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`
`State of Maryland, Montgomery County
`
`1, Marlene S. Bobka, under oath, hereby depose andstate as follows:
`
`Ls
`
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`ao.
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`Marlene $. Bobka
`
`Date
`
`SUBSCRIBED AND SWORN before me on YESENIA SANCHEZ BUSTOS
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`My commission expires: May , 03 202
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`NOTARY PUBLIC
`MONTGOMERY COUNTY
`MARYLAND
`MY COMMISSION EXPIRES MAY 03,2021
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`~-.
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`MYLAN- EXHIBIT 1006
`0001
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`

`EXHIBIT A
`
`
`
`0002
`
`

`

`|
`
`IMI
`
`*523 Wl
`
`:*T
`
`*Bx
`
`5236149
`
`B
`
`Vivelle-DOT (Novartis) 05/03/2002 Supplemental Approval [Label
`Revisions]: $12, $14, $15 Approvable Letter; Final Labeling;
`Approval Letter
`
`This document was provided by:
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`0003
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`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Packagefor:
`
`APPLICATION NUMBER:
`20-538/S-015
`
`Trade Name:
`
`Vivelle-Dot
`
`Generic Name:
`
`estradiol transdermal system
`
`Sponsor:
`Approval Date:
`
`Indications:
`
`Novartis Pharmaceuticals Corporation
`
`May3, 2002
`
`Provides for the prevention of postmenopausal
`osteoporosis indication in at-risk patients for the .025
`mg/day strengths.
`
`SOlh
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`20-538/S-015
`
`CONTENTS
`
`
`
`| Reviews / Information Includedin this NDA Review.
`
`
`Approval Letter
`Approvable Letter
`Final Printed Labeling
`Medical Review(s
`Chemistry Review(s
`EA/FONSI
`Pharmacology Review(s
`Statistical Review(s)
`_
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`7
`Administrative Document(s
`
`Correspondence.
`
`-
`
`ee
`
`
`
`
`.
`
`;
`
`
`
`0005
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`20-538/S-015
`
`APPROVAL LETTER
`
`
`
`0006
`
`

`

`
`wt
`
`¢ DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`Food and Drug Administration
`
`Rockville MD 20857
`
`NDA 20-538/5-012, 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 S05(b) of the Federal Food, Dmig, and Cosmetic Act for Vivelle-Dot® (estradiol transdermal
`system).
`
`Weacknowledgereceipt 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 changesfor the use of Vivelle-Dot® as follows:
`
`1. Revised labeling to incorporate safety information requested by the Agency im a Jetter dated Augus
`10, 2000, (S-012),
`‘
`
`2. Removal ofthe restrictive language, regarding vasomotor symptoms associated with the
`menopause, that some women taking the 0.0375 mg/day dosage may experience a delayed onset of
`efficacy and revision of the Clinical Pharmacology section of the Package Insert to be consistent
`with the FDA draft labeling guidance (S-014), and
`
`3. Addition of the prevention of postmenopausal osteoporosis indication in at-risk patients for the
`-025 mg/day strength (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 productis safe and effective for use as
`recommendedin the agreed upon labeling text. Accordingly, these supplemental applications are approved
`effective on the date ofthis letter.
`
`Thefinal printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert and text for
`the patient package insert).
`
`
`
`0007
`
`

`

`NDA 20-538/S-012, 5-014, 8-015
`Page 2
`
`Please submit the copies offinal 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 afterit is printed.
`Please individually mount ten of the copies on heavy-weight paper or similar material. For administrative
`purposes, these submissions should be designated “FPL for approved supplement NDA 20-538/S-012, 5-014,
`5-015." Approvalof these submissions by FDA is not required before the labeling is used.
`
`If a letter communicating importantinformation aboutthis drug product(i.e., a "Dear Health Care Professional"
`letter) is issued to physicians and others responsible for patient care, we request that you submit a copy ofthe
`letter to this NDA 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 Domette Spell-LeSane, NP-C, Regulatory Project Manager, at (301) 827-4260.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Daniel Shames, M.D.
`Acting Director
`Division of Reproductive and Urologic Drug Products
`Office of Drug Evaluation HI
`Center for Drug Evaluation and Research
`
`Enclosure
`
`Appears This Way
`On Original
`
`
`
`0008
`
`

`

`
`
`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
` aOEeneaeeegsageeweeem
`
`/s/
`
`Dena Hixon
`5/3/02 03:11:15 PM
`for Daniel Shames, MD
`
`Appears This Way
`On Original
`
`
`
`0009
`
`

`

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

`

`NDA 20-538/8-015
`Vivelle-Dot™ (estradiol transdermal system) 0.0025 mg/day
`Novartis Pharmaceuticals Corporation
`
`Approved Labeling
`
`This supplemental application is not being approved during the first review cycle. An
`approved label has not been achieved.
`
`
`
`0011
`
`

`

`NDA 20-538/S-012, S-014, S-015
`Page 2
`
`tb NOVARTIS
`
`®
`Vivelle-Dot
`(estradiol transdermal system)
`
`Continuous delivery for twice-weekly application
`
`Rx only
`
`T2000-56/T2000-57
`89001003
`
`Prescribing Information
`
`ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER.
`
`Close clinical surveillance of all womentaking estrogensis important. Adequate diagnostic measures,
`including endometrial sampling when indicated, should be undertaken to rule out malignancyin ail
`cases ofundiagnosed persistent or recurring abnormal vaginal bleeding. There is currently no evidence
`that the use of“natural” estrogens results in a different endometrialrisk profile than synthetic estrogens
`
`of equivalent estrogen dose.
`
`DESCRIPTION
`®
`
`(estradiol transdermal system) contains estradiol!in a multipolymeric adhesive. The system is
`Vivelle-Dot
`designed to release estradiol continuously upon application to intact skin.
`
`Five dosage strengths of Vivelle-Dot are available to provide nominalin vivo delivery rates of 0.025,
`0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin. Each corresponding system has an active
`surface area of2.5, 3.75, 5.0, 7.5, or 10.0 cm and contains 0.39, 0.585, 0.78, 1.17, or 1.56 mg ofestradiol
`USP,respectively. The composition of the systems per unit area is identical.
`Estradiol! USPis a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17B-diol.
`
`The structural formulais
`
`
`
`The molecular formula ofestradiol is C,,H,,O,. 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 (1) a translucentpolyolefin film (2) an adhesive formulation containing estradiol,
`acrylic adhesive, silicone adhesive, oley! alcohol, povidone and dipropylene glycol, and (3) a polyester
`release liner which is attachedto the adhesive surface and must be removed before the system can be used.
`
` 
`
`0012
`
`

`

`7. SOARSta?MERE cee Je
`
`NDA 20-538/S-012, 8-014, S-015
`Page 3
`
`VIII,
`S
`RRONP
` Oeee BO
`B
`ASheSSRNEHD
`
`
`-—- (3) Protective Liner
`
`The active component of the system is estradiol. The remaining components of the system are
`pharmacologically inactive.
`
`CLINICAL PHARMACOLOGY
`
`Estrogensare largely responsible for the development and maintenance ofthe female reproductive system
`and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of
`metabolic interconversions, estradio) is the principal intracellular human estrogen andis 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 follicte, which secretes 70 to 500 yg of estradiol daily,
`depending on the phase of the menstrual cycle. After menopause, most endogenousestrogen 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-responsivetissues. To date, two estrogen
`receptors have been identified. They vary in proportion from tissue to tissue. Circulating estrogens
`modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH)andfollicle stimulating
`hormone (FSH)through a negative feedback mechanism. Estrogen replacement therapy acts to reduce the
`elevated levels of these hormones seen in postmenopausal women.
`
`Pharmacokinetics
`
`The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradio} ts rapidly
`metabolized by theliver to estrone and its conjugates, givingrise to highercirculating levels of estrone
`than estradiol. Therefore, transderma)] administration produces therapeutic plasmalevels of estradiol with
`lowercirculating levels of estrone and estrone conjugates and requires smaller total doses than does oral
`therapy.
`
`Absorption
`In a multiple-dose study consisting of three consecutive system applications of the original formulation
`(Vivelle® (estradiol transdermal system)] which was conducted in 17 healthy, postmenopausal women,
`blood levels of estradiol and estrone were compared following application of these units to sites on the
`abdomen and buttocks in a crossover fashion. Systems that deliver nominal estradiol doses of
`approximately 0.0375 mg/day and 0.1 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
`concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and
`
` 
`
`0013
`
`

`

`0 eSgoST
`
`NDA20-538/S-012, S-014, S-015
`Page 4
`
`61 pg/mL forthe buttocks. While plasma concentrationsofestradiol and estrone remainedslightly above
`baselineat 12 hours following removalofthe systemsin this study, results from another study show these
`levels to return to baseline values within 24 hours following removal of the systems.
`Figure1 illustrates the mean plasma concentrationsofestradiolat steady-state during application ofthese
`patchesat four different dosages.
`
`Figure 1
`
`Steady-State Estradiol Plasma Concentrations for Systems Applied to the Abdomen
`
`Nonbaseline-corrected levels
`
`160
`
`120
`
`og 0.1 mg/day
`x 0.075 mg/day
`A 0.05 mg/day
`
`
`
` @ 0.0375 mg/day Concentration(pg/mL) S
`
`0
`
`1
`
`2
`Time (days)
`The corresponding pharmacokinetic parameters are summarized in the table below.
`
`3
`
`4
`
`Table 1.
`
`Steady-State Estradiol Pharmacokinetic Parameters for
`Systems Applied to the Abdomen (mean + standard deviation)
`
`Nonbaseline-corrected data*
`Cmaxt
`Cart
`Dosage
`(pg/mL)
`(pg/mL)
`(mg/day)
`46 + 16
`34410
`0.0375
`83441
`57 + 234
`0.05
`99+35
`72 +24
`0.075
`133 + 51
`69 + 38
`|
`145471
`104 452
`0.11
`*Meanbaseline estradiol concentration = 11.7 pg/mL
`tPeak plasma concentration
`+Average plasma concentration
`§Minimum plasma concentration at 64 br
`#Maasured over 80 hr
`WApplied to the buttocks
`Vivelle-Dot, the revised formulation with smaller system sizes, was shown to be bioequivalent to the
`original! formulation, Vivelle, used in the clinical!trials.
`
`Coun (84 hr)S
`(pg/mL)
`30 +10
`44¢11#
`60 + 24
`90444
`85247
`
` 
`
`0014
`
`

`

`NDA 20-538/8-012, $-014, S-O15
`Page 5
`
`Distribution
`
`No specific investigation ofthe tissue distribution of estradiol absorbed from Vivelle in humanshas been
`conducted. The distribution of exogenous estrogens is similar to that of endogenousestrogens. Estrogens
`are widely distributed in the body and are generally found in higher concentrations in the sex hormone
`target organs. Estrogenscirculate in the blood largely bound to sex hormone binding globulin (SHBG) and
`albumin.
`
`Metabolism
`
`Exogenousestrogens are metabolized in the same manneras endogenousestrogens. Circulating estrogens
`exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in
`the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the
`major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide
`conjugation in theliver, biliary secretion ofconjugatesinto the intestine, and hydrolysis in the gut followed
`by reabsorption. In postmenopausal! womena 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 andestriol 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 wasinvestigated in postmenopausal women. No pharmacokinetic studies were conducted in
`other special populations.
`
`Drug Interactions
`
`in vitro and in vivo studies have shown thatestrogens are metabolized partially by cytochrome P4506 3A4
`(CYP3A4). Therefore, inducers or inhibitors of CYP3A4 mayaffect estrogen drug metabolism. Inducers
`of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, phenytoin,
`carbamazepine, rifampin and dexamethasone may reduce plasma concentrations of estrogens, possibly
`resulting in a decrease in therapeutic effects and/or changesin the uterine bleeding profile. Inhibitors of
`CYP3A4 such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and
`grapefruit juice may increase plasma concentrations of estrogens and mayresult in side effects.
`
`Adhesion
`
`Based on combined data from three short-term clinical trials consisting of 471 observations, 85% of
`Vivelle-Dot adhered completely to the skin over the 3.5 day wear period. Three (3%) of the systems
`detached and were reapplied or replaced during the 3.5 day wear period. Approximately 80% of the
`transdermal! systems evaluated in these studies were Vivelle-Dot 0.05 mg/day.
`
`Clinical Studies
`
`Effects on vasomotor symptoms
`
` 
`
`0015
`
`

`

`NDA 20-538/S-012, S-014, $-015
`Page 6
`
`In a pharmacokinetic study, Vivelle-Dot was shown to be bioequivalent to Vivelle. In two controlled
`clinical tials 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 oftreatment.
`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 numberofhotflushes in
`these 255 patients was 11.5. Results at Weeks 4,8, and 12 oftreatment are shown in thefigure below. (See
`Figure 2.)
`
`Figure 2
`
`Mean (SD) change from baseline in mean dally number of flushes for
`Vivelle 0.0375 mg versus Placebo in a 12-weektrial.
`
`Week 12°
`Week 8"
`Week 4"
`Ld
`
`
`
`0
`24
`
`.
`
`8.45.6)
`n=129
`TEBE vivette 0.0375 mg/day
`Placebo
`
`
`
`
`ae 3914.8)
`
`
`n=1Z25
`ao
` Pe 5.55.0)
`
`n=120 Ag
`66(5.3)
`Me
`n=118
`-B.A(5.7)
`n=130
`
`rabeseh
`2n=126
`
` Mean(SD)reductionfrombaseline 8
`
`"Indicates statistically significant difference (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 Weck 4 and maintained efficacy through Weeks 8 and 12 of treatment. All doses of Vivelle
`(0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg) are effective for the control of vasomotor symptoms.
`
`Effects on bone mineral density
`
`Efficacy and safety ofVivelle in the prevention ofpostmenopausal 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
`deviations 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 (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to
`placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-
`hysterectomized womenreceived oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.
`Thestudy population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (61%)
`or nonhysterectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years); the mean
`
`0arm
`
` 
`
`0016
`
`

`

`y
`
`eee Tem ee
`
`NDA 20-538/S-012, 8-014, §-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 supplementaldietary calcium (1000 mg elemental calcium/day) but no supplemental
`vitamin D. There was an increase in BMDofthe AP lumbar spinein 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)atall tume points with the exception of Vivelie 0.05 mg/day at 6
`months. The highest dose of Vivelle was superior to the three lower doses. There were nostatistically
`significant differences in pairwise comparisons among the three lower doses. (See Figure 3.)
`
`Figure 3
`Bone mineral density - AP Lumbar spine
`Least squares means of percentage change from baseline
`All randomized patients with a! least one post-Daseline assessment available
`. with last post-baseline observation camied forward
`
`T
`26&
`
`43
`
`¥ 334
`
`E
`
`§
`
`2=B
`
`o1
`2
`
`Analysis of percent change from baseline in femoral neck BMD,a secondary efficacy outcome variable,
`showed qualitatively similar results; all doses ofVivelle were significantly superior to placebo (p<0.05) at
`24 months. The highest Vivelle dose was superior to placebo at all time points. A mixture of significant
`and non-significant results were obtained for the lower dose groups at earlier ime points. The highest
`Vivelle dose was superior to the three lower doses, and there were no significant differences among the
`three lower doses atthis skeletal site. (See Figure 4.)
`
` 
`
`0017
`
`

`

`TT leeheegTo
`
`NDA 20-538/S-012, S-014, 8-015
`Page 8
`
`Figure 4
`Bone minera! density - Femoral neck
`Least squares means of percentage change from baaeline
`All randomized patients with at least one post-baseline assessment
`available with last post-baseline observation carried forward
`
`
`
`%changefrombaseline
`
`hOnNSosenwacnay
`
`AGC vi P: po0.05
`
`AB.C.D va P; p<0.05
`
`AB.CO va P: px.05
`— Se -Vivella 0.025 mo/day (0) —e— Placebo (P}
`
`Ae eee,IEeereeleSTOT,
`oo
`
`Week 26
`
`Week 52
`
`Week 78
`
`Weok 104
`
`Treatment duration
`
`——@—Vivelle 0.1 mofday (A) = =IB- = ‘Vivelle 0.05 motday (B) — dh — Vivella 0.0375 mo/day(C)
`
`The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-
`telopeptides of type | collagen (a marker of bone resorption) decreased numerically in mostofthe active
`treatment groupsrelative to baseline. However, the decreases in both markers were inconsistent across
`treatment groups and the differences between active treatment groups and placebo werenotstatistically
`Significant.
`
`INDICATIONS AND USAGE
`
`Vivelle-Dotis indicated in:
`
`»wh
`
`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 replacementtherapy reduces bone resorption
`and retards postmenopausal bone loss. When estrogen therapy is discontinued, bone mass declines
`at a rate comparableto that of the immediate postmenopausalperiod.
`
`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 mg/day
`ofelemental] 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 maybe helpful!
`for women with suboptimaldietary intake. Vitamin D supplementation of400-800 FU/day mayalso
`be required to ensure adequate daily intake in postmenopausal women.
`
`Early menopauseis one of the strongest predictors for the development of osteoporosis. Other
`factors associated with osteoporosis include genetic factors (small build, family history), lifestyle
`
` 
`
`0018
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`

`

`
`
`NDA 20-538/S-012, 5-014, 8-015
`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 ofthe 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 abnormalgenital 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 conditions.
`
`Known hypersensitivity to any of the components of Vivelle-Dot
`
`WARNINGS
`
`1,
`
`Induction of Malignant Neoplasms.
`
`a.
`
`Endometrial cancer.
`
`The reported endomemial cancerrisk among unopposed estrogen users is about2 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 estrogensfor 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 persistfor 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 mayincreasetherisk for breast cancer over that noted in non-hormoneusers
`more significantly (by about 24 to 40%), although this is based solely on epidemiologic studies, and
`definitive conclusions await prospective, controlled clinicaltrials.
`Women without a uterus who require hormone replacementshould receive estrogen-alonetherapy,
`and should not be exposed unnecessarily to progestins. Women with a uterus who are candidates for
`short-term combination estrogen/progestin therapy (for reliefofvasomotor symptoms)are notfelt 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 ofbreast cancer).
`All womenshould 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 andrisk factors.
`
` 
`
`0019
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`

`NDA 20-538/S-012, S-014, S-015
`Page 10
`
`2.
`
`Thromboembolic Disorders.
`
`The physician should be aware ofthe possibility ofthrombotic disorders (thrombophlebitis,retinal
`thrombosis, cerebral embolism, and pulmonary embolism) using estrogen replacementtherapy and
`be alert to their earliest manifestations. Should any of these occur or be suspected, estrogen
`replacement therapy shouid be discontinued immediately. Patients who have risk factors for
`thrombotic disorders should be kept under careful observation.
`
`Venous thromboembolism. Several epidemiologic studies have found an increased risk of
`thromboembolism (VTE) in users of estrogen replacement therapy (ERT) who did not have
`predisposing conditions for VTE, such as past history ofcardiovascular 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 transdermal doses, with a possible dose-dependenteffect 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 peryear.
`
`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 ofnonfatal myocardial infarction, pulmonary embolism,
`and thrombophlebitis.
`
`Gallbladder Disease. A 2 to 4-fold increasein 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 dmg should be stopped and appropriate
`measures taken to reduce the serum calcium level.
`
`3.
`
`4,
`
`PRECAUTIONS
`
`A.
`
`General
`
`Addition ofaprogestin when a woman has not had a hysterectomy. Studies of the addition of a
`1.
`progestin for 10 or more days of a cycle of estrogen administration have reported a lower incidence of
`endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may
`be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the
`use of progestins in estrogen replacement regimens. These include adverse effects on lipoprotein
`metabolism (e.g., lowering HDL and raising LDL) and impairment ofglucose tolerance. The choice of
`progestin, its dose, and its regimen may be important in minimizing these adverse effects.
`
`Cardiovascularrisk. The effects ofestrogen replacement on the risk ofcardiovascular disease have
`%
`not been adequately studied. However, data from the Heart and Estrogen/Progestin Replacement Study
`
`
`
`0020
`
`

`

`OFee -
`
`NDA 20-538/S-012, S-014, S-015
`Page 11
`
`(HERS), 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 hormonetreated group than in the placebo groupin year 1, but fewer events in
`years 3 through 5.
`
`Elevatedbloodpressure. In a sma){ number ofcase reports, substantial increases in blood pressure
`3.
`during estrogen replacement therapy have beenattributed to idiosyncratic reactions to estrogens. ina large,
`randomized, placebo-controlled clinicaltrial, a generalized effect of estrogen therapy on blood pressure
`was not seen.
`
`Familial hyperlipoproteinemia. In patients with familia] defects of lipoprotein metabolism,
`4,
`estrogen therapy may be associated with elevations ofplasma tnglycerides 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 norma] 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 whoarealso receiving estrogens may require increased doses oftheir
`thyroid replacementtherapy. These patients should have their thyroid function monitored in order to maintain their
`free thyroid hormonelevels in an acceptable range.
`
`Fluid retention. Because estrogens may cause somedegreeoffluid retention, conditions which
`7.
`might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction,
`warrant careful observation when estrogens are prescribed.
`
`Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of
`8.
`estrogen therapy.
`9.
`Hypocalcemia. Estrogens should be used with