AFFIDAVIT
`
`State of Maryland, Montgomery County
`
`I, Marlene S. Bobka, under oath, hereby depose and state as follows:
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`1.
`
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`so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United
`States Code.
`
`B M
`
`arlene S. Bobka
`
`mamas at, czar?
`
`Date
`
`SUBSCRIBED
`
`D SWORN before me on
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`Nmary puhhc
`My commission expires:Ml
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`'
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`YESENIA SANCHEZ BUSTOS
`NOTARY PUBLIC TY
`MONTGOMERY COUN
`MARYLAND
`2021
`MY COMMISSION EXPIRES MAY 03.
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`

 
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`MYLAN - EXHIBIT 1008
`
`0001
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`

`

`EXHIBIT A
`
`
`
`0002
`
`

`

`
`
`
`
`*5210567*
`
`
`
`
`
`
`
`
`
`
`
`*A*
`
`5210567
`
`A
`
`Vivelle Transdermal System (Novartis) 08/16/2000
`Approval & Supplemental Approval [Postmenopausal
`Osteoporosis & New 0.025mg Dosage Strength]:
`NDA 21-167, NDA 21-323/823 Approval Letter;
`LabeHng
`
`This document was provided by: FOI Services, Inc
`11 Firstfield Road
`
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`Fax:
`301-975-0702
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`
`any of the information in these documents: the documents will be faithful copies of the information supplied to FOI Services, Inc.
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`Information Act. We have millions of pages of unpublished documentation already on file and available for
`immediate delivery.
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`www.foiservices.com
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`Freedom of Information Act and are therefore available to the general public. FOI Services. lnc. does not guarantee the accuracy of
`
`
`
`0003
`
`

`

`l
`
`\l
`. *F‘2'9
`I:-5a:u:l
`T'e
`1.;‘l‘ .
`‘lv‘m
`
`_/ DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Nov 0 5 m
`
`In Response Refer to File:
`
`FU3—10620
`
`FOI Services Inc.
`
`11 Firstfield Road
`
`Gaithcrsburg. MD 20878-1704
`
`Dear Requester.
`
`Public Health Service
`
`Center for Drug Evaluation and Research
`Office of Regulatory Policy
`Division ot'lnformation Disclosure Policy
`5000 Fishers Lane. HFD-l3
`Rockville. Maryland 20857
`
`October 28. 2004
`
`This is in response to your request ofJuly 31. 2003, in which you requested inlbnnation on the
`approval for Vivelle, NDA 21-167 and NBA 20-323/3023. your control number 5210567. Your
`request was received in the Center for Drug Evaluation and Research on August I, 2003.
`
`The documents you have requested are enclosed.
`
`Computer time $0) will be
`Search $9.00. Review $0. Reproduction
`Charges of
`included in a monthly invoice. DO NOT SEND ANY PAYMENT UNTIL YOU RECEIVE AN
`INVOICE. The above total may not reflect final charges for this request.
`
`If there are any problems with this response, please notify us E writing of your specific
`problem(s). Please reference the above file number.
`
`This concludes the response for the Center for Drug Evaluation and Research.
`
`Sincerely.
`
`
`
`Paralegal Specialist
`Office of Regulatory Policy
`Division oi'Information Disclosure Policy. ”FD-13
`
`line: NDA 2l-167 and NBA 20-323E3023
`
`23trpages
`
`
`
`0004
`
`

`

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

`

`NDA 21-167
`NDA 203235-023
`
`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 dmg application NDA 21-167 dated October 19, 1999, received October 20,
`1999, and supplemental NDA 20-32315-023 dated April 19, 2000, received April 20, 2000,
`submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act for Vivelle
`(esuadiol transdermal system).
`
`We acknowledge receipt of your submissions to NBA 21-167 dated November 29 and
`December 3, 1999, and February 14, March 6, April 19, June 15, July ll (2), 26, and 27,
`and August 2 and 14, 2000.
`
`'
`
`We also acknowledge receipt of your submissions to NBA 20-323 dated July 11 and 27, 2000.
`
`'lhis 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
`.r
`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 drafi 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.
`
`Please submit 20 paper copies ofthe FPL as soon as it is available, in no case more than 30 days
`afler it is printed. Please individually mount ten of the copies on heavy-weight paper or similar
`material. Alternatively, you may submit the FPL electronically according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Formal - NDA: (January 1999). For
`administrative purposes, this submission should be designated "FPL for approved NDA 20-323!
`8-023." Approval of this submission by FDA is not required before the labeling is used.
`
`
`
`0006
`
`

`

`N'DA 21-167
`
`NBA 20-323/5-023
`
`Page 2
`
`Be advised that, as of April 1, I999, all 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 2] 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 drafi or mock-up form, not final
`print. Please submit two copies to the Division of Reproductive and Urologic Drug Produots 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, 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 product at the Division of
`Reproductive and Urologic Drug products (HFD-SBO), not to NDA 21-167. In the future, no
`submissions should be made to NDA 21-167.
`
`
`
`0007
`
`

`

`NDA 21-167
`
`NDA 20—323/8-023
`
`Page 3
`
`Ifyou have any questions regarding NDA 20-32318-023, 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,
`
`I
`, S
`
`I
`
`John K Jenkins, MD.
`
`Acting Director
`Division of Metabolic and
`
`Endocrine Drug Products
`Office of Drug Evaluation 1]
`Center for Drug Evaluation and Research
`
`
`
`0008
`
`

`

`NDA 21-167
`NDA' 20-323/S-023
`
`Page 4
`cc:
`
`Archival NDA 21-167
`
`NDA 20-323lS—023
`l-IFD-S l OfDiv. Files
`
`HFD-SSO/Div. Files
`HFD-SlO/WKoch
`
`HFD-SlOfReviewers and Team Leaders
`
`HFD-SSO/DMoorelSAllen
`
`RFD-5 SOIReviewers and Team Leaders
`
`l-IF-ZIMedWatch (with labeling)
`HFD-OO2/ORM (with labeling)
`HFD-l OZIADRA (with labeling)
`HFD- l 02fPost-Marketing PM
`HFD-l 04/Peds/V.Kao (with labeling)
`HFD- l 04/Pedsfl'.Crescenzi (with labeling)
`HFD-42/DDMAC (with labeling)
`HFl-20/Press Ofiice (with labeling)
`HFD—400/OPDRA (with labeling)
`HFD-6l3/OGD (with labeling)
`HFD-O95/DDMS-IMT (with labeling)
`HFD-SZO/DNDC Division Director
`DISTRICT OFFICE
`
`Drafted by: WKoch/08.07.00
`lnitialed by: EGaJlierstS. 10.00
`final: WKoch/O8.l4.00
`
`filename: C:/Windowstesktop.’NDA21 l67/LTRapNDA.doc
`
`APPROVAL (AP)
`
`
`
`0009
`
`

`

`NDA 21-167
`
`Vivelle (estradiol 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
`
`Disci - line
`
`B Schneider, MD.
`
`Medical Officer
`
`E. Colman, MD.
`
`Medical Team
`Leader
`
`J. Eli-Iage, PhD.
`
`Phannaeology Team
`Leader
`
`M 0......
`
`M Rhee, PhD.
`
`R. Shore, PharmD.
`
`H. Ahn. PhD.
`
`Chemistry Team
`Leader]
`
`Biopharmaceutics
`Team Leader
`
`S. Wang, PhD.
`
`Biometrics 2
`reviewer
`
`T. Sahlroot, Ph.D.
`
`Biometrics 2
`
`Team Leader
`
`E. Galliers
`
`
`
`
`
`J. Jenkins, MD.
`
`Acting Division
`Director
`
`
`
`
`
`
`
`Chief, Project Mgt.
`Staff
`
`
`
`
`
`
`0010
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 - 1 67
`
`APPROVED LABELING
`
`
`
`0011
`
`

`

`U) NOVARTIS
`
`T2000-OB
`89008101
`
`Vivelle-
`
`estradioi transdermal system
`
`Continuous delivery for twice-weekly application
`
`Rx only
`
`Prescribing Infomlation
`
`
`
`ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF
`ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN.
`
`
`
`
`
`Close clinical surveillance of all women taking estrogens is important Adequate diagnostic measures,
`including endometrial sampling when indicated, should be tmdertakcn to rule out malignancy in all
`cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that
`"natmal" estrogens are more or less hazardous than "synthetic" estrogcns at equiestrogenic doses.
`
`
`
`
`DESCRIPTION
`
`The Vivelle estradiol transdennal system contains estradiol in a multipolymen'c adhesive. The system
`
`is designed to release cstradiol continuously upon application to intact skin.
`
`Five systems are available to provide nominal in vivo delivery of 0.025, 0.0375. 0.05, 0.075,
`or 0.1 mg of estradiol per day via skin of average permeability. Each corresponding system having an
`active surface area of 7.25, l 1.0, 14.5, 22.0 or 29.0 cm2 contains 2.17, 3.28, 4.33, 6.57. or
`8.66 mg ofestradiol USP, respectively. The composition of the systems per unit area is
`identical.
`
`Estradiol USP is a white. crystalline powder, chemically described as emu-1,3,5
`(10)-triene-3. l 7B—diol.
`
`The Salmon] formula is
`
`
`
`The molecular formula ofwtradiol is CiSHHOZ' 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 (l) a translucent flexible film consisting of an ethylene
`
` 
`
`0012
`
`

`

`Page 2
`
`vinyl alcohol copolymer film, a polyurethane film, methane polymer and epoxy resin, (2) an adhesive
`formulation containing estradioL acrylic adhesive, polyisobutylene, ethylene vinyl acetate copolyrner,
`1,3 butylene glycol, styrene-butadiene 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.
`
`
`lll'lllllillll’lllllll
`IIIIIIIIIIIIIIIIIIII
`IIIIIIIIII‘III‘IIIIII
`
`
`
`
`
`
`
`
`0)Bm*ha
`
`.
`
`(2) Adhesive eontahlng astradior
`
`\. (3) Protective llner
`
`The active component of the system is cstradiol. The remaining components of the
`systernarepharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`Vivelle system provides systemic estrogen replacement therapy by releasing estradiol, the major
`
`Estrogens are largely responsible for the -
`estrogcnic hormone secreted by the human ovary.
`development
`and maintenance of the
`female reproductive system and secondary sexual
`characteristics. Although circulating estrogens exist
`in a dynamic equilitrium of metabolic
`intereonversions, 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 pg of estradiol daily, depending on the phase of the menstrual cycle. Alter menOpause,
`most endogenous estrogen is produced by conversion of androstenedionc, secreted by the adrenal
`cortex,
`to
`estrone
`by
`peripheral
`tissues.
`Thus,
`estrone
`and
`the
`
`sulfate conjugated fonn, estrone sulfate, are the nrost abundant circulating estrogens
`
`in
`
`postanenOpausal women.
`
`luteinin'ng
`Circulating ectrogens 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 seen 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
`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 estmdiol doses of approximately
`0.0375 mg/day and 0.! mg/day were applied to abdominal application sites while the 0.] mg/day
`doses were also applied to sites on the buttocks. These systems increased ectradiol 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
`obsech 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 Mo! and estrone remained
`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 within 24 hours following removal of the patches.
`
`The figure (see Figure 1) illustrates the mum plasma concentrations of cstradiol at steady-
`
`state during application of these patches at four different dosages.
`
`Page 3
`
`Figure 1. Steady-State Estradlol Plasma Concentrations
`for Systems Applied to the Abdomen
`Nonbaseiine-eorreci‘ed levels
`
`120
`
`I 0.1 mgiday
`it 0.075 mgfday
`A 0.05 mg/dny
`0 0.0375 mglday
`
`§
`
`
`
`Concentration(pgi'rnL) 8»8
`
`1
`
`2
`
`Time (days)
`
` 
`
`0014
`
`

`

`The corresponding pharmacolcinetic parameters are sumarized in the table below.
`
`Page 4
`
`Steady-State Estradlol Pharmacokinetic Parameters
`
`for Systems Applied to the Abdomen (mean 1: standard deviation)
`Nonbaseline-corrected data'
`
`Dosage
`ImsLdarJ
`0.0375
`
`0.05
`0.075
`
`0.1
`
`0.1‘
`
`0...:
`(£191le
`46116
`
`83141
`99 r: 35
`
`133151
`
`145171
`
`0.;
`£29th
`34:10
`
`57:23“
`72 r 24
`
`89138
`
`104152
`
`c,,-.,rs4 hr)!
`Iranian
`30:10
`
`41111'
`so 1 24
`
`90:44
`
`8514?
`
`'Mean baseline estradiol concentration = 11.7 ngmL
`
`'Peak plasma concentration
`
`*Averaga plasma concentration
`5lil‘linin'mm plasma concentration at 84 hr
`llMeasured over 80 hr
`
`'Applied to the buttocks
`
`Distribution
`
`The distribution of exogenous estrogens is similar to that of endogenous estrogen; Estrogens are
`widelydistributedinthebodyandaregcnerally fotmdinhigherconoentrationsinthesexhormom
`target organs. Estradiol and other naturally occurring estrogens are bound mainly to sex hormone
`binding globulin (SHBG), and to a lesser degree to albumin.
`
`Metabolism
`
`Exogenous estrogens are metabolized in the same manner as endogenous cstrogens. Circulating
`estrogens exist in a dynamic equilibrium of metabolic interoonversions. These transfonnatr'ons take
`place mainly in the liver. Estradiol is converted reversibly to estrme. and both can be converted to
`estriol, which is the major urinary metabolite. Estrogcns also undergo cnterohwatic recirculation via
`sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and
`hydrolysis in the gut followed by mbsorption. 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, estr’one, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
`Studies conducted with the Vivelle system show the drug has an apparent mean half-life of 4.4 :1: 2.3
`
` 
`
`0015
`
`

`

`hours. After removal of the transdermal systems. serum concentrations of estradiol and estrone
`returned to baseline levels within 24 hours.
`
`Special Populations
`
`The Vivelle system has been studied only in healthy postmenopausal women (approximately 90%
`Caucasian). The ViveIle system has not been studied in patients with renal or hepatic impairment.
`
`Page 5
`
`Drug Interactions
`
`No drug interaction 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.
`
`Clinical Studies
`
`the OIWS and 0.1 mg doses were superior to
`In two controlled clinical trials of 356 subjects.
`placebo in relieving vasomotor symptoms at Week 4. and maintained efiicaey 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 placebo-controlled study in 255 patients was perfonned 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 [1.5. 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 at flushes tor
`Vlvelle 0.0375 mg versus Placebo In a 12-week trial.
`
`Week 4“
`
`Week 8"
`
`Week 12‘
`
`do 43.4(51)
`
`"=13”
`
`-9.4(5.6)
`
`
`
`MeantSD)reductionlrornbaseline
`
`
`
`
`
`_'.M
`
`B Vivene 0.0375 mgrday
`
`Placebo
`
`'lndicates statistically significant ditterence [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 treatrncnt. 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 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., 2 0.827 g’cm") were enrolled in
`this study; 194 patients were randomized to one of the four doses of Vivelle (0.], 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. Nonhysterectomizcd women received oral rnedroxy progesterone
`acetate (2.5 mg/day) throughout the study.
`
`The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized
`(61%) or nonhystcrectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years;
`the mean duration of men0pause was 3|.7 months (range 2 to 72 months). Two hundred thirty two
`(89%) of randomized subjects (I73 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 mlciumlday)
`but no supplemental vitamin D. There was an increase in BMD of the AP lm'nhar spine in all Vivclle
`
` 
`
`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<1).05) at all time points with the
`exception of Vivelle 005 mg/day at 6 months. The highest dose of Vivelle was superior to the three
`low doses. There were no statistically significant differences in pairwise comparisons among the
`
`three lower doses. (See Figure 3.)
`
`Page 7
`
`FIgunlBonomhorIldarufly-APLunbar-spho
`Leaststparssmomaofpementagsdranostmrnbaselha
`Alrendmizedpaflorflsmihatbastonepoat—basalheasmflavaidflo
`
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`
`Std-tumu-
`
`Analysis of percent change from baseline in femoral neck BMD, at 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 mixtm'e 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 three lower doses, and there were
`no significant difi‘ermces among the three lower doses at this skeletal site. (See Figure 4).
`
`Floors 4. Bone mlnonl donslty - Femoral nlclr
`Least more: mam cl percentage change trorn baseline
`All randomized patients with at least one post-baseline assessment available
`with last post-Insatina observation carried forward
`
`7ssa32
`
`ito
`-1
`E4
`3 3
`
`-—II-P|ombo(P)
`
`Treatment duration
`
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`--l--Vwotls0025rrWy(D)
`
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`
`-+—Vuaihoaorrmgiu-yrci
`
` 
`
`0018
`
`

`

`Page 8
`
`The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-
`
`telopeptides of type I 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
`
`vii/cite" (estradiol transdermal system) is named in the following:
`
`1. Treatment of modaate-tosevere vasomotor symptoms associated with the menopause.
`
`2. Treatment of 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
`period.
`
`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 gencu'c factors (small build, family 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 ISOO mg/day of elemental calcium to remain in
`neutral calcitun balance. The average calcium intake in the USA in 400-600 mg/day. Therefore.
`when not contraindicated, caleitun supplementation may be helpfitl for women with suboptimal
`dietary intake.
`
`CONTRAINDICATIONS
`
`Patients with known hypersensitivity to any of the components of the therapeutic system should not
`use Vivelle.
`
`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.
`
`i.
`
`2.
`
`3.
`
`4.
`
` 
`
`0019
`
`

`

`5.
`
`Active thrombOphlebin's or thromboembolic disorders, or a documented history of these
`conditions.
`
`Page 9
`
`WARNINGS
`
`1.
`
`Induction ofMalignant Neoplasm.
`
`Breast cancer. Some studies 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 excem
`of [0 years. The majority of undies, 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 endomctrial cancer risk among unopposed estrogen
`b.
`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 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 alter 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 dining 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
`laterin life;tn males, unrgcnital and possibly testicular abnonnalities. Although some ofthese changes
`are benign, it is not lorown 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 poshnenopausal 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),
`3.
`comparable to those used to treat cancer of the prostate and breast, have been shown in a large
`
`pmspectiveclinimlttialinmcntoincreasetherisksofnoniatal myocardial infarctionpulmonary
`embolism, and thrombophlcbitis. "these risks cannot necessarily be extrapolated from men to
`women. However, to avoid the theoretical cardiovascular risk to women caused by high estrogen
`doses, the dose for estrogen replacement therapy should not exceed the lowest effective dose.
`
`increases during estrogen
`Elevated Blood Pressure. Occasional blood pressure
`4.
`replacement therapy have been attributed to idiosyncratic reactions to estrogens. More otten, blood
`
`pressure has remained the same or has dmpped. Postmenopausal estrogen use does not increase the
`risk of stroke. Nonetheless, blood pressure should be monitored at regular intervals with estrogen
`use, cSpecialIy if high doses are uscd. Ethinyl estradiol and conjugated estrogens have been shown to
`
`
`
`0020
`
`

`

`increase rcnin substrate. In contrast to these oral estrogens, transderrnally administered cstradiol
`does not affect renin substrate.
`
`Hypercalcemia. Administration of estrogen may lead to severe 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 ofa Progesrr'n. Studies of the addition of a progestin for 10 or more days of a
`1.
`cycle ofestrogen administration or daily in an estrogen/progestin continuous regimen have reported a
`lower incidence of endometrial hyperplasia than would be induwd 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 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 ell'ect of estrogen therapy (see PRECAUTIONS,
`below);
`
`(2)
`
`impainnent of glucose tolerance; and
`
`possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiologic
`(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 finthcr‘ study before they are clarified.
`
`Cardiovascular Risk. A causal relationship between estrogen replacement therapy and
`2.
`reduction of cardiovascular disease in postmenopausal women has not been proven. Furthen-none,
`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-efiect
`relationship between postmenopausal oral estrogen replacement therapy without added progestr'ns
`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 by life-style and medical characteristics of the women studied with the
`result that healthier women were selected for estrogen therapy. In general, treated women were of
`
`
`
`0021
`
`

`

`P