ERTiLLT .ND SI ERILIT\
`AU
`JOL
`1999
`.JUI
`lsii Amirran
`
`Cupydght
`
`SucStv
`
`fir Ripriductrvi
`
`Methuno
`
`Paintiffs Exhibit
`Pie 11Q4$-JAPTJB
`Ce Ku 1Fac292-JAPTJfl
`PTX 091
`
`iJJJ
`
`Effect of 21day and 24day oral
`contraceptive regimens containing
`gestodene 60
`and ethinyl estradiol
`15
`on ovarian activity
`
`Helen Sullivan MD Hilary Furniss
`Max Eltein MD
`
`ChB Jurgen Spona Ph.D and
`
`University
`
`of Manchester Manchester
`
`United Kingdom
`
`and Ludwig Boltzmann Institute
`
`for Experimental
`
`Endocrinology
`
`University
`
`of Vienna Vienna Austria
`
`Objectie
`low-dose
`
`Desii
`
`To compare mulation inhibition
`oral contraceptive COC containing
`combined
`
`and
`
`osarian
`
`activity with 21-day
`regimens of
`60 jg of gestodenc and 15 rg of ethinyl estradiol
`
`and 24-day
`
`Intcr entional
`
`obsersational
`
`study
`
`Setting Reproductive medicine unit
`
`Patients Fifty-eight
`
`healthy
`
`volunteers
`
`aged
`
`18
`
`35 years
`
`Published
`
`bu
`
`Elsevier
`
`Srtiice
`
`Inc
`
`Printed
`
`in acid-free
`
`paper
`
`in
`
`Received
`
`November
`
`111
`
`1998 revised and
`February 26
`
`accepted
`
`1999
`
`by Wyeth
`Supported
`Paris
`Ayerst Research
`France
`
`Helen
`Reprint
`requests
`Sullivan M.D Department
`of Obstetrics
`Gynaecoiogy
`and Reproducbve
`
`of
`
`Interventions
`
`diameters
`
`of
`
`cycles
`
`was monitored
`and blood
`
`c.xere
`
`Ovarian actisity
`every other
`follicle-lire structures
`serum concentrations
`samples to measure
`and posttreatment
`observed for five cycles pretreatment
`progesterone
`Subjects
`in which the COC was administered
`foi either 21 or 24 days of each cycle
`
`day with the use of ultrasound
`
`to measure
`of 17f3-E2
`and three
`control cycles
`
`the
`
`and
`
`Main Outcome Measures Occurrence
`
`01 os ulation and evidence of ovarian
`
`activity
`
`the 30 subjects who received
`The studs was completed by 27 900
`Results
`24 79o of
`the 28 subjects who received
`the 21-day regimen Osulation was
`24-day group and in 74 of 75 cycles
`in no
`follicles were
`in the 21-day group
`Luteinized
`unruptured
`seen
`cycles with the 24-day regimen and in 8o of75
`cycles with the 21-day regimen Mean oarian follicular
`and serum 17f3-h and
`lower in the 24-day group
`levels were
`
`of
`
`the 24-day regimen and bs
`inhibited
`in the
`
`in all cycles
`
`deselopinent
`
`progesterone
`
`The 24-day regimen is an innosatise
`stiategy for maintaimng
`Conclusions
`l999 115
`20
`at ultra-low doses ot contraceptive
`steroids
`lertil Steril5
`Reproductive Medicine
`Key Words Combined oral contraceptive gestodene
`
`inhibition
`
`ovulation
`
`effectisc mutation inhibition
`
`1999 by American
`
`Society
`
`for
`
`ultrasound
`
`Successis
`
`reductions
`
`and
`
`doses
`
`have
`
`that pill omission might lead
`finding suggests
`to os ulation and
`
`more readily
`
`Healthcare
`
`University
`
`Manchester Manchester
`United Kingdom FAX 44-
`161-276-6134
`
`Department
`of Obstetrics
`logy and
`
`t3ynaeco
`
`Reproductive
`of Manchester
`
`Healthcare
`
`University
`
`of Obstetrics
`
`Department
`and Gynaecology Ludwig
`Boltzmann
`
`Institute
`
`for
`
`be fully explored
`
`Preparations
`
`that contain 20 jzg of ethinyl
`estradiol FE appear
`
`to
`
`suppress
`
`osulation
`
`consistently
`
`in
`
`traditional
`
`Experimental
`
`regimen with
`
`7-day
`
`pill-free
`
`Endocrinology
`
`Division
`
`of
`
`combined with 150
`
`Cellular
`
`University
`
`Endocrinology
`of Vienna
`
`Vienna
`
`Austria
`
`001 5-0282199/$20.OO
`P11 S001 5-02829900205-8
`
`of gestodene
`
`jag of desogestrel or 75 jtg
`However
`des el
`
`follicular
`
`opment
`
`and circulating E2 levels are greater
`
`compared with
`the pill-free
`during
`preparations that contain 30 jag of FE
`
`interval
`
`This
`
`in the estrogen
`impros ed the risk-to-
`progestin
`ratio of combined
`
`oral
`
`contracepirs es
`
`benefit
`
`failure
`
`COCs
`gen dose
`
`Further
`
`reductions
`
`in the estro
`
`in combination
`
`with the lowest effec
`
`din with
`of EE and 75
`
`Reduction
`
`contraceptive
`of the pill-free interval
`preparation that contains 20 p.g
`
`to
`
`jzg of gestodene
`
`is associated
`
`tive
`
`doses of
`
`the newer progestins
`
`ha-se
`
`ci
`
`to
`
`with reduced ovarian activity
`
`compared with
`
`1-day active pill
`when
`
`interval
`
`low-dose
`
`preparations
`
`safety
`
`conventional
`
`reginnen with
`
`interval
`
`duced pill-free
`
`that
`
`7-day pill-five
`re
`This finding suggests
`interval may improve the mar
`with the use of
`gin of contraceptive
`in susceptible women
`
`We examined the effects
`
`of
`
`further reduc
`
`tions
`
`on
`and progestin
`doses
`in the estrogen
`ovarian actis ity using an ultmlow -dose COC
`with 15 pg of EE and
`60 tg of gestodene
`rugimen with
`4day pill-five interval
`
`and
`
`These
`
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`
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`
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`
`

`
`doses of BE and
`
`gestodene were mvcstigated
`
`ith an extra
`
`days of active
`
`treatment
`
`in each 28-din
`
`because even
`dc
`
`dose
`reduction compared ii ith
`they represented
`preparations that contain 20 jig of EE and 75 jig of gestodene
`
`significant
`
`Grading
`
`scale for ovarian actvty
`
`1ATERIALS AND METHODS
`
`to assess the effects
`
`on
`
`Two open-label studies were conducted
`health women
`arian adu ity of COC regimens of
`in each
`cycle with
`treatment
`28-day
`
`and 24 days
`
`of
`
`21
`
`fonnulations
`BE
`
`that contained
`
`60 jig of gestodene
`randomtied double-blind
`
`and 15 jig of
`
`design was not considered
`
`Grading scale
`
`no activity
`
`potential actl\lty
`
`nonacti
`
`follicle
`
`likc structure
`
`active
`
`follide-liku
`
`siructur
`
`feasible
`
`There would have
`
`been logistical
`
`problems in in
`
`lutemized
`
`unruptured
`
`follicle
`
`Diameur ot
`
`follicle
`
`liki
`
`Leel of
`
`struure
`
`mm
`
`Le\
`ci of
`pg mL
`
`pro5tcrone
`ng rnL
`
`10
`
`10 11
`
`13
`13
`
`13
`
`1.6
`
`.6
`
`vestigating
`
`this number of volunteers
`
`relatively
`
`small
`
`reproducti
`
`medicine
`
`in
`
`in one
`study
`unit We also be
`ould be
`
`that
`
`it
`
`lieved
`
`70 in months
`
`proach would enhance
`
`on the basis of our experience
`wInch regimen each
`to the tin estigators
`apparent
`mm as taking Because of the intensity
`of the schedule
`ire believed that an open candid ap
`relationship with the volunteers
`our
`
`oman
`
`of
`
`isits
`
`needed
`
`to perform such
`
`studs
`
`The studies mm crc conducted
`
`according
`
`to the Declaration
`
`of Helsinki
`
`guidelines
`
`and with the approval
`
`of our institu
`
`tional
`
`review board Written informed consent was obtained
`
`from all participants
`
`Study Subjects
`mm omen mm ho were 1835 rears old were within
`Healthr
`limit of normal weight and smoked 10
`20% of the upper
`per day were eligible to participate
`in the study
`All subjects had three regular 25- to
`1-day menstrual
`
`cigarettes
`
`osulation
`
`13
`
`\ore
`
`Table
`
`adapted
`
`1mm Fitzgeiald em al
`
`30
`30
`30
`30
`
`either
`
`for 21 days with
`
`7-day pill-free inters al or for
`
`days of placebo
`
`tablets in each
`
`28-day
`
`cycle
`
`started
`
`first
`
`given
`24 days with
`Treatment
`day of menstruation
`was
`on file
`Compliance was assessed from the diaiy cards
`kept by the
`subjects No woman omitted
`than 24 hours
`pill for
`longer
`in either study At the start of each cycle the weight
`blood pressure of each subject was checked
`
`and
`
`Ovarian Activity
`The
`outcome measure was
`
`ovarian activity
`
`activity
`
`cycles before the start of the pretreatment
`were required to use
`
`medicalls
`
`acceptable
`
`cs cle All subjects
`
`nonhormonal
`
`form of contraception
`
`during the study
`
`Subjects were excluded
`
`from
`
`the study if they had
`
`histomy
`
`of or the presence of anm medical
`
`condition know ml to
`
`be
`risk factor
`Women mu ho had
`
`ruth COCs
`for adverse
`ements associated
`historu of previous failure of an OC
`with previous OC use or undi
`months also
`
`experience
`
`bleeding witlun the previous
`No
`
`mu as allowed
`
`to use any other
`
`serious adverse
`
`agnosed genital
`
`were excluded
`
`interfere
`
`mu
`
`subject
`hormone or any other concomitant
`ith study assessments
`
`medication
`
`that
`
`could
`
`All women
`
`had normal
`
`tests and cervical smear test
`routine blood
`at the start
`of the study Only mu omen who or ulated in the pretreatment
`control cycle were eligible to start treatment
`
`Three
`
`subjects
`
`results
`
`primary
`which was determined
`by ultrasound obserm ation of follicle-
`and by honnone
`assays of serum B2 proges
`like structures
`terone FSH and LH Ultrasound
`and hormone assessments
`were made em cry
`cycles Ovarian
`days during the five
`to the scale Table
`was graded
`
`according
`
`reported
`
`by Fitzgerald et al
`
`Ovulation
`
`structure
`
`mm as defined as the presence of
`that was 13 mm in diameter and ruptured within
`48 hours
`combined with
`serum l7p-E2 and progesterone
`concentrations of 30 pg/niL
`and 1.6 ng/mL respectim ely
`The definition of
`in the same cycle
`luteinized unruptumud
`
`follicle-like
`
`follicle was the same
`there mm as no evidence
`except
`rupture on ultrasound examination
`
`follicle
`
`that
`
`of
`
`Ultrasound
`
`Examination
`
`struc
`
`or
`
`trans
`
`Plus
`
`Laboratories
`
`in did
`
`I-day group and one
`
`in the 24-day
`
`group
`
`failed
`
`to
`
`fulfill entmy
`
`requirements
`
`Study Design
`Each
`subject was
`
`cycles
`
`treatment cycles
`
`return of ovulation
`COC that
`
`contained
`
`pretreatment
`and
`
`scheduled
`
`to be monitored
`
`over
`
`five
`
`cycle to establish ovulation
`
`three
`
`posttreatment
`The
`
`treatment
`
`cycle to docmnent
`
`the
`
`for each
`
`subject was
`and 15 jig
`of EE
`
`60 jig
`
`of gestodene
`
`116
`
`Sullim an et al
`
`21-day versus
`
`24-day COC regiment
`
`The diameters of right and left ovarian follicle-like
`tures were measured by 5-MHz transabdorninal
`and an Ultramark
`ultrasound
`transducers
`vaginal
`ultrasound machine Advanced Technology
`Bothwell WA For each subject
`the same met hod of ultra
`the study The di
`as the
`structures were calculated
`
`sound examination
`
`was used
`
`throughout
`
`amneters of
`
`follicle-like
`
`mean of
`
`ent planes
`
`three ultrasound measurements
`
`taken in two differ
`
`Hormone Assays
`The blood collected for measurement of hormone con
`and the serum frozen
`
`centrations was centrifuged
`
`Anals sis
`
`was perfonned in batches
`
`one cycle at
`
`time under
`
`the
`
`Vol 72 No
`
`July 1999
`
`WC_LP0405703
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2024, Pg. 2
`
`

`
`Details
`
`of the radloimmunoassays
`sensitivities
`
`used and their
`
`Baseline demographic
`volunteers
`
`characteristics
`
`of 58 healthy
`
`hormone
`measud
`
`F2
`
`Progesterone
`
`FSH
`
`iH
`
`Manufacturer
`
`Sensitis
`
`it
`
`SludI
`
`group
`
`83 pg mL
`
`Characteristic
`
`21-day
`
`regimen
`
`24-dat
`
`regimen
`
`is
`
`28
`
`is
`
`30
`
`Products Corporation
`Diagnostic
`4ngeles GA
`
`Los
`
`Products Corporation
`Diaostic
`thgeles CA
`
`Los
`
`4.84
`
`0.02
`
`0.01 ng mL
`
`Behnng
`
`institute
`
`Marhurg Germany
`
`Sorin Saluggia
`
`Italy
`
`184
`
`009 IL
`
`38
`
`54 IC
`
`Mean 81 age
`
`in
`
`years range
`
`Mean SD weight
`
`in
`
`kilograms
`
`range
`
`No
`
`of patients
`
`with
`
`indicated
`
`parity
`
`36
`
`29.6
`230
`
`285
`
`3.7
`
`220
`
`35.0
`
`63.4
`
`9.4
`
`63.0
`
`7.3
`
`48
`
`87
`
`48.0 85.0
`
`725
`725
`1450
`00
`00
`
`1240
`1033
`723
`00
`
`Sensitivitl
`
`is defined
`
`the -on-entration at 95c of the bindmg at
`
`as
`
`the
`
`minimum
`
`delectable
`
`dose bmding at z.ro concentration
`
`direction of one of the in estigators TS at
`in Vienna Austria Samples were sent to the labora
`tow to be assayed
`time Table
`one ccle at
`in batehes
`the RIAs used Intra-assay and interassa
`were 5%9%
`of vanation
`
`ratoiy
`
`shows
`
`details
`
`of
`
`coefficients
`
`central
`
`labo
`
`Cervical Mucus
`Cerical mucus hostility was assessed
`
`when the ultra
`
`changes
`
`from baseline blood pressure weight or laboratoiy
`values were reported
`
`sound examination
`
`suggested
`
`ovarian
`
`activity
`mechamsins are most
`
`This was
`
`ovulation
`
`is great
`
`Effects on Ovulation and Cervical Mucus
`Assessment
`
`total of 84 cycles were completed in the 24-day
`
`group
`was inhibited in all
`
`and 75 in the 21-day
`
`group Ovulation
`group and in 74 of 75 cycles in the
`cycles in the 24-day
`21-day group The one ovulation
`that occurred
`was atypical
`primarily on the basis
`but fulfilled the grading classification
`of ultrasound findings How ever
`the maximum progesterone
`ng/mL which was not sustained
`let el was
`
`Luteimzed unruptured
`
`follicles were seen
`
`in no cycles
`
`with the 24-day
`
`regimen and in six cycles with the 21-day
`
`and
`
`cycles
`in two cy
`in
`
`follicles
`
`level
`
`them occurred
`in treatment
`regimen all of
`One woman had luteinized unruptured
`des The mean maximum progesterone
`observed
`cycles was 6.4 ngmL
`these
`luteinized unruptured
`424 2.32 ng/mL The mean maximum diameter of
`measured was 29 mm but
`the follicle-like
`there
`
`done because
`adjuvant
`contracepth
`important when the risk of breakthrough
`est Mucus was not collected
`in the presence
`
`of
`
`aginal
`
`bleeding
`
`Cycle Control Assessments
`and intensity
`noted
`the timing
`Subjects
`
`bleeding in
`
`diary
`
`cycle was classified
`
`of all aginal
`as nonual if the
`
`onset of
`
`the withdrawal
`
`bleed did not extend
`
`beyond
`
`days
`
`after
`
`ingestion of
`
`the last active pill and
`
`there was
`
`no
`
`breakthrough
`
`bleeding
`
`or spotting
`
`during the rest of
`
`the
`
`cycle Bleeding
`
`intensity
`
`was rated using the following
`
`scale
`
`none
`
`spotting very slight breakthrough
`
`bleeding
`
`that did not
`
`require sanitars
`
`protection
`
`light
`
`moderate
`
`and
`
`heavy
`
`RESULTS
`
`The baseline demographic
`the women
`who started each study are show
`The study was
`completed by 24 79% of 28 subjects in the 21-day
`group
`and by 27 90 of 30 subjects in the 24-day
`group Four
`in the 24-day
`
`women
`
`in the 21-day
`
`group and
`
`group
`
`characteristics
`
`of
`
`in Table
`
`discontinued
`
`not
`
`related
`
`their participation after
`treatment
`the COC Only
`to use of
`reasons
`cycles are included in the anah sis
`
`starting
`
`for
`
`completed
`
`There were no serious
`reported minor side effects were headache
`pain and breast pain No
`
`adverse
`
`events
`
`and
`
`the most
`ab
`
`clinically
`
`significant
`
`commonly
`
`donminal
`
`range
`
`structures
`
`follicle
`
`was no evidence
`
`of follicular
`
`rupture
`
`SD maximum cervical
`The mean
`cycles for the women who took
`the 21-day
`
`score in the control
`
`preparation was
`
`10.9
`
`68
`
`ds des studied it was reduced
`1.8 in the treatment
`For the women who took the 24-day preparation
`SD maximum cervical
`score was 106
`the mean
`1.9 in
`the control cycles and 4.1
`1.1 in the treatment cycles
`
`to
`
`In the posttrealment
`
`cycle ovulation was obsers ed in all
`regimen and in 18 of 24 subjects
`subjects with the 24-day
`women all had lutein
`with the 21-day
`regimen The other
`ized unruptured
`
`follicle cycles
`
`FERTILITY
`
`STERILITY5
`
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`
`Mean diameter of largest
`--0-- 24-day
`
`interval
`
`follicle-like
`
`structure with 21- and 24-day regimens
`
`7-day
`
`pill-free interval
`
`4-day placebo-pill
`
`21-day
`
`17
`
`27
`
`Effects on Ovarian Activity Diameters
`and Levels of
`of Follicle4ike Structures
`
`with the 21-day
`
`regimen However
`
`there was marked variation
`
`between individuals
`
`especially
`
`during the pill-free intervals
`
`bleeding that was more substantial
`in 16 21% of 75 treatment cycles in
`than spotting occurred
`and 35 42% of 84 treatment cycles in the
`the 21-day
`group
`dc breakthrough
`bleed
`24-thy group By the third treatment
`ing occurred in 25% of 24 subjects
`in the 21-day gmup and
`12 42% of 28 subjects
`in the 24-day group Three women in
`woman in the 24-day
`and
`the 21-day
`
`ingestion of the last acti\
`
`group failed
`pill The
`
`to
`
`Cycle Control
`Overall
`
`breakthrough
`
`group
`in the
`
`bleed
`
`days after
`
`Ovarian Steroids
`
`like structure
`
`follicle-like
`
`structures
`
`follicle-
`
`The mean diameters of the largest
`of each subject at each assessment
`for the two regimens are
`The mean diameter of the largest
`shown in Figure
`regimen remained at 10 turn
`for the 24-day
`the three treatment cycles With the 21-day
`throughout
`reg
`imen the mean diameter of
`the largest
`rose to 13 mm in treatment
`
`follicle-like
`
`stmcture
`
`es des
`
`and
`
`The mean semm l7-E concentrutions
`In both groups
`reduction in mean levels occurred
`The 17 level
`remained at
`during the treatment cycles
`50 pg/mL during treatment with the 24-day
`to 100 pg/mL
`during treatment
`cycles
`regimen Serum B2 concentrations
`rose with
`with the 21-day
`during the pill-free interval Mean progester
`both regimens
`regimens How
`remained at
`for both
`ng/rnL
`rise in mean pmgesterone le els was seen in the
`ho took
`the 21 -day preparation in treatment es des
`
`Figure
`
`increased
`
`one levels
`
`ever
`
`slight
`
`women
`
`are shown
`
`in
`
`regimen but
`and
`
`and
`
`because
`
`of
`
`the luteiniied
`
`unmptured
`
`follicles
`
`observed
`
`Levels
`
`onli
`
`little
`
`with
`
`of LH were suppressed
`during treatment
`rise seen during the pill-free intervals The mean
`small
`le els during treatment were all 10 mlLT/mL
`There was
`regimens Con
`difference between the 21- and 24-day
`centrations of FSH were suppressed with active treatment
`However during each pill-free interval with both regimens
`FSH rose to levels similar to those seen in the control cycles
`There was better
`
`suppression
`
`with the 24-day
`
`regimen than
`
`mean duration
`
`bleeding was
`in the
`of withdrawal
`days
`in the 24-day groups The median
`group
`of bleeding was light
`in both groups
`
`and
`
`days
`
`21-day
`
`intensity
`
`DISCUSSION
`
`It
`
`the doses of estrogen
`is desirable to mnnunuze
`progestins in COCs to reduce the incidence
`and side effects
`has been concern that
`There
`
`of adverse
`
`reducing
`
`and
`
`events
`
`ste
`
`roid doses might reduce the margin of contraceptive efficacy
`iduals and lead to poorer cycle control
`in susceptible mndi\
`that contain 20 rg of EE
`Combined oral contraceptives
`are known to inhibit
`rg of gestodene
`75
`ovulation
`and to decrease
`
`and
`
`effectively
`
`24-day
`
`regimen
`
`of geslodene
`
`represents
`
`en with
`EE and 60
`total BE dose
`
`contain 20
`
`dene dose
`
`cervical mucus
`scores
`COC that contains
`15 j.tg of
`14% reduction in the
`regimnens of OCs that
`per cycle over 21-day
`9% reduction in the total gesto
`of BE and
`over OCs that contain 75 Hg of gestodene
`
`118
`
`Sullivan et aL
`
`21-day ersus 24-day COC regimens
`
`Vnl 72 No
`
`July
`
`lQQ
`
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`
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`
`

`
`Mean serum 17-p-E2
`concentration with 21- and 24-day regimens
`--0-- 24-day i-- 21-day
`
`7-day pUt-free
`
`interval
`
`4-day
`
`placebo-pifi
`
`interval
`
`Before
`
`trea4mvnt
`
`200
`
`treatment cycles
`
`Met
`
`treatment
`
`13
`
`19
`
`25
`
`31
`
`Il
`
`17
`
`23
`
`13
`
`19
`
`25
`
`15
`
`21
`
`27
`
`11
`
`17
`
`23
`
`29
`
`Day of cycle
`
`from days
`20 jg of
`to be associated
`
`to
`
`days
`
`75
`
`of stemid thempy With the
`profoundly by the commencement
`and 24 da of active
`risk of breakthrough
`
`shorter 4-clar pill-free interval
`
`per cycle there was
`
`reduced
`
`treainieni
`
`ovulation
`
`Reduction
`of the pill-free
`COC thai
`
`with
`
`contains
`
`interval
`
`gestodene
`
`has been shown
`
`follicular
`
`thai
`
`and
`
`tg of
`is ith better ovar
`
`follicular
`
`develop
`
`Extension
`
`After
`
`treatment with the 24-day
`
`regimen there
`
`was
`
`ariation
`
`in the interval
`
`greater
`treatment and us ulation Because of this variation the mean
`
`between cessation of actii
`
`E2 level
`
`each day was low er This could
`
`represent
`
`the rela
`
`tis
`
`of individuals
`
`ovulation
`
`ian suppression
`as evidenced
`by reduced
`ment and lower serum 17J3-E2 concentrations
`inten al has been shown
`of the pill-free
`to allow increased
`development 10 The results of this study suggest
`COC that contains
`15 rg of EE
`regimen of
`24-day
`and 60 tg of gestodene
`ovulation
`They
`and may
`individuals
`
`also
`
`suggest
`
`that
`
`21-day
`
`regimen is less effectis
`
`effectively
`
`inhibits
`
`ovulation
`
`in susceptible
`
`the adjunctive
`
`contraceptive mechanism
`
`of cervi
`
`cal mucus
`
`hostility
`
`is maintained
`
`allow breakthrough
`However
`
`cacy
`
`of this ultra--low
`
`thousand
`
`the effi
`
`at
`
`interval
`
`Phase 111 studies were peifonned to ins esligate
`-dose COC with
`regimen in
`24-day
`twenty women who fol
`Two
`larger population
`lowed the regimen for 21 521 cycles showed
`Pearl
`Index of
`024 11 This is comparable to that
`seen with COCs that
`contain 30 j.tg of Eli and gestodene 12
`It has been established that maximmn ovarian activity
`is
`with COCs thai
`the end of
`the pill-free
`seen
`In our study of COC that contains
`contain 20 mg of EE
`and 15 j.rg of EE with
`60 mg of geslodene
`21-day
`active
`7-day pill-free mterval al
`treatment
`regimen the standard
`lowed more time for follicles
`so the obsen ed
`
`follicle diameters were larger and the 17 concentrations
`
`to develop
`
`were higher
`
`In addition
`
`the longer pill-free
`
`interval
`
`to allow recruitment
`
`peared
`of development
`
`that
`
`of
`
`follicle
`
`to
`
`ap
`size and stage
`and less
`as suppressed more slow
`
`FERTILITY
`
`STER1LITY
`
`A.know1edgmenr
`
`The authors
`
`thank
`
`the
`
`olunteer
`
`ss ithout
`
`sahorn the
`
`vc ork would not has
`
`been possible
`
`They also
`
`are grateful
`
`to the staff ot
`
`the
`
`119
`
`WC_LP0405706
`
`susceptibility
`
`to breakthrough
`
`This possibility
`
`currently is being explored
`COC with an ultra-low dose of estrogen 15 p.g would
`somew hat more unscheduled
`be expected
`to cause
`aginal
`COC with
`of estrogen Our
`dose
`bleeding than
`higher
`data are consistent with this expectation However other
`studies is ith similar higher-dose preparations 13 14 has
`bleeding The numbers
`reported incidences
`of breakthrough
`of subjects in these studies are too small
`to assess cycle
`is available from larger
`
`control
`
`information
`
`and more useful
`studies 11
`and
`The 60-g dose of gestodene
`5-pg dose of EE in the
`COC used
`in this study are low er than those of am marketed
`The 24-day
`regimen is an innos alive strategs
`is bile maintaining effec
`total contraceptis
`inhibition and tolerability
`
`clinical
`
`formulation
`
`lower
`
`the
`
`tive ovulation
`
`dose
`
`to
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2024, Pg. 5
`
`

`
`Reproductive
`
`EKdicine Unit University
`
`hospital of South Manchester for
`
`their assistance
`
`and
`
`cardiosascular
`
`disease
`
`Is
`
`Lngl
`
`Vcssec
`
`Is coutraccptn
`infarction Report
`1991.98
`1245
`53
`
`use still
`
`contra
`
`egetti
`
`Parazzini
`
`Ovarian
`
`actic
`
`lB
`
`of
`
`ceptives
`
`Ciocignani
`
`Westergaard
`
`Akerlund
`
`Rode
`ity cycle control and
`150
`rg detogestrel
`ontnining
`oestradiol Br Obstet GInsecol
`Lahtcenmaki
`Moorrecs
`
`side effects
`
`of
`
`either
`
`of reliabil
`
`ethinll
`
`Comparative
`profiles
`formulations
`two oral contraceptic
`30 zg or 20 jag
`and
`1993100.832
`Dc Prcst
`
`three da
`
`in oral
`
`contraceptic
`
`users
`
`Extension
`
`of
`
`the pill
`Eds Contracept
`
`free
`1995
`
`period
`1137
`10 Ksllick SR Bancroft
`duration
`the pill
`inters al during
`Edv Contraccpt
`19906 33
`ii Belaiseb
`
`Oelbauni
`
`Morris
`
`Elstein
`
`Extending
`
`the
`
`ot
`
`free
`
`combined
`
`oral
`
`cnntrcception
`
`40
`
`regimen of gcstodene
`ness paradigm
`
`fur
`
`loss
`
`60 jag ethmyi
`dose
`
`oral
`
`cstradiol
`
`contraception
`
`Clinical
`
`efficacy
`
`of
`
`24 day
`
`cy1e control and tolerability
`15 jag Svnsposiurn
`report
`Fifth Corigresc of
`
`References
`Stadel BV Oral
`contraceptises
`Med l98U305.6l2
`Mann
`Thorogood
`Murpls
`associated cc
`ith an increased risk of fatal mvocardial
`case control study Br Obstet Gbnaecol
`\\ Spona
`Elstein
`Ludiclce
`Muller
`Fitzgerald
`Feichtinger
`of two monophasic low dose
`et al coniparison of the effects
`on the inhibition
`PG lesta
`during regular oral
`contraceptic
`
`of ovufttion Mv Contracept 994 18
`use Contraception 996
`
`MaliJIacleli
`
`Clinical
`
`with Mercilon
`
`expeneoce
`reference to ovarian function
`
`Geburtsh
`
`and Marvelon with
`1991
`
`Frauenheilk
`
`15
`June
`Soiiety of Conti aception
`European
`12 Wide MI Balfour
`JA Gestodene.Areciecc
`in combined
`and
`
`contraceptic
`
`efficacy
`tolerability
`199550.364 95
`
`1998
`
`of
`
`its
`
`Prague
`pharmacology
`
`preparations
`
`Drugs
`
`particular
`5134
`
`follicular
`
`lacIer
`
`ccis
`
`.J Elsicin
`
`free
`
`\l Sullivan
`Feiehtsngei
`in combined
`
`intcrcal
`
`Spona
`al Shorter pill
`dec elopment Contraception
`Melmed
`Fichenhrenncr
`
`ical score
`simple
`cc dc Int
`
`menstrual
`
`Gsnaecol
`
`semiquantitatis
`
`for monitoring
`
`Judicke
`
`Muller
`
`ci
`
`13
`
`Saleh
`
`Vs
`
`Burkinan
`
`cc
`
`decreases
`
`RT Zacur HA
`of bleeding
`contracepta Cs comparison
`In Obstet Gynecol
`lcls
`and
`sternal
`MI Waugh MS higgins
`and other
`on sporting
`90
`
`The
`
`the
`
`14 Rosenbeig
`
`gestodene
`19965385
`
`factors
`
`randomized
`
`trial of three oral
`
`patterns by contraccptic
`1740
`1993168
`JE The effect
`and bleeding
`
`of decogesael
`
`Contraception
`
`types
`
`oral
`contraecptis
`19965471
`Sen DM unenfeld
`method
`Obstet 1972
`
`120
`
`Sdllhan et al
`
`21das sctsus
`
`24da5 COC regimdns
`
`Vol 72No
`
`July 1099
`
`WC_LP0405707
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2024, Pg. 6