ORIGINAL ESEARC4 ARTICLE
`
`Oral Contraceptive Estrogen Dose
`Considerations
`
`Andrew M.KauflitZ
`
`conttacepthe OC
`
`steroid
`
`dose
`
`the
`
`candiastes may appropriately use any OC formula
`rico th 50
`they -moke
`EE whether or not
`
`should
`
`before
`
`established
`
`lit
`
`reduction
`
`prescribthg
`
`to
`
`pjdiongh the trend with oral
`presihing-ba been to reducetbe
`frirther dose
`risks and.bcnefiisof
`oeethiai
`be cansidered
`that
`axe changed
`the frequency
`is possible
`patterns
`of some of the advantaged ssbaatedwith the 30-
`estradiol Ei formuiationsgood cycle
`35.g ethinyl
`control and many tioncentracepsive benefitsmay be
`reduced with the use of 2O-ag estrogen dose formula-
`tions Clinicians should weigh these factors
`in the
`and clinical profile
`ot eaci patient historc
`contxr
`the estrogen dose of an OC formula-
`when se1ecthxg
`non
`
`Breast Cancer
`iisk
`The Collaborative Group on Hox-moual
`Factors in
`Breast Cancer
`recently xe-evaluated
`the relationship
`bei- een breast
`cancer and oral contraception
`hives-
`lim
`-information
`epidemiologic
`data from
`
`including
`
`this
`
`t.iators incoxprated
`2S nations
`their database
`53.297 women with
`breast
`cancer
`and
`li0239
`women without Overall
`encom
`reana1yb
`passed 90% of
`the epidemiologic
`data published to
`date on this subject The results were highly zeassur
`ing with the overall
`risk of breast cancer diagnosis
`by OC use among women who bad
`increased
`not
`topped using 0Cc 10 to 2$ years earlier
`Current users and women
`ho had used OCs in the
`to
`to be at
`years appeared
`slightly
`cancer diagnosis with relauve
`increased risk ot breast
`risks of 114 95% oaædence
`L15 to 1.33l
`interval
`and
`1J6 1.08
`to 1.23 respectively
`As Figure
`shows women who ceased use between
`and
`years
`earlier showed only
`incicase in relative
`marginal
`risk 1.07 95% confidence
`1.02 to 1.13i
`interval
`iii women who were using
`Breast c-ancets
`diagnosed
`or previously bad used OCs were less clinically
`ad
`vanced
`than those presenting in age-matched
`never
`users OC users had
`rechiced
`relative
`sigriificazidy
`that had spread beyond
`risk for diagnosis of cancers
`the breast compared with nonusexsthe
`relative
`risk
`was 0.88 i95% confidence
`in erval L8l
`to 0.95
`that breast
`These findings
`cancer
`0.002
`suggest
`detected earlier in current or fonner OC users than in
`nonusers Women who use OCt may be
`age-matched
`more consistern in performing
`self ezarauna
`they ray undergo more regular clinical
`ions anti
`examinations
`and
`than non-
`studies
`rnarrimographic
`increased
`The slightly
`risk of diatosis
`recent-past OC users
`breast cancer
`an current
`cr
`due
`compared so nomisers may be partially
`tc detec
`uon bias
`
`CardiovasctzLjz
`
`.cecornrnendci
`
`rioaszook.ing
`
`Eients
`Some Lhnlcians have
`that 20-i.g fur-
`be used exclusively by OC users under age
`mulacions
`35 who smoke This recornrocndauou
`is nased
`on
`and
`is nor suppo-red
`cvi-
`by epidemologic
`theory
`tinder age 35 who smoke and take OCs
`d-nce Women
`thromboem-
`do not have
`an increased
`risk of veucsus
`holism ii couapaied with ncnsmokei Their risk
`infarction MI and stroke is low and
`of mocardiai
`the isk is reduced
`there
`are no cLita
`that
`indicating
`to 35 p.g OC
`with the use of 20-rig compared with 30-
`Among normotensive
`iormulations
`wcinen without otner risk tators for cardiovascular
`
`diea5C CVI use of 30 to 3Sq.g foimulatrons
`has
`been shown to have eliminated extess risk of Ml and
`stroke
`The ns of VTE has been
`but not ehmi-
`reduced
`nated by he use of 30-
`so 35-g LE Iormulador
`that VTE risk could
`he euected
`be further
`20 pg pills Howeer
`in th
`a- described
`by On
`CardovacuLar
`in that
`-i.ppleLYieflt
`of Oral Contraceptives
`no indicatior
`this occurs
`provide
`from the
`
`It
`
`iri.ght
`
`reducrc
`
`anice
`
`Stkety
`
`epioer-uologrc
`
`data
`
`that
`
`perspecuve
`
`c-aydiosascuiar
`
`Therefore
`safety OC
`
`previous
`
`ascrs
`
`breast
`
`is
`
`cix
`
`ari-ii of crt-
`5-d
`juo
`
`v5rtisi
`
`feafO er-i
`
`CyfeCi0 unvo
`p0cOeArthiw MflMrofc
`tt3-l Wot Z.r1h 35 a. v5s
`
`hahI
`
`raiss
`
`risk was riot
`lireast cancer
`estrgen dose Oxai
`vides strong Mence
`
`that
`
`to vary by OC
`this massive
`rear22ysr
`pio
`in tIre older age group
`
`found
`
`Cnce
`
`Al ht rr
`
`OUW
`
`PiaintifVs Exhibit
`
`xl-
`
`-Orft1i3-JAF
`No 12-I 25-jP-Tj5
`
`PTX 048
`
`551
`
`iOlt 624t3
`
`WC_LP0405323
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 1
`
`

`
`l6S Kaunitz
`
`Contraception
`19985915S-.aiS
`
`Figure
`time snce
`
`Relative
`
`risk of breast
`
`last use of combined
`
`cancer
`
`by
`oral contra
`
`PRSD
`
`CaaesfContids
`
`RR99%O
`
`Neveruser
`
`1.000.014
`
`28200/55220
`
`Current user
`
`1.240.038
`
`2356/4328
`
`Time
`
`since
`
`last use
`
`1.4y1
`
`5-9yr
`
`10.14
`
`yr
`
`yr
`
`1.160.032
`
`271714851
`
`1.070.024
`
`4239/7688
`
`0.980.022
`
`4384/8182
`
`1.030.025
`
`443Q8285
`
`0.0
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`breast
`
`epidemiologic
`
`of
`
`is most common prior OC use
`when breast cancer
`cancer
`risk
`does not affect
`in the preceding
`As indicated
`cunent
`sections
`for the safety
`data provide evidence
`OCs formulated with 50 jag EL The principal
`chal-
`OC users and
`their health
`lenge facing contemporary
`high OC
`care providers therefore relates to achieving
`efficacy Accordingly mnirnizing OC compliance
`and continuation assumes
`high priority as clinicians
`help their patients to select which OC formulation to
`use
`
`ceptives
`
`Test
`
`x2
`
`for
`
`41.5
`dl
`within users
`0.00001
`31.7
`dl
`Adapted with permission from Collaborative
`in Breast Can
`on Hormonal
`Factors
`Group
`cer Collaborative
`of
`individual
`reanalysis
`data on 53297 women with breast
`and 100239
`women without breast
`from 54
`studies
`epidemiological
`199634717I327
`01996
`
`within users
`for heterogeneity
`0.00001 Test
`
`trend
`
`cancer
`
`cancer
`
`Lancet
`
`The Lancer
`
`Ltd
`
`been
`
`an
`
`Cycle Control
`With the safety
`
`resolved clinicians
`
`Breakthrough
`
`and
`
`involving OC use largely
`issues
`can now concentrate
`more on
`and continuation rates
`improving compliance
`bleeding Em is an
`unscheduled
`inconvenient
`This side
`
`noying
`primary reason reported for brand/strength switching
`as cited by nearly one-quarter of the respondents
`in
`and women who experience
`BTB are
`to discontinue OCs than
`more likely
`substantially
`these problems.9 Women who dis
`women without
`continue OCs frequently fail
`to adopt use of another
`and they are in consequence
`contraceptive
`reliable
`pregnancy
`at higher risk for unintended
`endoinetnal
`the estrogen
`By providing
`support
`
`..
`AcoixliigJy 20-gEOCs have
`also dechuI(cid:224)
`found
`to have bigher
`rates of breakthrough
`bleeding
`and spotthigthan Mi- to 3-ig EL formulations
`obieiSW4edtthnoretbindroneaŁ(cid:224)aas
`well as with desogestrel
`formulations
`In
`randomized
`study
`comparative
`siiigle-bliæd
`examined the efficacy
`and side
`Appel and colleagues3
`effects associated with the use of OCs containing 1.0
`and either 20 30 or
`or 1.5
`acetate
`ag norethindrone
`in 426 women between
`50 pg ethinyl estradiol
`18 and
`36 years of age As shown
`in Table
`these investi
`of Em or spotting
`that
`the incidence
`gators found
`the amount
`in the formula
`of estrogen
`decreased as
`tion increasedi with the 20-p.g pill 44% had ETh or
`spotting with the 30-p.g pill 27% experienced
`these
`and 23% had Wit or spotting with the
`
`side
`effects
`5O-g pill
`Alcerlund and
`conducted
`double-
`colleagues12
`blind randomized study comparing reliability cycle
`two OC formulations
`and
`of
`side
`control
`effects
`150 jag desogestrel and either
`30 or 20 p.g
`containing
`EL One thousand women aged 18 to 40 were enrolled
`in the year-long study Bothpills bad high contracep
`tive reliability and were well
`tolerated but as shown
`cycle control was less effective with the
`in Figure
`
`effect
`
`is
`
`the
`
`recent survey5
`
`Table
`
`Number percent
`
`of patients with breakthrough bleeding spotting
`
`or both during
`
`treatment
`
`Formulation
`
`Total
`
`sub jects/eycles
`
`Breakthrough
`
`bleeding
`
`Breakthrough
`
`spotting
`
`1.0 mg norethindrone
`acetate
`20 jig ethinyl estradiol
`acetate
`1.5 mg norethindrone
`30
`jig ethinyl estradiol
`acetate
`1.0 mg norethindrone
`50
`jig etbinyl estrsdiol
`
`and
`
`and
`
`and
`
`Reprinted
`
`inch
`
`permission
`
`contraceptives
`
`Coocaception
`
`from Elsevier Science
`9s73S52331
`
`Both
`
`203 44.2
`
`134 27.1
`
`10323.4
`
`102/459
`
`117/494
`
`100/441
`
`110124.0
`
`43 8.7
`
`43 9.8
`
`93 20.3
`
`91 18.4
`
`64113.6
`
`Inc from Appel eta
`
`comparison
`
`of
`
`new graduated
`
`esaogeo
`
`formulation
`
`with three constant-dosed
`
`oral
`
`WC_LP 0405324
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 2
`
`

`
`Contraception
`
`i998
`
`so
`
`40
`
`20
`
`10
`
`Irsatneni 0e
`
`15W20pg
`
`050/ES
`
`Th03Opg
`
`OSO/EC
`
`815 spat
`
`30
`
`20
`
`10
`
`versely
`
`varied
`
`DC Estrogen Dose Considerations
`
`17S
`
`relevant
`
`for women who
`
`clinical
`
`trials studied
`
`the issue
`is also particularly
`smoke cigarettes
`smoking ad
`recent study showed
`that
`cigarette
`in users of OCs.5 Three
`affeots cycle control
`956
`randomized
`open-label
`OC users for 16506 cycles The proportion of smok
`ers who used CC and
`reported spotting or bleeding
`from 59% in the first cycle to 14% in the sixth
`cycle averaging 23% per cycle In contrast
`the pro
`portion of nonsmokers who reported bleeding ranged
`from 52% in the first cycle to 9% in the sixth cycle
`19% per cycle for all six cycles Among CC
`averaging
`users who smoked
`compared to nonsmokers
`the
`bleeding was elevated
`relative
`risk forbreakthrough
`for every cycle with the difference
`being statistically
`in five of six cycles Adusting for recency
`significant
`of OC use and the progestin compo
`and consistency
`nent smokers were 47% more likely to have spotting
`of CC
`or bleeding than nonsmokers during six cycles
`use
`Consistent with the findings of other studies255
`the risk of spotting or bleeding also was found to be
`cycle among women using 20-rg
`in each
`higher
`formulations
`than among those using 30-p.g
`formula
`the statistical
`the authors did not report
`this finding.5 These results
`of
`strongly
`significance
`and that
`that smoking impairs cycle control
`related to the estrogen dose
`this effect
`also
`causal mechanism might be
`the increased
`hepatic
`catabolism of estrogen known to occur
`in smokers5
`
`8Th or sporting
`in percent
`Figure
`Inegular
`DSC desogestrel
`of women per
`treatment
`Eli
`cycle
`age
`Adapted with permission
`of Blackwell
`ethinyl esrradiol
`Ltd from Akerlund
`et al Comparative profiles of
`and side effects of two oral contra
`control
`and
`150 p.g
`oestradiol
`
`bleeding
`
`Science
`
`reliability cycle
`
`formulations
`
`containing
`
`ceptive
`20
`either 30
`or
`sg ethinyl
`Cynaecol 19931008328.12
`
`p.g
`
`desogestrel
`Obstet
`
`Br
`
`combination
`
`formula
`
`spottingj
`
`significantly
`
`higher
`
`randomly
`
`distributed
`
`over
`
`were
`Bleeding
`problems
`women using the 150/20
`least
`with
`at
`compared
`
`than with the 150/30
`150/20
`bleeding brealcthrough
`bleeding or
`tion irregular
`occurred more frequently with the 150/20
`in all cycles and the incidence
`was
`combination
`in about
`two-thirds
`of the cycles
`the duration of the study
`least 15% of
`reported by at
`combination
`in all 12 cycles
`8% of women using the
`formulation
`Because
`of side effects primarily
`150/30
`bleeding problems more women using the 150/20
`and women
`discontinued
`the srudy
`combination
`to consider
`using this pill were
`the trial
`the study drug
`are consistent with other observations
`
`continuing
`
`These
`
`findings
`
`also
`
`less willing
`the end of
`
`at
`
`that bleeding problems
`
`are
`
`major obstacle to corn-
`
`pliance.9
`
`Data
`
`taming
`
`on efficacy
`2O-Rg Et
`
`recently
`
`and
`
`safety
`
`of
`
`and
`
`100
`
`21-day OCs con-
`were
`levonorgestrel
`p.g
`the multi-
`interim results
`that
`
`of
`
`trial
`
`published.4
`center open-label noncomparative
`suggest
`associated with this formula-
`bleeding irregularities
`tion are common and can be persistent Breakthrough
`or both were reported by 253%
`bleeding spotting
`18.2% of women during cycles
`and
`and 12 respec-
`
`tions but
`
`suggest
`
`is
`
`received
`
`acne.37
`
`Benefits of 00
`Noncontraceptive
`of OC use have
`been highly
`Although the risks
`women remain largely
`unaware
`of
`the
`publicized
`health benefits associated with their use important
`health benefits have
`been clearly
`and consistently
`studies OCs protect
`documented in epidemiologic
`women against endometrial
`cancer1
`can-
`cer 1721-25
`pelvic inflammatory
`ectopic pregnancy25
`breast disease4
`loss of bone
`benign
`disease27
`density5 ovarian cysts32 dysmenorrheaM and
`the triphasic CC
`Cne formulation
`menorrhagia.25
`and ethinyl estradiol has
`norgestimate
`containing
`shown in randomized
`been
`to reduce
`the amount
`of
`US regulatory
`the studies that demonstrated
`In all of
`non-
`contraceptive benefits of OCs the formulations used
`30 p.g or more of BE Therefore
`contained
`each
`these
`uncertain whether
`of
`benefits
`be
`will
`of ben
`the same magnitude
`maintained
`and achieve
`efits with CCs formulated with lower estrogen doses
`35% and 50% of cortical
`Between
`and
`trabecular
`womans hletime and
`bone mass
`over
`lost
`
`arian
`
`and
`
`placebo-controlled trial
`acne37
`has recently
`treatment
`
`approval
`
`as
`
`for
`
`effect
`
`BE formulations
`
`on
`
`cycle
`
`tively.4
`The negative
`of 20-sg
`control may be especially
`problematic for par-
`of women such
`and
`as adolescents
`ticular subgroups
`women who are using CC in order to
`perimenopausal
`control As discussed below
`
`establish
`
`or restore cycle
`
`is
`
`it
`
`is
`
`WC_LP 0405 325
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 3
`
`

`
`18S Kaunitz
`
`Contraception
`
`1998
`
`Table
`
`Distribution
`
`of women by bone mineral
`
`density BMD interval and history of oral contraceptive
`BMD interval
`category No
`
`use
`
`Oral contraceptive
`
`use
`
`Yes
`No
`Total
`
`AmutAgC
`
`Adapted
`
`teat
`
`for trend
`
`front
`
`Itletrekoper
`
`et
`
`Low
`
`28 140
`172 860
`200
`
`15322.5
`527 77.5
`680
`
`373333
`72666.1
`1099
`
`High
`
`12746.0
`149 54.0
`276
`
`Total
`
`681130.2
`157469.8
`2255
`
`525
`
`53
`
`1O2
`Oral contraceptive
`
`usc nay protect
`
`against
`
`low bone mass Arch Intern MS 1991t5l197-6
`
`negative
`
`Cigarette
`
`loss having
`
`bone mass correlated
`with the dose of ethinyl
`cortical
`loss of bone
`occurred
`estradiol Although
`net gain was observed
`doses of EE
`15 pg
`at
`25 sag At doses between 15 and
`doses
`25 pg daily
`bone was neither gained nor lost
`
`net
`
`at
`
`osteoporosis affects about 20 million
`postmenopausal
`women in the United
`for more
`States accounting
`annualiy
`than
`one million fractures
`the process of bone
`smoking exacerbates
`density BMD
`on bone mineral
`impact
`to place both men and women at
`is sufficient
`that
`increased risk for fractureSP
`that use of
`Evidence
`from several
`studies
`suggests
`OCs in reproductive age women may stabilize or even
`bone mass.3 Eight of 12 published studies
`increase
`have shown that women using OCs have
`bone
`mass than nonusers5 with the greatest BMD benefit
`noted in women who have
`used OCs for at
`10
`years.4
`
`greater
`
`least
`
`Kleerekoper
`
`sectional
`
`retrospective
`
`distribution
`
`history
`
`against
`
`interval
`
`0.2.3
`
`analysis
`
`available
`
`12
`
`centers
`
`and colleagues conducted
`cross-
`study to inves
`epidemiologic
`tigate risk factors for low BMD in
`group of women
`76% of whom were
`postmenopausal
`Reproductive
`of CC use BMD mea
`including history
`information
`and other data were
`from 2297
`surements
`women screened
`in
`for osteoporosis at
`divided the BMD
`1987 The investigators
`1986
`and
`within each center into quartiles
`of CC use was found
`to be protective
`low BMD odds ratio 0.35
`95% confidence
`to 0.53 As shown in Table
`although
`CC users
`only 14% of the women in the
`comprised
`lowest BMI quartile nearly half of the women in the
`highest BMD quartile
`were OC users Multivariate
`these results
`and
`suggested that
`confirmed
`the degree of protection from lower BMD is related to
`duration of CC exposure.4
`Because OCs have only been in use since
`epidemiologic data regarding the possible
`use for preventing osteoporotic fractures
`among post-
`menopausal women is limited However
`it is thought
`bone density provided
`that
`the possible
`enhanced
`CC use3140 may reduce the incidence
`of vertebral
`hip fractures
`BMD
`The optimal CC estrogen dose
`for stabilizing
`the bone-spar
`has not been detennined.1
`However
`ing effects of estrogen are known
`to be dose-related.33
`Horsman and colleagues2
`reported that
`in postmeno
`pausal women receiving
`in
`estrogen therapy changes
`
`the 1960s
`effect of CC
`
`by
`
`and
`
`in later life
`
`Prevention
`of Functional Ovarian Cysts
`Functional ovarian cysts usually disappear
`spontane
`ously and require only expectant management
`unless
`they cause
`pain or are large
`enough to
`substantial
`intra-abdominal
`rupture with consequent
`bleeding
`functional ovarian
`or to cause
`torsion Nonetheless
`represent the fourth most common gynecologic
`for hospitalization and most hospitalizations
`in surgery.C The
`incidence
`in
`result
`is highest
`women aged
`iS to 3540
`population well-suited for
`CC use All currently available
`monophasic OCs
`reduce
`the incidence
`functional
`ovaiian cysts
`is somewhat at
`the degree of suppression
`although
`contnining 50 pg
`com
`tenuated
`in knnulations
`pared with the S0-g formulation.as
`are no
`There
`of formula
`published data assessing the effectiveness
`tions with 20
`pg EE for
`the incidence
`
`cysts
`cause
`
`of
`
`reducing
`
`of
`
`ovarian cysts
`
`Approximately
`
`F.ndometriaj Cancer
`34000 new cases of endometrial
`in the United
`each
`cer are diagnosed
`States
`year
`6000 deatbs OCs have
`resulting in approximately
`been well-documented
`as providing strong duration-
`cancer.ts
`protection against endometrial
`dependent
`As
`shown
`endometrial
`cancer
`in Figure
`declines with duration of CC use The 22 risk esti
`by SchIesselman7
`are
`plotted in this figure
`mates
`on 10 epidemiologic studies
`published between
`based
`1980 and 1994 CC use reduces
`the risk of endome
`50% within
`years of
`trial cancer
`by approximately
`use79 and the risk maybe reduced by 72% after
`12
`years of use.7 For every 100000 women aged 20 to 54
`States who never use OCs approxi
`in the United
`the endometrium
`mately 438 will develop cancer of
`100000 women using OCs for
`years 197
`For every
`cases would be expected
`fewer
`Because
`
`can
`
`risk
`
`this protec
`
`WC_LP 0405326
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 4
`
`

`
`Contraception
`1998581562tS
`
`OC Estrogen
`
`Dose Considerations
`
`19S
`
`10
`
`0.1
`
`4.4
`
`0.5
`
`10
`
`12
`
`14
`
`16
`
`16
`
`0.1
`
`Total Years
`
`at Combined
`
`OCs
`
`10
`
`12
`
`14
`
`Duration Yen at CC Use
`
`Relative
`
`risk of
`
`endometrial
`
`cancer
`
`by total
`Figure
`DC use Reproduced
`with
`years of oral
`contraceptive
`from the American College
`of oral contra
`from Schiesselman Net effect
`in women in the United
`cepr.ive
`States Obstet Gynecol 199585l93_8OI.t7
`
`permission
`
`Gynecologists
`use on the risk of cancer
`
`of Obstetricians
`
`and
`
`least
`
`after CC discon
`or older can
`tnid-30s
`during which they
`incidence
`of this
`
`two decades
`don persists for at
`tinuation20 CC users in their
`risk for those decades
`reduce their
`would otherwise experience
`peak
`common gynecologic malignancy.7
`The epidemiologic
`evidence
`regarding the protec
`tion provided by CC use as summarized in Figure
`based on experience with OCs
`by studies
`is provided
`EL At doses of 35 p.g EE and
`least 35
`the degree of protection appears independent
`higher
`of estrogen dose20 The effect of OCs containing
`CO p.g EE upon endometrial
`cancer has not been
`
`containing at
`
`analyzed
`
`Ovarian Cancer
`
`of
`
`is
`
`ft
`
`diagnosed with this
`until
`
`years
`
`than
`
`In general primary prevention that
`is avoidance
`disease
`to secondary
`or tertiary preven
`is preferable
`tion early detection and
`treatment
`respectively.5
`than
`in no disease
`this more true
`for
`Perhaps
`is estimated that more than 26000
`ovarian cancer
`women in the United
`States were
`in 996 Often
`lethal
`disease
`asymptomatic
`stage III or LV ovarian cancer
`in its development
`causes more deaths in the United
`than
`States
`any
`cancer
`45% of
`Fewer
`other
`gynecologic
`women survive
`after diagnosis
`OCs have
`been well-documented
`as protecting
`1721-15
`few women
`ovarian cancer
`although
`against
`this fact No other prescription
`are aware
`of
`have
`shown to confer
`been
`such
`potent protection
`As seen in Figure
`lethal malignancy.5
`eifect of OC use on the incidence
`of ovarian
`beneficial
`cancer appears to be duration-dependent
`and may
`
`late
`
`against
`
`drugs
`
`the
`
`Relative
`risk of ovarian
`cancer
`Figure
`ceptive OC1 use findings of 15 studies
`Study
`categories
`from smallest weight
`indicating category weights ranging
`in bottom 25% of range to largest weight
`in top 25% of
`smallest
`dark crosses
`range squares
`pluses
`from the
`with permission
`stars
`largest Adapted
`American College of Obstetricians
`and Gynecologists
`Hankinson et al
`assessment of oral contra
`use and
`cancer Obstet Gynecol
`
`by oral contra
`
`from
`
`ceptive
`1992SO708_14.h1
`
`quantitative
`
`risk of ovarian
`
`decades
`
`be related to suppression
`of ovulation
`although
`other
`mechanisms are also possible.2 Risk
`is reduced by
`approximately 40% after
`years of use after 10 to 12
`years it is reduced by as much as 60% to
`The protective effect of OCs lasts for at
`least 20 years
`OC users in
`after discontinuation7
`Therefore
`can reduce their risk for those
`and older
`their mid.30s
`in life when they would otherwise experience
`for
`this
`lethal malignancy Por
`risk
`peak
`every
`100000 women between the ages of 20 and 54 in the
`States who never use OCs approximately 369
`United
`For
`100000
`ovarian
`cancer
`will
`develop
`every
`women using OCs for
`cases would
`years 193 fewer
`to occur17
`be expected
`evidence
`the epidemiologic
`Almost all
`regarding
`the protection against ovarian cancer provided by OC
`on experience with OCs containing at
`use is based
`least 30 sg RE No studies have analyzed
`the effects of
`upon ovarian cancee and it
`lO-tg EE formulations
`has not yet been detennined
`whether
`the prophylac
`when the estrogen
`is maintained
`dose
`tic effect
`is
`reduced below 30 pg
`
`Benign Breast Disease
`Previous
`studies of benign
`breast
`disease
`in users of
`p.g or mote of estrogen
`formulations
`containing
`risk among users compared with
`formulations
`nonusers.2829 Current use of high-dose
`was associated with reductions in the risk of benign
`
`found
`
`decreased
`
`50
`
`WC_LP 0405 327
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 5
`
`

`
`20S Kaunitz
`
`Contraception
`
`1998
`
`JG Hambleton
`18. Population-based
`venous
`thromboexnbohsm
`associated
`1997349838
`on Hormonal
`Factors
`and
`hormonal
`
`study of risk of
`with
`
`various
`
`oral
`
`Lancet
`
`Group
`
`in Breast
`
`cancer
`
`contraceptives
`
`Collaborative
`Cancer
`
`Breast
`
`breast
`
`disease
`
`and
`
`breast
`
`fibroadenoma chronic cystic disease
`lumps not subject
`to biopsy Past
`demonstrated
`no current benefits.29
`More recently
`French study confirmed
`risk of benign breast disease
`is reduced with the use of
`OCs containing 50 jig estrogen
`as well
`as with
`higher-dose fornaulations.3
`is not known whether
`the use of 20-jig EE OCs will have
`tive effect on the incidence
`of benign breast
`do OCs with n30 jag EE
`
`users
`
`that
`
`the
`
`It
`
`similarly protec
`
`disease
`
`as
`
`it
`
`patients
`informed
`
`the only
`
`as
`
`as
`
`from
`
`Balanced consideration of the risks and benefits
`asso
`ciated with different
`doses of estrogen in combination
`OCs will help clinicians
`advise
`their
`to
`and permit women to make
`judiciously
`but
`is not
`choices Safety is paramount
`to be
`considered
`Side effectssuch
`bleedingare important
`as they affect
`breakthrough
`OC compliance
`and ultimately risk
`continuation
`OC
`for unintended
`pregnancy
`Noncontraceptive
`health benefits while not widely recognized by wom
`en16
`from
`are increasingly assuming importance
`health policy perspective as well
`clinical perspective
`on
`analysis of safety cycle
`comparative
`benefits OCs contain
`and noncontraceptive
`control
`the first
`ing 50-jig EL should
`choice
`remain
`for
`virtually all OC candidates
`Use of 50-jig Eli
`formu
`lations may be appropriate for women taking hepatic
`such
`carbam
`drugs
`as phenytoin
`enzyme-inducing
`and
`from the
`However
`Iifampin.14
`and noncontra
`cycle control
`of safety
`OCs formulated with 30 tosS jag EL
`initial choice for most candidates
`prudent
`
`parameter
`
`public
`
`Based
`
`azepine
`
`perspectives
`
`ceptive
`
`benefits
`
`represent
`
`and progestin
`components
`to vascular
`disease
`
`of
`
`References
`Can
`
`Dry
`
`Estrogen
`
`oral
`
`Contraception
`
`Contraception
`
`of Cardiovascular
`
`Disease
`
`Jick
`
`Risk
`
`of
`
`contraceptives
`relationship
`i997526772
`Dry HW Cardiovascular
`of oral contraceptives
`safety
`199858suppl9S.-l3S
`World Health Organization WHO Collaborative
`Study
`and Steroid Hormone Con
`in low ocs
`Effect of different
`traception
`progestagcns
`thromboembolic
`trogen oral contraceptives
`on venous
`199534615828
`disease
`Lancet
`Myers MW Vasilakis
`Jick SS Gurcwich
`and nonfatal
`cardiovascular
`death
`idiopathic
`throinboembolism in women using oral contra
`venous
`ceptives with differing progcstagen
`Lancet
`components
`1995346158993
`Lewis MA Heinemann
`increased risk of venous
`
`LAJ MacRae KD et at The
`thromboembolism and the use
`role of bias in obser
`progestagens
`199654513
`Farmer RDT Lawrenson RA Thompson CR Kennedy
`
`of
`
`third
`
`vational
`
`generation
`research
`
`Contraception
`
`contraceptives
`collaborative
`data on 53297
`individual
`reanalysis
`and 1002.39 women without
`women with breast
`cancer
`from 54 epidemiological
`studies
`breast
`cancer
`Lancet
`1996347171327
`1997 Annual Birth Control Study Raritan NJ Onho
`Pharmaceutical Corp 1997
`Hillard PJA The patients
`to side effects of oral
`reaction
`Am Obstet Gynecol 198916114125
`contraceptives
`10 Rosenberg NJ Waugh MS Long
`Unintended
`preg
`and use misuse and
`discontinuation
`of oral
`Reprod Med 19954035560
`contraceptives
`11 Preston SN
`report of
`collaborative
`dose-response
`clinical study
`of combination
`doses
`decreasing
`using
`oral contraceptives
`197267-35
`Contraception
`Rode
`12 Akerlund
`Comparative pro
`Westergaard
`files of reliability cycle control
`and side effects of two
`150
`oral
`formulations
`containing
`contraceptive
`and either 30 jig or 20 jag ethinyl oestradiol
`desogestrel
`Br Obatet Gynaecol 19931008328
`13 Appel TB Arman KA Birdsall
`et al
`new graduated
`formulation
`estrogen
`stant-dosed
`oral contraceptives
`3552332
`14 Archer DF Maheux
`et aL
`DelConte
`new
`combination
`low-dose monophasic
`oral contraceptive
`Alesses with levonorgestrel
`100 jig and ethinyl eros
`diol 20 jig Contraception
`19975513944
`15 Rosenberg MJ Waugh MS Stevens CM Smoking
`and
`users Am
`among oral
`control
`cycle
`contraceptive
`Obstet Gynecol 199617462832
`Gutmann
`16 Piepert
`Oral contraceptive
`risk assess
`survey of 247 educated women Obstet Cynecol
`mentr
`199382112.i
`17 Schlesselman fl Net effect of oral contraceptive
`in women
`the risk of
`in the United
`cancer
`Obstet Gynecol 199585793801
`18 World Health Organization WHO Collaborative
`and Steroid Contraceptives
`of Neoplasia
`oral contraceptives
`and combined
`cancer
`miol
`l98817-.2639
`19 Cancer and Steroid Hormone CASH Study of
`Centers for Disease Control and the National
`Institute
`of Child Health and Human Development
`Combina
`and the risk of endometrial
`use
`tion oral contraceptive
`cancer JAMA 1987257796800
`20 Jick SS Walker AM Jick
`Oral
`contraceptives
`endometrisl cancer Obstet Gynecol 199382931S
`SE Colditz GA Hunter DL Rotncr
`21 Hankinson
`assessment of oral contraceptive
`use and
`cancer Obstet Gynecol 19928070814
`risk of ovarian
`and Steroid Hormone CASH Study of
`22 Cancer
`Centers for Disease Control and the National
`of Child Health and Human Development
`The reduc
`associated with oral-
`tion in risk of ovarian
`cancer
`Med 19873166505
`use
`Palmer JR Zauber AG et al
`case-
`and invasive
`study of oral contraceptive
`cancer Am Epidemiol 1994139
`ovarian
`
`Conclusions
`
`nancies
`
`of
`
`jig
`
`comparison of
`with three
`con
`1987
`
`Contraception
`
`use on
`
`States
`
`Study
`Endometrial
`
`Tnt
`
`Epide
`
`the
`
`and
`
`the
`
`Institute
`
`EngI
`
`use
`
`KA Thomas Dli Noouan
`
`EA et al High-
`
`WC_LP 0405 328
`
`quantitative
`
`contraceptive
`23 Rosenberg
`control
`
`epithelial
`654-61
`24 Rosenblatt
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 6
`
`

`
`Contraception
`9985815S21S
`
`OC Estrogen
`
`Dose ConsLderations
`
`21S
`
`dose and
`
`low-dose
`
`combined
`
`epitheli.al
`
`tract
`
`oral contraceptives
`pro
`and the length
`ovarian
`cancer
`tection against
`effect Eur Cancer 19922818726
`of the protective
`25 Schlesselman fl Cancer of the breast
`and reproductive
`Contra
`in relation
`to use of oral contraceptives
`l99940138
`ception
`26 Franks AL Bent
`Jr Hogue CJR Contracep
`Cates
`pregnancy risk Am Obstet Gynecol
`tion and ectopic
`199016l1203
`27 Pansa LA Pbipps WR Type of oral contraceptive
`inflamma
`relation to acute
`of pelvic
`initial
`episodes
`tory disease Contraception
`I991439l9
`28 Royal College of General Practitioners Oral Contracep
`tins and Health New York Pitnian
`1974
`29 Brtnton LA Vessey MP flavel
`It Yeates
`disease Am Epidemiol
`for benign breast
`21314
`30 Charreau
`plu-Burean
`MG Oral
`J-M
`Cuinebretifre
`contraceptive
`French
`disease in
`risk of benign breast
`case-control
`study of young women Eur Cancer Prey 19932147
`54-
`31 DeCherney
`of oral contra
`Am Obstet Gynecol 19961741520
`ceptives
`32 Ory MW Functional
`cysts and oral contracep
`ovarian
`JAMA
`confirmed surgically
`thea negative
`l97422.8689
`33 Lanes SF Bixmanfl
`and
`functional
`traceptive
`type
`Obstet Cynecol 199246695661
`34 Larsson
`Milsorn
`Lindstedt
`low-dose
`combined
`oral
`contraceptive
`ence
`blood loss and iron status
`mensanial
`19924327-34
`35 Milaons
`Stmdell
`
`in
`
`Risk factors
`198 1413
`
`Contesso
`use and
`
`Bachelor
`
`Bone-sparing
`
`properties
`
`association
`
`of
`
`Walker AM Singer
`
`ovarian
`
`Oral con
`cysts Am
`
`Itybo
`
`The influ
`
`on
`
`Contraception
`
`Andersch
`
`The
`
`influence
`
`of
`
`lence
`
`oral
`
`contraceptives
`of dysnaenorrbea
`
`on the preva
`Contraception
`
`diol in the treatment
`
`combined
`different
`and severity
`199042497506
`36 Nilsson
`of menorrhagia AnJ
`Treatment
`Rybo
`Obstet Gynecol 197lll071320
`37 Redmond CP Olson WH Lippman
`IS Kafrissen ME
`Jones ml Jotizze TL Norgestintate
`and ethinyl
`estra
`of acne vulgaris
`randomized
`trial Obstet Cynecol 199789615
`
`Cigarette
`
`SL Hol
`density
`
`bones and fewer
`
`LB et aL Oral
`low bone mass
`
`against
`
`Engi
`
`placebo-controlled
`22
`IA Barrett-Connor
`38 Hollenbach
`Edeistein
`brook
`smoking and bone mineral
`in older men and women Am Public Health 199383
`1265-70
`have
`JO Smokers
`39 Johnston
`less dense
`JR Soc Health 19944142659
`teeth
`40 Ileerekoper
`Brienza
`P.5 Schultz
`use may protect
`contraceptive
`Arch Intern Med 199115119716
`41 Corson SL Oral
`for the prevention of
`contraceptives
`osteoporosis Reprod Med 1293381015-20
`42 Horsinan
`The effect of
`it Nordin
`Francis
`Jones
`bone loss
`dose
`on posimenopausal
`estrogen
`Med 198330914057
`cysts in Pnnd
`43 Westhoff
`Clark CJG Benign ovarian
`and in the United States BrJ Obstet Gynae
`and Wales
`cot 199299-229-32
`44 American Cancer Society Cancer Facts and Figures
`1996
`45 Crimes DA Economy XL Pthnaa-y prevention
`of gyne
`cancers Am Obstet Cynecol
`l99517222735
`46 Mattson R$ Rebar RW Contraceptive
`methods
`for
`Am Obstet Gy
`women with neurologic
`necol
`l993l682027-fl.
`
`cologic
`
`disorders
`
`WC_LP 0405329
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 7
`
`

`
`WC_LP 0405330
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2010, Pg. 8