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`Date
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`VESENIA SANCHEZ BUSTOS
`NOTARY PUBLIC
`MONTGOMERY COUNTY
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`MY COMMISSION EXPIRES MAY 03. 2021
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`0002
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`foi
`
`5236149
`
`B
`
`* 5 2 3 6 1 4 9 *
`
`* B *
`
`Vivelle-DOT (Novartis) 05/03/2002 Supplemental Approval [Label
`Revisions]: S12, S14, S15 Approvable Letter; Final Labeling;
`Approval Letter
`
`This document was provided by: FOI Services, Inc
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`
`0003
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER:
`20-538/S-015
`
`Trade Name: Vivelle-Dot
`
`Generic Name: estradiol transdermal system
`
`Sponsor:
`
`Novartis Pharmaceuticals Corporation
`
`Approval Date: May 3, 2002
`
`Indications:
`
`Provides for the prevention of postmenopausal
`osteoporosis indication in at-risk patients for the .025
`mg/day strengths.
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`20-538/S-015
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Approvable Letter
`Final Printed Labeling
`Medical Revlew(s)
`Chemistry Review(s)
`EA/FONSI
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/ Biopharmaceutics Review(s)
`Administrative Document(s)
`Correspondence
`
`X
`
`X
`X
`X
`
`X
`
`X
`X
`X
`
`0005
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPL1CA TION NUMBER:
`20-538/S-015
`
`APPROVAL LETTER
`
`0006
`
`
`
`*
`e
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Pubfic Health Service
`
`Food snd Drug Administration
`RockvUle MO 20857
`
`APPROVAL LETTER
`
`NDA 20-538^-012, S-0i4f S-015
`
`Novaitis Phannaceuticals Corporation
`Attention: Lynn Meilor
`Associate Director, Drug Regulatory Affairs
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Dear Ms. Mellor:
`
`Please refer (o your supplemental new drug applications dated March 1,2002, received March 4,2002, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for VsveiSe-Dot® (estradiol transdermal
`system).
`
`We acknowledge receipt of your submission dated April 24, 2002. Your submission of March 1,2002,
`constituted a complete response to our November 19, 2001 action tetter.
`
`These supplemental new drug applications propose changes for the use of Vivclle-Dot® as follows:
`
`i. Revised labeling to incorporate safety information requested by the Agency in a letter dated August
`10, 2000, (S-012),
`
`2. Removal of the restrictive language, regarding vasomotor symptoms associated with the
`menopause, that some women taking the 0.0375 rog/day dosage may experience a delayed onset of
`efficacy and revision of the Clinical Pharmacology section of the Package Insert to be consistent
`with the FDA draft labeling guidance (S-014), and
`
`3. Addition of the prevention of postmenopausal osteoporosis indication in at-risk patients for the
`.025 mg/day strength (S-015),
`
`We have completed the review of these supplemental applications, as amended, and have concluded that
`adequate information has been presented to demonstrate that the drag product is safe and effective for use as
`recommended in the agreed upon labeling text Accordingly, these supplemental applications are approved
`effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert and text for
`the patient package insert).
`
`0007
`
`
`
`NDA 20-538/3-012, S-014, S-015
`Page 2
`
`Please submit the copies of final printed labeling (FPL) electronically to the application according to the guidance
`for industry titled Providing Regulatory Submissions in Electronic Format - NDA (January 1999). Aitematively,
`you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it is printed
`Please individually mount ten of the copies on heavy-weight paper or similar material. For administrative
`purposes, these submissions should be designated "FPL for approved supplement NDA 20-538/S-012, S-014,
`S-015." Approval of these submissions by FDA is not required before the labeling is used.
`
`If a letter communicating important information about this drug product (i.e.. a "Dear Health Care Professional"
`letter) is issued to physicians and others responsible for patient care, we request that you submit a copy of the
`letter to this NDA and a copy to the following address:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`RockviHe, MD 20857
`
`We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR
`314.80 and 314.81.
`
`If you have any questions, call Domette Spell-LcSane, NP-C, Regulatory Project Manager, at (301) 827-4260.
`
`Sincerely,
`
`{See appended electronic signature page)
`
`Daniel Shames, M.D.
`Acting Director
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation HI
`Center for Drug Evaluation and Research
`
`Appears This Way
`On Original
`
`0008
`
`Enclosure
`
`I
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Dena Hixon
`5 / 3 / 0 2 0 3 : 1 1 i 1 5 PM
`for Daniel Shames, MD
`
`Appears TWs Way
`On Original
`
`0009
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`20-538/S-015
`
`APPROVED LABELING
`
`0010
`
`
`
`NDA 20-53 8/S-015
`Vivelle-Dot™ (estradiol transdermal system) 0.0025 mg/day
`Novartis Pharmaceuticals Corporation
`
`Approved Labeling
`
`This supplemental application is not being approved during the first review cycle. An
`approved label has not been achieved.
`
`V 4 . t . I
`
`(
`
`I
`
`0011
`
`
`
`NDA 20-538/S-012, S-014, S-015
`Page 2
`
`i!> NOVARTIS
`
`T2000-56/T2000-57
`89001003
`
`Vivelle-Dot*
`(estradiol transdermal system)
`Continuous delivery for twice-weekly application
`Rx only
`Prescribing Information
`ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER .
`Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
`including endometrial sampling when indicated, should be undertaken to rule out malignancy in ail
`cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is currently no evidence
`that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens
`of equivalent estrogen dose.
`
`DESCRIPTION
`
`Vivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is
`designed to release estradiol continuously upon application to intact skin.
`Five dosage strengths of Vivelle-Dot are available to provide nominal in vivo delivery rates of 0.025,
`0.0375,0.05,0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active
`surface area of 2.5,3.75, 5.0,7.5, or 10.0 cm" and contains 0.39,0.585,0.78,1.17, or 1.56 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-3,17B-diol.
`The structural formula is
`
`OH
`
`- j j
`
`CH
`
`o
`
`HO
`The molecular formula of estradiol is CHH24O2. The molecular weight is 272.39.
`Vivelle-Dot is comprised of three layers. Proceeding from the visible surface toward the surface attached to
`the skin, these layers are (1) a translucent polyolefin film (2) an adhesive formulation containing estradiol,
`acrylic adhesive, silicone adhesive, oleyl alcohol, povidone and dipropylene glycol, and (3) a polyester
`release liner which is attached to the adhesive surface and must be removed before the system can be used.
`
`H
`
`H
`
`0012
`
`
`
`- .
`
`—v.Jmun II
`
`NDA 20-538/S-012, S-014, S-015
`Page 3
`
`v.v.vv.;.;.\».vv.v,v/,v>v.^;^
`
`(2) Adhesive Confainmg Estradiol
`
`(3) Protcclive Liner
`
`The active component of tbe system is estradiol. The remaining components of the system are
`pharmacoiogically 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 equilibrium of
`metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more
`potent than its metabolites, estrone and estriol, at tbe receptor level. The primary source of estrogen in
`normally cycling adult women is the ovarian follicle, which secretes 70 to 500 jig 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, arc 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 They 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. Estrogen replacement therapy acts to reduce the
`elevated levels of these hormones seen in postmenopausal women.
`
`Pharmacokinetics
`The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly
`metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone
`than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with
`lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral
`therapy.
`Absorption
`In a multiple-dose study consisting of three consecutive system applications of the original formulation
`[Vivelle® (estradiol transdermal system)] which was conducted in 17 healthy, postmenopausal women,
`blood levels of estradiol and estrone were compared following application of these units to sites on the
`abdomen and buttocks in a crossover fashion. Systems that deliver nominal estradiol doses of
`approximately 0.0375 mg/day and 0.1 mgi'day were applied to abdominal application sites while the 0.1
`mg/day doses were also applied to sites on the buttocks. These systems increased estradiol levels above
`baseline within 4 hours and maintained respective mean levels of 25 and 79 pg/mL above baseline
`following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were
`observed following application to the buttocks. At the same time, increases in estrone plasma
`concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and
`
`0013
`
`
`
`•
`
`STv^—
`
`NDA 20-538/S-012, S-014, S-015
`Page 4
`
`61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above
`baseline at 12 hours following removal of the systems in this study, results from another study show these
`levels to return to baseline values within 24 hours following removal of the systems.
`Figure 1 illustrates the mean plasma concentrations of estradiol at steady-state during application of these
`patches at four different dosages.
`
`Figure 1
`
`Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen
`
`NonbaseUne-corr&cted levels
`D 0.1 mgAiay
`* 0.075 mg/day
`A 0.05 mg/day
`• 0.0375 mg/day
`
`-•
`
`160 n
`
`£
`D.
`C
`-S 80-
`<0
`c
`8 40
`c
`o o
`
`0
`
`0
`
`T
`1
`
`3
`
`4
`
`2
`Time (days)
`The corresponding pharmacokinetic parameters are summarized in the table below.
`Table 1.
`
`Steady-State Estradiol Pharmacokinetic Parameters for
`Systems Applied to the Abdomen (mean ± standard deviation)
`
`Nonbaseline-corTBcted data*
`C(nin (84 lir)§
`(pg/mL)
`301:10
`41 ±11#
`60 ±24
`90 ±44
`85 ±47
`
`Dosage
`(pg/mL)
`(mg/day)
`46116
`0.0375
`0.05
`S3 ±41
`0.075
`99 ±35
`0.1
`133 ±51
`o.iK
`145 ± 71
`•Mean baseline estradiol concentration = 11.7 pg/mL
`tPeak plasma concentration
`^Average plasma concentration
`§Minimum plasma concentration at 64 hr
`^Measured over SO hr
`lAppiiad to the buttocks
`Vivelle-Dot, the revised formulation with smaller system sizes, was shown to be bioequivalent to the
`original formulation, Vivelle, used in the clinical trials.
`
`(pg/mL)
`34 ±10
`57 ± 23#
`72 ±24
`89 ±38
`104±52
`
`0014
`
`
`
`NDA 20-538/S-012, S-014, S-015
`Page 5
`
`Distribution
`No specific investigation of the tissue distribution of estradiol absorbed from Vivelle in humans has been
`conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens
`are widely distributed in the body and are generally found in higher concentrations in the sex hormone
`target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and
`albumin.
`Metabolism
`Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens
`exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in
`the liver. Estradiol is converted reversibly to estrone, and both can be converted to eStrioi, 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 reabsorpdon. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate
`conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more
`active estrogens.
`Excretion
`Estradiol, estrone and estrio! are excreted in the urine along with glucuronide and sulfate conjugates. The
`half-life values calculated after dosing with the Vivelle-Dot ranged from 5.9 to 7.7 hours. After removal
`of the systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours.
`Special Populations
`Vivelle-Dot was investigated in postmenopausal women. No pharmacokinetic studies were conducted in
`other special populations.
`
`Drug Interactions
`In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4
`(CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers
`of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, phenytoin,
`carbamazepine, rifampin and dexatnethasone 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 cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and
`grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
`Adhesion
`Based on combined data from three short-term clinical trials consisting of 471 observations, 85% of
`Vivelle-Dot adhered completely to the skin over the 3.5 day wear period. Three (3%) of the systems
`detached and were reapplied or replaced during the 3.5 day wear period. Approximately 80% of the
`transdermal systems evaluated in these studies were Vivelle-Dot 0.05 mg/day.
`
`Clinical Studies
`Effects en vasomotor symptoms
`
`0015
`
`
`
`, -m'-
`
`NDA 20-538/8-012, S-014, S-015
`Page 6
`
`In, a pharmacokinetic study, Vivcllc-Dot was shown to be bioequivalcnt to Vivelle. In two controlled
`clinical trials with Vivelle, of 356 subjects, the 0.075 and 0,1 tng doses were superior to placebo in
`relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatment.
`The 0.0375 and 0.05 mg doses, however, did not differ from placebo until approximately Week 6.
`Therefore, an additional 12-week pjacebo-controlled study is 255 patients was performed with Vivelle to
`establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in
`these 255 patients was 11.5. Results at Weeks 4,8, and 12 of treatment are shown in the figure below. (See
`Figure 2.)
`
`Figure 2
`Mean (SDJ changa from baseline tn mean dally number of flushes for
`Vivelle 0.0375 mg versus Placebo In a 12-we«k trial.
`
`Week A-
`
`WeekS-
`
`Week \2'
`
`0~5
`
`I -2-
`XI
`E o
`6
`-o
`£ .g -
`
`•4.9(4.8)
`n=125
`
`•5.8(5-0)
`n=l20
`
`rJ.-;
`
`•5.6{S.3)
`ns118
`
`•8.4{5.7J
`ns130
`
`JO
`c -TO"
`2
`-12
`
`-8.4(5.6)
`n=129
`ViveHe 0.0375 m^day
`I Placebo
`I
`'Indicates stalislicaNy significan! difference (p<0.05| between Vivelle and pfaceS>o
`
`-9.8(5.9)
`n=126
`
`The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor
`symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. All doses ofVivellc
`(0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of vasomotor symptoms.
`
`Effects on bone mineral density
`Efficacy and safety of Vivelle in the prevention of postmenopausal osteoporosis have been studied in a 2-
`year double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized
`(161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of
`menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard
`'
`•
`5
`•
`•
`deviations of average peak bone mass, i.e., & 0.827 g/cm ) were enrolled in this study; 194 patients were
`randomized to one of the four doses of Vivelle (0,1,0.05,0.0375, or 0.025 mg/day) and 67 patients to
`placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-
`hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.
`The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (61 %)
`or nonhysterectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years); the mean
`
`0016
`
`
`
`NDA 20-538/S-012, S-014, S-0i5
`Page?
`
`duration of menopause was 31,7 mouths (range 2 to 72 months). Two hundred thirty-two (89%) of
`randomized subjects {173 on active drug, 59 on placebo) contributed data to the analysis of percent change
`from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable.
`Patients were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental
`vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to
`this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were
`significantly superior to placebo (p<0.05) at all time points with the exception ofVivelle 0.05 mg/dayat 6
`months. The highest dose of Vivelle was superior to the three lower doses. There were no statistically
`significant differences in pairwise comparisons among the three lower doses. (See Figure 3.)
`
`I «
`
`I *,
`2
`
`-2
`
`Figum 3
`Bans mineral density - AP Lumbar spirt®
`Least squares means of torn fesseHne
`All randixnizad patwnts with a) )e«sl one posl-bnoflne tusessmenl avaH«t><e
`• with last post-bsseh'ne c&servslicn cairM forwanl
`
`m- * —r- z.w
`
`- flL-
`.-r.T
`
`Jmm"
`
`* —
`
`WmiSS
`
`W®«!(53
`TrwDntiK fiursilan
`
`*-
`
`Ww.m
`
`WteskttM
`
`•Vttvte O.lni^diy
`- VhKfc QjeSmuMtv
`
`- • - -Vtafc) o asme'ilay — ~ vsrafej (U>}79m9n«)r
`Ptocabo
`.
`.
`
`—
`
`Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable,
`showed qualitatively similar results; all doses ofVivelle were significantly superior to placebo (p<0.05) at
`24 months. The highest Vivelle dose was superior to placebo at ail time points. A mixture of significant
`and non-significant results were obtained foi the lower dose groups at earlier time points. The highest
`Vivelle dose was superior to the three lower doses, and there were no significant differences among the
`three lower doses at this skeletal site. (See Figure 4.)
`
`0017
`
`
`
`-#-ii
`
`""
`
`NDA 20-538/S-0I2, 5-014, S-015
`Page 8
`
`Figure 4
`Ban* mineral density - Femoral neck
`Least squares means of percentage change from basaline
`All randomized patients with al least one post-basel'me assessment
`available with last post-beseline observation carried forward
`
`? 6
`•K &
`s * S _
`I »
`a> 1
`R -
`•B -1
`* -z
`
`AnP: p-cO.OS
`w
`
`A.B.CnP:p^D.DS
`
`Week 26
`
`Week 52
`
`A,B.C,0 V» P-. p<0,0&
`«
`A.-
`K-
`
`*
`Week 78
`
`Afl-CD V. P; p<0 OS
`•
`
`Week 104
`
`Treetment duration
`
`Vwdl* 0.1 mg/day (A) -
`
`- Vivalts Q.0S mgUay (B) — A — Vw«JI» 0.0375 m^day (C)
`
`-M- -Well. 0.025 mo/dly (0)
`
`Ptacfto JP)
`
`The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-
`telopeptides of type 1 collagen (a marker of bone resorption) decreased numerically in most of the active
`treatment groups relative to baseline. However, the decreases in both markers were inconsistent across
`treatment groups and the differences between active treatment groups and placebo were not statistically
`significant.
`
`INDICATIONS AND USAGE
`Vivelle-Dot is indicated in:
`1.
`Treatment of moderate-to-severe vasomotor symptoms associated with the menopause.
`2.
`Treatment of vulvar and vaginal atrophy.
`3.
`Treatment of hypocstrogenism due to hypogonadism, castration, or primary ovarian failure.
`4.
`Prevention of postmenopausal osteoporosis. Estrogen replacement therapy reduces bone resorption
`and retards postmenopausal bone loss. When estrogen therapy is discontinued, bone mass declines
`at a rate comparable to that of the immediate postmenopausal period.
`The mainstays of prevention of postmenopausal osteoporosis arc weight-bearing exercise, adequate
`calcium and vitamin D intake and, when indicated, estrogen. Postmenopausal women absorb
`dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day
`of elemental calcium to remain in neutral calcium balance. The average calcium intake in the USA
`is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful
`for women with suboptimal dietary intake. Vitamin D supplementation of400-800 lU/day may also
`be required to ensure adequate daily intake in postmenopausal women.
`
`Early menopause is one of the strongest predictors for the development of osteoporosis. Other
`factors associated with osteoporosis include genetic factors (small build, family history), lifestyle
`
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`(cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body
`weight and dietary calcium intake).
`
`2.
`
`CONTRAINDICATIONS
`Estrogens should not be used in individuals with any of the following conditions:
`Known or suspected pregnancy. See PRECAUTIONS. Estrogen may cause fetal harm when
`administered to a pregnant woman.
`Undiagnosed abnormal genital blesding.
`Known or suspected cancer of the breast.
`Known or suspected estrogen-dependent neoplasia.
`Active deep vein thrombosis/pulmonary embolism or a history of these conditions.
`Known hypersensitivity to any of the components of Vivelle-Dot
`
`6.
`
`WARNINGS
`1.
`Induction of Malignant Neoplasms.
`Endometrial cancer.
`a.
`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
`five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after
`estrogen therapy is discontinued.
`Breast cancer.
`b.
`While some epidemiologic studies suggest a very modest increase in breast cancer risk for estrogen
`alone users versus non-users, other studies have not shown any increased risk. The addition of
`progestin to estrogen may increase the risk for breast cancer over that noted in non-hormone users
`more significantly (by about 24 to 40%), although this is based solely on epidemiologic studies, and
`definitive conclusions await prospective, controlled clinical trials.
`Women without a uterus who require hormone replacement should receive estrogen-alone therapy,
`and should not be exposed unnecessarily to progestins. Women with a uterus who are candidates for
`short-term combination estrogen/progestin thsrapy (for reliefof vasomotor symptoms) are not felt to be
`at a substantially increased risk for breast cancer. Women with a uterus who are candidates for
`long-term use of estrogen/progestin therapy should be advised of potential benefits and risks
`(including the potential for an increased risk of breast cancer).
`A11 women should receive yearly breast exams by a healthcare provider and perform monthly breast
`self-examinations. In addition, mammography examinations should be scheduled as suggested by
`providers based on patient age and risk factors.
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`2.
`
`Thromboembolic Disorders.
`The physician should be aware of the possibility of thrornbotic disorders (thrombophlebitis, retina!
`thrombosis, cerebral embolism, and pulmonary embolism) using estrogen replacement therapy and
`be alert to their earliest manifestations. Should any of these occur or be suspected, estrogen
`replacement iherapy should be discontinued immediately. Patients who have risk factors for
`thrombotic disorders should be kept under carefu! observation.
`Venous thromboembolism. Several epidemiologic studies have found an increased risk of
`thromboembolism (VTE) in users of estrogen replacement therapy (ERT) who did not have
`predisposing conditions for VTE, such as past history of cardiovascular disease or a recent history
`of pregnancy, surgery, trauma, or serious illness. The increased risk was found only in current ERT
`users; it did not persist in former users. The risk appeared to be higher in the first year of use and
`decreased thereafter. The findings were similar for ERT alone or with added progestin and pertain
`to commonly used oral and transdermal doses, with a possible dose-dependent effect on risk. The
`studies found the VTE risk to be about one case per 10,000 women per year among women not
`using ERT and without predisposing conditions. The risk in current ERT users was increased to 2
`to 3 cases per 10,000 women per year.
`Cerebrovascular disease. Embolic cerebrovascular events have been reported in postmenopausal
`women receiving estrogens.
`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.
`Gallbladder Disease. A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in
`postmenopausal women receiving estrogens has been reported.
`
`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
`A.
`General
`Addition of a progestin when a woman has not had a hysiereclomy. Studies of the addition of a
`1.
`progestin for 10 or more days of a cycle of estrogen administration have reported a lower 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 in estrogen replacement regimens. These include adverse effects on lipoprotein
`metabolism (e.g., lowering HOL and raising LDL) and impairment of glucose tolerance. The choice of
`progestin, its dose, and its regimen may be important in minimizing these adverse effects.
`
`Cardio vascular risk. The effects of estrogen replacement on the risk of cardiovascular disease have
`t.
`not been adequately studied. However, data from the Heart and Estrogcn/Progestin Replacement Study
`
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`NDA 20-538/S-012, S-014, S-015
`Page I!
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`(HERS), a controlled ciinical trial of secondary prevention of 2,763 postmenopausal women with
`documented heart disease^ demonstrated no benefit. During an average follow-up of 4.1 years, treatment
`with oral conjugated estrogen plus medroxyprogesterone acetate did not reduce the overall rate of coronary
`heart disease (CHD) events in post-menopausal women with established coronary disease. There were
`more CHD events in the hormone treated group than in the placebo group in year 1, but fewer events in
`years 3 through 5,
`3.
`Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure
`during estrogen replacement therapy have been attributed to idiosyncratic reactions to estrogens. In a large,
`randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure
`was not seen.
`
`Familial hyperlipoproteinemia. In patients with familial defects of lipoprotein metabolism,
`4.
`estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other
`complications—
`Impaired liver function. Estrogens may be poorly metabolized in patients with impaired liver
`5.
`function and should be administered with caution.
`Hypothroidism. Estrogen administration leads to incre