`373.6 + 272.0
`28
`
`“numberof 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
`
`Nospecific studies have been conducted using Esclim in any special populations.
`
`Drug Interactions
`
`Nospecific 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
`
`Edition Date: August 3, 1998
`
`
`
`Physician Package Insert
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 9
`
`the mean reduction in the moderate to severe vasomotor symptoms
`After 4 weeks of treatment,
`(MSVS) wasup to 8.6 MSVSperdayin 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 10.7 in the Esclim
`0.1 group and remainedstable at 5.2 in the placebo group.
`
`Table 4:
`
`Changes from Baseline in Frequency of MSVS
`
`Week
`
`Week 0
`(Baseline)
`Mean + SD
`Week 4
`Mean Reduction + SD
`% Reduction)
`Week 8
`Mean Reduction + SD
`(% Reduction)
`Week 12
`Mean Reduction + SD
`(% Reduction)
`
`Placebo
`
`(N=54)
`
`Esclim
`0.025 mg/day
`(N=48)
`
`Esclim
`0.05 mg/day
`(N=47)
`
`Esclim
`0.1 mg/day
`(N=47)
`
`11.44+3.7
`
`11.6+5.4
`
`10.9+4.2
`
`11.2+2.8
`
`-§.3+4.]
`(-48.9%)
`
`5.5447
`(-51.5%)
`
`-5.2+5.1
`(-50.3%)
`
`-8.6+5,7*
`(-72.6%)
`
`-9.44+5,7*
`(-79.8%)
`
`-9.9 + 5.8*
`(-83.4%)
`
`-9.2+4 5*
`(-84.4%)
`
`-10.2 + 2.9%
`(-92.0%)
`
`-10.3+4.3*
`(-94.0%)
`
`-10.4+4.2*
`(-95.3%)
`
`-10.6 + 2.8*
`(-95.4%)
`
`-10.7 + 2.8*
`(-95.6%)
`
`*Statistically different difference from placebo in mean reduction (Dunnett’s test)
`-a--Esclim”0.05 —eEsclim” 0.1
`
`Figure 4: Reduction of MSVS During Double-Blind, Placebo-Controlled Study
`
`Weeks of Treatment
`
`
`—* Placebo
`
`—m—Esclim”’ 0.025
`
`Reference: NDA #20-847
`
`Version: Final
`0009
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 10
`
`Physician Package Insert
`
`Maintenanceofthe 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:
`
`l.
`
`be
`
`a
`
`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 vulval 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 abnormalgenital bleeding.
`
`. Knownor suspected cancer of the breast except in appropriately selected patients being treated for
`
`metastatic disease.
`
`. Known or suspected estrogen—dependentneoplasia.
`
`. Active thrombophlebitis or thromboembolic disorders.
`
`WARNINGS
`
`1. Induction of Malignant Neoplasms. Some studies have suggested a possible increased incidence of
`breast cancer in those womentaking 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 after 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 Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 11
`
`Physician Package Insert
`
`estrogen withdrawal. Concurrent progestin therapy may offset this risk, but the overall health
`impact in postmenopausal womenis 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,
`squamouscell dysplasia of the cervix, and clear cell vaginal cancerlater 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 mento increasethe risks of nonfatal myocardial infarction, pulmonary embolism, and
`thrombophlebitis.
`
`to avoid the
`These risks cannot necessarily be extrapolated from men to women. However,
`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, transdermally—administered estradiol
`does not affect renin substrate.
`
`5. Hypercalcemia. 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. Addition ofa 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
`0011
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 12
`
`Physician Package Insert
`
`that 10 to 14 days of progestin are needed to provide maximal maturation of the
`suggest
`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:
`
`(1) adverse effects on lipoprotein metabolism (lowering HDL and raising LDL), which could
`diminish the purported cardioprotective effect of estrogen therapy (see PRECAUTIONS,
`below);
`
`(2) impairmentof 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 progestins on this putative benefit is not yet known.
`
`there may be a cause-effect
`In recent years, many published studies have suggested that
`relationship between postmenopausal oral estrogen replacement therapy without added progestins
`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 life-style and medical characteristics
`of the womenstudied 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, andless likely to
`have diabetes than the untreated women. Although some studies attempted to control for these
`selection factors,
`it
`is common for properly—designed randomizedtrials 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
`
`Reference: NDA #20-847
`
`Version: Final
`0012
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 13
`
`Physician Package Insert
`
`progestins on the risk of ischemic heart disease are not known,all available progestins reverse
`at least some ofthe favorable effects of estrogens on HDL and LDLlevels.
`
`(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).
`
`Becauserelatively 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-examiningthe patient.
`
`4. Hypercoagulability. 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 Hyperlipoproteinemia. Estrogen therapy may be associated with massive elevations of
`plasmatriglycerides leading to pancreatitis and other complications in patients with familial defects
`of lipoprotein metabolism.
`
`6. Fluid Retention. Because estrogens may cause some degreeoffluid retention, conditions that might
`be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction,
`require careful observation.
`
`7. Uterine Bleeding and Mastodynia. Certain patients may develop undesirable manifestations of
`estrogenic stimulation, such as abnormaluterine bleeding and mastodynia.
`
`Reference: NDA #20-847
`
`Version: Final
`0013
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 14
`
`Physician Package Insert
`
`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 SUPPLIEDsection.
`
`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):
`
`1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased
`platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, [X, X, XII,
`VII-X complex, I—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 andactivity.
`
`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,1.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—1—antitrypsin, ceruloplasmin).
`
`4. Increased plasma HDL and HDL-2 subfraction concentrations,
`concentration, increased triglyceride levels.
`
`reduced LDL cholesterol
`
`5. Impaired glucosetolerance.
`
`6. Reduced response to metyraponetest.
`
`Reference: NDA #20-847
`
`Version: Final
`0014
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 15
`
`Physician Package Insert
`
`7. Reduced serum folate concentration.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`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
`CONTRAINDICATIONSand WARNINGS).
`
`Pregnancy Category X
`
`Estrogens should not be used during pregnancy (see CONTRAINDICATIONS and Boxed Warning).
`
`Nursing Mothers
`
`Asa 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
`
`the
`See WARNINGS and Boxed Warning regarding the potential adverse effects on the fetus,
`induction of malignant neoplasms, gallbladder disease, cardiovascular disease, elevated blood pressure
`and hypercalcemia.
`
`In controlled clinical studies with Esclim, the most commonly reported adverse events
`Skin irritation:
`were topical reactions of erythema and/or 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%
`(3/317) 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.
`
`Reference: NDA #20-847
`
`Version: Final
`0015
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 16
`
`Physician Package Insert
`
`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 mg/day
`0.05 mg/day
`0.1 mg/day
`
`Adverse Event
`(N=54)
`(N=48)
`(N=47)
`(N=47)
`Breast Pain
`3.7
`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
`3.7
`10.4
`4.3
`2.1
`Anxiety
`0
`8.3
`21
`0
`Emotional Lability
`1.9
`8.3
`2.1
`6.4
`Arthalgia
`1.9
`6.3
`2.1
`43
`Flu Syndrome
`74
`6.3
`6.4
`8.5
`Joint Disorder
`0
`6.3
`0
`0
`Pruritis
`1.9
`6.3
`12.8
`0
`Rhinitis
`1.9
`6.3
`43
`43
`Abdominal Pain
`9.3
`4.2
`10.6
`2.1
`General Edema
`1.9
`4.2
`6.4
`6.4
`Monilia Vagina
`5.6
`4.2
`8.5
`4.3
`Nausea
`1.9
`4.2
`10.6
`8.5
`Peripheral Edema
`0
`4.2
`2.1
`6.4
`Sinusitis
`7.4
`4.2
`2.1
`4.3
`Asthenia
`1.9
`2.1
`10.6
`6.4
`Back Pain
`3.7
`Zt
`2.1
`6.4
`Diarrhea
`1.9
`2.1
`8.5
`0
`Dysmenorrhea
`0
`2.1
`2.1
`6.4
`Enlarged Abdomen
`0
`2.1
`2.1
`6.4
`Enlarged Breast
`0
`il
`2.)
`8.5
`Rash
`5.6
`2.1
`43
`2.1
`Anemia
`0
`0
`6.4
`4.3
`Gastroenteritis
`i)
`0
`0
`6.4
`Hyperlipemia
`5.6
`0
`0
`2.1
`Leukorrhea
`0
`0
`12.8
`0
`Paresthesia
`1.9
`0
`6.4
`0
`
`In the US placebo-
`(See Precautions: Addition of a progestin):
`Urogenital Adverse Events:
`controlled study, 72 patients were included whohadintact uteri. As expected, after 12-13 weeks of
`continuous unopposedtherapy, findings of endometrial hyperplasia (diagnosed either by endometrial
`biopsy and/or ultrasonography) were increased with increasing doses of estradiol (placebo: 0/18
`patients; Esclim 0.025: 1/14 (7.1%); Esclim 0.05: 12/22 (54.5%); Esclim 0.1: 10/18 (55.6%).
`In
`the 86 patients who had not previously undergoneatotal hysterectomy, vaginal bleeding was also
`increased with increasing doses of estradiol (placebo: 2/21 patients (9.5%); Esclim 0.025:
`6/19
`(31.6%); Esclim 0.05: 14/25 (56.0%); Esclim 0.1: 12/21 (57.1%).
`
`Reference: NDA #20-847
`
`Version: Final
`0016
`
`Edition Date: August 3, 1998
`
`
`
`NDA20, 847 (ESCLIM®estradiol transdermal system)
`Page 17
`
`Physician Package Insert
`
`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 have been reported with estrogen therapy:
`
`1. Genitourinary System. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or
`flow; breakthrough bleeding, spotting; increase in size of uterine leiomyomata; vaginal candidiasis;
`change in amountofcervical secretion.
`
`2. Breasts. Tenderness, enlargement.
`
`3. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; gallbladder
`
`disease.
`
`4. Skin. Chloasma or melasma that may persist wh