CONTRACEPTION
`
`RANDOMIZED
`COMBINED
`
`DOUBLEBLIND
`STUDY
`ORAL
`CONTRACEPTIVES
`
`OF SIX
`
`Task
`
`Force
`
`on Oral Contraceptives
`
`WIlD Special Programme
`Research
`Training
`
`of Research Development
`in Haraan Reproduction
`
`Cud
`
`liriwt
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`ljrrkiur
`
`trod
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`ot Mcd ceo
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`unto nd
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`for puhli.nr.ioo
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`
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`in Rosen Reproduc
`
`Men
`
`Id lieai
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`11 Cereva 27 Sw It er land
`
`Lii
`
`MARCH 1982 VOL.25 NO
`
`arS
`
`231
`
`in tiff
`
`Mm
`cr Ni.
`
`.(cid:231)
`
`lt.C5.iJ
`
`WCLP0405745
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 1
`
`

`
`CONTRACEPTION
`
`ABSTRACT
`
`clinical
`
`tontraceptives
`Collaborating Centres
`the
`women
`2430
`lowdose
`combined
`
`entered
`
`oral
`
`rates
`
`with
`
`400pg
`rates
`
`differ
`
`Women
`
`bLeeding
`
`preparations
`vomiting
`
`tended
`
`the
`
`tended
`
`IHTRODUCTIOH
`
`trial comparing six combined
`randomized controlled
`oral
`undertaken
`with
`ot
`ieaa
`estradiol
`of ethinyl
`wee
`SOpg
`for Clinical Research
`in Human Reproduction
`trial
`and were
`obaerved
`for 2g077
`womancycles
`contraceptives demonstrated
`equivalent
`of
`one
`to six percent
`However
`pregnancy
`oneyear
`differed significantly between
`for medical
`reasons
`rates
`groups
`the preparation containing 20pg
`eetradiol
`and
`that
`containing
`ethinyl
`norethieterone acetate
`associated with higher discontinuation
`being
`Even among
`which
`did
`the
`due
`to bieedingdiaturbances
`preparations
`for discontinuation
`did differ
`in discontinuation
`rates
`reasons
`to discontinue because
`norethisterone preparations
`receiving
`those
`receiving the
`disturbances white
`levonorgestretcontaining
`to discontinue because
`of eoapiaints
`of
`and
`
`in 10 WHO
`of
`
`total
`
`All
`
`with
`efficacy
`discontinuation
`
`the
`
`treatment
`
`not
`
`of
`
`nausea
`
`tess
`
`part
`of ethinyt
`
`estradiol
`
`oral
`
`It
`
`than
`40 different
`combined
`oral
`more
`ten years
`the past
`During
`bean commercially available or provided
`contraceptive preparations have
`countries
`planning programmes in developed and developing
`through
`family
`50 milLion women
`is estimated
`than
`that more
`annually now
`use
`hormonal
`contraeeptivesl
`for
`the moat
`combined
`oral contraceptive preparations
`in combination
`or aeatranot
`with
`containing SDgig
`or
`progeatogen
`The
`rationale
`for choosing
`contraceptives avaiisbte is not
`of clinical
`and
`laboratory
`reports
`trials comparing the effectiveness
`of discontinuation
`for different
`towdose
`
`clinical
`
`rates
`
`between
`
`based
`
`on
`
`of
`
`fertility
`
`combined
`
`oral
`
`plethora
`
`of
`
`and
`
`into
`
`of
`
`lowdose
`the many
`on scientific study
`Despite
`individual
`preparations
`reports
`incidence
`of aideeffects
`fewl2
`preparations are
`the safety
`and efficacy
`issued
`in developing
`countries
`and Research Training in
`doubleblind
`randomized
`
`its ongoing
`Aa part
`investigations
`those
`control
`especially
`methods
`the WHO
`Progrseae of Research
`Special
`undertaken
`Human Reproduction
`has
`towdose
`combined
`of aix
`study
`
`Development
`multicentred
`contraceptives
`
`oral
`
`The
`
`in
`
`the
`
`were
`preparations
`widespread use
`their existing or
`expected
`to determine
`the difference between
`estradiot ER with
`constant
`3Dpg and
`SDpg
`tevonorgestrst LHC one preparation not
`yet commercially available
`of
`included
`
`selected
`
`on
`
`developing
`sffects
`of
`
`the basis
`countries
`
`of either
`
`In order
`
`dose
`
`of ethinyl
`
`level
`
`was
`
`type
`
`in the preparations Included
`Progestogens
`and norethistsrone
`sines
`both
`norgestrel
`other
`progestsrons receptors and nearly all
`progestogsna
`are metabolized
`to norethiaterone before being
`active
`
`are
`
`known
`
`study were
`in the
`limited
`to act direetty on
`l9norstsroid
`the
`to this way
`
`to
`
`of
`
`232
`
`MARCH 1982 VOL 25 NO
`
`WC_LP0405746
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 2
`
`

`
`METHODS
`
`AND MATERIALS
`
`CONTRACEPTION
`
`total
`
`of
`
`2762
`
`and
`
`28
`
`days
`
`to have
`
`to have
`
`least
`
`165
`
`any
`
`during
`
`her
`
`ptanning
`between
`woaen
`attending
`famity
`clinics
`November
`in ten WHO Collaborating Centres
`for Clinical Research
`1979
`January
`1975
`Reproduction CCCRsC volunteered
`Of
`in the study
`to participate
`in Wuean
`women
`the criteria for
`2430
`started
`after
`in the study
`these
`satisfying
`to have
`to be healthy
`woaan had
`in the
`To
`be
`included
`trial
`inclusion
`no contreineicationa
`such
`as hypertension
`for oral
`contraceptive use
`diabetes etc to have
`between
`of
`and
`the ages
`been
`diaeaae
`heart
`if poatpartum to be at
`poatpartum and
`least
`inclusive
`been
`lactating at
`if lactating
`reestablished menstruation
`reestablished menstruation
`to have
`used
`oral contraceptives
`and
`not
`hormonal contraceptives within 90
`or
`28 days
`longacting
`injectable
`regular menstrual cycles
`to have
`had
`of starting
`the treatment
`groups
`In addition
`the woman
`to 35 days inclusive
`length within 21
`the usual
`contraceptive methods
`have
`not
`to use
`other
`agreed
`must
`participation in the trial
`to withdraw from the
`Women
`were
`able
`diacontinued
`and
`were
`or when severe medical
`
`had
`
`days
`
`within
`
`days
`
`with
`
`request
`
`diagnosed
`disease
`
`by
`
`hypertension or
`
`liver
`
`trial
`
`at
`time at
`their
`own
`any
`trial staff when pregnancy was
`the clinical
`as cardiovascular
`conditions developed such
`disease
`
`Preparations
`
`The
`
`six preparations
`
`compared
`
`were
`
`27
`
`ethinyl
`
`estradiol
`
`edtrmdioi
`ethinyl
`mestranol SOpg
`estradioi
`ethinyl
`eatradiol
`
`ethinyl
`
`ethinyl
`
`estradiol
`
`l5Opg
`
`SOpg
`
`SOpg
`
`2Opg
`
`tevonorgestrel
`levonorgeatrel
`3Opg
`iSOjig
`norethiaterone 1mg
`PIES
`50
`nnrethisterone acetate
`norethisterone acetate
`norethisterone acetate
`
`LNG 150
`iso
`LNO
`
`1mg
`
`MAc
`
`MAc
`
`NAc
`
`400
`
`SE 50
`55 30
`NET 1mg
`ES 50
`SE 20
`SE 35
`
`1mg
`400pg
`
`351ig
`
`the manufacturerm
`identified
`by
`random
`the women
`the
`
`but
`
`that
`
`uaed
`
`repackaged in twenty
`in such
`numbers
`way
`which preparation wsa
`knew
`women voiunteering ann
`the aix oral
`one of
`to receive
`
`centres
`assigned
`
`The pills were
`four 28day cycle
`neither
`the clinical
`trial staff
`particular womsn
`to participate
`eligible
`were
`contraceptive preparations
`fifth day
`the pill
`In all circumstances
`on
`regimen was
`at
`to the clinics
`menstrual
`cycle
`women
`scheduled
`to return
`were
`24 cyciee
`84
`regular visits
`of
`three
`for
`intervals
`days
`to eight
`cycles
`up
`was discontinued from the
`per women
`if
`the first
`14 or more
`woman
`discontinuation
`piils were missed
`cycle
`Pregnancies
`occurring after
`in
`were
`of 28077
`included
`in the analysis
`total
`womancycles
`information on age
`collection
`was atandardized
`and
`included
`past medical
`contraceptive use menstrual data
`previous
`complaints and
`examination
`including
`physical
`followup visits complaints
`examination
`blood
`pressure ane weight
`were maintained
`cards
`the women
`by
`
`produced
`
`packets
`
`by
`and
`
`by
`
`At
`
`each
`
`nor
`
`of
`
`randomly
`
`The
`
`not
`were
`observed
`
`obstetric
`
`Oats
`history
`history current
`examination
`
`On
`
`physical
`
`diary
`
`begun
`
`the
`
`of
`
`the
`
`trial
`
`on
`findings
`significant
`recorded
`Menstrual
`
`were
`
`pelvic
`
`Hospital Bangkok Institute for Research
`in Siriraj
`in Reproduction
`Bombay
`Institute of Medical Education
`and Research
`Poatgrsdumte
`tbsdmn Family Planning
`Institute
`Chandigmrh University
`Lusaka University
`Ljubljans University
`of
`the Philippines
`of
`Zambia
`Manila University
`Rsndang Kerbau Hospital
`of Chile Santiago
`for
`Women Singapore University Medical School
`Szeged
`
`Ibmdmn
`
`of
`
`One
`
`woman
`
`in one
`
`was
`
`able
`
`to identify
`
`centre
`examined
`the company
`
`her pills with
`
`magnifying glmes
`
`and
`
`imprint
`
`on her pills
`
`MARCH 1982 VOL 25 NO
`
`233
`
`WC_LP0405747
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 3
`
`

`
`CONTRACEPTION
`
`At
`
`the end of
`
`the
`
`trial
`
`the
`
`steroid
`
`from each
`
`was measured
`content
`the centres
`
`of
`
`For
`
`in both
`
`opened
`
`the
`
`temperate
`from 92 to
`from the
`samples
`
`Levels
`
`to
`
`packs
`
`ranged
`
`the similar
`mean 9b.47i
`
`and
`
`sealed
`
`samples
`
`levels
`
`of
`
`the
`
`stated
`
`unosed pill
`the hormone
`countries
`1045 mean 99.4g
`tropics countries
`were
`
`opened
`
`packets
`
`Analysis
`
`the
`
`range
`
`slightly
`
`in pills from unopened
`for
`dosage
`level
`was
`91.15
`to 101.51
`lower
`
`rates
`
`were
`
`calculated
`
`according
`
`The
`variance
`
`statistical
`or X2
`
`test
`
`test
`size
`
`procedores
`on contingency
`counts
`for heterogeneity of
`which
`discontinustion
`Net
`life table
`test34
`
`used
`
`included
`tables
`
`standard
`Extensive
`
`ignores
`
`alight
`
`tlests analysis
`use
`was
`made
`of
`differences
`
`of
`
`the
`
`in sample
`to the
`
`logrank
`Life
`
`period
`
`as
`
`from other
`
`was calculated from the
`first
`table
`analysis
`the patient
`in which pills were
`or
`was
`terminated
`until
`considered
`of use
`after
`Loss
`followup
`to
`cycles
`the study
`was
`completed
`in the all reason discontinuation
`and was
`included
`termination of
`use
`rate Although
`these
`in theory
`be obtaining oral
`women might
`contraceptives
`in practice the
`few
`studies
`that exist
`that
`the
`sources
`suggest
`discontinued the methodS Since
`cumuistive
`such
`have
`mejority of
`women
`discontinuation
`the sum
`estimates
`involve
`for competing risks
`adjustment
`discontinuation
`than
`the overall
`is greater
`
`day
`
`of
`
`the menstrual
`
`net
`
`started
`
`24
`
`reasons
`
`segment
`
`was
`
`rate
`of
`the rates
`for specific
`rate for all reasons
`Definitions
`standardized
`were
`one menstruallike
`
`bleeding
`
`bleeding episode
`cards were
`defined
`
`as
`
`defined
`as
`from the start of
`the next menstruallike
`fo the start of
`episode
`from the menstrual
`disturbances derived
`Bleeding
`follows
`
`diary
`
`amenorrhea
`
`longest
`
`bleedingfree
`
`segment
`
`greater
`
`than
`
`60 daye
`
`infrequent
`
`bleeding
`
`bleedingfree
`longest
`60
`not over
`
`days
`
`mod
`
`segment
`
`greeter
`
`than
`
`35
`
`days
`
`frequent
`
`bleeding
`
`shortest
`
`complete segment
`
`lees
`
`than
`
`24
`
`days
`
`irregular bleeding
`
`shortest
`segment
`complete
`longest menstrual segment
`
`less then
`
`greeter
`
`24 days
`than
`35
`
`and
`
`days
`
`prolonged bleeding
`
`bleeding/spotting
`
`episode
`
`longer
`
`than
`
`days
`
`from the menstrual diary
`In addition to these
`categories derfved
`cards
`the womens
`complaints of bleeding disturbance were
`and
`included
`bleeding
`prolonged bleeding
`irregular
`
`categorized
`bleeding mod
`
`light
`
`amenorrhea
`spotting
`
`Although
`followup
`for
`
`amenorrhea is commonly
`visits
`in segments
`were
`the deffoition was
`found
`
`days
`
`defined
`
`in terms
`
`of
`
`of
`
`84
`
`days
`
`to be more
`
`14 days
`convenient
`
`because
`
`90 days
`the use
`in the analysts
`
`of
`
`60
`
`234
`
`MARCH 1982 VOL 25 NO
`
`WC_LP0405748
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 4
`
`

`
`CONTRACEPTION
`
`RESULTS
`
`trial
`
`resutted
`
`in
`
`treataent
`
`there
`
`the
`within
`
`in
`
`subjects
`
`womcn
`participating in the
`nt
`of subjects
`in each
`the ais
`
`groups
`to participating centres
`the
`be expected among
`the women
`in the characteristics
`of
`startang
`of
`the random atincation of
`
`Random
`
`of
`
`allocation
`numbers
`
`differences
`
`relatively equni
`As would
`Table
`were
`wide
`trial
`
`as
`
`consequence
`22 variables
`recorded
`
`However
`of
`each
`centre
`statistically
`of
`the
`
`isst
`
`and
`
`of
`
`was
`
`personal
`
`Sy
`between
`
`because
`
`two
`
`outcome
`the length
`cycle
`to be ot practical
`or affecting
`not
`importance
`the differences were smati
`of
`the magnitudes
`statistical
`teats
`the probabiLity
`performed
`0.095
`about
`aignificant
`Furthermore
`admission characteristics
`of
`the
`other
`any
`nor
`of continuation in the
`triat
`preguancy
`for discontinuation
`reasons
`years discontinuation
`treatment
`groups
`being
`of aideeffects
`
`on admission
`0.05 between
`thc six groups
`the
`Table
`pregnancy
`the usuat menstrual
`
`differed
`only
`These variables were
`of
`the
`
`the
`
`bsrth
`open
`these differences
`
`inrervai
`
`length
`considered
`
`We
`
`results
`the
`and with
`of
`tinding
`neither
`
`of
`
`the
`
`the number
`
`study
`of
`
`since
`
`three
`
`tests
`
`these
`
`three
`
`variables
`the probability
`or medical
`
`correlated
`aideeffects
`
`with
`
`or
`
`ct
`
`rates
`
`toss
`
`sit
`
`to six percent
`numbers
`of
`
`reasons
`
`and
`
`for medicat
`
`reasons
`
`Table Ii
`cardiovascular
`lesions
`
`breast
`
`reasons
`
`did
`
`rates
`for all
`Oneyear
`from 23.9%
`to 34.7%
`from 47.8%
`ranged
`Distontinuations
`pressure 55
`for
`increased
`blood
`liver dysfunction is cases
`cases
`disease
`cases
`case
`or other
`postcoitat
`bleeding
`the
`not differ
`treatment
`groups
`among
`Diseontinuations
`200
`for bteeding
`eases were generally mote
`problems
`in association with
`the norethisterone or notethisterone
`acetate
`estradiol
`and
`containing 2Oug
`1mg
`ethinyl
`much higher
`of diaeontiouatioos
`for bleeding
`rate
`Disrontinuations
`than
`tot
`the
`other
`any of
`preparations
`36 cases
`and vomiting 26
`wets
`eases
`preparations Table Ii
`not differ
`rsedieat
`complaints did
`cases
`complaints 18
`gynseeotogieat
`groups
`57 eases
`gastrointestinal complaints or perceived
`weight
`change
`complaints 19
`cases
`and
`dizsiness
`central
`headache
`162 cases
`system or psychological
`
`or personal
`to folLowup
`the one nor
`Neither
`twoyear
`significantly between
`treatment
`Tabte II Although
`to the study
`none
`centres
`for
`to
`
`of
`
`the
`
`were
`
`rates
`for alt
`reasons
`differed
`argnificantiy
`nainty attributabLe
`to discootinuations
`Oiscontinuations because
`or medical
`complications
`Table LI
`between
`reasons
`did
`not difter
`groups
`iifetable pregnancy
`rates differed
`net
`groups which ranged
`from one
`cootriouted similar
`ten centres
`38 were
`recorded
`
`in the
`
`two
`
`and
`
`three
`
`other
`
`centres
`
`subjects
`
`tndian
`accounted
`
`72 pregnancies
`recorded
`in one centre
`each
`pregnancies
`discontinuation
`
`to 56.0%
`
`and
`
`respectively
`cases
`other
`nonmalignant
`emjor medieal
`
`common
`The
`preparations
`preparations
`norefhisterone acetate
`63 cases
`of
`nausea
`
`problems
`
`symptoms
`
`had
`
`the
`
`two
`levonorgeatrel-jcontaining
`Discontinuation
`for other
`
`minor
`
`These
`
`included
`
`other
`
`more
`
`common
`
`with
`
`among
`
`other
`
`skin
`
`symptoms
`
`and
`
`other
`
`nervous
`
`reasons
`Other major medical
`case other
`malignancy
`ehotalithiasis
`eases
`emaes
`pyelonephritis
`and
`one
`each
`cases
`
`case
`
`for discontinuation
`included
`case pulmonary
`neoplasias
`cases
`Papinaneolou
`smear
`grade
`eases
`fever
`hyperthyroidiam
`typhoid
`disorder
`seizure
`of migraine and
`
`breast
`
`tuberculosis
`eases
`
`III
`
`MARCH 1982 VOL 25 NO
`
`235
`
`WC_LP0405749
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 5
`
`

`
`WC_LP0405750
`
`6.3
`
`30.0
`
`63.5
`
`5.6
`
`29.9
`
`64.0
`
`6.3
`
`23.8
`
`70.0
`
`6.8
`
`31.4
`
`61.8
`
`5.8
`
`27.8
`
`66.3
`
`4.77
`26.0
`
`4.69
`26.0
`
`4.69
`26.1
`
`4.70
`26.2
`
`5.03
`26.3
`
`1196
`
`2430
`
`197
`
`411
`
`181
`
`416
`
`192
`
`398
`
`203
`
`400
`
`184
`
`23
`
`32
`
`33
`
`36
`
`148
`
`29
`
`15
`
`29
`
`22
`
`2762
`
`463
`
`463
`
`460
`
`458
`
`-3
`
`Total
`
`NAc0.4
`
`NAc1.0
`
`1.0
`
`.035
`
`EE
`
`.02
`
`EE
`
`.05
`
`NRc
`
`EE
`
`NET1.0
`
`.05
`
`MES
`
`TOPARTICIPATE
`
`CHARACTERISTICS
`
`PATIENT
`
`5.2
`
`35.7
`
`59.1
`
`8.3
`
`31.6
`59.9
`
`none
`
`Percent
`
`abortiona
`livebirth
`
`Percent
`
`Percent
`
`laatpregnancy
`
`Outcome
`
`4.73
`26.0
`
`4.74
`25.4
`
`age
`
`sd
`Nean
`
`209
`
`406
`
`214
`
`399
`
`at
`
`obaerved
`
`number
`
`t2thcycle
`Total
`
`Totalatartingtrial
`
`contraceptivea
`
`24
`
`36
`
`oral
`
`etarted
`
`Never
`
`allocation
`
`group
`
`treatment
`
`incorrect
`
`or
`
`age
`
`criteria
`
`reasone
`
`medical
`gynaecological
`
`22
`
`31
`
`or
`
`forobatetric
`
`Excluded
`
`452
`
`466
`
`toparticipate
`
`volunteering
`
`Number
`
`.15
`
`.03
`
`LNG
`
`EE
`
`.15
`
`.05
`
`LNG
`
`EE
`
`VOLUNTEERING
`
`OFWOMEN
`
`SELECTED
`
`AND
`
`RECRUITMENT
`
`Table
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 6
`
`

`
`WC_LP0405751
`
`0.039
`0.244
`
`0.374
`0.001
`0.024
`
`0.001
`0.130
`
`0.255
`0.002
`
`0.0001
`
`0.0001
`
`0.067
`
`a-k-pco.ool
`
`63.5
`11.2
`
`31.9
`39.4
`4.0
`
`9.0
`
`1.6
`
`1.5
`
`8.5
`
`2.6
`
`15.6
`
`6.0
`
`68.8
`10.9
`
`34.5
`46.4
`1.7
`
`5.3
`
`2.4
`1.8
`
`4.2
`
`13.7
`
`23.2
`
`5.0
`
`0.056
`0.003
`0.068
`
`52.3
`31.8
`
`6.0
`
`56.0
`34.7
`
`4.5
`
`64.9
`7.7
`
`36.2
`40.3
`2.2
`
`6.8
`
`2.0
`
`1.2
`
`6.2
`
`3.3
`
`13.4
`
`4.2
`
`53.5
`32.4
`
`3.5
`
`0.8
`
`2.8
`
`2.2
`
`0.3
`2.8
`
`9.2
`
`1.0
`
`1.0
`
`teat
`
`MAc0.4
`
`1.0
`
`MAc
`
`1.0
`
`MAc
`
`rank
`value
`
`log
`
`.035
`
`EN
`
`.02
`
`EE
`
`.05
`
`SE
`
`1.0
`
`.05
`
`REASONS
`
`RATES
`
`aapQ
`
`pCOO5
`
`60.4
`8.2
`
`37.3
`30.9
`
`3.3
`
`49.8
`23.9
`
`62.0
`10.8
`
`34.3
`35.0
`
`4.6
`
`2.8
`
`0.0
`0.3
`
`2.8
`
`1.5
`
`5.5
`
`5.1
`
`47.8
`26.1
`
`3.5
`
`60.6
`9.4
`
`34.3
`33.8
`
`4.7
`
`2.9
`
`1.2
`
`0.7
`
`2.6
`0.5
`
`6.2
`
`4.2
`
`48.9
`27.9
`
`3.6
`
`NET
`
`MES
`
`LNO.15
`
`.15
`
`LNC
`
`.03
`
`ES
`
`EN.05
`
`ANOALLMEDICAL
`
`REASONS
`
`FORALL
`
`NETLIFETABLEDISCONTINUATION
`
`CUMULATIVE
`
`TableII
`
`tJ
`
`reasons-a
`
`tofollowup
`
`All
`Loaa
`
`reaaonaa
`
`reasons
`
`Personal
`Allmedical
`
`andvomiting
`
`Nauaea
`
`Spottingae
`
`Lightbleeding
`Prolonged
`Irregularbleedinga
`Aiaenorrhoaa
`
`bleeding
`
`pregnancy
`
`Allmenatrualaa
`Accidental
`
`ratesat
`
`Discontinuation
`
`days
`
`676
`
`reaaons
`
`pregnancy
`
`All
`reasons
`Allmedical
`Accidental
`
`rateaat
`
`Diacontinuation
`
`daya
`
`360
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 7
`
`

`
`CONTRACEPTION
`
`complaints
`
`there
`
`treatment
`
`with
`
`the
`
`by
`
`rates
`
`treatment
`as
`group
`of discontinuation
`
`recorded
`
`on
`
`for bleeding
`By all categories of
`the women
`in
`
`among
`
`and
`
`the
`
`of bleeding abnormalities
`The
`pattern
`the
`the menstrual diary
`cards
`paralleled
`and
`the uvereli
`rate
`of bleeding complaints
`differences
`abnormalities
`were
`significant
`bleeding
`the different
`levonorgestrel
`two
`groups
`preparations
`least
`in that order
`norethisterone 1mg having
`the meatraunl
`SOpg
`III
`Table
`the bleeding patterns
`During
`disruption of
`the
`first
`three
`receiving the
`cycles significantly more woaen
`levunorgestrelcontaining
`The
`bleeding patterns
`containing SDpg
`had
`normal
`preparstions
`preparations
`estradiui
`of norethisterone or norethisterone
`and
`af mestranol or ethinyl
`somewhat
`incidence
`of normal
`the
`iDth
`less
`cycles
`By
`frequent
`the differences
`between
`these
`four preparations
`fo 12th cycle
`whereas
`the differences
`between
`these
`four
`completely disappears
`1mg nnrethieterone
`estradiol
`and
`the preparationa containing 2Dpg
`norethisterone acetate
`estradiol
`Table
`acetate
`and
`ethinyl
`the 35pg
`tli
`
`acetate
`
`hed
`
`latter
`
`persisted
`
`1mg
`
`ethinyl
`
`4DDpg
`
`DISCUBSIDB
`
`of clinical
`
`trials
`
`of
`
`of
`
`the
`
`clinical
`
`the same
`
`most
`published reports
`exceptions
`few
`been limited
`have
`to the description
`contraceptives
`continuation rates
`aideeffecta
`and bleeding patterns
`effectivenesa
`associated
`with
`either
`preparation or
`steroidai
`combinatinna
`single
`At
`the
`same
`
`With
`
`steroidat
`
`in different
`
`doaes
`
`or
`
`ratios
`
`published
`
`reports
`
`time there
`contrast
`
`baa
`
`been
`in the
`with the
`
`of
`
`the
`the
`impression that
`developing
`world
`published experiences within the
`programmes
`planning
`family
`rarely
`continuation rates
`countries
`in terms
`of effectiveness
`developing
`aideeffects
`disturbances
`and
`other
`of bleeding patterns
`not
`the oneyear
`comparable
`Although
`than might
`is higher
`be
`current
`studies
`expected
`rates
`of different
`Peari
`In published
`and progeatogen in combined
`contraceptives
`oral
`tenfold
`difference in pregnaocy
`rates
`the highest
`rates
`reported
`though
`Dbviously
`experience
`than
`no greater
`1.5 pregnancies/1DD womenyears
`statistical
`contribute to differences
`in
`chance
`including
`factors
`many
`the pregnancy
`In our
`vary widely in
`pregnancy rates
`studies
`2Db
`to as
`in one centre
`low as
`different centres
`women
`none
`among
`in another
`The nature
`of
`the participating
`high
`aa 2D
`among
`of compliance with
`recruitment
`and
`the
`the selectivity in case
`degree
`contributed to the variation between
`In have
`
`life table
`
`pregnancy
`
`on
`
`the basis
`
`reports
`
`ratios
`
`and
`
`doses
`
`there
`
`appears
`
`own
`
`as
`being
`women
`
`233
`
`rates
`
`of
`
`in the
`rates
`the published
`of estrogen
`as much
`as
`
`are
`
`centre
`pilltaking
`appear
`regimens
`rates
`in pregnancy
`centrea
`conclude
`afudiea we
`can
`significantly different
`from any
`preventing undesired
`pregnancies
`planning administrator
`is also
`concerned
`However
`woman discontinues oral
`occurring after
`contraceptive
`undesired
`pregnmncies
`to the contraceptive sideeffects
`In this instance
`or complications
`use
`due
`eslradiol end
`the preparation with 2Dpg
`that with 4DDpg
`of ethinyl
`norelhisterone
`because
`acetate
`can
`be
`considered
`as unsatisfactory
`higher discontinuation
`rates
`preparation wee
`significantly less acceptable
`controlled
`in
`ievonorgestrel
`gingdnm2
`is an effective
`estrogen
`Hestrenol
`by various end
`eatradinl
`As measured
`
`that
`
`the higher
`Despite
`pregnancy
`of
`the preparations studied
`of
`in terms
`the others
`
`rates
`in our
`none was
`
`own
`
`of efficacy
`
`in
`
`the
`
`family
`
`with
`
`The
`former
`and effective
`
`than
`
`efhinyl
`
`ldDpg
`
`clinical
`
`trial
`
`reported
`
`of
`
`the
`
`ahnwn
`
`to be
`
`esfradinl
`3Dpg
`from the United
`
`only
`
`points
`
`afler
`
`conversion
`
`such
`
`as
`
`changes
`
`to ethinyl
`in vaginal
`
`238
`
`MARCH 1982 VOL 25 NO.3
`
`WC_LP0405752
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 8
`
`

`
`WC_LP0405753
`
`tTl
`
`-4
`
`PC0.001
`
`and
`
`24days
`24days
`
`60days
`
`over
`
`andnot
`
`days
`
`than
`
`longer
`
`35days
`
`than
`
`than
`
`less
`
`segment
`
`segment
`
`than
`35days
`
`lees
`
`than
`
`greater
`
`67
`
`155
`
`302
`
`15.8
`
`5.6
`
`46.0
`
`11.6
`
`65.8
`
`65.2
`
`45.4
`
`70
`
`172
`
`314
`
`14.8
`
`10.6
`
`42.6
`
`20.0
`
`68.8
`
`59.3
`
`46.2
`
`64
`
`150
`
`312
`
`11.7
`
`4.5
`
`27.1
`
`11.1
`
`68
`
`160
`
`288
`
`SEGMENT
`
`BYCYCLE
`
`5.7
`
`1.3
`
`20.3
`
`8.6
`
`85
`
`2.2
`
`cycles13
`
`PATTERNS
`
`BLENDING
`
`92.7
`
`78.1
`
`64.9
`
`88.2
`
`83.2
`
`71.1
`
`PATTERNS
`
`BLEEDING
`
`NORMAL
`
`0.4
`
`NAc
`
`NE0.035
`
`1.0
`
`NAc
`
`BE0.02
`
`1.0
`
`NAc
`
`REo.o5
`
`1.0
`
`0.05
`
`NET
`
`NES
`
`0.15
`
`CALENDARS
`
`BLEEDING
`
`ON
`
`BASED
`
`III
`
`segment
`
`tJa
`
`3cycle
`bleeding
`
`theentire
`
`for
`
`calendars
`
`completed
`
`who
`
`those
`
`only
`
`includes
`
`exclusive
`
`observed
`
`ofwomen
`arenotmutually
`
`number
`
`The
`
`Conditions
`
`NOTE
`
`episode
`
`orspotting
`
`Bleeding
`
`bleeding
`
`Prolonged
`
`greater
`
`segment
`
`longest
`
`menstrual
`
`menstrual
`
`segment
`
`complete
`
`complete
`
`menstrual
`
`Shortest
`
`Shortest
`
`Longest
`
`bleeding
`
`Irregular
`
`bleeding
`
`bleeding
`
`Frequent
`
`Infrequent
`
`Bleeding
`
`ofAbnormal
`
`Definitions
`
`167
`
`315
`
`80
`
`165
`
`317
`
`DESERVED
`
`OFWOMEN
`
`NUMBER
`
`10.1
`
`19.9
`
`7.6
`
`4.7
`
`1.3
`
`12.3
`
`6.9
`
`192
`1012
`13
`
`Cycles
`
`bleeding
`bleedinga
`bleeding
`
`bleeding
`
`Prolonged
`
`Irregular
`
`Frequent
`
`Infrequent
`
`ABNORMAL
`
`WITH
`
`WOMEN
`
`OF
`
`PERCENT
`
`87.1
`
`86.6
`
`72.6
`
`87.5
`
`83.6
`
`80.4
`
`OFWOMENWITN
`
`PERCENT
`
`LNG
`
`NEo.o3
`
`LNG0.15
`NE0.05
`
`IRREGULARITIES
`
`BLEEDING
`
`Table
`
`19_21
`l0_12
`l_3
`
`Cycles
`
`Cd
`
`00
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 9
`
`

`
`CONTRACEPTION
`
`follicle
`
`stimulating
`doses
`
`in equal
`
`and effects
`
`of ovulation and
`hormone
`suppression
`smear
`to ethinyl
`lipid metabolism mestranol compared
`estrsdiol
`on
`is
`to 0.68 In having either
`less or
`from
`considered
`to vary in equivaLence
`rate and
`estradiol
`than
`cthioyl
`equivalent activity
`and
`compared
`discontinuation
`EE/NAc
`1188/NET
`rates
`unexpected
`was
`statisticsl variation although
`They msy just
`difficult
`to explain
`in one
`shown
`to differ
`when
`MEg
`snd
`report bleeding patterns
`recent
`compsred9
`gg preparations have
`been
`gven
`where
`the discontinuation
`in instances
`rates
`for medical
`symptom complaint associated with discontinuation
`were similar
`between
`oral contraceptives
`the combined
`containing levonorgestrel
`in
`containing norethisterone or norethisterone acetate
`If
`women
`bleeding disturbances or headaches
`do not
`tolerate
`reason for discontinuation
`of
`the combined
`the major
`symptoms
`planning administrator might
`the
`family
`then
`contraceptives
`expect
`whereas
`orsl contraceptive to be more satisfactory
`lmvonorgestrelcontsining
`the cause
`of discontinuation
`often
`if gsstrointestinsl
`complaints are more
`be preferred
`then norethisterone preparations might
`bleeding cycLes
`The
`incidence
`of normal
`higher
`is only psrtialiy accounted
`of orsl contraceptive use
`in the
`women with
`bleeding disturbances discontinuing
`to 21
`of normsl cycles
`after
`rate
`the persistently lower
`19
`norethisterone acetate
`estrsdioi
`receiving ethinyi
`2Opg
`norethisterone acetate
`estradiol
`400pg
`l5jig
`of bleeding disturbances of
`these
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`in contrast
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`of estrogen
`optimal
`of bleeding cycles67
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`the
`
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`
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`
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`
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`
`on
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`as
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`
`and
`1mg
`The persistently
`
`latter
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`two
`
`preparations
`
`preparations
`end progestogen
`
`suggests
`to obtain
`
`that
`
`the
`
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`
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`ethinyl
`higher
`
`rate
`
`throughout
`
`there
`
`is
`
`so
`
`disruption
`
`240
`
`MARCH 1982 VOL 25 NO.3
`
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`
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`WC Ex. 2018, Pg. 10
`
`

`
`CONTRACEPTION
`
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`An
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`end points
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`for
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`JW Brandon
`Goldzieher
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`Contraception
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`blood pressure
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`snd
`
`MARCH 1982 VOL 25 NO
`
`241
`
`WC_LP0405755
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2018, Pg. 11