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`State of Maryland, Montgomery County
`
`1, Marlene S. Bobka, under oath, hereby depose and state as follows:
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`I am the president of F.O.I., Inc. dsz‘a F0] Services, lnc. (“FOI Services”).
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`£5
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`Marlene S. Bobka
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`Augus‘l‘ 0’, 61017”
`
`Date
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`SUBSCRIBED AND SWORN before me on
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` YESENIA SANCHEZ BUSTOS
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` Notary Publ'
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`NOTARY PUBLIC
`MONTGOMERY COUNTY
`MARYLAND
`MY coumssmm EXPlRES MAY 03. 2021
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`My commission expires: HE , 93 20“
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`~ -
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`-
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` 
`

 
`
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`MYLAN - EXHIBIT 1006
`
`0001
`
`

`

`EXHIBIT A
`
`
`
`0002
`
`

`

`'
`
`5236149
`
`B
`
`|||l|||
`
`*5523
`
`illwill
`
`1‘49I
`
`'.-r
`
`*B*
`
`Vivelle-DOT (Novartis) 05/03/2002 Supplemental Approval [Label
`Revisions]: S12, S14, S15 Approvable Letter; Final Labeling;
`Approval Letter
`
`This document was provided by:
`
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`704 Quince Orchard Road - Suite 275
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`0003
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`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER:
`
`20-538/S-015
`
`Trade Name:
`
`Vivelle-Dot
`
`Generic Name: estradiol transdermal system
`
`Sponsor:
`
`Novartis Pharmaceuticals Corporation
`
`Approval Date: May 3, 2002
`
`Indications:
`
`Provides for the prevention of postmenopausal
`osteoporosis indication in at-risk patients for the .025
`mg/day strengths.
`
`
`
`W‘aib‘fl‘glfifi
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-538/S-015
`
`CONTENTS
`
`
`‘ Reviews / Information Ilncuded in this NDA Review.
`
`
`
`
`
`A roval Letter
`
`A rovable Letter
`Final P_rint_ed Labeling
`Medical Review s
`
`Chemistr Review s
`
`EA/FON SI
`
`_
`
`_
`
`_
`
`
`
`
`._
`
`Pharmacolo_ Review s
`S_tatistica1Reviewgs!_______
`Microbiolo_ Review s)
`Clinical Pharmacology]_Biogharmaceutics Review s)
`Administrative Document s
`_
`__
`
`_(Mmse __._..._._ ___—...—
`
`__
`
`
`
`0005
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-538/8-015
`
`APPROVAL LETTER
`
`
`
`0006
`
`

`

`
`“2
`
`é DEPARTMENTOFHEALTH Jr. HUMAN SERVICES PublicHealth Service
`Food and Drug Administration
`ROCkville MD 2085?
`
`NBA 206385-012, 8-014, 5-015
`
`Novartis Pharmaceuticals Corporation
`Attention: Lynn Mellor
`Associate Director, Drug Regulatory Affairs
`One Health Plaza
`
`East Hanover, NJ 07936-1080
`
`Dear Ms. Mellor:
`
`APPROVAL LETTER
`
`Please refer to your supplemental new drug applications dated March 1. 2002, received March 4, 2002. submitted
`under section SOSfb) of the Federal Food. Drug, and Cosmetic Act for Vivelle-Dot® (estradiol transdermal
`system).
`
`We acknowledge receipt of your submission dated April 24, 2002. Your submission of March 1, 2002,
`constituted a complete response to our November 19, 2001 action letter.
`
`These supplemental new drug applications propose changes for the use of Vivelle—Dot® as follows:
`
`1. Revised labeling to incorporate safety information requested by the Agency in a letter dated Angus
`10. 2000, (5-012).
`.
`
`2. Removal of the restrictive language, regarding vasomotor symptoms associated with the
`menopause, that some women taking the 0.0375 tug/day dosage may experience a delayed onset of
`efficacy and revision of the Clinical Pharmacology Section of the Package Insert to be consistent
`with the FDA drafi labeling guidance (5-014), and
`
`3. Addition of the prevention of postmenopausal osteoporosis indication in rat-risk patients for the
`.025 mglday strength (5-015).
`
`We have completed the review of these supplemental applications, as amended. and have concluded that
`adequate information has been presented to demonstrate that the drug product is safe and effective for use as
`recommended in the agreed upon labeling text. Accordingly, these supplemental applications are approved
`effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert and text for
`the patient package insert).
`
`
`
`0007
`
`

`

`th———-——___._____
`
`NDA 20-538/3-012, 8-014, 3-015
`Page 2
`
`Please submit the copies of final printed labeling (FPL) electronically to the application according to the guidance
`for industry titled Providing Regulatory Submissions in Electronic Format - NDA (January 1999). Alternatively.
`you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days afier it is printed.
`Please individually mount ten of the copies on heavy-weight paper or similar material. For administrative
`purposes, these submissions should be designated “FPL for approved supplement NDA 20-53818-012, 5—014,
`5-015." Approval of these submissions by FDA is not required before the labeling is used.
`
`[fa letter communicating important information about this drug product (i.e.. :1 "Dear Health Care Professional"
`letter) is issued to physicians and others responsible for patient care, we request that you submit a copy of the
`letter to this NBA and a copy to the following address:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR
`314.80 and 314.81.
`
`Ifyou have any questions, call Domettc Spell-LeSane, NP-C, Regulatory Project Manager. at (301) 827-4260.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Daniel Shames, MD.
`Acting Director
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation 111
`Center for Drug Evaluation and Research
`
`Enclosure
`
`Appears This Way
`0n Original
`
`
`
`0008
`
`

`

`
`
`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
` “mmm—um—fl-mfln
`
`ls/
`.._....__..___-.__._......_..__
`
`Dena Hixon
`5/3/02 03:11:15 PM
`for Daniel Shame-s, MD
`
`Appears This Way
`On Original
`
`
`
`0009
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-538/S—015
`
`APPROVED LABELING
`
`
`
`0010
`
`

`

`NDA 20-53815-015
`
`‘i/ivelle-Dot1M (estradiol transdermal system) 0.0025 mg/day
`Novanis Pharmaceuticals Corporation
`
`Approved Labeling
`
`This supplemental application is not being approved during the first review cycle. An
`approved label has not been achieved.
`
`
`
`0011
`
`

`

`NDA 20-538/8-012. 8-014, 8-015
`Page 2
`
`U) N 0 VA RT 1 s
`
`0
`
`VivelIe-Dot
`
`(estradiol transdermal system)
`
`Continuous delivery for twiceaweekly application
`
`Rx only
`
`Prescribing lnfon-nation
`
`12000-56/1‘2000-57
`89001003
`
`ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER .
`
`Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures,
`including endometrial sampling when indicated, should be undertaken to rule out malignancy in all
`cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is currently no evidence
`that the use of “natural" esu'ogens results in a different endometrial risk profile than synthetic estrogens
`
`of equivalent estrogen dose.
`
`DESCRIPTION
`o
`
`(estradiol transderrnal system) contains cstradiol in a multipolymeric adhesive. The system is
`Vivelle-Dot
`designed to release estradiol continuously upon application to intact skin.
`
`Five dosage strengths of Vivelie-Dot are available to provide nominal in viva delivery rates of 0.025,
`0.0375, 0.05, 0.075, or 0.1 mg ofestradiol per day via the skirt. Each corresponding system has an active
`surface area of2.5, 3.75, 5.0, 7.5, or 10.0 cm2 and contains 0.39, 0.585, 0.78, 1.17, or 1.56 mg ofestradiol
`USP, respectively. The composition of the systems per unit area is identical.
`
`Estradiol USP is a white, crystalline powder, chemically described as estra-l,3,5 (lO)-triene-3,l?B-diol.
`
`The structural formula is
`
`
`
`The molecular formula of cstradiol is Gal-12,02. The molecular weight is 272.39.
`
`Vivelle-Dot is comprised ofthree layers. Proceeding from the visible surface toward the surface attached to
`the-skin, these layers are (l) a translucent polyolefin fihn (2) an adhesive formulation containing estradiol,
`rcrylic adhesive, silicone adhesive, oleyl alcohol, povidonc and dipropylene glycol, and (3) a polyester
`release liner which is attached to the adhesive surface and must be removed before the system can be used.
`
` 
`
`0012
`
`

`

`NDA 20-538fS-012, 8-014, 5-015
`Page 3
`
`///////////////////////////////////////////. ~— (I) Backing
`H5"..:{g.oP“..-.'1‘;‘1.‘13...“ana...
`D ‘
`U.Q.
` :9:o:o”:5
`.,.I:Us“..‘.50f"....‘._'I...
`
`-—- (3) Protective Liner
`
`The active component of the system is esn'adiol. The remaining components of the system are
`pharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`Estrogens are largely responsible for the development and maintenance of the female reproductive system
`and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of
`metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more
`potent than its metabolites, estrone and estn'ol, 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 androstenedione, 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.
`
`Estrogens act through binding to nuclear receptors in estrogen—responsive tissues. To date‘, two estrogen
`receptors have been identified. They vary in proportion from tissue to tissue. Circulating estrogens
`modulate the pituitary secretion of the gouadotropius, luteinizing hormone (Ll-I) and follicle stimulating
`hormone (FSH) through a negative feedback mechanism. Estrogen replacement therapy acts to reduce the
`elevated levels of these hormones Seen in postmenopausal women.
`
`Pharmacokinetics
`
`The skin metabolizes esnadiol only to a small extent. in contrast, orally administered esnadiol is rapidly
`metaboliZed by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone
`than esn'adiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with
`lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral
`therapy.
`
`Absorption
`
`In a multiple-dose study consisting of three consecutive system applications of the original formulation
`[Vivelle® (esuadiol transdermal system)] which was conducted in 17 healthy, postmempausal women,
`blood levels of esnadiol and estrone were compared following application of these units to sites on the
`abdomen and buttocks in a crossover fashion. Systems that deliVer nominal estradiol doses of
`approximately 0.0375 rug/day and 0.1 trig/day were applied to abdominal application sites while the 0.1
`mglday 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 ngmL above baseline were
`observed following application to the buttocks. At
`the same time.
`increases in estrone plasma
`concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and
`
` 
`
`0013
`
`

`

`'
`
`.'.':=-5-:....-- 'mnmrrr—
`
`NDA 20-538/8-012, 8-014, 8-015
`Page 4
`
`61 pg/mL for the buttocks. While plasma concentrations ol‘estradiol and estrone remained slightly above
`baseline at 12 hours following removal of the systems in this study, results from another study show these
`levels to return to baseline values within 24 hours following removal of the systems.
`
`Figure 1 illustrates the mean plasma concentrations ofestradiol at steady-state during application ofthese
`patches at four different dosages.
`
`Figure I
`
`Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen
`
`ii
`
`i?
`
`
`
`Concentration(pg/mi.) 88
`
`Nonbasellne-conecled levels
`
`a 0.1 mglday
`X 0.075 mglday
`A 0.05 mglday
`0 0.0375 mg/day
`
`
`
`o
`
`1
`
`2
`
`a
`
`4
`
`Time (days)
`
`The corresponding pharmacokinetic parameters are summarized in the table below.
`
`Table l.
`
`Steady-State Estradiol Pharmacokinetic Parameters for
`Systems Applied to the Abdomen (mean 1: standard deviation)
`
`Nonbaseline-corrected data‘
`
`Dosage
`(molday)
`0.0375
`
`0.05
`0.075
`0.1
`
`mil
`
`cmt
`(ngmL)
`4s 1 16
`
`83141
`99 1 35
`133151
`
`145 1 71
`
`cw:
`(pgimL)
`34 1 1o
`
`5T:l:23#
`72 1 24
`89:38
`
`104 a 52
`
`cm... (34 hr)§
`(ngmI-i
`30 :10
`
`41 $1114!
`so 1 24
`90144
`
`as a 47
`
`'Mean baseline estradiol concentration = 11.7 ngmL
`TPeak plasma concentration
`iAvarage plasma concentration
`§Minimum plasma concentration at 84 hr
`#Measured over 80 hr
`iAppiiad to the buttocks
`
`Vivelle-Dot. the revised formulation with smaller system sizes, was show to be bioequivalent to the
`Otiginal formulation. Vivelle. used in the clinical trials.
`
` 
`
`0014
`
`

`

`NDA 20-538iS-012, 8-014, 5-015
`Page 5
`
`Distribution
`
`No specific investigation of the tissue distribution of estradiol absorbed from Vivelle in humans has been
`conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens
`are widely distributed in the body and are generally found in higher concentrations in the sex hormone
`target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and
`albumin.
`
`Metabolism
`
`Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens
`exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in
`the liver. Estradiol is converted reversibly to estrone, and both can be converted to estn'oI, which is the
`major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide
`conjugation in the liver, biliary secretion ofconjugates into the intestine, and hydrolysis in the gut followed
`by reabsorption. In postmenopausal women a significant portion ofthe circulating estrogens exist as sulfate
`conjugates, eSpecially estrone sulfate, which serves as a circulating reservoir for the formation of more
`active estrogens.
`
`Excretion
`
`Estradiol. estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The
`half-life values calculated after dosing with the Vivelle-Dot ranged from 5.9 to 7.7 hours. After removal
`of the systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours.
`
`Special Populations
`
`Vivelle-Dot was- investigated in postmenopausal women. No pharrnacokinetic studies were conducted in
`other special pupulations.
`
`Drug interactions
`
`in vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4
`(CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. inducers
`of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, phenytoin,
`carbamazepine, rifampin and dexarnethasone may reduce plasma concentrations of estrogens, possibly
`resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of
`CYP3A4 such as cirnetidine, erythrornycin, clarithromycin, ketoconazole, itracomzole, ritonavir, and
`grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
`
`Adhesion
`
`Based on combined data from three short-tenn clinical trials consisting of 471 observations, 85% of
`Vivelle-Dot adhered cOmpletely to the skin over the 3.5 day wear period. Three (3%) of the systems
`detached and were reapplied or replaced during the 3.5 day wear period. Approximately 80% of the
`transdermal systems evaluated in these studies were Vivelle-Dot 0.05 mg/day.
`
`Clinical Studies
`
`Effects on vasomotor symptoms
`
` 
`
`0015
`
`

`

`- -'.AA=.-
`
` 
`
`0016
`
`NDA 20-538lS-012, 8-014. 8-015
`Page 6
`
`in a pharmacokinetie study, Vivelle-Dot was shown to be bioequivalent to Vivelle. In two controlled
`clinical trials with Vivelle, of 356 subjects, the 0.075 and 0.1 mg doses were superior to placebo in
`relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatrn eat.
`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 performed with Vivelle to
`establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number ofhot flushes in
`these 255 patients was I 1.5. Results at Weeks 4, 8, and 12 of treatment are shown in the figure below. (See
`Figure 2.)
`
`Figure 2
`
`Mean (SD) change irom baseline in mean daily number of flushes tor
`Vivelle 0.0375 mg versus Placebo in a 12-week trial.
`
`Week 12"
`Week 8'
`Week 4'
`L_._._—_.—L___.._.___._I
`
`o
`
`G)
`
`5 §
`
`-2a
`
`5 .4
`
`5g
`
`a=
`'D
`
`9 a
`5}
`'-'
`g 40
`E
`
`-a.4{5.7i
`
`n=130
`_
`9.26.6)
`9.35.9)
`""129
`n=126
`-12 - Vivelle 0.0375 mglday
`Placebo
`
`'indicales statistically significant diflerence $40.05) between Viveile 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 Vivellc
`(0.0375 mg, 0.05 mg, 0.075 mg, and OJ mg) are effective for the control of vasomotor symptoms.
`
`Eflects on bone mineral densig:
`
`Efficacy and safety of Viveile in the prevention ofpostmenopausal osteopomsis 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), surgicaily or namrally menopausal women (within 5 years of
`menopause), with no evidence of osteopororis (lumbar spine bone mineral density within 2 standard
`deviations of average peak bone mass, i.e., 2 0.82? 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 mglday) and 67 patients to
`placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non~
`hysterectomized women received oral medroxyprogcsterone acetate (2.5 mglday) throughout the study.
`
`The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (til %)
`or nonhysterectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years); the mean
`
`

`

`NDA 20-538/3-012, 8-014, 8-015
`Page 7
`
`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 ofpercent change
`from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable.
`Patients were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental
`vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to
`this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were
`significantly superior to placebo (p<0.05) at all time points with the exception of Vivelle 0.05 mg/day at 6
`months. The highest dOSe of Vivelle was superior to the three lower doses. There were no statistically
`significant differences in pairwise comparisons among the three lower doses. (See Figure 3.)
`
`Figure 3
`acne mineral density - AP Lumbar spine
`Least squares means of percentage change from baseline
`All randomized patients with at least one post-baseline essessmenl available
`- with last post-baseline observation carried forward
`
`7
`goa
`
`:23.4
`
`43
`
`e
`
`2
`1
`£
`§o1
`s
`2
`
`Analysis 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 time points. A mixture of significant
`and non—significant results were obtained for the lower dose groups at earlier time points. The highest
`Vivelle dose was superior to the three lower doses, and there were no significant differences among the
`three lower doses at this skeletal site. (See Figure 4.)
`
` 
`
`0017
`
`

`

`NDA 20—538/8-012, 5-014, 8-015
`Page 8
`
`Figure 4
`Bme mineral density - Femoral neck
`Least equates means of percentage change from baaeline
`All randomized patients with at least one post-baseline assessment
`available with last poet-baseline observation carried forward
`
`
`
`itmargetronbaselha
`
`Lenioenusmoq
`
`LEG VI P: ”.05
`
`A813,!) u p: P4105
`
`LEGO H P: pares
`
`...........fl-
`.---
`
`----------------------
`
`
`
`Wlak 25
`
`Wick 52
`
`Wook 78
`
`Wash: 104
`
`Trauma-1| duration
`
`+vwn 0.1 mulday (A) - -I- - -Vtvolllt (105 my (a) - ‘ —Vtvdle 0.0375 may (cl - +6 -VNOIII 0.025 Willy (D) + Placebo {P}
`
`The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-
`telopeptides of type I collagen (a marker ofbone resorption) decreased numerically in most ofthe active
`treatment groups relative to baseline. However, the decreases in both markers were inconsistent across
`treatment groups and the differences between active treatment groups and placebo were not statistically
`significant.
`
`INDICATIONS AND USAGE
`
`Vivelle-Dot is indicated in:
`
`PP!“
`
`Treatment of moderate-to-severe vasomotor symptoms associated with the menOpause.
`
`_ Treatment of vulvar and vaginal atrophy.
`Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
`
`Prevention ofpostmenopausal osteOporosis. Estrogen replacement therapy reduces bone resorption
`and retards postmenopausal bone loss. When estrogen therapy is discontinued, bone mass declines
`at a rate comparable to that of the immediate postmenopausal period.
`
`The mainstays ofprevention ofpostmenopausal osteoporosis are weight-bearing exercise, adequate
`calcium and vitamin D intake and, when indicated. estrogen. Postmenopausal women absorb
`dietary calcium less efficiently than premenopausal women and require an average of 1500 rug/day
`ofe] emental calcium to remain in neutral calcium balance. The average calcium intake in the USA
`is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful
`for women with suboptimal dietary intake. Vitamin D supplementation of400-800 lU/day may also
`be required to ensure adequate daily intake in postmenopausal women.
`
`Early menopause is one of the strongest predictors for the development of osteoporosis. Other
`factors associated with osteoporosis include genetic factors (small build, family history), Iifester
`
` 
`
`0018
`
`

`

`
`
`NDA 20-538/8-012, 5-014, 3—015
`Page 9
`
`(cigarette smoking. alcohol abuse, sedentary exercise habits) and nutrition (below average body
`weight and dietary calcium intake).
`'
`
`CONTRAINDICATIONS
`
`Estrogens should not be used in individuals with any of the following conditions:
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`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.
`
`Active deep vein thrombosis/pulmonary embolism or a history of these couditions.
`
`Known hypersensitivity to any of the components of Vivelle-Dot
`
`WARNINGS
`
`1.
`
`Induction of Malignant Neoplasms.
`
`a.
`
`Endomem'al cancer.
`
`The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12—fold greater
`than in nonusers and appears dependent on duration of treatment and on estrogen dose. Most
`studies show no significant increased risk associated with the use of estrogens for less than 1 year.
`The greatest risk appears associated with prolonged use with increased risks of 15 to 24-fold for
`five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after
`estrogen therapy is discontinued.
`
`b.
`
`Breast cancer.
`
`While some epidemiologic studies suggest a very modest increase in breast cancer risk for estrogen
`alone users versus non-users, other studies have not shown any increased risk. The addition of
`progestin to estrogen may increase the risk for breast cancer over that noted in non—hormone users
`more significantly (by about 24 to 40%), although this is based solely on epidemiologic studies, and
`definitive conclusions await prospective, controlled clinical trials.
`
`Women without a uterus who require hormone replacement should receive estrogen-alone therapy,
`and should not be exposed unnecessarily to progestins. Women with a utems who are candidates for
`short-term combination estrogenfprogestin therapy (for reliefofvasomotor symptoms) are not felt to be
`at a substantially increased risk for breast cancer. Women with a uterus who are candidates for
`long-term use of estrogen/progestin therapy should be advised of potential benefits and risks
`(including the potential for an increased risk of breast cancer).
`
`All women should receive yearly breast exams by a healthcare provider and perform monthly breast
`self-examinations. In addition, mammography examinations should be scheduled as suggested by
`providers based on patient age and risk factors.
`
` 
`
`0019
`
`

`

`NDA 20-538/5-012, 5-014. 8-015
`Page ii)
`
`2.
`
`Thromboembollc Disorders.
`
`The physician should be aware ofthe possibility ofthrombotic disorders (thrombophlebiris, retinal
`thrombosis, cerebral embolism, and pulmonary embolism) using estrogen replacement therapy and
`be alert to their earliest manifestations. Should any of these occur or be snapected, estrogen
`replacement therapy should be discontinued immediately. Patients who have risk factors for
`thrombotic disorders should be kept under carefiil observation.
`
`Venous thromboembalism. Several epidemiologic studies have found an increased risk of
`thromboembolism (VTE) in users of estrogen replacement therapy (ERT) who did not have
`prediSposing conditions for VTE, such as past history ofcardi ovascular disease or a recent history
`ofpregnancy, surgery, trauma, or serious illness. The increased risk was found only in current ERT
`users; it did not persist in former users. The risk appeared to be higher in the first year ofuse and
`decreased thereafter. The findings were similar for ERT alone or with added progestin and pertain
`to commonly used oral and transderrnal doses, with a possible dose-dependent effect on risk. The
`studies found the VTE risk to be about One case per 10,000 women per year among women not
`using ERT and without predisposing conditions. The risk in current ERT users was increased to 2
`to 3 cases per 10,000 women per year.
`
`Cerebrovascular disease. Embolic cerebrovascular events have been reported in postmenOpausal
`women receiving estrogens.
`
`Cardiovascular disease. Large doses of estrogen (5 mg conjugated estrogens per day), comparable
`to those used to treat cancer of the prostate and breast, have been shown in a large prospective
`clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism,
`and thrombophlebitis.
`
`Gallbladder Disease. A 2 to 4-fold increase in the risk ofgallbladder disease requiring surgery in
`postmenopausal women receiving estrogens has been reported.
`
`Hypercalcemia. Administration of estrogen may lead to severe hypercalcemia in patients with
`breast cancer and bone metastases. if this occurs, the drug should be stopped and appropriate
`measures taken to reduce the serum calcium level.
`
`3.
`
`4.
`
`PRECAUUONS
`
`A.
`
`General
`
`Addition ofa progestr‘n when a woman has not had a hysterectomy. Studies of the addition of a
`1.
`progestin for [0 or more days of a cycle of estrogen administration have reported a lower incidence of
`endometrial hyperplasia than would be induced by estrogen treatment alone. Endornetrial hyperplasia may
`be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the
`use of progestins in estrogen replacement regimens. These include adverse effects on lipoprorein
`metabolism (cg, lowering HDL and raising LDL) and impairment of glucose tolerance. The choice of
`progestin, its dose, and its regimen may be important in minimizing these adverse effects.
`
`Cardin vascular risk. The effects ofestrogen replacement on the risk ofcardiovascular disease have
`I.
`not been adequately studied. However, data from the Heart and Estrogen/Progestin Replacement Study
`
`
`
`0020
`
`

`

`NDA 20-538/8-012, 8-014, 8-015
`Page II
`
`(l-lERS), a controlled clinical trial of secondary prevention of 2,763 postmenopausal women with
`documented heart disease, demonstrated no benefit. During an average follow-up of4.1 years, treatment
`with oral conjugated estrogen plus medroxyprogesterone acetate did not reduce the overall rate ofcoronary
`heart disease (CHD) events in post-menopausal women with established coronary disease. There were
`more CHD events in the hormone treated group than in the placebo group in year I, but fewer events in
`years 3 through 5.
`
`Elevated Moodpressure. In a small number ofme reports, substantial increases in blood pressure
`3.
`during estrogen replacement therapy have been attributed to idiosyncratic reactions to estrogens. In a large,
`randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure
`was not seen.
`
`Familial hyperlipaproreinemia. In patients with familial defects of lipoprotein metabolism,
`4.
`estrogen therapy may be associated with elevations ofplasma triglycerides leading to pancreatitis and other
`complications...
`
`Impaired liver function. Estrogens may be poorly metabolized in patients with impaired liver
`5.
`function and should be administered with caution.
`
`Hypothroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.
`6.
`Patients with normal thyroid function can compensate for the increased TBG by making more thyroid
`hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent
`on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their
`thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their
`fine thyroid hormone levels in an acceptable range