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`EXHIBIT A
`EXHIBIT A
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`0002 
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`0002
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`

`

`foi
`
`5210567 A
`
`* 5 2 1 0 5 6 7 *
`
`* A *
`
`Vivelle Transdermal System (Novartis) 08/16/2000
`Approval & Supplemental Approval [Postmenopausal
`Osteoporosis & New 0.025mg Dosage Strength]:
`NDA 21-167, NDA 21-323/S23 Approval Letter;
`Labeling
`
`This document was provided by: FOI Services, Inc
`11 Firstfield Road
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`0003 
`
`

`

`4 MPARTMENT OF H EALTH AND lilMAN SRRVICES
`
`HOVO 5 20W
`
`Public Health Service
`Center for Drug F.valuatioii and Research
`Office of Regulatory Policy
`Division of Information Disclosure Policy
`5e>00 Fishers Lane. HFD-13
`Rockville. Maryland 20S57
`
`October 28, 2004
`
`In Response Refer to File:
`
`FU3-10620
`
`FOI Services Inc.
`11 Firstfield Road
`Gaithcrsburg, MD 20878-1704
`
`Dear Requestor,
`
`This is in response to your request of July 31, 2003. in which you requested information on the
`approval for Vivellc, NDA 21 -167 and NDA 20-323/S023, your control number 5210567. Your
`request was received in the Center for Dmg Evaluation and Research on August 1, 2003.
`
`The documents you have requested are enclosed.
`
`^Search S9.00, Review $0, Reproduction
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`Computer time $0) will be
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`
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`
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`
`Paralegal Specialist
`Office of Regulatory Policy
`Division of Information Disclosure Policy, EIFD-13
`
`line: NDA 21-167 and NDA 20-323/S023
`
`23(ipages
`
`0004 
`
`

`

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

`

`NDA 21-167
`NDA 20-323/5-023
`
`Novartis Fhannaceuticats Corporation
`Attention: Lynn Mellor
`Associate Director, Drug Regulatory Affairs
`59 Route 10
`East Hanover, New Jersey 07936-1080
`
`Dear Ms. Melfor:
`
`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 Act for Vivelle
`(estradiol transdermal system).
`
`We acknowledge receipt of your 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.
`
`We also 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
`postmenopausal osteoporosis. In addition, a new lower strength, 0.025 mg, system is
`proposed for the indication of prevention of postmenopausal osteoporosis.
`
`We have 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 effective
`on the date of this letter.
`
`The final 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
`labels submitted April 19,2000, and backing labels submitted July 26,2000). Marketing the product
`with FPL that is not identical to the approved labeling text may render the product misbranded and
`an unapproved new drug.
`
`Piease submit 20 paper copies of the FPL as soon as it is available, in no case more than 30 days
`after it is printed. Please Individually mount ten of the copies on heavy-weight paper or similar
`material. Alternatively, you may submit the FPL eleetrodicaJly according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Formal - 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 is not required before the labeling is used.
`
`I
`
`0006 
`
`

`

`NDA 21-167
`NDA 20-323/S-023
`Page 2
`
`Be advised that, as of April 1,1999, ail applications for new active ingredients, new dosage forms,
`new indications, new routes of administration, and new dosing regimens are required to contain an
`assessment of the safety and effectiveness of the product in pediatric patients unless this requirement
`is waived or deferred (63 FR 66632). We note that you have not fulfilled 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, not final
`print. Please submit two copies to the Division of Reproductive and Urologic Drug Products and
`two copies of both the promotional materials and the package insert 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 of the 0.025 mg strength drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81. To comply with these regulations, ail 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 product at the Division of
`Reproductive and Urologic Drug products (HFD-5S0), 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
`
`If you 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, m
`
`John K Jenkins, M.D.
`Acting Director
`Division of Metabolic and
`. Endocrine Drug Products
`Office of Drug Evaluation D
`Center for Drug Evaluation and Research
`
`0008 
`
`

`

`NDA 21-167
`NDA 20-323/S-023
`Page 4
`cc:
`ArchivaJ NDA 21-167
`NDA 20-323/S-023
`HFD-510/Div. Files
`HFD-580/Div. Files
`HFD-510/WKoch
`HFD-510/Revicwers and Team Leaders
`HFD-580/DMoore/S Allen
`HFD-5 80/Reviewers and Team Leaders
`HF-2/McdWatch (with labeling)
`HFD-002/ORM (with labeling)
`HFD-102/ADRA (with labeling)
`HFD-I02/Post-Marketing PM
`HFD-104/Pcds/V.Kao (with labeling)
`HFD-104/Peds/T.Crescenzi (with labeling)
`HFD-42/DDMAC (with labeling)
`HFl-20/Prcss Office (with labeling)
`HFD-400/OPDRA (wi^h 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
`Vivclle (estradiol transderma] system), 0.025 mg, 0.0375 rag, 0.05 mg, 0.075 mg & 0.1 mg
`
`The preceding Action Letter has bees reviewed by the undersigned;
`
`Name
`Discipline
`B. Schneider, M-D. Medical Officer
`E. Colman, M.D.
`Medical Team
`Leader
`
`l ElHage, Ph.D.
`
`Phannacology Team
`Leader
`
`M- Ortwerth. Ph.D.
`
`Chemist
`
`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.
`
`Chemistry Team
`Leader I
`Biopharmaceutics
`Biopharmaceutics
`Team Leader
`Biometrics 2
`reviewer
`Biometrics 2
`Team Leader
`Chief, Project Mgt.
`Staff
`
`Acting Division
`Director
`
`Date
`f/s-/ "
`iro
`
`of. A' r
`
`J[ll5}oo
`%/lS'l<n)
`
`" "ihelOO
`
`1
`
`<?/»/
`O-J
`
`j^Signature
`
`/s/
`/s/
`
`/S/
`
`/S/
`/s/
`ISl
`/s/
`/s/
`
`o
`
`V
`
`^ i i t y f j )
`
`C\ C\ -| r\
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA
`21-167
`
`TION
`
`APPROVED LABELING
`
`oou
`
`

`

`('> NOVARTIS
`
`T2000-08
`89008101
`
`Vivelle*
`estradiol transdermal system
`
`Continuous delivery for twice-weekly application
`Rx only
`
`Prescribing Information
`
`INCREASE THE RISK OF
`ESTROGENS HAVE BEEN REPORTED TO
`ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
`Close clinical surveillance of all women taking estrogens is important Adequate diagnostic measures,
`including endometna! sampling when indicated, should be undertaken to rule out malignancy in all
`cases of undsagnosed persistent or recurring abnormal vaginal bieedmg. 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 multipolymeric adhesive. The system
`is designed to release estradiol continuously upon application to intact skin.
`Five systems are available to provide nominal in vivo delivery of0.025,0.0375,0.05,0.075,
`or 0.1 mg of estradiol per day via skin of average permeabitity. Each corresponding system having an
`active surface area of7.25,11.0, 14.5,22.0 or 29.0 cm2 contains 2.17,3.28,4.33,6.57, or
`8.66 mg of estradiol USP, respectively. The composition of tire systems per unit area is
`identical.
`Estradiol USP is a white, ciystalline powder, chemically described as estra-1,3,5
`(I0}-triene-3,170-diol.
`The structural formula is
`
`Q
`
`lH
`
`j
`
`H
`
`wrv
`The molecular weight is 272.39.
`The molecular formula of estradiol is
`The Vivelle system comprises three layers. Proceeding from the visible surface toward the
`surface attached to the skin, these layers are (1) a translucent flexible film consisting of an ethylene
`
`0012 
`
`

`

`Page 2
`
`vinyl alcohol copolymer film, a polyurethsne film, urethane polymer arid epoxy resin, (2) an adhesive
`foitnulatioa oontaming estradiol, aoylic adh^ive, polyisobutylene, e<hylenc vinyl acetate copolymer,
`1,3 butylene glycol, styrene-botadierie rubber, oleic acid, lecithin, propylene glycol, bentonite,
`mineral oil, 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.
`(1) Backing
`(2) Adhesive containing estradiol
`(3) PnstecHvs liner
`
`The active componenl of the system is estradiol. The remaining components of the
`system are phaxmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`Viveile system provides systemic estrogen replacement therapy by releasing estradiol, 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 equilibrium of metabolic
`mterconversions, estiadiol is the principal intracellular human es&ogen and is substanhalty 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 jig of estradiol daily, depending on the phase of the menstrual cycle. After menopause,
`most endogenous estrogen is produced by conversion of androstenodione, secreted by the adrenal
`cortex, to
`estrone
`by
`peripheral
`tissues,
`Thus,
`estrone
`and
`the
`sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens
`in
`postmenopausal women.
`Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing
`hormone (LH) and follicle stimulatmg honnone (FSII) through a negative feedback mechanism and
`estrogen
`replacement
`therapy
`acts
`to reduce
`the
`elevated
`levels
`of
`tliese
`honrsones seen in postmenopausal women.
`
`Pharmacokinetics
`
`Absorption
`In a multiple-dose study consisting of three consecutive patch applications of the Viveile
`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. Patches that deliver nominal estiadiol 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 pgAnL, respectively, following application to the abdomen
`and 61 pg/niL for the buttocks. While plasma concentrations of estradiol md ssimm iraained
`slightly above baseline at 12 hours following removal of the patches in this study, results from another
`study show these levels to return to baseline values wisliin 24 houes following removal of the patches.
`Use figure (see Figure I) illustrates the mean plasma concentrations of estradiol at steady-
`state during application of these patches at four different dosages.
`
`Page 3
`
`Figure 1. St«ady-State Estradiol Plasma Concentrations
`for Systams Applied to the Abdomen
`NonbiseltoB-corrected levafs
`
`120-,
`I m~
`
`c
`.2 60
`
`I E 40
`I S 2D —
`
`• S.l mg/day
`X 0.075 mg/day
`A 0.C5 mg/day
`• 0.0375 mg/day
`
`-»
`
`%
`
`*
`4
`
`*
`-A.
`
`U
`
`0
`
`0
`
`I
`I
`
`i
`2
`Time (days)
`
`x
`
`3
`
`0014 
`
`

`

`The corresponding pharniacoksnetic parameters are summaiized in the table below.
`
`Page 4
`
`Steady-State Estradiol Pharmacokinetic Parameters
`for Systems Applied to the Abdomen {mean ± standard deviation)
`Nonbasefine-corrected data*
`
`Dosage
`IsnaMaiJ
`0.0375
`0.05
`0.075
`0.1
`0.1*
`
`C™1
`(pg/oaU
`46 116
`83 ±41
`99*35
`133 ±51
`145 ±71
`
`c *
`(Po/mU
`34 t 10
`57 ± 23*
`72 ±24
`39 ± 38
`104 ± 52
`
`Cni,(84 hr)s
`(po/mL)
`30 110
`41 ± 11*
`SO ± 24
`90 t 44
`85 ±47
`
`'Mean baseline estradiol concentration = 11,7 pg/ml
`'Peak plasma concentration
`'Average plasma concentration
`'Minimum plasma concentration at 84 tw
`"Measured over 80 hr
`^Applied to the buttocks
`
`Distribution
`Hie distribution of exogenous esteogens is similar to that of endogenous estrogens. Estrogens are
`widely distributed in the body and are generally found in higher concsentetions in the sex hormone
`target organs. Estradiol and other naturaliy ocairring estrogens are bound mainly to sex hormone
`binding globulin (SHBG), and to a lesser degree to albumin.
`Metabolism
`Exogenous estrogens ate metabolized in the same manner as endogenous estrogens. Circulating
`estrogens exist in a dynamic equilibrium of metabolic intcrconversions. These transformations take
`place mainly in the liver. Estradiol is converted reverabty to estrone, and both can be converted to
`estriol, which is the major urinary metabolite. Eslrogens also undago enterohepatk reciiculation via
`sulfate and ghrcuronide conjugation in the liver, biUaiy secretion of conjugate into the intesdne, and
`hydrolysis in the gut followed by reabsorptioa In postmenopausal women a significant portion of the
`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 sulfate conjugates.
`Studies conducted with the Vivelle system show the drag has an apparent mean half-life of 4.4 ± 2.3
`
`0015 
`
`

`

`Page 5
`
`hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone
`returned to baseline levels within 24 hours.
`
`Special Populations
`The Vivdle system has been studied only in healthy postmenopausal women (approximately 90%
`Caucasian). The ViveUe system has not been studied in patients with renal or hepatic impairment.
`
`Drug Interactions
`No drug interaction studies were conducted with the Vivdle system.
`
`Adhesion
`Data showing the number of systems in controlled studies that required replacement due to
`inadequate adhesion is not available.
`Clinical Studies
`In two controlled clinical trials of 356 subjects, the 0.075 and 0.1 mg doses weir 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 piscebo-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 die
`figure below (see Figure 2).
`
`0016 
`
`

`

`Page 6
`
`Rgurc 2.
`Moan (SD) change from basetina In nrMan daily number of flushes for
`\hvelte 0.0375 mg wemis Piaoefeo in a •tS-weak trial.
`
`Week 4'
`
`lAteek 8s
`
`Week 12'
`
`O-i
`
`rt
`
`-2 -
`
`-6 •"
`
`-4.9(4.8)
`rv=125
`
`••5,0(5.0)
`i»=120
`
`!-6.6{5.3)
`rt=U8
`
`2
`B 2
`8
`•s
`i B . g „
`o
`c -10-
`1
`S
`
`-8.4(5.7)
`n-130
`
`-9.8(5.9)
`0=120
`
`-9.4(56)
`n-izs
`Viveile 0.0375 mg/day
`Placebo
`•Indicates slatisticaity significant difference (p<0 05) between Vivelle and placebo
`
`-12 J
`
`The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of
`vasomotor symptoms at Week 4 and maintamed 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 safety of the Vivelle system in the prevention of postmenopausal osteoporosis have
`been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total
`of 26 i hysterectomised (161) and non-hysterectomized (100), surgically or naturally menopausal
`women (within 5 years of menopause), with no evidence of osteopoiosis (lumbar spine bone tninera!
`density within 2 standard deviation of average peak bone mass, i.e., > 0.827 g/cm2) 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. 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 nonhystcrcctomizcd (39%) women with a mean age of 52.0 years (range 27 to 62 yeans;
`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 lombar spine, the primaiy
`efficacy variable. Patients were given supplemental dietary cakium (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 (j><0.05) at all time points with the
`exception of ViveUe 0.05 mg/day at 6 months. The highest doss of Vivelle was superior to the three
`lower doses. There were no slatisfcally significant differences in palrwise comparisons among the
`three lower doses. (See Figure 3.)
`
`Page 7
`
`Rgura 3. Bon* mlnwal daraity - AP Lumbar spin*
`Least squares means cf percentage change Inxn baseline
`AM randomized patents with at least one post-basetine assessment avaiabte
`wWi last post-baselne observation carried forward
`
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`
`VFVftte O.lmgUay
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`Ptobo
`
`-
`
`Amlysis of percent chsmge from kiseline 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 of significant and non significant results were obtained for the lower dose groups at earlier
`time points. Again, the highest Vivelle dose was superior to the thro lower doses, and there were
`no significant differences among the three lower doses at this skeletal site. (See Figure 4).
`
`Ftgur* 4. Bon* mlntril density • Famoriil ntck
`Least squaras means of percentage ctaangs from baselm
`AH randomized patients with at least one post-beseiine sssessfflent fmOUt**
`wfth tel post-baseline observation earned forwan)
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`0018 
`
`

`

`Pag® 8
`
`The mean serum osteocafc-yi (a markra* of bone formadon) and unnary exaretson of cross-link N-
`tsiopeplidsa of type 1 collagen (a marker of bone fesorpdon) decreased numericaUy in most of the
`active treatment groups
`relative to baseline. However, the decreases in both markets were
`inconsistent across treatment groups and the differences between active treatment groups and
`placebo were not statistically significant.
`
`INDICATIONS AND USAGE
`ViveUe* (estradiol transdenna] system) is indicated in the following:
`1. Treatment of moderaie-to-severe vasomotor symptoms associated with the menopause.
`2. Tiraterrat of vulvar and vagiml atrophy.
`3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian
`failure.
`therapy
`4. Prevention of postmenopausal osteoporosis (in at risk patients). Estrogen replacement
`reduces tons
`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.
`
`White and Asian women arc 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, family history), lifestyle
`(cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body
`weight and dietary calciiim intake).
`
`Essential to the prevention and management of osteoporosis are weight bearing exercise,
`adequate calcium intake. Postmenopaiisal women sbsort? 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 in 400-600 mg/day. Therefore,
`when not contnaimiicated, calcium supplementadon may be helpful for women with suboptimal
`dietary intake.
`
`CONTRAINDICATIONS
`Patients with known hypersensitivity to any of the components of the therapeutic system should not
`use ViveUe.
`
`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 bleeding.
`Known or suspected cancer of the breast.
`Known or suspected estrogen-dependent neoplasia.
`
`3.
`4.
`
`0019 
`
`

`

`Pag® 9
`
`5.
`
`Active thrombophlebitis or thromboembolic disorders, or a documented history of these
`condition.
`
`WARNINGS
`Induction of Malignant Neoplasms.
`Breast cancer. Some studies have suggested a possible increased incidence of beast cancer
`a.
`in women taking estrogen therapy at higher doses for prolonged periods of lime, specially in excess
`of 10 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 beast
`examinations and should be instructed in breast seif-exsmiaa^on.
`Endometrial cancer. The reported endometrial cancer risk among unoprposed estrogen
`b.
`users is about 2- to i 2-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 ten
`1
`year. Hie greatest risk
`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 after cessation of
`estrogen treatment. In one study, a significant decrease in the incidence of endometrial
`cancer occurred six months after estrogen withdrawa). 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 fete! congenital reproductive tract disoiders. In female offspring, there is an
`increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear cell vaginal cancer
`late in life; in males, urogemtal and possibly tetiaikr abnonnalities. Although some of these 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
`surgically confirmed gaUbiadder disease in postmenopausal women receiving oral 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),
`comparable to those used to treat cancer of the prostate and breast, have been shown in a iatge
`prospective clinical trial in rnsn to increase the risks of nonlatal myocardial infarction, puhnonary
`embolism, and thrombophlebitis. These risks cannot necessarily be extrapolated fom men to
`women. However, to avoid the theoretical cardiovascular risk to women caused by high estrogen
`doses, the dose for estrogen replacement therapy should not exceed the lowest effective dose.
`
`increases during estogen
`Elevated Blood Pressure. Occasional blood pressure
`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, Wood 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 
`
`

`

`Page 10
`
`increase renin substrate. In contest to these oral estrogens, transdeimally administered estradiol
`does not affect renin substrate.
`Hypercalcemia. Administration of estrogen may lead to severe hypercalcemia in patients
`with breast cancer and bone metastases. If this occurs, the drag should be stopped and appropriate
`measures taken to reduce the serum calcium level.
`
`PRECAUTIONS
`General
`I .
`Addition of a Progestin. Studies of the addition of a progestin for 10 or more days of a
`cycle of estrogen administration or daily in an estroger/progesfe continuous regimen have reported a
`lower incidence of endometrial hyperplasia than would be induced by estrogen treatment akme.
`Morphologic and biochemical studies of endometria suggest that 10 to 14 days of progestin are
`needed to provide maximal maturation of the endometrium and to
`reduce the likelihood of
`hyperplastic changes.
`that may be associated with the use of progestins in
`There are, however, possible risks
`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);
`impairment of glucose tolerance; and
`(2)
`possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiologsc
`(3)
`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.
`therapy and
`2.
`Cardiovascular Risk. A causal relationship between estrogen replacement
`reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore,
`the effect of added progestins on this putative benefit is no