AFFIDAVIT
`State of Maryland, Montgomery County
`
`I, Marlene S. Bobka, under oath, hereby depose andstate as follows:
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`BP
`pugust 4, 201F
`
`Marlene S. Bobka
`
`Date
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`SUBSCRIBED
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`AND SWORNbefore me on
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`YESENIA SANCHEZ BUSTOS
`NOTARY PUBLIC -
`MONTGOMERY COUN
`MARYLAND _
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`MYLAN- EXHIBIT 1008
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`EXHIBIT A
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`
`0002
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`

`

`
`
`
`452 10567%
`
`
`
`
`
`
`x A*
`
`5210567
`
`A
`
`Vivelle Transdermal System (Novartis) 08/16/2000
`Approval & Supplemental Approval [Postmenopausal
`Osteoporosis & New 0.025mg DosageStrength]:
`NDA 21-167, NDA 21-323/S23 Approval Letter;
`Labeling
`
`This document was provided by: FOI Services, Inc
`11 Firstfield Road
`Gaithersburg MD 20878-1704 USA
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`301-975-0702
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`infofoi@foiservices.com
`
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`
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`Freedom ofInformation Act and are therefore available to the general public. FOI Services, Inc. does not guarantee the accuracy of
`
`
`
`0003
`
`

`

`whet...
`
`Me
`
`i SG DEPARTMENTOF HEALTH AND HUMAN SERVICES
`
`®
`
`ah
`“thaag
`
`NOV 0 5 2004
`
`Public Health Service
`
`Center for Drug Evaluation and Research
`Office of Regulatory Policy
`Division of Information Disclosure Policy
`S000 Fishers Lane. HFD-13
`Rockville. Maryland 20857
`
`October 28, 2004
`
`In Response Refer to File:=FU3-10620
`
`FOI Services Inc.
`11 Firstficld Road
`Gaithersburg, MD 20878-1704
`
`Dear Requestor,
`
`This is in response to your request of July 31, 2003, in which you requested information onthe
`approval for Vivelle, NDA 21-167 and NDA 20-323/S023, your control number 5210567. Your
`request was reccived in the Center for Drug Evaluation and Research on August 1, 2003.
`
`The documents you have requested are enclosed.
`
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`‘Search $9.00, Review $0, Reproduction
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`included in a monthly invoice. DO NOT SEND ANY PAYMENT UNTIL YOU RECEIVE AN
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`problem(s). Please reference the above file number.
`
`This concludes the response for the Center for Drug Evatuation and Research.
`
`Sincerely,
`
`a - fy
`
`Cynthea Dunant
`
`
`“
`Paralegal Specialist
`Office of Regulatory Policy
`Division of Information Disclosure Policy, FIFD-13
`
`Linc: NDA 21-167 and NDA 20-323/8023
`
`J3opayes
`
`
`
`0004
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-167
`
`APPROVAL LETTER
`
`
`
`0005
`
`

`

`NDA21-167
`NDA 20-323/S-023
`
`Novartis Pharmaceuticals Corporation
`Attention: Lynn Mellor
`Associate Director, Drug Regulatory Affairs
`59 Route 10
`East Hanover, New Jersey 07936-1080
`
`Dear Ms. Mellor:
`
`Please refer to your new drug application NDA 21-167 dated October 19, 1999, received October 20,
`1999, and supplemental NDA 20-323/S-023 dated April 19, 2000, received April 20, 2000,
`submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Actfor Vivelle
`(estradiol transdermal system).
`
`We acknowledgereceipt ofyour submissions to NDA 21-167 dated November 29 and
`December 3, 1999, and February 14, March 6, April 19, June 15, July 11 (2), 26, and 27,
`and August 2 and 14, 2000.
`
`Wealso acknowledge receipt of your submissions to NDA 20-323 dated July 11 and 27, 2000.
`
`This new drug application provides for the use of Vivelle (estradiol transdermal system) in
`0.0375 mg, 0.05 mg, 0.075 mg and 0.1 mg strengths for the new indication of the prevention of
`posuncnopausal osteoporosis. In addition, a new lower strength, 0.025 mg, system is
`proposed for the indication of prevention of postmenopausal osteoporosis.
`
`Wehave completed the review of these applications, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug product is safe and effective for use as
`recommended in the agreed upon labeling text. Accordingly, the applications are approved e7fective
`on the dateofthisletter.
`
`Thefinal printed labeling (FPL) must be identical to the submitted draft labeling (package insert
`submitted August 14, 2000, patient package insert submitted August 14, 2000, immediate container
`iabels submitted April 19, 2000, and backing Jabels submitted July 26, 2000). Marketing the product
`with FPL thatis not identical to the approved labeling text may render the product misbranded and
`an unapproved new drug.
`
`Piease submit 20 paper copies ofthe FPL as soonas it is available, in no case more than 30 days
`afterit is printed. Please individua)ly mountten of the copies on heavy-weight paper or similar
`material. Alternatively, you may submit the FPL electronically according to the guidance for
`industrytitled Providing Regulatory Submissions in Electronic Format - NDAs (January 1999). For
`administrative purposes, this submission should be designated "FPL for approved NDA 20-323/
`S-023." Approval of this submission by FDA ts not required before the labeling is used.
`
`
`
`0006
`
`

`

`NDA21-167
`NDA 20-323/S-023
`Page 2
`
`Be advised that, as of April 1, 1999,all applications for new active ingredients, new dosage forms,
`new indications, new routes of administration, and new dosing regimens are required to contain an
`assessmentofthe safety and effectiveness of the product in pediatric patients unless this requirement
`is waived or deferred (63 FR 66632). We note that you have notfulfilled the requirements of 21]
`CFR 314.55.
`
`Reference is made to your correspondence dated December 3, 1999, requesting a waiver for pediatric
`studies under 21 CFR 314.55(c). We have reviewed the information you have submitted and agree
`that a waiver is justified for Vivelle for prevention of postmenopausal osteoporosis for the pediatric
`population. Accordingly a waiver for pediatric studies for these applications is granted under 21
`CFR 314.55 at this time.
`
`In addition, please submit three copies of the introductory promotional materials that you propose to
`use for this product. All proposed materials should be submitted in draft or mock-up form,notfinal
`print. Please submit two copies to the Division of Reproductive and Urologic Drug Products and
`two copies of both the promotional materials and the packageinsert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Please submit one market package ofthe 0.025 mg strength drug product whenit isavailable.
`
`Weremind you that you must comply with the requirements for an approved NDAset forth under
`21 CFR 314.80 and 314.81. To comply with these regulations, all 7-day and 15-day alert reports,
`periodic adverse drug experience (ADE)reports,field alerts, annual reports, supplements and other
`submissions should be addressed to the original NDA 20-323 for this drug productat the Division of
`Reproductive and Urologic Drug products (HFD-580), not to NDA 21-167. In the future, no
`submissions should be made to NDA 21-167.
`
`
`
`0007
`
`

`

`NDA 21-167
`NDA 20-323/S-023
`Page 3
`
`Ifyou have any questions regarding NDA 20-323/S-023, call Diane V. Moore, Regulatory Project
`Manager,at (301) 827-4236. Questions regarding NDA 21-167 should be directed to William C.
`Koch, Regulatory Project Manager, at (301) 827-6412.
`
`.
`
`Sincerely,
`
`fIS!
`
`John K Jenkins, M.D.
`Acting Director
`Division of Metabolic and
`_ Endocrine Drug Products
`Office of Drug Evaluation
`Center for Drug Evaluation and Research
`
`
`
`0008
`
`

`

`NDA 21-167
`NDA20-323/S-023
`Page 4
`ce:
`
`Archival NDA 21-167
`NDA 20-323/S-023
`HFD-510/Div.Files
`HFD-580/Div.Files
`HFD-510/WKoch
`HFD-510/Reviewers and Team Leaders
`HFD-580/DMoore/SAllen
`HFD-580/Reviewers and Team Leaders
`HF-2/MedWatch (with labeling)
`HFD-002/ORM (with labeling)
`HFD-102/ADRA (with labeling)
`HFD-102/Post-Marketing PM
`HFD-104/Peds/V.Kao (with labeling)
`HFD-104/Peds/T.Crescenzi (with labeling)
`HFD-42/DDMAC(with labeling)
`HFI-20/Press Office (with labeling)
`HFD-400/OPDRA (with labeling)
`HFD-613/OGD (with labeling)
`HFD-095/DDMS-IMT(with labeling)
`HFD-820/DNDC Division Director
`DISTRICT OFFICE
`
`Drafted by: WKoch/08.07.00
`Initialed by: EGalliers/08.10.00
`final: WKoch/08.14.00
`filename: C:/Windows/Desktop‘NDA21167/LTRapNDA.doc
`
`APPROVAL (AP)
`
`
`
`0009
`
`

`

`NDA 21-167
`Vivelle (estradio] transdermal system), 0.025 mg, 0.0375 mg, 0.05 mg, 0.075 mg & 0.1 mg
`
`The preceding Action Letter has been reviewed by the undersigned:
`
`
`
`
`
`
`
`
`
`
`
`,
`
`Name
`
`B. Schneider, M.D.
`
`E. Colman, M.D.
`
`J. ElHage, Ph.D.
`
`M. Orewerth, PhD
`
`M.Rhee, Ph.D.
`
`R. Shore, Pharm.D.
`
`H. Ahn. Ph.D.
`
`S. Wang, Ph.D.
`
`T. Sahlroot, Ph.D.
`
`E. Galliers
`
`J. Jenkins, M.D.
`
`Pharmacology Team
`Leader
`
`
`
`
`
`
`
`
`
`Discipline
`|
`
`Medical Officer
`
`Medical Team
`Leader
`
`Chemistry Team
`LeaderI
`
`Biopharmaceutics
`Team Leader
`
`Biometrics 2
`reviewer
`
`Biometrics 2
`Team Leader
`
`Chief, Project Mgt.
`Staff
`
`Acting Division
`Director
`
`
`
`0010
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-167
`
`APPROVED LABELING
`
`
`
`0011
`
`

`

`Uy NOVARTIS
`
`vooooas
`
`89008101
`
`Vivelle-
`estradio! transdermal system
`
`Continuous delivery for twice-weekly application
`
`Rx only
`
`Prescribing Information
`
`
`
`ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF
`
`ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
`
`
`
`Close clinical surveillance ofall women taking estrogens is important. Adequate diagnostic measures,
`including endometnal sampling when indicated, should be undertaken to nile out malignancy im 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.
`
`
`
`DESCRIPTION
`
`The Vivelle estradiol! transdermal system contains estradiol in a multipolymenc adhesive. The system
`is designed to release 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 ofestradiol per day via skin of average permeability. Each corresponding system having an
`active surface area of 7.25, 11.0, 14.5, 22.0 or 29.0 cm’ contains 2.17, 3.28, 4.33, 6.57, or
`8.66 mgofestradiol 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-3,178-dial.
`
`The structural formula is
`
`
`
`The molecular formula ofestradiol is C|,H,4O>. The molecular weight is 272.39.
`
`The Vivelle system comprises three layers. Proceeding from the visible surface toward the
`surface attached to the skin, these layers are (1) a trans}ucent flexible film consisting of an ethylene
`
` 
`
`0012
`
`

`

`viny! alcohol copolymer film, a polyurethane film, urethane polymer and epoxy resin, (2) an adhesive
`formulation containing estradiol, acrylic adhesive, polyisobutylene, ethylene vinyl acetate copolymer,
`1,3 butylene glycol, styrene-butadiene rubber, oleic acid,
`lecithin, propylene glycol, bentonite,
`mineraloil, and dipropylene glycol, and (3) a polyester release liner that is attached to the adhesive
`surface and must be removed before the system can be used.
`.
`_-— _{l) Backing
`
` peersieiirrrrria
`
`
`BRSRGR SERS ESSERE
`(2) Adhesive containing estradiol
`PARE
`
`
`(3) Protective iiner
`
`———.._
`
`Page 2
`
`The active component of the system is estradiol. The remainig components of the
`system are pharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`Vivelle system provides systemic estrogen replacement therapy by releasing estradicl, the major
`estrogenic hormone secreted by the human ovary.
`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 equilibrum 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 1g 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
`ani
`the
`sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens
`in
`postmenopausal women.
`
`luteinizing
`Circulating estrogens modulate the pituitary secretion of the gonadotropins,
`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 secn in postmenopausal women.
`
`Pharmacokinetics
`
`Absorption
`
`In a multiple-dose study consisting of three consecutive patch applications of the Vivelle
`system, which was conducted in
`17 healthy, postmenopausal women, blood levels of
`estradio] and estrone were compared following application ofthese units to sites on the abdomen and
`buttocks in a crossover fashion. Patches that deliver nominal estradiol doses of approximately
`0.0375 mg/day and 0.1 mg/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
`
` 
`
`0013
`
`

`

`concentrations averaged about 12 and 50 pg/mL,respectively, following application to the abdomen
`and 61 pg/mL for the buttocks. While plasma concentrations of estradio! and estrone remained
`slightly above baseline at 12 hours following removal ofthe patches in this study, results from another
`study show these levels to return to baseline values within 24 hours following removal of the patches.
`
`The figure (see Figure 1) illustrates the mean plasma concentrations of estradiol at steady-
`state during application of these patches at four different dosages.
`
`Page 3
`
`Figure 1. Steady-State Estradiol Plasma Concentrations
`for Systems Applied to the Abdomen
`Nonbaseline-corrected levels
`
`120
`= 100
`= 90
`ere
`§ 6
`3
`£ yo
`g 20
`
`U
`
`ad
`?
`
`U
`-Les
`
`0
`
`0
`
`w 0.1 mg/day
`X 0.075 mg/day
`40.05 mg/day
`© 0.0375 mg/day
`
`1
`
`2
`Time (days)
`
`3
`
` 
`
`0014
`
`

`

`The corresponding pharmacokinetic parameters are summarized in the table below.
`
`Page 4
`
`Steady-State Estradiol Pharmacokinetic Parameters
`for Systems Applied to the Abdomen (mean t standard deviation)
`Nonbaseline-corrected data*
`
`Dosage
`(ma/day)
`0.0375
`0.05
`0.075
`
`0.1
`
`0.1!
`
`Cie
`(pa/mi)
`46416
`83441
`99 +35
`
`133 +51
`
`145471
`
`C.'
`(pg/mL)
`342410
`57 + 23°
`72424
`
`89 +38
`
`104 + 52
`
`Cn{84 hry8
`(pg/ml)
`30410
`41411"
`60 + 24
`
`90 + 44
`
`85447
`
`*Mean baseline estradiol concentration = 11.7 pg/mL
`‘Peak plasma concentration
`‘average plasma concentration
`‘Minimum plasma concentration at 84 hr
`"Measured over 80 hr
`lapplied to the buttocks
`
`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),andto a 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 ghucuronide 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 ofthe
`circulating estrogens exist as sulfate conjugated, especially estrone sulfate, which serves as a
`circulating reservoir for the formation of more active estrogens.
`
`Excretion
`
`Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and suifate conjugates.
`Studies conducted with the Vivelle system show the drug has an apparent meanhalf-life of 4.4 4+ 2.3
`
` 
`
`0015
`
`

`

`hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone
`retumed to baseline levels within 24 hours.
`
`Special Populations
`
`The Vivelle system has been studied only in healthy postmenopausal women (approximately 90%
`Caucasian). The Vivelle system has not been studied in patients with renal or hepatic impairment.
`
`Page 5
`
`Drug Interactions
`
`Nodruginteraction studies were conducted with the Vivelle system.
`
`Adhesion
`
`Data showing the number of systems in controlled studies that required replacement due to
`inadequate adhesion is not available.
`
`Clinica! Studies
`
`the 0.075 and 0.1 mg doses were superior to
`{n two controlled clinical tials of 356 subjects,
`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 Week6.
`
`Therefore, an additional 12-week placebo-controlled study in 255 patients was performed 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).
`
` 
`
`0016
`
`

`

`Page 6
`
`Figure 2.
`
`Mean (SD) change from baseline in mean daily number of flushes for
`Vivelle 0.0375 mg versus Placebo in a 12-week trial.
`
`Week 12°
`Week &*
`Week 4*
`Ld
`
`0
`
`-2
`
`2a
`
`8B
`
`4 53=
`
`8
`3
`-8.4(5.7)
`
`= -10
`n=130
`-9.4(5.6)
`eI
`é
`gale
`n=126
`42 i Vivelle 0.0375 mg/day
`
`Placebo
`
`‘Indicates statistically significant difierence (p<0.05) between Vivelle and placebo
`
`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 of Vivelle (0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of
`vasomotor symptoms.
`
`Efficacy and safcty of the Vivelle system in the prevention of postmenopausal osteoporosis have
`been studied in a 2-year double-blind, randomized, placebo-controlied, parallel group study.Atotal
`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 deviation of average peak bone mass,i.c., > 0.827 g/cm’) were enrolled in
`this study; 194 paticnts were randomized to one ofthe 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. Nonhysterectomized women received oral medroxy progesterone
`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 of52.0 years (range 27 to 62 years;
`the mean duration of menopause was 31.7 months (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 vanable. 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
`
` 
`
`0017
`
`

`

`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 al] time points with the
`exception of Vivelle 0.05 mg/day at 6 months. The highest dose of Vivelle was superior to the three
`lower doses. There were nostatistically significant differences in pairwise comparisons among the
`three lower doses. (See Figure 3.)
`
`Page 7
`
`765432101234 A
`
`Figure 3. Bone mineral density - AP Lumbar spine
`Least squares means of percentage change from baselina
`Al randomized patients with at least one post-baseline assessment available
`with last post-baseline observation carried forward
`
`nalysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome
`variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to
`placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all timepoints.
`A mixture ofsignificant and non significant results were obtained for the lower dose groups atearlier
`time points. Again, the highest Vivelle dose was superior to the three lower doses, and there were
`no significant differences amongthe three lower doses at this skeletal site. (See Figure 4).
`
`Figure 4. Bone mineral density - Femoral neck
`Least squares means of percentage change from baseline
`All randomized patients with at least one post-baselina assessment available
`with last post-basoline observation carried forward
`
`boboounwewan
`
`—-M- = Vivelle 0 025mpMday (D)1—=-— Placebo [P}
`
`Treatment duration
`
`——0—Vivelle 0 Imgttay (A)
`
`- --I-- Vivelle 0 0Singiday (B)
`
` — ~- — Vivelle 0 0375morday (C)
`
` 
`
`0018
`
`

`

`Page 8
`
`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 im 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® (estradiol transdermal system)is indicated in the following:
`1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause.
`2. Treatmentof vulvar and vaginal atrophy.
`3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian
`failure.
`4. Prevention of postmenopausal osteoporosis (in at risk patients). 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
`pened.
`
`White and Asian women are at higher risk for osteoporosis than black women, and thin women
`are at a higher risk than heavier women, who generally have higher endogenous estrogen levels.
`Early menopause is one of the strongest predictors for the develpoment of osteoporosis. Other
`factors associated with osteoporosis include genetic factors (small build, farnily history), lifestyle
`(cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body
`weight and dietary calcium intake).
`
`to the prevention and management of osteoporosis are weight bearing exercise,
`Essential
`adequate calcium intake. Postmenopausal women absorb dietary calcium less efficiently than
`premenopausal women and require an average of 1500 mg/dayofelemental calcium to remain in
`neutral calcrum balance. The average calcium intake in the USA in 400-600 mg/day. Therefore,
`when not contraindicated, calcium supplementation may be helpful for women with suboptimal
`dietary intake.
`
`CONTRAINDICATIONS
`
`Patients with known hypersensitivity to any of the components ofthe therapeutic system should not
`use Vivelle.
`
`Estrogens should net 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 bleeding.
`Knownor suspected cancer ofthe breast.
`Known or suspected estrogen-dependent neoplasia.
`
`I.
`
`3
`4,
`
` 
`
`0019
`
`

`

`5.
`
`Active thrombophlebitis or thromboembolic disorders, or a documented history of these
`conditions.
`
`Page 9
`
`WARNINGS
`
`1.
`
`Induction ofMalignant Neoplasms.
`
`Breast cancer. Somestudies have suggested a possible increased incidence of breast cancer
`a.
`in women taking estrogen therapy at higher doses for prolonged periods of time, especially in excess
`of LO years. 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.
`
`Endometrial cancer. The reported endometrial cancer nsk among unopposed estrogen
`b.
`users is about 2- to 12-fold greater than in nonusers and appears dependent on duration oftreatment
`and on estrogen dose. Most studies show no significant increased risk associated with the use of
`estrogens
`for
`less
`than
`1
`year.
`The
`greatest msk
`appears
`associated with
`prolonged use with increased risks of 15- to 24-fold for five to 10 years or more. In three studies,
`persistence of
`risk was
`demonstrated
`for
`8
`to over
`15
`years
`afler
`cessation of
`estrogen treatment.
`In one study, a significant decrease in the incidence of endometrial
`cancer occurred six months after estrogen withdrawal. Concurrent progestin therapy may
`offset
`this
`risk, but
`the overall health impact
`in postmenopausal women is not known
`(see PRECAUTIONS).
`
`Congenital reproductive tract disorders. Estrogen therapy during pregnancy is associated
`c.
`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 ofthese changes
`are benign, it is not known whether they are precursors of malignancy.
`
`Gallbladder Disease. Two studies have reported a 2- to 4-fold increase in the risk of
`2.
`surgically confirmed gallbladder disease in postmenopausal women receiving cral estrogen
`replacement
`therapy,
`similar
`to the 2-fold increase previously noted in users of oral
`contraceptives.
`
`Cardiovascular Disease. Large doses of estrogen (5 mg conjugated estrogens per day),
`3.
`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 nsks of nonfatal myocardial infarction, pulmonary
`embolism, and thrombophicbitis. 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 replacementtherapy should not exceed the lowest effective dose.
`
`increases during estrogen
`Elevated Blood Pressure. Occasional blood pressure
`4.
`replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often, blood
`pressure has remained the same or has dropped. Postmenopausal estrogen use docs 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
`
`
`
`0020
`
`

`

`increase renin substrate. In contrast to these oral estrogens, transdermally administered estradiol
`does not affect renin substrate.
`
`Hypercalcemia. Administration of estrogen may lead to scvere hypercalcemia in patients
`5.
`with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate
`measures taken to reduce the serum calcium level.
`
`Page 10
`
`PRECAUTIONS
`
`General
`
`Addition of a Progestin. Studies of the addition of a progestin for 10 or more days of a
`1.
`cycle of estrogen administration or daily in an estrogen/progestin continuous regimen have reported a
`lower incidence of endometrial hyperplasia than would be induced by estrogen treatment alone.
`Morphologic and biochemical studies of cndometria suggest that 10 to 14 days of progestin are
`needed to provide maximal maturation of the endometrium and to reduce the likclihood 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)
`
`impairment of glucose tolerance; and
`
`(3)_pessible enhancementof mitotic activity in breast epithelial tissue, although few epidemiologic
`data are available to address this pomt (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.
`
`Cardiovascular Risk. A causal relationship between estrogen replacement therapy and
`2.
`reduction of cardiovascular disease in postmencpausal women has not been proven. Furthermore,
`the effect of added progestins 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 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:
`
`Because only one of these studies was randomized and it was too small to yield statistically
`(1)
`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 bylife-style and medical characteristics of the women studied with the
`result that healthier women were sclected for estrogen therapy. In general, treated women were of
`
`
`
`0021
`
`

`

`Page 11
`
`higher socioeconomic and educational